Second Edition

HARRISONS
Neurology in
Clinical Medicine
 Derived from Harrisons Principles of Internal Medicine, 17th Edition

Editors
ANTHONY S. FAUCI, MD EUGENE BRAUNWALD, MD
Chief, Laboratory of Immunoregulation; Distinguished Hersey Professor of Medicine,
Director, National Institute of Allergy and Infectious Diseases, Harvard Medical School; Chairman,TIMI Study Group,
National Institutes of Health, Bethesda Brigham and Womens Hospital, Boston

DENNIS L. KASPER, MD STEPHEN L. HAUSER, MD

William Ellery Channing Professor of Medicine, Professor of Robert A. Fishman Distinguished Professor and Chairman,
Microbiology and Molecular Genetics, Harvard Medical School; Department of Neurology, University of California, San Francisco
Director, Channing Laboratory, Department of Medicine,
Brigham and Womens Hospital, Boston
J. LARRY JAMESON, MD, PhD
Professor of Medicine;
DAN L. LONGO, MD Vice President for Medical Affairs
Scientic Director, National Institute on Aging, and Lewis Landsberg Dean,
National Institutes of Health, Northwestern University Feinberg
Bethesda and Baltimore School of Medicine, Chicago

JOSEPH LOSCALZO, MD, PhD

Hersey Professor of Theory and Practice of Medicine,
Harvard Medical School; Chairman, Department of Medicine;
Physician-in-Chief, Brigham and Womens Hospital, Boston
 Second Edition

HARRISONS
Neurology in
Clinical Medicine
Editor
Stephen L. Hauser, MD
Robert A. Fishman Distinguished Professor and Chairman,
Department of Neurology, University of California, San Francisco

Associate Editor
Scott Andrew Josephson, MD
Assistant Clinical Professor of Neurology,
University of California, San Francisco

New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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 Raymond D.Adams, MD
19112008

For Ray Adams, editor of Harrisons Principles of Internal Medicine for more than three decades.

A mentor who taught by example,

a colleague who continues to inspire, and
a friend who is deeply missed.

Stephen L. Hauser, MD, for the Editors of Harrisons

This page intentionally left blank
 CONTENTS

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi 12 Numbness,Tingling, and Sensory Loss . . . . . . . 116

Michael J.Aminoff,Arthur K.Asbury
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
13 Confusion and Delirium . . . . . . . . . . . . . . . . . 122
SECTION I Scott Andrew Josephson, Bruce L. Miller
INTRODUCTION TO NEUROLOGY
14 Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
1 Approach to the Patient with Allan H. Ropper
Neurologic Disease . . . . . . . . . . . . . . . . . . . . . . . 2
Daniel H. Lowenstein, Joseph B. Martin, 15 Aphasia, Memory Loss, and Other Focal
Stephen L. Hauser Cerebral Disorders. . . . . . . . . . . . . . . . . . . . . . 140
M.-Marsel Mesulam
2 Neuroimaging in Neurologic Disorders . . . . . . . 11
William P. Dillon 16 Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . 155
Charles A. Czeisler, John W.Winkelman,
3 Electrodiagnostic Studies of Nervous Gary S. Richardson
System Disorders: EEG, Evoked Potentials,
and EMG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 17 Disorders of Vision . . . . . . . . . . . . . . . . . . . . . 170
Michael J.Aminoff Jonathan C. Horton

4 Lumbar Puncture . . . . . . . . . . . . . . . . . . . . . . . 33 18 Disorders of Smell,Taste, and Hearing . . . . . . . 193

Elizabeth Robbins, Stephen L. Hauser Anil K. Lalwani

SECTION II SECTION III

CLINICAL MANIFESTATIONS OF DISEASES OF THE CENTRAL
NEUROLOGIC DISEASE NERVOUS SYSTEM

5 Pain: Pathophysiology and Management . . . . . . . 40 19 Mechanisms of Neurologic Diseases . . . . . . . . . 210

Howard L. Fields, Joseph B. Martin Stephen L. Hauser, M. Flint Beal

6 Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 20 Seizures and Epilepsy. . . . . . . . . . . . . . . . . . . . 222

Peter J. Goadsby, Neil H. Raskin Daniel H. Lowenstein

7 Back and Neck Pain . . . . . . . . . . . . . . . . . . . . . 70 21 Cerebrovascular Diseases . . . . . . . . . . . . . . . . . 246

John W. Engstrom Wade S. Smith, Joey D. English,
S. Claiborne Johnston
8 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Mark D. Carlson 22 Neurologic Critical Care, Including
Hypoxic-Ischemic Encephalopathy and
9 Dizziness and Vertigo . . . . . . . . . . . . . . . . . . . . . 96 Subarachnoid Hemorrhage . . . . . . . . . . . . . . . 282
Robert B. Daroff J. Claude Hemphill, III,Wade S. Smith

10 Weakness and Paralysis. . . . . . . . . . . . . . . . . . . 102 23 Alzheimers Disease and Other

Michael J.Aminoff Dementias. . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
Thomas D. Bird, Bruce L. Miller
11 Gait and Balance Disorders . . . . . . . . . . . . . . . 109
Lewis Sudarsky

vii
 viii Contents

24 Parkinsons Disease and Other Extrapyramidal 39 Paraneoplastic Neurologic Syndromes . . . . . . . 516

Movement Disorders . . . . . . . . . . . . . . . . . . . . 320 Josep Dalmau, Myrna R. Rosenfeld
Mahlon R. DeLong, Jorge L. Juncos
40 Peripheral Neuropathy. . . . . . . . . . . . . . . . . . . 525
25 Hyperkinetic Movement Disorders. . . . . . . . . . 337 Vinay Chaudhry
C.Warren Olanow
41 Guillain-Barr Syndrome and Other
26 Ataxic Disorders . . . . . . . . . . . . . . . . . . . . . . . 346 Immune-Mediated Neuropathies . . . . . . . . . . . 550
Roger N. Rosenberg Stephen L. Hauser,Arthur K.Asbury

27 Amyotrophic Lateral Sclerosis and Other 42 Myasthenia Gravis and Other Diseases
Motor Neuron Diseases . . . . . . . . . . . . . . . . . . 358 of the Neuromuscular Junction . . . . . . . . . . . . 559
Robert H. Brown, Jr. Daniel B. Drachman

28 Disorders of the Autonomic 43 Muscular Dystrophies and Other

Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . 366 Muscle Diseases. . . . . . . . . . . . . . . . . . . . . . . . 568
Phillip A. Low, John W. Engstrom Robert H. Brown, Jr.,Anthony A.Amato,
Jerry R. Mendell
29 Trigeminal Neuralgia, Bells Palsy, and
Other Cranial Nerve Disorders . . . . . . . . . . . . 377 44 Polymyositis, Dermatomyositis, and
M. Flint Beal, Stephen L. Hauser Inclusion Body Myositis . . . . . . . . . . . . . . . . . 597
Marinos C. Dalakas
30 Diseases of the Spinal Cord . . . . . . . . . . . . . . . 385
Stephen L. Hauser,Allan H. Ropper 45 Special Issues in Inpatient Neurologic
Consultation . . . . . . . . . . . . . . . . . . . . . . . . . . 609
31 Concussion and Other Head Injuries . . . . . . . . 400 Scott Andrew Josephson, Martin A. Samuels
Allan H. Ropper
46 Atlas of Neuroimaging . . . . . . . . . . . . . . . . . . 617
32 Primary and Metastatic Tumors of the Andre Furtado,William P. Dillon
Nervous System . . . . . . . . . . . . . . . . . . . . . . . 408
Stephen M. Sagar, Mark A. Israel
SECTION IV
33 Neurologic Disorders of the Pituitary CHRONIC FATIGUE SYNDROME
and Hypothalamus. . . . . . . . . . . . . . . . . . . . . . 423
Shlomo Melmed, J. Larry Jameson, 47 Chronic Fatigue Syndrome . . . . . . . . . . . . . . . 650
Gary L. Robertson Stephen E. Straus

34 Multiple Sclerosis and Other

SECTION V
Demyelinating Diseases . . . . . . . . . . . . . . . . . . 435
Stephen L. Hauser, Douglas S. Goodin PSYCHIATRIC DISORDERS

35 Meningitis, Encephalitis, Brain Abscess, 48 Biology of Psychiatric Disorders. . . . . . . . . . . . 654

and Empyema . . . . . . . . . . . . . . . . . . . . . . . . . 451 Steven E. Hyman, Eric Kandel
Karen L. Roos, Kenneth L.Tyler
49 Mental Disorders. . . . . . . . . . . . . . . . . . . . . . . 662
36 Chronic and Recurrent Meningitis . . . . . . . . . 484 Victor I. Reus
Walter J. Koroshetz, Morton N. Swartz
SECTION VI
37 HIV Neurology . . . . . . . . . . . . . . . . . . . . . . . 493 ALCOHOLISM AND DRUG
Anthony S. Fauci, H. Clifford Lane
DEPENDENCY
38 Prion Diseases. . . . . . . . . . . . . . . . . . . . . . . . . 507
50 Alcohol and Alcoholism. . . . . . . . . . . . . . . . . . 686
Stanley B. Prusiner, Bruce L. Miller
Marc A. Schuckit
 Contents ix

51 Opioid Drug Abuse and Dependence . . . . . . . . 696 Review and Self-Assessment . . . . . . . . . . . . . . . 709
Marc A. Schuckit Charles Wiener, Gerald Bloomeld,
Cynthia D. Brown, Joshua Schiffer,Adam Spivak
52 Cocaine and Other Commonly
Abused Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 702
Jack H. Mendelson, Nancy K. Mello Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
This page intentionally left blank
 CONTRIBUTORS

Numbers in brackets refer to the chapter(s) written or co-written by the contributor.

ANTHONY A. AMATO, MD ROBERT B. DAROFF, MD
Associate Professor of Neurology, Harvard Medical School; Chief, Gilbert W. Humphrey Professor of Neurology and Interim Chair,
Division of Neuromuscular Diseases, Department of Neurology, Department of Neurology, Case Western Reserve University
Brigham and Womens Hospital, Boston [43] School of Medicine and University Hospitals Case Medical Center,
Cleveland [9]
MICHAEL J. AMINOFF, MD, DSc
Professor of Neurology, School of Medicine, MAHLON R. DELONG, MD
University of California, San Francisco [3, 10, 12] Timmie Professor of Neurology, Emory University School of
Medicine,Atlanta [24]
ARTHUR K. ASBURY, MD
Van Meter Professor of Neurology Emeritus, University of WILLIAM P. DILLON, MD
Pennsylvania School of Medicine, Philadelphia [12, 41] Professor of Radiology, Neurology, and Neurosurgery;Vice-Chair,
Department of Radiology; Chief, Neuroradiology, University of
M. FLINT BEAL, MD California, San Francisco [2, 46]
Anne Parrish Titzel Professor and Chair, Department of Neurology
and Neuroscience,Weill Medical College of Cornell University; DANIEL B. DRACHMAN, MD
Neurologist-in-Chief, New York Presbyterian Hospital, Professor of Neurology & Neuroscience;WW Smith Charitable
New York [19, 29] Trust Professor of Neuroimmunology,The Johns Hopkins University
School of Medicine, Baltimore [42]
THOMAS D. BIRD, MD
Professor, Neurology and Medicine, University of Washington; JOEY D. ENGLISH, MD, PhD
Research Neurologist, Geriatric Research Education and Clinical Assistant Professor of Neurology, University of California, San
Center,VA Puget Sound Health Care System, Seattle [23] Francisco [21]

GERALD BLOOMFIELD, MD, MPH JOHN W. ENGSTROM, MD

Department of Internal Medicine,The Johns Hopkins University Professor of Neurology; Clinical Chief of Service; Neurology
School of Medicine, Baltimore [Review and Self-Assessment] Residency Program Director, University of California,
San Francisco [7, 28]
CYNTHIA D. BROWN, MD
Department of Internal Medicine,The Johns Hopkins University ANTHONY S. FAUCI, MD, DSc (Hon), DM&S (Hon), DHL
School of Medicine, Baltimore [Review and Self-Assessment] (Hon), DPS (Hon), DLM (Hon), DMS (Hon)
Chief, Laboratory of Immunoregulation; Director, National Institute
ROBERT H. BROWN, JR., MD, DPhil of Allergy and Infectious Diseases, National Institutes of Health,
Neurologist, Massachusetts General Hospital; Professor of Neurology, Bethesda [37]
Harvard Medical School, Boston [27, 43]
HOWARD L. FIELDS, MD, PhD
MARK D. CARLSON, MD, MA Professor of Neurology; Director,Wheeler Center for Neurobiology
Chief Medical Ofcer and Senior Vice President, Clinical Affairs, St. of Addiction, University of California, San Francisco [5]
Jude Medical, Sylmar;Adjunct Professor of Medicine, Case Western
Reserve University, Cleveland [8] ANDRE FURTADO, MD
Associate Specialist at the Department of Radiology, Neuroradiology
VINAY CHAUDHRY, MD Section, University of California, San Francisco [46]
Professor and Vice Chair,The Johns Hopkins University School of
Medicine; Co-Director, EMG Laboratory, Johns Hopkins Hospital, PETER J. GOADSBY, MD, PhD, DSc
Baltimore [40] Professor of Clinical Neurology, Institute of Neurology, Queen
Square London; Professor of Neurology, Department of Neurology,
CHARLES A. CZEISLER, MD, PhD University of California, San Francisco [6]
Baldino Professor of Sleep Medicine, and Director, Division of Sleep
Medicine, Harvard Medical School; Chief, Division of Sleep DOUGLAS S. GOODIN, MD
Medicine, Department of Medicine, Brigham and Womens Hospital, Professor of Neurology, University of California, San Francisco [34]
Boston [16]
STEPHEN L. HAUSER, MD
MARINOS C. DALAKAS, MD Robert A. Fishman Distinguished Professor and Chairman,
Professor of Neurology; Chief, Neuromuscular Diseases Section, Department of Neurology, University of California, San Francisco
NINDS, National Institute of Health, Bethesda [44] [1, 4, 19, 29, 30, 34, 41]

JOSEP DALMAU, MD, PhD J. CLAUDE HEMPHILL, III, MD, MAS

Professor of Neurology, Division Neuro-Oncology, Department of Associate Professor of Clinical Neurology and Neurological Surgery,
Neurology, Philadelphia [39] University of California, San Francisco; Director, Neurocritical Care
Program, San Francisco General Hospital, San Francisco [22]

xi
 xii Contributors

JONATHAN C. HORTON, MD, PhD NANCY K. MELLO, PhD

William F. Hoyt Professor of Neuro-Ophthalmology; Professor of Professor of Psychology (Neuroscience), Harvard Medical School,
Ophthalmology, Neurology, and Physiology, University of California, Boston [52]
San Francisco [17]
SHLOMO MELMED, MD
STEVEN E. HYMAN, MD Senior Vice President,Academic Affairs;Associate Dean, Cedars Sinai
Provost, Harvard University; Professor of Neurobiology, Harvard Medical Center, David Geffen School of Medicine at UCLA,
Medical School, Boston [48] Los Angeles [33]

MARK A. ISRAEL, MD JERRY R. MENDELL, MD

Professor of Pediatrics and Genetics, Dartmouth Medical School; Professor of Pediatrics, Neurology and Pathology,The Ohio State
Director, Norris Cotton Cancer Center, Dartmouth-Hitchcock University; Director, Center for Gene Therapy,The Research
Medical Center, Lebanon [32] Institute at Nationwide Childrens Hospital, Columbus [43]

J. LARRY JAMESON, MD, PhD JACK H. MENDELSON, MD

Professor of Medicine;Vice President for Medical Affairs and Lewis Professor of Psychiatry (Neuroscience), Harvard Medical School,
Landsberg Dean, Northwestern University Feinberg School of Belmont [52]
Medicine, Chicago [33]
M.-MARSEL MESULAM, MD
S. CLAIBORNE JOHNSTON, MD, PhD Director, Cognitive Neurology and Alzheimers Disease Center;
Professor, Neurology; Professor, Epidemiology and Biostatistics; Dunbar Professor of Neurology and Psychiatry, Northwestern
Director, University of California, San Francisco Stroke Service, University Feinberg School of Medicine, Chicago [15]
San Francisco [21]
BRUCE L. MILLER, MD
SCOTT ANDREW JOSEPHSON, MD AW and Mary Margaret Clausen Distinguished Professor of
Assistant Clinical Professor of Neurology, University of California, Neurology, University of California, San Francisco School of
San Francisco [13, 45] Medicine, San Francisco [13, 23, 38]
JORGE L. JUNCOS, MD C. WARREN OLANOW, MD
Associate Professor of Neurology, Emory University School of Henry P. and Georgette Goldschmidt Professor and Chairman of the
Medicine; Director of Neurology,Wesley Woods Hospital, Department of Neurology, Professor of Neuroscience,The Mount
Atlanta [24] Sinai School of Medicine, New York [25]
ERIC KANDEL, MD STANLEY B. PRUSINER, MD
University Professor; Fred Kavli Professor and Director, Kavli Director, Institute for Neurodegenerative Diseases; Professor,
Institute for Brain Sciences; Senior Investigator, Howard Hughes Department of Neurology; Professor, Department of Biochemistry
Medical Institute, Columbia University, New York [48] and Biophysics, University of California, San Francisco [38]
WALTER J. KOROSHETZ, MD NEIL H. RASKIN, MD
Deputy Director, National Institute of Neurological Disorders and Professor of Neurology, University of California, San Francisco [6]
Stroke, National Institutes of Health, Bethesda [36]
VICTOR I. REUS, MD
ANIL K. LALWANI, MD Professor, Department of Psychiatry, University of California, San
Mendik Foundation Professor and Chairman, Department of Francisco School of Medicine;Attending Physician, Langley Porter
Otolaryngology; Professor, Department of Pediatrics; Professor, Hospital and Clinics, San Francisco [49]
Department of Physiology and Neuroscience, New York University
School of Medicine, New York [18] GARY S. RICHARDSON, MD
Assistant Professor of Psychiatry, Case Western Reserve University,
H. CLIFFORD LANE, MD Cleveland; Senior Research Scientist, Sleep Disorders and Research
Clinical Director; Director, Division of Clinical Research; Deputy Center, Henry Ford Hospital, Detroit [16]
Director, Clinical Research and Special Projects; Chief, Clinical and
Molecular Retrovirology Section, Laboratory of Immunoregulation, ELIZABETH ROBBINS, MD
National Institute of Allergy and Infectious Diseases, National Associate Clinical Professor, University of California,
Institutes of Health, Bethesda [37] San Francisco [4]

PHILLIP A. LOW, MD GARY L. ROBERTSON, MD

Robert D and Patricia E Kern Professor of Neurology, Emeritus Professor of Medicine, Northwestern University Feinberg
Mayo Clinic College of Medicine, Rochester [28] School of Medicine, Chicago [33]

DANIEL H. LOWENSTEIN, MD KAREN L. ROOS, MD

Professor of Neurology; Director, University of California, San John and Nancy Nelson Professor of Neurology, Indiana University
Francisco Epilepsy Center;Associate Dean for Clinical/Translational School of Medicine, Indianapolis [35]
Research, San Francisco [1, 20]
ALLAN H. ROPPER, MD
JOSEPH B. MARTIN, MD, PhD, MA (Hon) Executive Vice-Chair, Department of Neurology, Brigham and
Dean Emeritus of the Faculty of Medicine, Edward R. and Womens Hospital, Harvard Medical School, Boston [14, 30, 31]
Anne G. Leer Professor of Neurobiology, Harvard Medical School,
Boston [1, 5]

Deceased.
 Contributors xiii

ROGER N. ROSENBERG, MD STEPHEN E. STRAUS, MD

Zale Distinguished Chair and Professor of Neurology, Department of Senior Investigator, Laboratory of Clinical Investigation, National
Neurology, University of Texas Southwestern Medical Center, Institute of Allergy and Infectious Diseases; Director, National
Dallas [26] Center for Complementary and Alternative Medicine, National
Institutes of Health, Bethesda [47]
MYRNA R. ROSENFELD, MD, PhD
Associate Professor of Neurology, Division Neuro-Oncology, LEWIS SUDARSKY, MD
Department of Neurology, University of Pennsylvania, Associate Professor of Neurology, Harvard Medical School;
Philadelphia [39] Director of Movement Disorders, Brigham and Womens Hospital,
Boston [11]
STEPHEN M. SAGAR, MD
Professor of Neurology, Case Western Reserve School of Medicine; MORTON N. SWARTZ, MD
Director of Neuro-Oncology, Ireland Cancer Center, University Professor of Medicine, Harvard Medical School; Chief, Jackson Firm
Hospitals of Cleveland, Cleveland [32] Medical Service and Infectious Disease Unit, Massachusetts General
Hospital, Boston [36]
MARTIN A. SAMUELS, MD, DSc (Hon)
Chairman, Department of Neurology, Brigham and Womens KENNETH L. TYLER, MD
Hospital; Professor of Neurology, Harvard Medical Center, Reuler-Lewin Family Professor of Neurology and Professor of
Boston [45] Medicine and Microbiology, University of Colorado Health Sciences
Center; Chief, Neurology Service, Denver Veterans Affairs Medical
JOSHUA SCHIFFER, MD Center, Denver [35]
Department of Internal Medicine,The Johns Hopkins University
School of Medicine, Baltimore [Review and Self-Assessment] CHARLES WIENER, MD
Professor of Medicine and Physiology;Vice Chair, Department of
MARC A. SCHUCKIT, MD Medicine; Director, Osler Medical Training Program,The Johns
Distinguished Professor of Psychiatry, School of Medicine, University Hopkins University School of Medicine, Baltimore
of California, San Diego; Director,Alcohol Research Center,VA San [Review and Self-Assessment]
Diego Healthcare System, San Diego [50, 51]
JOHN W. WINKELMAN, MD, PhD
WADE S. SMITH, MD, PhD Assistant Professor of Psychiatry, Harvard Medical School; Medical
Professor of Neurology, Daryl R. Gress Endowed Chair of Director, Sleep Health Center, Brigham and Womens Hospital,
Neurocritical Care and Stroke; Director, University of California, Boston [16]
San Francisco Neurovascular Service, San Francisco [21, 22]

ADAM SPIVAK, MD
Department of Internal Medicine,The Johns Hopkins University
School of Medicine, Baltimore [Review and Self-Assessment]

Deceased.
This page intentionally left blank
 PREFACE

The rst edition of Harrisons Neurology in Clinical Medicine problems. All of these forces, acting within the fast-
was an unqualied success. Readers responded enthusiasti- paced environment of modern medical practice, can
cally to the convenient, attractive, expanded, and updated lead to an overreliance on unfocused neuroimaging
stand-alone volume, which was based upon the neurology tests, suboptimal patient care, and unfortunate out-
and psychiatry sections from Harrisons Principles of Internal comes. Because neurologists represent less than 1% of
Medicine. Our original goal was to provide, in an easy-to- all physicians, the vast majority of neurologic care
use format, full coverage of the most authoritative infor- must be delivered by nonspecialists who are often
mation available anywhere of clinically important topics in generalists and usually internists.
neurology and psychiatry, while retaining the focus on The old adage that neurologists know everything
pathophysiology and therapy that has always been charac- but do nothing has been rendered obsolete by advances
teristic of Harrisons. in molecular medicine, imaging, bioengineering, and
This new edition of Harrisons Neurology in Clinical clinical research. Examples of new therapies include:
Medicine has been extensively rewritten to highlight thrombolytic therapy for acute ischemic stroke; endovas-
recent advances in the understanding, diagnosis, treat- cular recanalization for cerebrovascular disorders; inten-
ment and prevention of neurologic and psychiatric sive monitoring of brain pressure and cerebral blood
diseases. New chapters discuss the pathogenesis and ow for brain injury; effective therapies for immune-
treatment of headache, the clinical approach to imbal- mediated neurologic disorders such as multiple sclerosis,
ance, and the causes of confusion and delirium. Notable immune neuropathies, myasthenia gravis, and myositis;
also are new chapters on essential tremor and move- new designer drugs for migraine; the first generation of
ment disorders, peripheral neuropathy, and on neuro- rational therapies for neurodegenerative diseases; neural
logic problems in hospitalized patients. Many illustrative stimulators for Parkinsons disease; drugs for narcolepsy
neuroimaging gures appear throughout the section, and other sleep disorders; and control of epilepsy by
and a new atlas of neuroimaging ndings has been surgical resection of small seizure foci precisely local-
added. Extensively updated coverage of the dementias, ized by functional imaging and electrophysiology. The
Parkinsons disease, and related neurodegenerative dis- pipeline continues to grow, stimulated by a quickening
orders highlight new ndings from genetics, molecular tempo of discoveries generating opportunities for
imaging, cell biology, and clinical research that have rational design of new diagnostics, interventions, and
transformed understanding of these common problems. drugs.
Another new chapter, authored by Steve Hyman and The founding editors of Harrisons Principles of Inter-
Eric Kandel, reviews progress in deciphering the patho- nal Medicine acknowledged the importance of neurol-
genesis of common psychiatric disorders and discusses ogy but were uncertain as to its proper role in a text-
the remaining challenges to development of more effec- book of internal medicine. An initial plan to exclude
tive treatments. neurology from the rst edition (1950) was reversed at
For many physicians, neurologic diseases represent the eleventh hour, and a neurology section was hastily
particularly challenging problems. Acquisition of the req- prepared by Houston Merritt. By the second edition,
uisite clinical skills is often viewed as time-consuming, the section was considerably enlarged by Raymond D.
difficult to master, and requiring a working knowl- Adams, whose inuence on the textbook was profound.
edge of obscure anatomic facts and laundry lists of The third neurology editor, Joseph B. Martin, brilliantly
diagnostic possibilities. The patients themselves may led the book during the 1980s and 1990s as neurology
be difficult, as neurologic disorders often alter an was transformed from a largely descriptive discipline to
individuals capacity to recount the history of an ill- one of the most dynamic and rapidly evolving areas of
ness or to even recognize that something is wrong. medicine. With these changes, the growth of neurology
An additional obstacle is the development of inde- coverage in Harrisons became so pronounced that
pendent neurology services, departments, and training Harrison suggested the book be retitled, The Details of
programs at many medical centers, reducing the ex- Neurology and Some Principles of Internal Medicine.
posure of trainees in internal medicine to neurologic His humorous comment, now legendary, underscores the

xv
 xvi Preface

depth of coverage of neurologic medicine in Harrisons be- NOTE TO READERS ON ELECTRONIC

tting its critical role in the practice of internal medicine. ACCESS TO THE FAMILY OF
The Editors are indebted to our authors, a group of HARRISONS PUBLICATIONS
internationally recognized authorities who have magnif- THE NEUROLOGIC METHOD
icently distilled a daunting body of information into the
The Harrisons collection of publications has expanded as in-
essential principles required to understand and manage
formation delivery technology has evolved. Harrisons Online
commonly encountered neurological problems. We are
(HOL) is now one of the standard informational resources
also grateful to Dr. Andrew Scott Josephson who over-
used in medical centers throughout the United States. In
saw the updating process for the second edition of
addition to the full content of the parent text, HOL offers
Harrisons Neurology in Clinical Medicine. Thanks also to
frequent updates from and links to the emerging scientic
Dr. Elizabeth Robbins, who has served for more than a
and clinical literature; an expanded collection of reference
decade as managing editor of the neurology section of
citations; audio recordings and Podcasts of lectures by
Harrisons; she has overseen the complex logistics re-
authorities in the various specialties of medicine; and other
quired to produce a multiauthored textbook, and has
helpful supplementary materials such as a complete database
promoted exceptional standards for clarity, language and
of pharmacologic therapeutics, self-assessment questions for
style. Finally, we wish to acknowledge and express our
examination and board review; and an expanded collection
great appreciation to our colleagues at McGraw-Hill.
of clinical photographs. Video clips of cardiac and endo-
This new volume was championed by James Shanahan
scopic imaging are also available on HOL. Future iterations
and impeccably managed by Kim Davis.
of HOL will include expanded use of such supplementary
We live in an electronic, wireless age. Information is
multimedia materials to illustrate further key concepts and
downloaded rather than pulled from the shelf. Some
clinical approaches discussed in the parent text.
have questioned the value of traditional books in this
In 2006, in recognition of the increasing time pres-
new era. We believe that as the volume of information,
sures placed on clinicians and the increasing use of elec-
and the ways to access this information, continues to
tronic medical records systems, Harrisons Practice of Medi-
grow, the need to grasp the essential concepts of medical
cine (HP) made its debut. HP is a comprehensive
practice becomes even more challenging. One of our
database of specic clinical topics built from the ground
young colleagues recently remarked that he uses the
up to provide authoritative guidance quickly at the
Internet to nd facts, but that he reads Harrisons to learn
point of care. HP is highly structured so that physicians
medicine. Our aim has always been to provide
and other health professionals can access the most salient
the reader with an integrated, organic summary of the
features of any one of more than 700 diseases and clini-
science and the practice of medicine rather than a mere
cal presentations within minutes. This innovative new
compendium of chapters, and we are delighted and
application is updated regularly and includes fully inte-
humbled by the continuing and quite remarkable growth
grated, detailed information on brand name and generic
in popularity of Harrisons at a time when many classics
drugs. In addition, hyperlinks throughout HP enable
in medicine seem less relevant than in years past.
quick access to the primary literature via PubMed. HP is
It is our sincere hope that you will enjoy using Harrisons
available via the Internet and on PDA.
Neurology in Clinical Medicine, Second Edition as an authorita-
tive source for the most up-to-date information in clinical
Stephen L. Hauser, MD
neurology.
 NOTICE
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher of this work have checked with
sources believed to be reliable in their efforts to provide information that is
complete and generally in accord with the standards accepted at the time of
publication. However, in view of the possibility of human error or changes
in medical sciences, neither the authors nor the publisher nor any other
party who has been involved in the preparation or publication of this work
warrants that the information contained herein is in every respect accurate
or complete, and they disclaim all responsibility for any errors or omissions
or for the results obtained from use of the information contained in this
work. Readers are encouraged to conrm the information contained herein
with other sources. For example and in particular, readers are advised to
check the product information sheet included in the package of each drug
they plan to administer to be certain that the information contained in this
work is accurate and that changes have not been made in the recommended
dose or in the contraindications for administration. This recommendation is
of particular importance in connection with new or infrequently used drugs.

Review and self-assessment questions and answers were taken from Wiener C,
Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J
(editors) Bloomeld G, Brown CD, Schiffer J, Spivak A (contributing editors).
Harrisons Principles of Internal Medicine Self-Assessment and Board Review, 17th ed.
New York, McGraw-Hill, 2008, ISBN 978-0-07-149619-3.

The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine
throughout the world.

The genetic icons identify a clinical issue with an explicit genetic relationship.
This page intentionally left blank
 SECTION I

INTRODUCTION TO
NEUROLOGY
 CHAPTER 1
APPROACH TO THE PATIENT WITH
NEUROLOGIC DISEASE
Daniel H. Lowenstein I Joseph B. Martin I Stephen L. Hauser

I The Neurologic Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

I The Neurologic History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
I The Neurologic Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
I Neurologic Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Neurologic diseases are common and costly. According symptoms restricted to the nervous system, or do they
to one estimate, 180 million Americans suffer from a arise in the context of a systemic illness? Is the problem
nervous system disorder, resulting in an annual cost of in the central nervous system (CNS), the peripheral ner-
over $700 billion. The aggregate cost is even greater vous system (PNS), or both? If in the CNS, is the cere-
than that for cardiovascular disease (Table 1-1). Glob- bral cortex, basal ganglia, brainstem, cerebellum, or
ally, these disorders are responsible for 28% of all years spinal cord responsible? Are the pain-sensitive meninges
lived with a disability. Most patients with neurologic involved? If in the PNS, could the disorder be located in
symptoms seek care from internists and other generalists peripheral nerves and, if so, are motor or sensory nerves
rather than from neurologists. Because therapies now primarily affected, or is a lesion in the neuromuscular
exist for many neurologic disorders, a skillful approach junction or muscle more likely?
to diagnosis is essential. Errors commonly result from an The rst clues to dening the anatomic area of
overreliance on costly neuroimaging procedures and involvement appear in the history, and the examination
laboratory tests, which, although useful, do not substi- is then directed to conrm or rule out these impressions
tute for an adequate history and examination. The and to clarify uncertainties. A more detailed examina-
proper approach to the patient with a neurologic illness tion of a particular region of the CNS or PNS is often
begins with the patient and focuses the clinical problem indicated. For example, the examination of a patient
rst in anatomic and then in pathophysiologic terms; who presents with a history of ascending paresthesias
only then should a specic diagnosis be entertained. and weakness should be directed toward deciding,
This method ensures that technology is judiciously among other things, if the location of the lesion is in the
applied, a correct diagnosis is established in an efcient spinal cord or peripheral nerves. Focal back pain, a spinal
manner, and treatment is promptly initiated. cord sensory level, and incontinence suggest a spinal
cord origin, whereas a stocking-glove pattern of sensory
loss suggests peripheral nerve disease; areexia usually
THE NEUROLOGIC METHOD indicates peripheral neuropathy but may also be present
with spinal shock in acute spinal cord disorders.
Locate the Lesion(s)
Deciding where the lesion is accomplishes the task
The rst priority is to identify the region of the nervous of limiting the possible etiologies to a manageable, nite
system that is likely to be responsible for the symptoms. number. In addition, this strategy safeguards against
Can the disorder be mapped to one specic location, is making serious errors. Symptoms of recurrent vertigo,
it multifocal, or is a diffuse process present? Are the diplopia, and nystagmus should not trigger multiple
2
TABLE 1-1 advancing visual scotoma with luminous edges, termed 3
PREVALENCE OF NEUROLOGIC AND PSYCHIATRIC fortication spectra, indicates spreading cortical depression,
DISEASES WORLDWIDE typically with migraine.

CHAPTER 1
DISORDER PATIENTS, MILLIONS

Nutritional disorders and 352 THE NEUROLOGIC HISTORY

neuropathies
Migraine 326 Attention to the description of the symptoms experi-
Trauma 170 enced by the patient and substantiated by family mem-
Depression 154 bers and others often permits an accurate localization

Approach to the Patient with Neurologic Disease

Alcoholism 91 and determination of the probable cause of the com-
Cerebrovascular diseases 61 plaints, even before the neurologic examination is per-
Epilepsy 50
formed. The history also helps to bring a focus to the
Schizophrenia 25
Dementia 24
neurologic examination that follows. Each complaint
Neurologic infections 18 should be pursued as far as possible to elucidate the
Drug abuse 15 location of the lesion, the likely underlying pathophysi-
ology, and potential etiologies. For example, a patient
Source: World Health Organization estimates, 20022005. complains of weakness of the right arm. What are the
associated features? Does the patient have difculty with
brushing hair or reaching upward (proximal) or button-
sclerosis as an answer (etiology) but brainstem or ing buttons or opening a twist-top bottle (distal)? Nega-
pons (location); then a diagnosis of brainstem arteri- tive associations may also be crucial. A patient with a
ovenous malformation will not be missed for lack of right hemiparesis without a language decit likely has a
consideration. Similarly, the combination of optic neuri- lesion (internal capsule, brainstem, or spinal cord) differ-
tis and spastic ataxic paraparesis should initially suggest ent from that of a patient with a right hemiparesis and
optic nerve and spinal cord disease; multiple sclerosis aphasia (left hemisphere). Other pertinent features of the
(MS), CNS syphilis, and vitamin B12 deciency are history include the following:
treatable disorders that can produce this syndrome. Once
the question, Where is the lesion? is answered, then 1. Temporal course of the illness. It is important to deter-
the question,What is the lesion? can be addressed. mine the precise time of appearance and rate of
progression of the symptoms experienced by the
patient. The rapid onset of a neurologic complaint,
Dene the Pathophysiology
occurring within seconds or minutes, usually indi-
Clues to the pathophysiology of the disease process may cates a vascular event, a seizure, or migraine. The
also be present in the history. Primary neuronal (gray onset of sensory symptoms located in one extremity
matter) disorders may present as early cognitive distur- that spread over a few seconds to adjacent portions
bances, movement disorders, or seizures, whereas white of that extremity and then to the other regions of
matter involvement produces predominantly long the body suggests a seizure. A more gradual onset
tract disorders of motor, sensory, visual, and cerebellar and less well localized symptoms point to the possi-
pathways. Progressive and symmetric symptoms often bility of a transient ischemic attack (TIA). A similar
have a metabolic or degenerative origin; in such cases but slower temporal march of symptoms accompa-
lesions are usually not sharply circumscribed. Thus, a nied by headache, nausea, or visual disturbance sug-
patient with paraparesis and a clear spinal cord sensory gests migraine. The presence of positive sensory
level is unlikely to have vitamin B12 deciency as the symptoms (e.g., tingling or sensations that are dif-
explanation. A Lhermitte symptom (electric shocklike cult to describe) or involuntary motor movements
sensations evoked by neck exion) is due to ectopic suggests a seizure; in contrast, transient loss of func-
impulse generation in white matter pathways and occurs tion (negative symptoms) suggests a TIA. A stutter-
with demyelination in the cervical spinal cord; among ing onset where symptoms appear, stabilize, and
many possible causes, this symptom may indicate MS in then progress over hours or days also suggests cere-
a young adult or compressive cervical spondylosis in an brovascular disease; an additional history of transient
older person. Symptoms that worsen after exposure to remission or regression indicates that the process is
heat or exercise may indicate conduction block in more likely due to ischemia rather than hemor-
demyelinated axons, as occurs in MS. A patient with rhage. A gradual evolution of symptoms over hours
recurrent episodes of diplopia and dysarthria associated or days suggests a toxic, metabolic, infectious, or
with exercise or fatigue may have a disorder of neuro- inammatory process. Progressing symptoms associ-
muscular transmission such as myasthenia gravis. Slowly ated with the systemic manifestations of fever, stiff
 4 neck, and altered level of consciousness imply an patient with underlying cancer. Patients with malig-
infectious process. Relapsing and remitting symp- nancy may also present with a neurologic paraneo-
toms involving different levels of the nervous system plastic syndrome (Chap. 39) or complications from
SECTION I

suggest MS or other inammatory processes; these chemotherapy or radiotherapy. Marfans syndrome and
disorders can occasionally produce new symptoms related collagen disorders predispose to dissection of
that are rapidly progressive over hours. Slowly pro- the cranial arteries and aneurysmal subarachnoid
gressive symptoms without remissions are character- hemorrhage; the latter may also occur with polycystic
istic of neurodegenerative disorders, chronic infec- kidney disease. Various neurologic disorders occur
tions, gradual intoxications, and neoplasms. with dysthyroid states or other endocrinopathies. It is
Introduction to Neurology

2. Patients descriptions of the complaint. The same words especially important to look for the presence of sys-
often mean different things to different patients. temic diseases in patients with peripheral neuropathy.
Dizziness may imply impending syncope, a sense Most patients with coma in a hospital setting have a
of disequilibrium, or true spinning vertigo. Numb- metabolic, toxic, or infectious cause.
ness may mean a complete loss of feeling, a positive 6. Drug use and abuse and toxin exposure. It is essential to
sensation such as tingling, or paralysis. Blurred inquire about the history of drug use, both pre-
vision may be used to describe unilateral visual scribed and illicit. Aminoglycoside antibiotics may
loss, as in transient monocular blindness, or diplopia. exacerbate symptoms of weakness in patients with
The interpretation of the true meaning of the words disorders of neuromuscular transmission, such as
used by patients to describe symptoms becomes myasthenia gravis, and may cause dizziness sec-
even more complex when there are differences in ondary to ototoxicity. Vincristine and other anti-
primary languages and cultures. neoplastic drugs can cause peripheral neuropathy,
3. Corroboration of the history by others. It is almost always and immunosuppressive agents such as cyclosporine
helpful to obtain additional information from fam- can produce encephalopathy. Excessive vitamin
ily, friends, or other observers to corroborate or ingestion can lead to disease; for example vitamin A
expand the patients description. Memory loss, apha- and pseudotumor cerebri, or pyridoxine and
sia, loss of insight, intoxication, and other factors peripheral neuropathy. Many patients are unaware
may impair the patients capacity to communicate that over-the-counter sleeping pills, cold prepara-
normally with the examiner or prevent openness tions, and diet pills are actually drugs. Alcohol, the
about factors that have contributed to the illness. most prevalent neurotoxin, is often not recognized
Episodes of loss of consciousness necessitate that as such by patients, and other drugs of abuse such as
details be sought from observers to ascertain pre- cocaine and heroin can cause a wide range of neu-
cisely what has happened during the event. rologic abnormalities. A history of environmental or
4. Family history. Many neurologic disorders have an industrial exposure to neurotoxins may provide an
underlying genetic component. The presence of a essential clue; consultation with the patients co-
Mendelian disorder, such as Huntingtons disease or workers or employer may be required.
Charcot-Marie-Tooth neuropathy, is often obvious 7. Formulating an impression of the patient. Use the
if family data are available. More detailed questions opportunity while taking the history to form an
about family history are often necessary in poly- impression of the patient. Is the information forth-
genic disorders such as MS, migraine, and many coming, or does it take a circuitous course? Is there
types of epilepsy. It is important to elicit family his- evidence of anxiety, depression, or hypochondriasis?
tory about all illnesses, in addition to neurologic and Are there any clues to defects in language, memory,
psychiatric disorders. A familial propensity to hyper- insight, or inappropriate behavior? The neurologic
tension or heart disease is relevant in a patient who assessment begins as soon as the patient comes into
presents with a stroke.There are numerous inherited the room and the rst introduction is made.
neurologic diseases that are associated with multisys-
tem manifestations that may provide clues to the
correct diagnosis (e.g., neurobromatosis, Wilsons THE NEUROLOGIC EXAMINATION
disease, neuro-ophthalmic syndromes).
5. Medical illnesses. Many neurologic diseases occur in the The neurologic examination is challenging and com-
context of systemic disorders. Diabetes mellitus, plex; it has many components and includes a number of
hypertension, and abnormalities of blood lipids predis- skills that can be mastered only through repeated use of
pose to cerebrovascular disease. A solitary mass lesion the same techniques on a large number of individuals
in the brain may be an abscess in a patient with valvu- with and without neurologic disease. Mastery of the
lar heart disease, a primary hemorrhage in a patient complete neurologic examination is usually important
with a coagulopathy, a lymphoma or toxoplasmosis in only for physicians in neurology and associated specialties.
a patient with AIDS (Chap. 37), or a metastasis in a However, knowledge of the basics of the examination,
especially those components that are effective in screen- The mental status examination is underway as soon as 5
ing for neurologic dysfunction, is essential for all clini- the physician begins observing and talking with the
cians, especially generalists. patient. If the history raises any concern for abnormali-

CHAPTER 1
There is no single, universally accepted sequence of ties of higher cortical function or if cognitive problems
the examination that must be followed, but most clini- are observed during the interview, then detailed testing
cians begin with assessment of mental status followed by of the mental status is indicated. The patients ability to
the cranial nerves, motor system, sensory system, coordi- understand the language used for the examination, cul-
nation, and gait. Whether the examination is basic or tural background, educational experience, sensory or
comprehensive, it is essential that it be performed in an motor problems, or comorbid conditions need to be

Approach to the Patient with Neurologic Disease

orderly and systematic fashion to avoid errors and seri- factored into the applicability of the tests and interpreta-
ous omissions. Thus, the best way to learn and gain tion of results.
expertise in the examination is to choose ones own The Folstein mini-mental status examination (MMSE)
approach and practice it frequently and do it in exactly (Table 23-5) is a standardized screening examination of
the same sequence each time. cognitive function that is extremely easy to administer
The detailed description of the neurologic examina- and takes <10 min to complete. Using age-adjusted val-
tion that follows describes the more commonly used ues for dening normal performance, the test is ~85%
parts of the examination, with a particular emphasis on sensitive and 85% specic for making the diagnosis of
the components that are considered most helpful for the dementia that is moderate or severe, especially in edu-
assessment of common neurologic problems. Each sec- cated patients. When there is sufcient time available,
tion also includes a brief description of the minimal the MMSE is one of the best methods for documenting
examination necessary for adequate screening for abnor- the current mental status of the patient, and this is espe-
malities in a patient who has no symptoms suggesting cially useful as a baseline assessment to which future
neurologic dysfunction. A screening examination done scores of the MMSE can be compared.
in this way can be completed in 35 min. Individual elements of the mental status examination
Several additional points about the examination are can be subdivided into level of consciousness, orienta-
worth noting. First, in recording observations, it is tion, speech and language, memory, fund of information,
important to describe what is found rather than to apply insight and judgment, abstract thought, and calculations.
a poorly dened medical term (e.g., patient groans to Level of consciousness is the patients relative state of
sternal rub rather than obtunded). Second, subtle awareness of the self and the environment, and ranges
CNS abnormalities are best detected by carefully com- from fully awake to comatose. When the patient is not
paring a patients performance on tasks that require fully awake, the examiner should describe the responses
simultaneous activation of both cerebral hemispheres to the minimum stimulus necessary to elicit a reaction,
(e.g., eliciting a pronator drift of an outstretched arm ranging from verbal commands to a brief, painful stimu-
with the eyes closed; extinction on one side of bilaterally lus such as a squeeze of the trapezius muscle. Responses
applied light touch, also with eyes closed; or decreased that are directed toward the stimulus and signify some
arm swing or a slight asymmetry when walking). Third, degree of intact cerebral function (e.g., opening the eyes
if the patients complaint is brought on by some activity, and looking at the examiner or reaching to push away a
reproduce the activity in the ofce. If the complaint is painful stimulus) must be distinguished from reex
of dizziness when the head is turned in one direction, responses of a spinal origin (e.g., triple exion response
have the patient do this and also look for associated signs exion at the ankle, knee, and hip in response to a
on examination (e.g., nystagmus or dysmetria). If pain painful stimulus to the foot).
occurs after walking two blocks, have the patient leave Orientation is tested by asking the patient to state his
the ofce and walk this distance and immediately or her name, location, and time (day of the week and
return, and repeat the relevant parts of the examination. date); time is usually the rst to be affected in a variety
Finally, the use of tests that are individually tailored to of conditions.
the patients problem can be of value in assessing Speech is assessed by observing articulation, rate,
changes over time. Tests of walking a 7.5-m (25-ft) dis- rhythm, and prosody (i.e., the changes in pitch and
tance (normal, 56 s; note assistance, if any), repetitive accentuation of syllable and words).
nger or toe tapping (normal, 2025 taps in 5 s), or hand- Language is assessed by observing the content of the
writing are examples. patients verbal and written output, response to spoken
commands, and ability to read. A typical testing
sequence is to ask the patient to name successively more
Mental Status Examination
detailed components of clothing, a watch or a pen;
The bare minimum: During the interview, look for difcul- repeat the phrase No ifs, ands, or buts; follow a three-
ties with communication and determine whether the patient has step, verbal command; write a sentence; and read and
recall and insight into recent and past events. respond to a written command.
 6 Memory should be analyzed according to three main visual elds in the plane that is equidistant between you
time scales: (1) immediate memory can be tested by say- and the patient. Instruct the patient to look directly at
ing a list of three items and having the patient repeat the the center of your face and to indicate when and where
SECTION I

list immediately, (2) short-term memory is assessed by he or she sees one of your ngers moving. Beginning
asking the patient to recall the same three items 5 and with the two inferior quadrants and then the two supe-
15 min later, and (3) long-term memory is evaluated by rior quadrants, move your index nger of the right
determining how well the patient is able to provide a hand, left hand, or both hands simultaneously and
coherent chronologic history of his or her illness or per- observe whether the patient detects the movements. A
sonal events. single small-amplitude movement of the nger is suf-
Introduction to Neurology

Fund of information is assessed by asking questions cient for a normal response. Focal perimetry and tangent
about major historic or current events, with special screen examinations should be used to map out visual
attention to educational level and life experiences. eld defects fully or to search for subtle abnormalities.
Abnormalities of insight and judgment are usually Optic fundi should be examined with an ophthalmo-
detected during the patient interview; a more detailed scope, and the color, size, and degree of swelling or ele-
assessment can be elicited by asking the patient to vation of the optic disc noted, as well as the color and
describe how he or she would respond to situations texture of the retina. The retinal vessels should be
having a variety of potential outcomes (e.g., What checked for size, regularity, arterial-venous nicking at
would you do if you found a wallet on the sidewalk?). crossing points, hemorrhage, exudates, etc.
Abstract thought can be tested by asking the patient to
describe similarities between various objects or concepts CN III, IV, VI (Oculomotor, Trochlear, Abducens)
(e.g., apple and orange, desk and chair, poetry and sculp- Describe the size and shape of pupils and reaction to
ture) or to list items having the same attributes (e.g., a light and accommodation (i.e., as the eyes converge
list of four-legged animals). while following your nger as it moves toward the
Calculation ability is assessed by having the patient bridge of the nose). To check extraocular movements,
carry out a computation that is appropriate to the ask the patient to keep his or her head still while track-
patients age and education (e.g., serial subtraction of 7 ing the movement of the tip of your nger. Move the
from 100 or 3 from 20; or word problems involving target slowly in the horizontal and vertical planes;
simple arithmetic). observe any paresis, nystagmus, or abnormalities of
smooth pursuit (saccades, oculomotor ataxia, etc.). If
necessary, the relative position of the two eyes, both in
Cranial Nerve Examination primary and multidirectional gaze, can be assessed by
The bare minimum: Check the fundi, visual elds, pupil size comparing the reections of a bright light off both
and reactivity, extraocular movements, and facial movements. pupils. However, in practice it is typically more useful to
The cranial nerves (CN) are best examined in determine whether the patient describes diplopia in any
numerical order, except for grouping together CN III, direction of gaze; true diplopia should almost always
IV, and VI because of their similar function. resolve with one eye closed. Horizontal nystagmus is
best assessed at 45 and not at extreme lateral gaze
(which is uncomfortable for the patient); the target must
CN I (Olfactory)
often be held at the lateral position for at least a few sec-
Testing is usually omitted unless there is suspicion for onds to detect an abnormality.
inferior frontal lobe disease (e.g., meningioma). With
eyes closed, ask the patient to sniff a mild stimulus such CN V (Trigeminal)
as toothpaste or coffee and identify the odorant. Examine sensation within the three territories of the
branches of the trigeminal nerve (ophthalmic, maxillary,
CN II (Optic) and mandibular) on each side of the face. As with other
Check visual acuity (with eyeglasses or contact lens cor- parts of the sensory examination, testing of two sensory
rection) using a Snellen chart or similar tool. Test the modalities derived from different anatomic pathways
visual elds by confrontation, i.e., by comparing the (e.g., light touch and temperature) is sufcient for a
patients visual elds to your own. As a screening test, it screening examination. Testing of other modalities, the
is usually sufcient to examine the visual elds of both corneal reex, and the motor component of CN V (jaw
eyes simultaneously; individual eye elds should be clenchmasseter muscle) is indicated when suggested
tested if there is any reason to suspect a problem of by the history.
vision by the history or other elements of the examina-
tion, or if the screening test reveals an abnormality. Face CN VII (Facial)
the patient at a distance of approximately 0.61.0 m Look for facial asymmetry at rest and with spontaneous
(23 ft) and place your hands at the periphery of your movements. Test eyebrow elevation, forehead wrinkling,
eye closure, smiling, and cheek puff. Look in particular Tone 7
for differences in the lower versus upper facial muscles; Muscle tone is tested by measuring the resistance to pas-
weakness of the lower two-thirds of the face with sive movement of a relaxed limb. Patients often have dif-

CHAPTER 1
preservation of the upper third suggests an upper motor culty relaxing during this procedure, so it is useful to
neuron lesion, whereas weakness of an entire side sug- distract the patient to minimize active movements. In
gests a lower motor neuron lesion. the upper limbs, tone is assessed by rapid pronation and
supination of the forearm and exion and extension at
CN VIII (Vestibulocochlear) the wrist. In the lower limbs, while the patient is supine
Check the patients ability to hear a nger rub or whis- the examiners hands are placed behind the knees and

Approach to the Patient with Neurologic Disease

pered voice with each ear. Further testing for air versus rapidly raised; with normal tone the ankles drag along
mastoid bone conduction (Rinne) and lateralization of a the table surface for a variable distance before rising,
512-Hz tuning fork placed at the center of the forehead whereas increased tone results in an immediate lift of
(Weber) should be done if an abnormality is detected by the heel off the surface. Decreased tone is most com-
history or examination. Any suspected problem should be monly due to lower motor neuron or peripheral nerve
followed up with formal audiometry. For further discus- disorders. Increased tone may be evident as spasticity
sion of assessing vestibular nerve function in the setting of (resistance determined by the angle and velocity of
dizziness or coma, see Chaps. 9 and 14, respectively. motion; corticospinal tract disease), rigidity (similar
resistance in all angles of motion; extrapyramidal dis-
CN IX, X (Glossopharyngeal, Vagus) ease), or paratonia (uctuating changes in resistance;
Observe the position and symmetry of the palate and frontal lobe pathways or normal difculty in relaxing).
uvula at rest and with phonation (aah). The pharyn- Cogwheel rigidity, in which passive motion elicits jerky
geal (gag) reex is evaluated by stimulating the poste- interruptions in resistance, is seen in parkinsonism.
rior pharyngeal wall on each side with a sterile, blunt
object (e.g., tongue blade), but the reex is often absent Strength
in normal individuals. Testing for pronator drift is an extremely useful method
for screening upper limb weakness.The patient is asked to
CN XI (Spinal Accessory)
hold both arms fully extended and parallel to the ground
Check shoulder shrug (trapezius muscle) and head rota- with eyes closed. This position should be maintained for
tion to each side (sternocleidomastoid) against resistance. ~10 s; any exion at the elbow or ngers or pronation of
the forearm, especially if asymmetric, is a sign of potential
weakness. Muscle strength is further assessed by having
CN XII (Hypoglossal)
the patient exert maximal effort for the particular muscle
Inspect the tongue for atrophy or fasciculations, position
or muscle group being tested. It is important to isolate the
with protrusion, and strength when extended against the
muscles as much as possible, i.e., hold the limb so that
inner surface of the cheeks on each side.
only the muscles of interest are active. It is also helpful to
palpate accessible muscles as they contract. Grading mus-
Motor Examination cle strength and evaluating the patients effort is an art
The bare minimum: Look for muscle atrophy and check extrem- that takes time and practice. Muscle strength is tradition-
ity tone. Assess upper extremity strength by checking for pronator ally graded using the following scale:
drift and strength of wrist or nger extensors.Tap the biceps, patel-
lar, and Achilles reexes.Test for lower extremity strength by having 0 = no movement
the patient walk normally and on heels and toes. 1 = icker or trace of contraction but no associated
The motor examination includes observations of movement at a joint
muscle appearance, tone, strength, and reexes. Although 2 = movement with gravity eliminated
gait is in part a test of motor function, it is usually evalu- 3 = movement against gravity but not against
ated separately at the end of the examination. resistance
4 = movement against a mild degree of resistance
Appearance 4 = movement against moderate resistance
Inspect and palpate muscle groups under good light and 4+ = movement against strong resistance
with the patient in a comfortable and symmetric posi- 5 = full power
tion. Check for muscle fasciculations, tenderness, and However, in many cases it is more practical to use the
atrophy or hypertrophy. Involuntary movements may be following terms:
present at rest (e.g., tics, myoclonus, choreoathetosis),
during maintained posture (pill-rolling tremor of Parkin- Paralysis = no movement
sons disease), or with voluntary movements (intention Severe weakness = movement with gravity
tremor of cerebellar disease or familial tremor). eliminated
 8 Moderate weakness = movement against gravity but toward the stimulated quadrant.With upper motor neu-
not against mild resistance ron lesions, these reexes are absent.They are most help-
Mild weakness = movement against moderate ful when there is preservation of the upper (spinal cord
SECTION I

resistance level T9) but not lower (T12) abdominal reexes, indi-
Full strength cating a spinal lesion between T9 and T12, or when the
response is asymmetric. Other useful cutaneous reexes
Noting the pattern of weakness is as important as include the cremasteric (ipsilateral elevation of the testi-
assessing the magnitude of weakness. Unilateral or bilat- cle following stroking of the medial thigh; mediated by
eral weakness of the upper limb extensors and lower L1 and L2) and anal (contraction of the anal sphincter
limb exors (pyramidal weakness) suggests a lesion of
Introduction to Neurology

when the perianal skin is scratched; mediated by S2, S3,

the pyramidal tract, bilateral proximal weakness suggests S4) reexes. It is particularly important to test for these
myopathy, and bilateral distal weakness suggests periph- reexes in any patient with suspected injury to the
eral neuropathy. spinal cord or lumbosacral roots.

Reexes Primitive Reexes

Muscle Stretch Reexes With disease of the frontal lobe pathways, several primi-
Those that are typically assessed include the biceps (C5, tive reexes not normally present in the adult may
C6), brachioradialis (C5, C6), and triceps (C7, C8) appear. The suck response is elicited by lightly touching
reexes in the upper limbs and the patellar or quadri- the center of the lips, and the root response the corner
ceps (L3, L4) and Achilles (S1, S2) reexes in the lower of the lips, with a tongue blade; the patient will move
limbs. The patient should be relaxed and the muscle the lips to suck or root in the direction of the stimulus.
positioned midway between full contraction and exten- The grasp reex is elicited by touching the palm
sion. Reexes may be enhanced by asking the patient to between the thumb and index nger with the exam-
voluntarily contract other, distant muscle groups (Jen- iners ngers; a positive response is a forced grasp of the
drassik maneuver). For example, upper limb reexes may examiners hand. In many instances stroking the back of
be reinforced by voluntary teeth-clenching, and the the hand will lead to its release. The palmomental
Achilles reex by hooking the exed ngers of the two response is contraction of the mentalis muscle (chin)
hands together and attempting to pull them apart. For ipsilateral to a scratch stimulus diagonally applied to the
each reex tested, the two sides should be tested palm.
sequentially, and it is important to determine the small-
est stimulus required to elicit a reex rather than the Sensory Examination
maximum response. Reexes are graded according to
the following scale: The bare minimum: Ask whether the patient can feel light
touch and the temperature of a cool object in each distal
0 = absent extremity. Check double simultaneous stimulation using light
1 = present but diminished touch on the hands.
2 = normoactive Evaluating sensation is usually the most unreliable
3 = exaggerated part of the examination, because it is subjective and is
4 = clonus difcult to quantify. In the compliant and discerning
patient, the sensory examination can be extremely help-
ful for the precise localization of a lesion. With patients
Cutaneous Reexes who are uncooperative or lack an understanding of the
The plantar reex is elicited by stroking, with a noxious tests, it may be useless. The examination should be
stimulus such as a tongue blade, the lateral surface of the focused on the suspected lesion. For example, in spinal
sole of the foot beginning near the heel and moving cord, spinal root, or peripheral nerve abnormalities, all
across the ball of the foot to the great toe. The normal major sensory modalities should be tested while looking
reex consists of plantar exion of the toes. With upper for a pattern consistent with a spinal level and der-
motor neuron lesions above the S1 level of the spinal matomal or nerve distribution. In patients with lesions
cord, a paradoxical extension of the toe is observed, at or above the brainstem, screening the primary sensory
associated with fanning and extension of the other toes modalities in the distal extremities along with tests of
(termed an extensor plantar response, or Babinski sign). cortical sensation is usually sufcient.
Supercial abdominal reexes are elicited by gently The ve primary sensory modalitieslight touch,
stroking the abdominal surface near the umbilicus in a pain, temperature, vibration, and joint positionare
diagonal fashion with a sharp object (e.g., the wooden tested in each limb. Light touch is assessed by stimulat-
end of a cotton-tipped swab) and observing the move- ing the skin with single, very gentle touches of the
ment of the umbilicus. Normally, the umbilicus will pull examiners nger or a wisp of cotton. Pain is tested
using a new pin, and temperature is assessed using a patient is asked to touch his or her index nger repeti- 9
metal object (e.g., tuning fork) that has been immersed tively to the nose and then to the examiners out-
in cold and warm water.Vibration is tested using a 128-Hz stretched nger, which moves with each repetition. A

CHAPTER 1
tuning fork applied to the distal phalynx of the great toe similar test in the lower extremity is to have the patient
or index nger just below the nailbed. By placing a n- raise the leg and touch the examiners nger with the
ger on the opposite side of the joint being tested, the great toe. Another cerebellar test in the lower limbs is
examiner compares the patients threshold of vibration the heel-knee-shin maneuver; in the supine position the
perception with his or her own. For joint position test- patient is asked to slide the heel of each foot from the
ing, the examiner grasps the digit or limb laterally and knee down the shin of the other leg. For all these move-

Approach to the Patient with Neurologic Disease

distal to the joint being assessed; small 1- to 2-mm ments, the accuracy, speed, and rhythm are noted.
excursions can usually be sensed.The Romberg maneu-
ver is primarily a test of proprioception. The patient is Gait Examination
asked to stand with the feet as close together as neces-
sary to maintain balance while the eyes are open, and The bare minimum: Observe the patient while walking nor-
the eyes are then closed. A loss of balance with the eyes mally, on the heels and toes, and along a straight line.
closed is an abnormal response. Watching the patient walk is the most important part
Cortical sensation is mediated by the parietal lobes of the neurologic examination. Normal gait requires that
and represents an integration of the primary sensory multiple systemsincluding strength, sensation, and
modalities; testing cortical sensation is only meaningful coordinationfunction in a highly integrated fashion.
when primary sensation is intact. Double simultaneous Unexpected abnormalities may be detected that prompt
stimulation is especially useful as a screening test for cor- the examiner to return, in more detail, to other aspects of
tical function; with the patients eyes closed, the exam- the examination. The patient should be observed while
iner lightly touches one or both hands and asks the walking and turning normally, walking on the heels,
patient to identify the stimuli. With a parietal lobe walking on the toes, and walking heel-to-toe along a
lesion, the patient may be unable to identify the stimulus straight line. The examination may reveal decreased arm
on the contralateral side when both hands are touched. swing on one side (corticospinal tract disease), a stooped
Other modalities relying on the parietal cortex include posture and short-stepped gait (parkinsonism), a broad-
the discrimination of two closely placed stimuli as sepa- based unstable gait (ataxia), scissoring (spasticity), or a
rate (two-point discrimination), identication of an high-stepped, slapping gait (posterior column or periph-
object by touch and manipulation alone (stereognosis), eral nerve disease), or the patient may appear to be stuck
and the identication of numbers or letters written on in place (apraxia with frontal lobe disease).
the skin surface (graphesthesia).
NEUROLOGIC DIAGNOSIS
Coordination Examination
The clinical data obtained from the history and exami-
The bare minimum:Test rapid alternating movements of the nation are interpreted to arrive at an anatomic localiza-
hands and the nger-to-nose and heel-knee-shin maneuvers. tion that best explains the clinical ndings ( Table 1-2),
Coordination refers to the orchestration and uidity to narrow the list of diagnostic possibilities, and to select
of movements. Even simple acts require cooperation of the laboratory tests most likely to be informative. The
agonist and antagonist muscles, maintenance of posture, laboratory assessment may include (1) serum elec-
and complex servomechanisms to control the rate and trolytes; complete blood count; and renal, hepatic,
range of movements. Part of this integration relies on endocrine, and immune studies; (2) cerebrospinal uid
normal function of the cerebellar and basal ganglia sys- examination; (3) focused neuroimaging studies (Chap. 2);
tems. However, coordination also requires intact muscle or (4) electrophysiologic studies (Chap. 3).The anatomic
strength and kinesthetic and proprioceptive informa- localization, mode of onset and course of illness, other
tion. Thus, if the examination has disclosed abnormali- medical data, and laboratory ndings are then integrated
ties of the motor or sensory systems, the patients coor- to establish an etiologic diagnosis.
dination should be assessed with these limitations in The neurologic examination may be normal even in
mind. patients with a serious neurologic disease, such as
Rapid alternating movements in the upper limbs are seizures, chronic meningitis, or a TIA. A comatose
tested separately on each side by having the patient patient may arrive with no available history, and in such
make a st, partially extend the index nger, and then cases the approach is as described in Chap. 14. In other
tap the index nger on the distal thumb as quickly as patients, an inadequate history may be overcome by a
possible. In the lower limb, the patient rapidly taps the succession of examinations from which the course of
foot against the oor or the examiners hand. Finger-to- the illness can be inferred. In perplexing cases it is useful
nose testing is primarily a test of cerebellar function; the to remember that uncommon presentations of common
 10 TABLE 1-2
FINDINGS HELPFUL FOR LOCALIZATION WITHIN THE NERVOUS SYSTEM

SIGNS
SECTION I

Cerebrum Abnormal mental status or cognitive impairment

Seizures
Unilateral weaknessa and sensory abnormalities including
head and limbs
Visual eld abnormalities
Movement abnormalities (e.g., diffuse incoordination,
Introduction to Neurology

tremor, chorea)
Brainstem Isolated cranial nerve abnormalities (single or multiple)
Crossed weaknessa and sensory abnormalities of head
and limbs (e.g., weakness of right face and left arm and leg)
Spinal cord Back pain or tenderness
Weaknessa and sensory abnormalities sparing the head
Mixed upper and lower motor neuron ndings
Sensory level
Sphincter dysfunction
Spinal roots Radiating limb pain
Weaknessb or sensory abnormalities following root
distribution (see Figs. 12-2 and 12-3)
Loss of reexes
Peripheral nerve Mid or distal limb pain
Weaknessb or sensory abnormalities following nerve
distribution (see Figs. 12-2 and 12-3)
Stocking or glove distribution of sensory loss
Loss of reexes
Neuromuscular Bilateral weakness including face (ptosis, diplopia,
junction dysphagia) and proximal limbs
Increasing weakness with exertion
Sparing of sensation
Muscle Bilateral proximal or distal weakness
Sparing of sensation

a
Weakness along with other abnormalities having an upper motor neuron pattern (i.e., spas-
ticity, weakness of extensors > exors in the upper extremity and exors > extensors in the
lower extremity, hyperreexia).
b
Weakness along with other abnormalities having a lower motor neuron pattern (i.e., accidity
and hyporeexia).

diseases are more likely than rare etiologies. Thus, even compression or other treatable mass lesions and arrange
in tertiary care settings, multiple strokes are usually due for immediate care.
to emboli and not vasculitis, and dementia with
myoclonus is usually Alzheimers disease and not due to FURTHER READINGS
a prion disorder or a paraneoplastic cause. Finally, the
most important task of a primary care physician faced BLUMENTHAL H: Neuroanatomy Through Clinical Cases, 2d ed. Sunder-
land, Massachusetts, Sinauer Associates, 2010
with a patient who has a new neurologic complaint is to CAMPBELL WW: DeJongs The Neurological Examination, 6th ed.
assess the urgency of referral to a specialist. Here, the Philadelphia, Lippincott Williams & Wilkins, 2005
imperative is to rapidly identify patients likely to have ROPPER AH, SAMUELS MA: Principles of Neurology, 9th ed. New York,
nervous system infections, acute strokes, and spinal cord McGraw-Hill, 2009
 CHAPTER 2

NEUROIMAGING IN NEUROLOGIC DISORDERS

William P. Dillon

I Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
I Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . 15 I Spine Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Discography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Complications and Contraindications . . . . . . . . . . . . . . . . . . . 17 Selective Nerve Root and Epidural Spinal Injections . . . . . . . . 22
I Magnetic Resonance Angiography . . . . . . . . . . . . . . . . . . . . . 18 I Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
I Echo-Planar MR Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
I Magnetic Resonance Neurography . . . . . . . . . . . . . . . . . . . . . 21 Spinal Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
I Positron Emission Tomography (PET) . . . . . . . . . . . . . . . . . . . 21 I Interventional Neuroradiology . . . . . . . . . . . . . . . . . . . . . . . . . 23
I Myelography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

The clinician caring for patients with neurologic symp- acute ischemic stroke and is also useful in the detection
toms is faced with an expanding number of imaging of encephalitis, abscesses, and prion diseases. CT, how-
options, including computed tomography (CT), CT ever, can be quickly obtained and is widely available,
angiography (CTA), perfusion CT (pCT), magnetic making it a pragmatic choice for the initial evaluation of
resonance imaging (MRI), MR angiography (MRA), patients with acute changes in mental status, suspected
functional MRI (fMRI), MR spectroscopy (MRS), MR acute stroke, hemorrhage, and intracranial or spinal
neurography, diffusion and diffusion track imaging trauma. CT is also more sensitive than MRI for visualiz-
(DTI), and perfusion MRI (pMRI). In addition, an ing ne osseous detail and is indicated in the initial eval-
increasing number of interventional neuroradiologic uation of conductive hearing loss as well as lesions
techniques are available, including angiography; emboliza- affecting the skull base and calvarium.
tion, coiling, and stenting of vascular structures; and
spine interventions such as discography, selective nerve
root injection, and epidural injections. Recent develop- COMPUTED TOMOGRAPHY
ments, such as multidetector CTA and gadolinium-
TECHNIQUE
enhanced MRA, have narrowed the indications for con-
ventional angiography, which is now reserved for The CT image is a cross-sectional representation of
patients in whom small-vessel detail is essential for diag- anatomy created by a computer-generated analysis of the
nosis or for whom interventional therapies are planned attenuation of x-ray beams passed through a section of
(Table 2-1). the body. As the x-ray beam, collimated to the desired
In general, MRI is more sensitive than CT for the slice width, rotates around the patient, it passes through
detection of lesions affecting the central nervous system selected regions in the body. X-rays that are not attenu-
(CNS), particularly those of the spinal cord, cranial ated by the body are detected by sensitive x-ray detectors
nerves, and posterior fossa structures. Diffusion MR, a aligned 180 from the x-ray tube. A computer calculates
sequence that detects reduction of microscopic motion a back projection image from the 360 x-ray attenua-
of water, is the most sensitive technique for detecting tion prole. Greater x-ray attenuation, e.g., as caused by
11
 12 TABLE 2-1
GUIDELINES FOR THE USE OF CT, ULTRASOUND, AND MRI

CONDITION RECOMMENDED TECHNIQUE

SECTION I

Hemorrhage
Acute parenchymal CT, MR
Subacute/chronic MRI
Subarachnoid hemorrhage CT, CTA, lumbar puncture angiography
Aneurysm Angiography > CTA, MRA
Ischemic infarction
Introduction to Neurology

Hemorrhagic infarction CT or MRI

Bland infarction MRI > CT, CTA, angiography
Carotid or vertebral dissection MRI/MRA
Vertebral basilar insufciency CTA, MRI/MRA
Carotid stenosis CTA > Doppler ultrasound, MRA
Suspected mass lesion
Neoplasm, primary or metastatic MRI + contrast
Infection/abscess MRI + contrast
Immunosuppressed with focal ndings MRI + contrast
Vascular malformation MRI +/ angiography
White matter disorders MRI
Demyelinating disease MRI +/ contrast
Dementia MRI > CT
Trauma
Acute trauma CT (noncontrast)
Shear injury/chronic hemorrhage MRI
Headache/migraine CT (noncontrast) / MRI
Seizure
First time, no focal neurologic decits CT as screen +/ contrast
Partial complex/refractory MRI with coronal T2W imaging
Cranial neuropathy MRI with contrast
Meningeal disease MRI with contrast
Spine
Low back pain
No neurologic decits MRI or CT after 4 weeks
With focal decits MRI > CT
Spinal stenosis MRI or CT
Cervical spondylosis MRI or CT myelography
Infection MRI + contrast, CT
Myelopathy MRI + contrast > myelography
Arteriovenous malformation MRI, myelography/angiography

Note: CT, computed tomography; MRI, magnetic resonance imaging; MRA, MR angiography; CTA, CT
angiography; T2W, T2-weighted.

bone, results in areas of high density, whereas soft tissue a helix of information that can be reformatted into
structures, which have poor attenuation of x-rays, are various slice thicknesses. Single or multiple (from 4 to 256)
lower in density. The resolution of an image depends on detectors positioned 180 to the x-ray source may result
the radiation dose, the detector size or collimation (slice in multiple slices per revolution of the beam around the
thickness), the eld of view, and the matrix size of the patient. Advantages of MDCT include shorter scan
display. A modern CT scanner is capable of obtaining times, reduced patient and organ motion, and the ability
sections as thin as 0.51 mm with submillimeter resolu- to acquire images dynamically during the infusion of
tion at a speed of 0.51 s per rotation; complete studies intravenous contrast that can be used to construct CT
of the brain can be completed in 210 s. angiograms of vascular structures and CT perfusion
Helical or multidetector CT (MDCT) is now stan- images (Figs. 2-1B, 2-2B, and 2-3B). CTA images are
dard in most radiology departments. Continuous CT post-processed for display in three dimensions to yield
information is obtained while the patient moves through angiogram-like images (Fig. 2-1C and see Fig. 21-4).
the x-ray beam. In the helical scan mode, the table moves CTA has proved useful in assessing the cervical and
continuously through the rotating x-ray beam, generating intracranial arterial and venous anatomy.
 Intravenous iodinated contrast is often administered 13
prior to or during a CT study to identify vascular struc-
tures and to detect defects in the blood-brain barrier

CHAPTER 2
(BBB) that are associated with disorders such as tumors,
infarcts, and infections. In the normal CNS, only vessels
and structures lacking a BBB (e.g., the pituitary gland,
choroid plexus, and dura) enhance after contrast admin-
istration. The use of iodinated contrast agents carries a
risk of allergic reaction and adds additional expense and

Neuroimaging in Neurologic Disorders

radiation dose. Although helpful in characterizing mass
lesions as well as essential for the acquisition of CTA
studies, the decision to use contrast material should
always be considered carefully.

INDICATIONS
CT is the primary study of choice in the evaluation of
an acute change in mental status, focal neurologic nd-
ings, acute trauma to the brain and spine, suspected sub-
arachnoid hemorrhage, and conductive hearing loss
(Table 2-1). CT is complementary to MR in the evalua-
tion of the skull base, orbit, and osseous structures of the
spine. In the spine, CT is useful in evaluating patients
with osseous spinal stenosis and spondylosis, but MRI is
often preferred in those with neurologic decits. CT
can also be obtained following intrathecal contrast injec-
tion to evaluate the intracranial cisterns (CT cisternogra-
phy) for cerebrospinal uid (CSF) stula, as well as the
spinal subarachnoid space (CT myelography).

COMPLICATIONS
CT is safe, fast, and reliable. Radiation exposure depends
on the dose used but is normally between 3 and 5 cGy
for a routine brain CT study. Care must be taken to
reduce exposure when imaging children. With the
advent of MDCT, CTA, and CT perfusion, care must be
taken to appropriately minimize radiation dose when-
ever possible. The most frequent complications are asso-
ciated with use of intravenous contrast agents. Two
broad categories of contrast media, ionic and nonionic,
are in use. Although ionic agents are relatively safe and
inexpensive, they are associated with a higher incidence
of reactions and side effects (Table 2-2). As a result,
FIGURE 2-1
ionic agents have been largely replaced by safer nonionic
CT angiography (CTA) of ruptured anterior cerebral artery
compounds.
aneurysm in a patient presenting with acute headache. Contrast nephropathy may result from hemodynamic
A. Noncontrast CT demonstrates subarachnoid hemorrhage changes, renal tubular obstruction and cell damage, or
and mild obstructive hydrocephalus. B. Axial maximum immunologic reactions to contrast agents. A rise in
intensity projection from CT angiography demonstrates serum creatinine of at least 85 mol/L (1 mg/dL)
enlargement of the anterior cerebral artery (arrow). C. 3D sur- within 48 h of contrast administration is often used as a
face reconstruction using a workstation conrms the anterior denition of contrast nephropathy, although other
cerebral aneurysm and demonstrates its orientation and rela- causes of acute renal failure must be excluded.The prog-
tionship to nearby vessels (arrow). CTA image is produced by nosis is usually favorable, with serum creatinine levels
0.51 mm helical CT scans performed during a rapid bolus returning to baseline within 12 weeks. Risk factors for
infusion of intravenous contrast medium. contrast nephropathy include advanced age (>80 years),
 14
SECTION I
Introduction to Neurology

FIGURE 2-2
Acute left hemiparesis due to middle cerebral artery right middle cerebral artery (arrow). Reconstitution of ow via
occlusion. A. Axial noncontrast CT scan demonstrates high collaterals is seen distal to the occlusion; however, the
density within the right middle cerebral artery (arrow) associ- patient sustained a right basal ganglia infarction. D. Sagittal
ated with subtle low density involving the right putamen reformation through the right internal carotid artery demon-
(arrowheads). B. Mean transit time map calculated from a CT strates a low-density lipid laden plaque (arrowheads) narrow-
perfusion study; prolongation of the mean transit time is visi- ing the lumen (black arrow) E. 3D surface CTA images from a
ble throughout the right hemisphere (arrows). C. Axial maxi- different patient demonstrate calcication and narrowing of
mum intensity projection from a CTA study through the Circle the right internal carotid artery (arrow), consistent with ather-
of Willis demonstrates an abrupt occlusion of the proximal osclerotic disease.
TABLE 2-2 TABLE 2-4 15
GUIDELINES FOR USE OF INTRAVENOUS CONTRAST GUIDELINES FOR PREMEDICATION OF PATIENTS
IN PATIENTS WITH IMPAIRED RENAL FUNCTION WITH PRIOR CONTRAST ALLERGY

CHAPTER 2
SERUM CREATININE, 12 h prior to examination:
mol/L (mg/dL)a RECOMMENDATION Prednisone, 50 mg PO or methylprednisolone, 32 mg PO
2 h prior to examination:
<133 (<1.5) Use either ionic or nonionic at
Prednisone, 50 mg PO or methylprednisolone,
2 mL/kg to 150 mL total
32 mg PO and
133177 (1.52.0) Nonionic; hydrate diabetics
Cimetidine, 300 mg PO or ranitidine, 150 mg PO
1 mL/kg per hour 10 h
Immediately prior to examination:

Neuroimaging in Neurologic Disorders

>177 (>2.0) Consider noncontrast CT or MRI;
Benadryl, 50 mg IV (alternatively, can be given PO 2 h
nonionic contrast if required
prior to exam)
177221 (2.02.5) Nonionic only if required (as above);
contraindicated in diabetics
>265 (>3.0) Nonionic IV contrast given only to
patients undergoing dialysis within
24 h which range from mild hives to bronchospasm, acute
anaphylaxis, and death.The pathogenesis of these allergic
a
Risk is greatest in patients with rising creatinine levels. reactions is not fully understood but is thought to
Note: CT, computed tomography; MRI, magnetic resonance imaging. include the release of mediators such as histamine,
antibody-antigen reactions, and complement activation.
Severe allergic reactions occur in ~0.04% of patients
preexisting renal disease (serum creatinine exceeding receiving nonionic media, sixfold fewer than with ionic
2.0 mg/dL), solitary kidney, diabetes mellitus, dehydration, media. Risk factors include a history of prior contrast
paraproteinemia, concurrent use of nephrotoxic medica- reaction, food allergies to shellsh, and atopy (asthma
tion or chemotherapeutic agents, and high contrast dose. and hay fever). In such patients, a noncontrast CT or
Patients with diabetes and those with mild renal failure MRI procedure should be considered as an alternative
should be well hydrated prior to the administration of to contrast administration. If iodinated contrast is
contrast agents, although careful consideration should be absolutely required, a nonionic agent should be used in
given to alternative imaging techniques, such as MR conjunction with pretreatment with glucocorticoids and
imaging or noncontrast examinations. Nonionic, low- antihistamines (Table 2-4). Patients with allergic reac-
osmolar media produce fewer abnormalities in renal tions to iodinated contrast material do not usually react
blood ow and less endothelial cell damage but should to gadolinium-based MR contrast material, although
still be used carefully in patients at risk for allergic reac- such reactions do occur. It would be wise to pretreat
tion (Table 2-3). patients with a prior allergic history to MR contrast
Other side effects are rare but include a sensation of administration in a similar fashion.
warmth throughout the body and a metallic taste during
intravenous administration of iodinated contrast media.
The most serious side effects are anaphylactic reactions, MAGNETIC RESONANCE IMAGING
TECHNIQUE
TABLE 2-3
INDICATIONS FOR USE OF NONIONIC CONTRAST Magnetic resonance is a complex interaction between
MEDIA hydrogen protons in biologic tissues, a static magnetic
eld (the magnet), and energy in the form of radiofre-
Prior adverse reaction to contrast media, with the
exception of heat, ushing, or an episode of nausea or
quency (Rf) waves of a specic frequency introduced by
vomiting coils placed next to the body part of interest. Field
Asthma or other serious lung disease strength of the magnet is directly related to signal-to-
History of atopic allergies (pretreatment with noise ratio. Although 1.5 Telsa magnets have become the
steroid/antihistamines recommended) standard high-eld MRI units, 3T8T magnets are now
Children younger than 2 years available and have distinct advantages in the brain and
Renal failure or creatinine >177 mol/L (>2.0 mg/dL) musculoskeletal systems. Spatial localization is achieved by
Cardiac dysfunction, including recent or imminent car-
magnetic gradients surrounding the main magnet, which
diac decompensation, severe arrhythmias, unstable
angina pectoris, recent myocardial infarction, and pul- impart slight changes in magnetic eld throughout the
monary hypertension imaging volume. The energy state of the hydrogen pro-
Diabetes tons is transiently excited by Rf, which is administered at
Severe debilitation a frequency specic for the eld strength of the magnet.
The subsequent return to equilibrium energy state
 16 (relaxation) of the protons results in a release of Rf energy (Fig. 2-3). T2W images are more sensitive than T1W
(the echo), which is detected by the coils that delivered the images to edema, demyelination, infarction, and chronic
Rf pulses. The echo is transformed by Fourier analysis hemorrhage, whereas T1W imaging is more sensitive to
SECTION I

into the information used to form an MR image. The subacute hemorrhage and fat-containing structures.
MR image thus consists of a map of the distribution of Many different MR pulse sequences exist, and each
hydrogen protons, with signal intensity imparted by both can be obtained in various planes (Figs. 2-3, 2-4, 2-5).
density of hydrogen protons and differences in the relax- The selection of a proper protocol that will best answer
ation times (see below) of hydrogen protons on different a clinical question depends on an accurate clinical history
molecules. Although clinical MRI currently makes use of and indication for the examination. Fluid-attenuated
Introduction to Neurology

the ubiquitous hydrogen proton, research into sodium inversion recovery (FLAIR) is a useful pulse sequence
and carbon imaging appears promising. that produces T2W images in which the normally high
signal intensity of CSF is suppressed (Fig. 2-5A). FLAIR
T1 and T2 Relaxation Times images are more sensitive than standard spin echo images
for any water-containing lesions or edema. Gradient
The rate of return to equilibrium of perturbed protons echo imaging is most sensitive to magnetic susceptibility
is called the relaxation rate. The relaxation rate varies generated by blood, calcium, and air and is indicated in
among normal and pathologic tissues. The relaxation patients with traumatic brain injury to assess for subtle
rate of a hydrogen proton in a tissue is inuenced by contusions and shear microhemorrhages. MR images
local interactions with surrounding molecules and can be generated in any plane without changing the
atomic neighbors.Two relaxation rates,T1 and T2, inu- patients position. Each sequence, however, must be
ence the signal intensity of the image.The T1 relaxation obtained separately and takes 15 min on average to
time is the time, measured in milliseconds, for 63% of complete. Three-dimensional volumetric imaging is also
the hydrogen protons to return to their normal equilib- possible with MRI, resulting in a volume of data that
rium state, while the T2 relaxation is the time for 63% can be reformatted in any orientation on a workstation
of the protons to become dephased owing to interac- to highlight certain disease processes.
tions among nearby protons. The intensity of the signal
within various tissues and image contrast can be modu-
MR Contrast Material
lated by altering acquisition parameters, such as the
interval between Rf pulses (TR) and the time between The heavy-metal element gadolinium forms the basis
the Rf pulse and the signal reception (TE). So-called of all currently approved intravenous MR contrast
T1-weighted (T1W) images are produced by keeping agents. Gadolinium is a paramagnetic substance, which
the TR and TE relatively short. T2-weighted (T2W) means that it reduces the T1 and T2 relaxation times of
images are produced by using longer TR and TE times. nearby water protons, resulting in a high signal on T1W
Fat and subacute hemorrhage have relatively shorter T1 images and a low signal on T2W images (the latter
relaxation rates and thus higher signal intensity than requires a sufcient local concentration, usually in the
brain on T1W images. Structures containing more form of an intravenous bolus). Unlike iodinated con-
water, such as CSF and edema, have long T1 and T2 trast agents, the effect of MR contrast agents depends
relaxation rates, resulting in relatively lower signal inten- on the presence of local hydrogen protons on which it
sity on T1W images and a higher signal intensity on must act to achieve the desired effect. Gadolinium is
T2W images (Table 2-5). Gray matter contains 1015% chelated to DTPA (diethylenetriaminepentaacetic acid),
more water than white matter, which accounts for much which allows safe renal excretion. Approximately 0.2
of the intrinsic contrast between the two on MRI mL/kg body weight is administered intravenously; the
cost is ~$60 per dose. Gadolinium-DTPA does not nor-
mally cross the intact BBB immediately but will
TABLE 2-5 enhance lesions lacking a BBB (Fig. 2-4A) and areas of
SOME COMMON INTENSITIES ON T1- AND the brain that normally are devoid of the BBB (pitu-
T2-WEIGHTED MRI SEQUENCES itary, choroid plexus). However, gadolinium contrast has
been noted to slowly cross an intact BBB if given over
SIGNAL INTENSITY
time and especially in the setting of reduced renal
IMAGE TR TE CSF FAT BRAIN EDEMA clearance.The agents are generally well tolerated; severe
allergic reactions are rare but have been reported. The
T1W Short Short Low High Low Low
T2W Long Long High Low High High
adverse reaction rate in patients with a prior history of
atopy or asthma is 3.7%; however, the reaction rate
Note: TR, interval between radiofrequency (Rf) pulses; TE, interval
increases to 6.3% in those patients with a prior history
between Rf pulse and signal reception; CSF, cerebrospinal uid; of unspecied allergic reaction to iodinated contrast
T1W and T2W, T1- and T2-weighted. agents. Gadolinium contrast material can be administered
 17

CHAPTER 2
Neuroimaging in Neurologic Disorders
FIGURE 2-3
A. Axial noncontrast CT scan in a patient with left hemipare- volume map shows reduced CBV involving an area within the
sis shows a subtle low density involving the right temporal defect shown in B, indicating infarction (arrows). D. Coronal
and frontal lobes (arrows). The hyperdense middle cerebral maximum intensity projection from MRA shows right middle
artery (arrowhead) indicates an embolic occlusion of the mid- cerebral artery (MCA) occlusion (arrow). E and F. Axial diffu-
dle cerebral artery. B. Mean transit time CT perfusion para- sion weighted image (E) and apparent diffusion coefcient
metric map indicating prolonged mean transit time involving image (F) documents the presence of a right middle cerebral
the right middle cerebral territory (arrows). C. Cerebral blood artery infarction.

safely to children as well as adults, although these agents widespread brosis of the skeletal muscle, bone, lungs,
are generally avoided in those younger than 6 months. pleura, pericardium, myocardium, kidney, muscle, bone,
Renal failure does not occur. testes, and dura.
A rare complication, nephrogenic systemic brosis
(NSF), has recently been reported in patients with renal
insufciency, who have been exposed to gadolinium
COMPLICATIONS AND CONTRAINDICATIONS
contrast agents. The onset of NSF has been reported
between 5 and 75 days following exposure; histologic fea- From the patients perspective, an MRI examination can
tures include thickened collagen bundles with surrounding be intimidating, and a higher level of cooperation is
clefts, mucin deposition, and increased numbers of required than with CT.The patient lies on a table that is
fibrocytes and elastic fibers in skin. In addition to moved into a long, narrow gap within the magnet.
dermatologic symptoms, other manifestations include Approximately 5% of the population experiences severe
 18
SECTION I
Introduction to Neurology

FIGURE 2-4
Cerebral abscess in a patient with fever and
a right hemiparesis. A. Coronal postcontrast
T1-weighted image demonstrates a ring enhanc-
ing mass in the left frontal lobe. B. Axial
diffusion-weighted image demonstrates restricted
diffusion (high signal intensity) within the lesion,
which in this setting is highly suggestive of
cerebral abscess. C. Single voxel proton spec-
troscopy (TE of 288 ms) reveals a reduced Naa
peak and abnormal peaks for acetate, alanine
(Ala), lactate (Lac), and amino acids (AA). These
ndings are highly suggestive of cerebral
abscess; at biopsy a streptococcal abscess
was identied.

claustrophobia in the MR environment. This can be is indicated in those with a history of metal work or
reduced by mild sedation but remains a problem for ocular metallic foreign bodies. Implanted cardiac pace-
some. Unlike CT, movement of the patient during an makers are generally a contraindication to MRI owing
MR sequence distorts all the images; therefore, uncoop- to the risk of induced arrhythmias; however, some
erative patients should either be sedated for the MR study newer pacemakers have been shown to be safe. All
or scanned with CT. Generally, children younger than health care personnel and patients must be screened and
10 years usually require conscious sedation in order to com- educated thoroughly to prevent such disasters as the
plete the MR examination without motion degradation. magnet is always on. Table 2-6 lists common con-
MRI is considered safe for patients, even at very high traindications for MRI.
eld strengths (>34 T). Serious injuries have been
caused, however, by attraction of ferromagnetic objects
into the magnet, which act as missiles if brought too MAGNETIC RESONANCE
close to the magnet. Likewise, ferromagnetic implants, ANGIOGRAPHY
such as aneurysm clips, may torque within the magnet,
causing damage to vessels and even death. Metallic for- MR angiography (MRA) is a general term describing sev-
eign bodies in the eye have moved and caused intraocu- eral MR techniques that result in vascular-weighted
lar hemorrhage; screening for ocular metallic fragments images. These provide a vascular ow map rather than
 19

CHAPTER 2
Neuroimaging in Neurologic Disorders
FIGURE 2-5
Herpes simplex encephalitis in a patient presenting with left medial temporal lobe and hippocampus (arrows). This is
altered mental status and fever. A. Coronal T2-weighted most consistent with neuronal death and can be seen in acute
FLAIR image demonstrates expansion and high signal intensity infarction as well as encephalitis and other inammatory con-
involving the left medial temporal lobe, insular cortex, and left ditions. The suspected diagnosis of herpes simplex encephali-
cingulate gyrus. B. Diffusion-weighted image demonstrates tis was conrmed by CSF PCR analysis. (Courtesy of Howard
high signal intensity indicating restricted diffusion involving the Rowley, MD, University of Wisconsin; with permission.)

the anatomic map shown by conventional angiography. intensity of moving protons in contrast to the low signal
On routine spin echo MR sequences, moving protons background intensity of stationary tissue. This creates
(e.g., owing blood, CSF) exhibit complex MR signals angiography-like images, which can be manipulated in
that range from high to low signal intensity relative to three dimensions to highlight vascular anatomy and
background stationary tissue. Fast-owing blood returns relationships.
no signal (ow void) on routine T1W or T2W spin Time-of-ight (TOF) imaging, currently the tech-
echo MR images. Slower-owing blood, as occurs in nique used most frequently, relies on the suppression of
veins or distal to arterial stenosis, may appear high in nonmoving tissue to provide a low-intensity back-
signal. However, using special pulse sequences called gra- ground for the high signal intensity of owing blood
dient echo sequences, it is possible to increase the signal entering the section; arterial or venous structures may
be highlighted. A typical TOF angiography sequence
results in a series of contiguous, thin MR sections
TABLE 2-6
(0.60.9 mm thick), which can be viewed as a stack and
COMMON CONTRAINDICATIONS TO MR IMAGING manipulated to create an angiographic image data set
Cardiac pacemaker or permanent pacemaker leads that can be reformatted and viewed in various planes
Internal debrillatory device and angles, much like that seen with conventional
Cochlear prostheses angiography (Fig. 2-3D).
Bone growth stimulators Phase-contrast MRA has a longer acquisition time
Spinal cord stimulators than TOF MRA, but in addition to providing anatomic
Electronic infusion devices
Intracranial aneurysm clips (some but not all)
information similar to that of TOF imaging, it can be
Ocular implants (some) or ocular metallic foreign body used to reveal the velocity and direction of blood ow
McGee stapedectomy piston prosthesis in a given vessel. Through the selection of different
Omniphase penile implant imaging parameters, differing blood velocities can be
Swan-Ganz catheter highlighted; selective venous and arterial MRA images
Magnetic stoma plugs can thus be obtained. One advantage of phase-contrast
Magnetic dental implants MRA is the excellent suppression of high signal inten-
Magnetic sphincters
sity background structures.
Ferromagnetic IVC lters, coils, stentssafe 6 weeks
after implantation MRA can also be acquired during infusion of con-
Tattooed eyeliner (contains ferromagnetic material and trast material. Advantages include faster imaging times
may irritate eyes) (12 min vs. 10 min), fewer ow-related artifacts, and
higher-resolution images. Recently, contrast-enhanced
 20 MRA has become the standard for extracranial vascular for processing an image is accumulated in 50150 ms,
MRA. This technique entails rapid imaging using coro- and the information for the entire brain is obtained in
nal three-dimensional TOF sequences during a bolus 12 min, depending on the degree of resolution
SECTION I

infusion of 1520 mL of gadolinium-DTPA. Proper required or desired. Fast MRI reduces patient and organ
technique and timing of acquisition relative to bolus motion, permitting diffusion imaging and tractography
arrival are critical for success. (Figs. 2-3, 2-4, 2-5, 2-6; and see Fig. 21-16), perfusion
MRA has lower spatial resolution compared with imaging during contrast infusion, fMRI, and kinematic
conventional lm-based angiography, and therefore the motion studies.
detection of small-vessel abnormalities, such as vasculitis Perfusion and diffusion imaging are EPI techniques
Introduction to Neurology

and distal vasospasm, is problematic. MRA is also less that are useful in early detection of ischemic injury of
sensitive to slowly owing blood and thus may not reli- the brain and may be useful together to demonstrate
ably differentiate complete from near-complete occlu- infarcted tissue as well as ischemic but potentially viable
sions. Motion, either by the patient or by anatomic tissue at risk of infarction (e.g., the ischemic penumbra).
structures, may distort the MRA images, creating arti- Diffusion-weighted imaging (DWI) assesses microscopic
facts. These limitations notwithstanding, MRA has motion of water; restriction of motion appears as relative
proved useful in evaluation of the extracranial carotid high signal intensity on diffusion-weighted images. DWI
and vertebral circulation as well as of larger-caliber is the most sensitive technique for detection of acute
intracranial arteries and dural sinuses. It has also proved cerebral infarction of <7 days duration and is also sensi-
useful in the noninvasive detection of intracranial tive to encephalitis and abscess formation, all of which
aneurysms and vascular malformations. have reduced diffusion and result in high signal on diffu-
sion-weighted images.
Perfusion MRI involves the acquisition of EPI images
ECHO-PLANAR MR IMAGING during a rapid intravenous bolus of gadolinium contrast
material. Relative perfusion abnormalities can be identi-
Recent improvements in gradients, software, and high- ed on images of the relative cerebral blood volume,
speed computer processors now permit extremely rapid mean transit time, and cerebral blood ow. Delay in
MRI of the brain. With echo-planar MRI (EPI), fast mean transit time and reduction in cerebral blood vol-
gradients are switched on and off at high speeds to cre- ume and cerebral blood ow are typical of infarction. In
ate the information used to form an image. In routine the setting of reduced blood ow, a prolonged mean
spin echo imaging, images of the brain can be obtained transit time of contrast but normal or elevated cerebral
in 510 min. With EPI, all of the information required blood volume may indicate tissue supplied by collateral

FIGURE 2-6
Diffusion tractography in cerebral glioma. A. An axial fast tractography superimposed on the image. This shows the
spin echo T2-weighted image shows a high signal intensity position of the internal capsule (arrows) relative to the enhanc-
glioma of the insular cortex lateral to the bers of the internal ing tumor.
capsule. B and C. Axial post-gadolinium images with diffusion
ow that is at risk of infarction. pMRI imaging can also 21
be used in the assessment of brain tumors to differenti-
MAGNETIC RESONANCE
ate intraaxial primary tumors from extraaxial tumors or NEUROGRAPHY

CHAPTER 2
metastasis. MR neurography is an MR technique that shows promise
Diffusion tract imaging (DTI) is derived from diffu- in detecting increased signal in irritated, inamed, or
sion MRI techniques. Preferential microscopic motion inltrated peripheral nerves. Images are obtained with
of water along white matter tracts is detected by diffu- fat-suppressed fast spin echo imaging or short inversion
sion MR, which can also indicate the direction of white recovery sequences. Irritated or inltrated nerves will
matter ber tracts. This new technique has great poten- demonstrate high signal on T2W imaging.

Neuroimaging in Neurologic Disorders

tial in the assessment of brain maturation as well as dis-
ease entities that undermine the integrity of the white
matter architecture (Fig. 2-7). POSITRON EMISSION
fMRI of the brain is an EPI technique that localizes TOMOGRAPHY (PET)
regions of activity in the brain following task activation.
Neuronal activity elicits a slight increase in the delivery PET relies on the detection of positrons emitted during
of oxygenated blood ow to a specic region of acti- the decay of a radionuclide that has been injected into a
vated brain.This results in an alteration in the balance of patient. The most frequently used moiety is 2-[18F]
oxyhemoglobin and deoxyhemoglobin, which yields a fluoro-2-deoxy-D-glucose (FDG), which is an ana-
23% increase in signal intensity within veins and local logue of glucose and is taken up by cells competitively
capillaries. Further studies will determine whether these with 2-deoxyglucose. Multiple images of glucose
techniques are cost-effective or clinically useful, but cur- uptake activity are formed after 4560 min. Images
rently preoperative somatosensory and auditory cortex reveal differences in regional glucose activity among
localization is possible. This technique has proved useful normal and pathologic brain structures. A lower activity
to neuroscientists interested in interrogating the local- of FDG in the parietal lobes has been associated with
ization of certain brain functions. Alzheimers disease. FDG PET is used primarily for the
detection of extracranial metastatic disease. Combina-
tion PET-CT scanners, in which both CT and PET are
obtained at one sitting, are replacing PET scans alone
for most clinical indications. Functional images super-
imposed on high-resolution CT scans result in more
precise anatomic diagnoses.

MYELOGRAPHY
TECHNIQUE
Myelography involves the intrathecal instillation of spe-
cially formulated water-soluble iodinated contrast
medium into the lumbar or cervical subarachnoid space.
CT scanning is usually performed after myelography
(CT myelography) to better demonstrate the spinal cord
and roots, which appear as lling defects in the opacied
subarachnoid space. Low-dose CT myelography, in which
CT is performed after the subarachnoid injection of a
small amount of relatively dilute contrast material, has
replaced conventional myelography for many indica-
tions, thereby reducing exposure to radiation and con-
trast media. Newer multidetector scanners now obtain
CT studies quickly so that reformations in sagittal and
coronal planes, equivalent to traditional myelography
FIGURE 2-7 projections, are now routine.
Diffusion tractography in a healthy individual obtained at
3T demonstrates the normal subcortical ber pathways. The INDICATIONS
direction of the tracts have been color-coded (red, left-right;
green, anterior-posterior; blue, superior-inferior). (Courtesy of Myelography has been largely replaced by CT myelog-
Pratik Mukherjee, MD, PhD; with permission.) raphy and MRI for diagnosis of diseases of the spinal
 22 canal and cord (Table 2-1). Remaining indications for arachnoid space. Seizures occur following myelography
conventional plain-lm myelography include the evalu- in 0.10.3% of patients. Risk factors include a preexist-
ation of suspected meningeal or arachnoid cysts and the ing seizure disorder and the use of a total iodine dose of
SECTION I

localization of spinal dural arteriovenous or CSF stulas. >4500 mg. Other reported complications include
Conventional myelography and CT myelography pro- hyperthermia, hallucinations, depression, and anxiety
vide the most precise information in patients with prior states.These side effects have been reduced by the devel-
spinal fusion and spinal xation hardware. opment of nonionic, water-soluble contrast agents, as
well as by head elevation and generous hydration fol-
lowing myelography.
CONTRAINDICATIONS
Introduction to Neurology

Myelography is relatively safe; however, it should be per-

formed with caution in any patient with elevated SPINE INTERVENTIONS
intracranial pressure, evidence of a spinal block, or a his-
tory of allergic reaction to intrathecal contrast media. In DISCOGRAPHY
patients with a suspected spinal block, MR is the pre- The evaluation of back pain and radiculopathy may require
ferred technique. If myelography is necessary, only a diagnostic procedures that attempt either to reproduce
small amount of contrast medium should be instilled the patients pain or relieve it, indicating its correct
below the lesion in order to minimize the risk of neuro- source prior to lumbar fusion. Discography is performed
logic deterioration. Lumbar puncture is to be avoided in by uoroscopic placement of a 22- to 25-gauge needle
patients with bleeding disorders, including patients into the intervertebral disc and subsequent injection of
receiving anticoagulant therapy, as well as in those with 13 mL of contrast media. The intradiscal pressure is
infections of the soft tissues. recorded, as is an assessment of the patients response to
the injection of contrast material. Typically little or no
pain is felt during injection of a normal disc, which does
COMPLICATIONS not accept much more than 1 mL of contrast material,
Headache, nausea, and vomiting are the most frequent even at pressures as high as 415690 kPa (60100
complications of myelography and are reported to occur lbs/in2). CT and plain lms are obtained following the
in up to 38% of patients. These symptoms result from procedure.
either neurotoxic effects of the contrast agent, persistent
leakage of CSF at the puncture site, or psychological
reactions to the procedure.Vasovagal syncope may occur SELECTIVE NERVE ROOT AND EPIDURAL
during lumbar puncture; it is accentuated by the upright SPINAL INJECTIONS
position used during lumbar myelography. Adequate Percutaneous selective nerve root and epidural blocks
hydration before and after myelography will reduce the with glucocorticoid and anesthetic mixtures may be
incidence of this complication. Postural headache both therapeutic and diagnostic, especially if a patients
(postlumbar puncture headache) is generally due to pain is relieved. Typically, 12 mL of an equal mixture
leakage of CSF from the puncture site, resulting in CSF of a long-acting glucocorticoid such as betamethasone
hypotension. Management of post-lumbar-puncture and a long-acting anesthetic such as bupivicain 0.75% is
headache is discussed in Chap. 4. instilled under CT or uoroscopic guidance in the
If signicant headache persists for longer than 48 hours, intraspinal epidural space or adjacent to an existing nerve
placement of an epidural blood patch should be consid- root.
ered. Hearing loss is a rare complication of myelography.
It may result from a direct toxic effect of the contrast
medium or from an alteration of the pressure equilib- ANGIOGRAPHY
rium between CSF and perilymph in the inner ear.
Puncture of the spinal cord is a rare but serious compli- Catheter angiography is indicated for evaluating
cation of cervical (C12) and high lumbar puncture. intracranial small-vessel pathology (such as vasculitis), for
The risk of cord puncture is greatest in patients with assessing vascular malformations and aneurysms, and in
spinal stenosis, Chiari malformations, or conditions that endovascular therapeutic procedures (Table 2-1).Angiog-
reduce CSF volume. In these settings, a low-dose lum- raphy has been replaced for many indications by CT/CTA
bar injection followed by thin-section CT or MRI is a or MRI/MRA.
safer alternative to cervical puncture. Intrathecal contrast Angiography carries the greatest risk of morbidity of
reactions are rare, but aseptic meningitis and encephalopa- all diagnostic imaging procedures, owing to the necessity
thy may occur. The latter is usually dose-related and of inserting a catheter into a blood vessel, directing the
associated with contrast entering the intracranial sub- catheter to the required location, injecting contrast material
to visualize the vessel, and removing the catheter while SPINAL ANGIOGRAPHY 23
maintaining hemostasis. Therapeutic transcatheter proce-
Spinal angiography may be indicated to evaluate vascular
dures (see below) have become important options for the
malformations and tumors and to identify the artery of

CHAPTER 2
treatment of some cerebrovascular diseases. The decision
Adamkiewicz (Chap. 30) prior to aortic aneurysm repair.
to undertake a diagnostic or therapeutic angiographic
The procedure is lengthy and requires the use of relatively
procedure requires careful assessment of the goals of the
large volumes of contrast; the incidence of serious com-
investigation and its attendant risks.
plications, including paraparesis, subjective visual blurring,
To improve tolerance to contrast agents, patients
and altered speech, is ~2%. Gadolinium-enhanced MRA
undergoing angiography should be well hydrated before
has been used successfully in this setting, as has iodinated

Neuroimaging in Neurologic Disorders

and after the procedure. Since the femoral route is used
contrast CTA, which has promise for replacing diagnostic
most commonly, the femoral artery must be compressed
spinal angiography for some indications.
after the procedure to prevent a hematoma from devel-
oping. The puncture site and distal pulses should be
evaluated carefully after the procedure; complications INTERVENTIONAL NEURORADIOLOGY
can include thigh hematoma or lower extremity emboli.
This rapidly developing eld is providing new therapeu-
tic options for patients with challenging neurovascular
COMPLICATIONS problems. Available procedures include detachable coil
therapy for aneurysms, particulate or liquid adhesive
A common femoral arterial puncture provides retro-
embolization of arteriovenous malformations, balloon
grade access via the aorta to the aortic arch and great
angioplasty and stenting of arterial stenosis or vasospasm,
vessels. The most feared complication of cerebral
transarterial or transvenous embolization of dural arteri-
angiography is stroke. Thrombus can form on or inside
ovenous stulas, balloon occlusion of carotid-cavernous
the tip of the catheter, and atherosclerotic thrombus or
and vertebral fistulas, endovascular treatment of vein-
plaque can be dislodged by the catheter or guide wire or
of-Galen malformations, preoperative embolization of
by the force of injection and can embolize distally in the
tumors, and thrombolysis of acute arterial or venous
cerebral circulation. Risk factors for ischemic complica-
thrombosis. Many of these disorders place the patient at
tions include limited experience on the part of the
high risk of cerebral hemorrhage, stroke, or death.
angiographer, atherosclerosis, vasospasm, low cardiac
The highest complication rates are found with the
output, decreased oxygen-carrying capacity, advanced
therapies designed to treat the highest-risk diseases. The
age, and prior history of migraine. The risk of a neuro-
advent of electrolytically detachable coils has ushered in
logic complication varies but is ~4% for transient
a new era in the treatment of cerebral aneurysms. One
ischemic attack and stroke, 1% for permanent decit,
randomized trial found a 28% reduction of morbidity
and <0.1% for death.
and mortality at 1 year among those treated for anterior
Ionic contrast material injected into the cerebral vas-
circulation aneurysm with detachable coils compared
culature can be neurotoxic if the BBB is breached,
with neurosurgical clipping. It remains to be determined
either by an underlying disease or by the injection of
what the role of coils will be relative to surgical options,
hyperosmolar contrast agent. Ionic contrast media are
but in many centers, coiling has become standard ther-
less well tolerated than nonionic media, probably
apy for many aneurysms.
because they can induce changes in cell membrane elec-
trical potentials. Patients with dolichoectasia of the basi-
FURTHER READINGS
lar artery can suffer reversible brainstem dysfunction and
acute short-term memory loss during angiography, DONNAN GA et al: Penumbral selection of patients for trials of acute
owing to the slow percolation of the contrast material stroke therapy. Lancet Neurol. 8:261, 2009
ROVARIS M et al: Diffusion tensor MR imaging. Neuroimaging Clin
and the consequent prolonged exposure of the brain.
N Am 19:37, 2009
Rarely, an intracranial aneurysm ruptures during an SCHAEFER PW: Diffusion-weighted imaging in acute stroke. Magn
angiographic contrast injection, causing subarachnoid Reson Imaging Clin N Am 14:141, 2006
hemorrhage, perhaps as a result of injection under high VERNOOIJ MW et al: Incidental ndings on brain MRI in the gen-
pressure. eral population. N Engl J Med 357:1821, 2007
 CHAPTER 3
ELECTRODIAGNOSTIC STUDIES OF NERVOUS
SYSTEM DISORDERS: EEG, EVOKED
POTENTIALS, AND EMG
Michael J. Aminoff

I Electroencephalography . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
The EEG and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
The EEG and Coma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
The EEG in Other Neurologic Disorders . . . . . . . . . . . . . . . . . 27
I Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Sensory Evoked Potentials . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Clinical Utility of SEPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Electrophysiologic Studies of Muscle and Nerve . . . . . . . . . . 28
Electromyography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

procedures are generally undertaken in an attempt to

ELECTROENCEPHALOGRAPHY provoke abnormalities. Such procedures commonly
The electrical activity of the brain [the electroencephalo- include hyperventilation (for 3 or 4 min), photic stimu-
gram (EEG)] is easily recorded from electrodes placed on lation, sleep, and sleep deprivation on the night prior to
the scalp. The potential difference between pairs of elec- the recording.
trodes on the scalp (bipolar derivation) or between indi- Electroencephalography is relatively inexpensive and
vidual scalp electrodes and a relatively inactive common may aid clinical management in several different contexts.
reference point (referential derivation) is amplied and
displayed on a computer monitor, oscilloscope, or paper.
THE EEG AND EPILEPSY
The characteristics of the normal EEG depend on the
patients age and level of arousal. The rhythmic activity The EEG is most useful in evaluating patients with sus-
normally recorded represents the postsynaptic potentials pected epilepsy. The presence of electrographic seizure
of vertically oriented pyramidal cells of the cerebral cor- activityi.e., of abnormal, repetitive, rhythmic activity
tex and is characterized by its frequency. In normal having an abrupt onset and termination and a character-
awake adults lying quietly with the eyes closed, an 8- to istic evolutionclearly establishes the diagnosis. The
13-Hz alpha rhythm is seen posteriorly in the EEG, absence of such electrocerebral accompaniment does
intermixed with a variable amount of generalized faster not exclude a seizure disorder, however, because there
(beta) activity (>13 Hz); the alpha rhythm is attenuated may be no change in the scalp-recorded EEG during
when the eyes are opened (Fig. 3-1). During drowsiness, simple or complex partial seizures. With generalized
the alpha rhythm is also attenuated; with light sleep, tonic-clonic seizures, however, the EEG is always abnor-
slower activity in the theta (47 Hz) and delta (<4 Hz) mal during the episode. It is often not possible to obtain
ranges becomes more conspicuous. an EEG during clinical events that may represent seizures,
The EEG is best recorded from several different elec- especially when such events occur unpredictably or infre-
trode arrangements (montages) in turn, and activating quently. Continuous monitoring for prolonged periods
24
 Eyes open 25
Fp1-F3 F3-C3
F3-C3 C3-P3

CHAPTER 3
C3-P3 P3-O1
P3-O1 F4-C4
Fp2-F4 C4-P4
F4-C4 P4-O2
C4-P4 T3-CZ
P4-O2 CZ-T4

Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG
A B

F3-A1
Fp1-F3
C3-A1 F3-C3
P3-A1 C3-P3
O1-A1 P3-O1
Fp2-F4
F4-A2
F4-C4
C4-A2
C4-P4
P4-A2 P4-O2
O2-A2
C D

FIGURE 3-1
A. Normal EEG showing a posteriorly situated 9-Hz alpha 300 V in other panels. (From Aminoff, 1999.) In this and the
rhythm that attenuates with eye opening. B. Abnormal EEG following gure, electrode placements are indicated at the
showing irregular diffuse slow activity in an obtunded patient left of each panel and accord with the international 10:20
with encephalitis. C. Irregular slow activity in the right central system. A, earlobe; C, central; F, frontal; Fp, frontal polar;
region, on a diffusely slowed background, in a patient with a P, parietal; T, temporal; O, occipital. Right-sided placements
right parietal glioma. D. Periodic complexes occurring once are indicated by even numbers, left-sided placements by
every second in a patient with Creutzfeldt-Jakob disease. odd numbers, and midline placements by Z.
Horizontal calibration: 1 s; vertical calibration: 200 V in A,

in video-EEG telemetry units for hospitalized patients episodic generalized spike-wave activity that occurs dur-
or the use of portable equipment to record the EEG ing and between seizures in patients with typical
continuously on cassettes for 24 h or longer in ambula- absence epilepsy contrasts with focal interictal epilepti-
tory patients has made it easier to capture the electro- form discharges or ictal patterns found in patients with
cerebral accompaniments of such clinical episodes. complex partial seizures. These latter seizures may have
Monitoring by these means is sometimes helpful in con- no correlates in the scalp-recorded EEG or may be asso-
rming that seizures are occurring, characterizing the ciated with abnormal rhythmic activity of variable fre-
nature of clinically equivocal episodes, and determining quency, a localized or generalized distribution, and a
the frequency of epileptic events. stereotyped pattern that varies with the patient. Focal or
The EEG ndings may also be helpful in the interictal lateralized epileptogenic lesions are important to recog-
period by showing certain abnormalities that are strongly nize, especially if surgical treatment is contemplated.
supportive of a diagnosis of epilepsy. Such epileptiform Intensive long-term monitoring of clinical behavior and
activity consists of bursts of abnormal discharges contain- the EEG is required for operative candidates, however,
ing spikes or sharp waves. The presence of epileptiform and this generally also involves recording from intracra-
activity is not specic for epilepsy, but it has a much nially placed electrodes (which may be subdural,
greater prevalence in epileptic patients than in normal extradural, or intracerebral in location).
individuals. However, even in an individual who is The ndings in the routine scalp-recorded EEG may
known to have epilepsy, the initial routine interictal EEG indicate the prognosis of seizure disorders: in general, a
may be normal up to 60% of the time. Thus, the EEG normal EEG implies a better prognosis than otherwise,
cannot establish the diagnosis of epilepsy in many cases. whereas an abnormal background or profuse epilepti-
The EEG ndings have been used in classifying form activity suggests a poor outlook.The EEG ndings
seizure disorders and selecting appropriate anticonvul- are not helpful in determining which patients with head
sant medication for individual patients (Fig. 3-2). The injuries, stroke, or brain tumors will go on to develop
 26 F3-C3 occur after withdrawal of anticonvulsant medication
C3-P3 despite a normal EEG or, conversely, may not occur
P3-O1
despite a continuing EEG abnormality. The decision to
SECTION I

discontinue anticonvulsant medication is made on clini-

F4-C4
cal grounds, and the EEG does not have a useful role in
C4-P4
this context except for providing guidance when there
P4-O2 is clinical ambiguity or the patient requires reassurance
T3-CZ about a particular course of action.
CZ-T4 The EEG has no role in the management of tonic-
Introduction to Neurology

A clonic status epilepticus except when there is clinical

uncertainty whether seizures are continuing in a
comatose patient. In patients treated by pentobarbital-
Fp1-F7
induced coma for refractory status epilepticus, the EEG
F7-T3
ndings are useful in indicating the level of anesthesia
T3-T5 and whether seizures are occurring. During status
T5-O1 epilepticus, the EEG shows repeated electrographic
seizures or continuous spike-wave discharges. In non-
Fp2-F8
convulsive status epilepticus, a disorder that may not be
F8-T4 recognized unless an EEG is performed, the EEG may
T4-T6 also show continuous spike-wave activity (spike-wave
T6-O2 stupor) or, less commonly, repetitive electrographic
B seizures (complex partial status epilepticus).

Fp1-A1 THE EEG AND COMA

F7-A1 In patients with an altered mental state or some degree of
T3-A1 obtundation, the EEG tends to become slower as con-
T5-A1
sciousness is depressed, regardless of the underlying cause
(Fig. 3-1). Other ndings may also be present and may
Fp2-A2 suggest diagnostic possibilities, as when electrographic
F8-A2 seizures are found or there is a focal abnormality indicat-
T4-A2 ing a structural lesion.The EEG generally slows in meta-
T6-A2
bolic encephalopathies, and triphasic waves may be pre-
C sent. The ndings do not permit differentiation of the
underlying metabolic disturbance but help to exclude
other encephalopathic processes by indicating the diffuse
FIGURE 3-2 extent of cerebral dysfunction. The response of the EEG
Electrographic seizures. A. Onset of a tonic seizure showing to external stimulation is helpful prognostically because
generalized repetitive sharp activity with synchronous onset electrocerebral responsiveness implies a lighter level of
over both hemispheres. B. Burst of repetitive spikes occur- coma than a nonreactive EEG. Serial records provide a
ring with sudden onset in the right temporal region during a better guide to prognosis than a single record and supple-
clinical spell characterized by transient impairment of external ment the clinical examination in following the course of
awareness. C. Generalized 3-Hz spike-wave activity occur- events. As the depth of coma increases, the EEG becomes
ring synchronously over both hemispheres during an absence nonreactive and may show a burst-suppression pattern,
(petit mal) attack. Horizontal calibration: 1 s; vertical calibra- with bursts of mixed-frequency activity separated by
tion: 400 mV in A, 200 mV in B, and 750 mV in C. (From intervals of relative cerebral inactivity. In other instances
Aminoff, 1999.) there is a reduction in amplitude of the EEG until even-
tually activity cannot be detected. Such electrocerebral
silence does not necessarily reect irreversible brain dam-
seizures, because in such circumstances epileptiform age, because it may occur in hypothermic patients or with
activity is commonly encountered regardless of whether drug overdose. The prognosis of electrocerebral silence,
seizures occur. The EEG ndings are sometimes used to when recorded using an adequate technique, depends
determine whether anticonvulsant medication can be upon the clinical context in which it is found. In patients
discontinued in epileptic patients who have been with severe cerebral anoxia, for example, electrocerebral
seizure-free for several years, but the ndings provide silence in a technically satisfactory record implies that
only a general guide to prognosis: further seizures may useful cognitive recovery will not occur.
 In patients with clinically suspected brain death, an stimuli have to be recorded and averaged with a com- 27
EEG, when recorded using appropriate technical stan- puter in order to permit their recognition and deni-
dards, may be conrmatory by showing electrocerebral tion. The background EEG activity, which has no xed

CHAPTER 3
silence. However, complicating disorders that may pro- temporal relationship to the stimulus, is averaged out by
duce a similar but reversible EEG appearance (e.g., this procedure.
hypothermia or drug intoxication) must be excluded. Visual evoked potentials (VEPs) are elicited by monocular
The presence of residual EEG activity in suspected brain stimulation with a reversing checkerboard pattern and are
death fails to conrm the diagnosis but does not exclude recorded from the occipital region in the midline and on
it.The EEG is usually normal in patients with locked-in either side of the scalp. The component of major clinical

Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG
syndrome and helps in distinguishing this disorder from importance is the so-called P100 response, a positive peak
the comatose state with which it is sometimes confused having a latency of approximately 100 ms. Its presence,
clinically. latency, and symmetry over the two sides of the scalp are
noted. Amplitude may also be measured, but changes in
size are much less helpful for the recognition of pathology.
THE EEG IN OTHER NEUROLOGIC
VEPs are most useful in detecting dysfunction of the
DISORDERS
visual pathways anterior to the optic chiasm. In patients
In the developed countries, CT scanning and MRI have with acute severe optic neuritis, the P100 is frequently lost
taken the place of EEG as a noninvasive means of screen- or grossly attenuated; as clinical recovery occurs and visual
ing for focal structural abnormalities of the brain, such as acuity improves, the P100 is restored but with an increased
tumors, infarcts, or hematomas (Fig. 3-1). Nonetheless, latency that generally remains abnormally prolonged
the EEG is still used for this purpose in many parts of the indenitely.The VEP ndings are therefore helpful in indi-
world, although infratentorial or slowly expanding cating previous or subclinical optic neuritis.They may also
lesions may fail to cause any abnormalities. Focal slow- be abnormal with ocular abnormalities and with other
wave disturbances, a localized loss of electrocerebral causes of optic nerve disease, such as ischemia or compres-
activity, or more generalized electrocerebral disturbances sion by a tumor. Normal VEPs may be elicited by ash
are common ndings but provide no reliable indication stimuli in patients with cortical blindness.
about the nature of the underlying pathology. Brainstem auditory evoked potentials (BAEPs) are elicited
In patients with an acute encephalopathy, focal or lat- by monaural stimulation with repetitive clicks and are
eralized periodic slow-wave complexes, sometimes with recorded between the vertex of the scalp and the mas-
a sharpened outline, suggest a diagnosis of herpes sim- toid process or earlobe. A series of potentials, designated
plex encephalitis, and periodic lateralized epileptiform by roman numerals, occurs in the rst 10 ms after the
discharges (PLEDs) are commonly found with acute stimulus and represents in part the sequential activation
hemispheric pathology such as a hematoma, abscess, or of different structures in the pathway between the audi-
rapidly expanding tumor.The EEG ndings in dementia tory nerve (wave I) and the inferior colliculus (wave V)
are usually nonspecic and do not distinguish between in the midbrain. The presence, latency, and interpeak
the different causes of cognitive decline except in rare latency of the rst ve positive potentials recorded at
instances when, for example, the presence of complexes the vertex are evaluated. The ndings are helpful in
occurring with a regular repetition rate (so-called peri- screening for acoustic neuromas, detecting brainstem
odic complexes) supports a diagnosis of Creutzfeldt- pathology, and evaluating comatose patients.The BAEPs
Jakob disease (Fig. 3-1) or subacute sclerosing panen- are normal in coma due to metabolic/toxic disorders or
cephalitis. In most patients with dementias, the EEG is bihemispheric disease but abnormal in the presence of
normal or diffusely slowed, and the EEG ndings alone brainstem pathology.
cannot indicate whether a patient is demented or distin- Somatosensory evoked potentials (SEPs) are recorded
guish between dementia and pseudodementia. over the scalp and spine in response to electrical stimu-
lation of a peripheral (mixed or cutaneous) nerve. The
conguration, polarity, and latency of the responses
EVOKED POTENTIALS depend on the nerve that is stimulated and on the record-
SENSORY EVOKED POTENTIALS ing arrangements. SEPs are used to evaluate proximal
(otherwise inaccessible) portions of the peripheral nervous
The noninvasive recording of spinal or cerebral poten- system and the integrity of the central somatosensory
tials elicited by stimulation of specic afferent pathways pathways.
is an important means of monitoring the functional
integrity of these pathways but does not indicate the
CLINICAL UTILITY OF SEPs
pathologic basis of lesions involving them. Such evoked
potentials (EPs) are so small compared to the back- EP studies may detect and localize lesions in afferent
ground EEG activity that the responses to a number of pathways in the central nervous system (CNS). They
 28 have been used particularly to investigate patients with latency in many patients with dementia, whereas it is
suspected multiple sclerosis (MS), the diagnosis of which generally normal in patients with depression or other
requires the recognition of lesions involving several dif- psychiatric disorders that might be mistaken for demen-
SECTION I

ferent regions of the central white matter. In patients tia. ERPs are therefore sometimes helpful in making this
with clinical evidence of only one lesion, the electro- distinction when there is clinical uncertainty, although a
physiologic recognition of abnormalities in other sites response of normal latency does not exclude dementia.
helps to suggest or support the diagnosis but does not
establish it unequivocally. Multimodality EP abnormali- Motor Evoked Potentials
ties are not specic for multiple sclerosis (MS); they may
The electrical potentials recorded from muscle or the
Introduction to Neurology

occur in AIDS, Lyme disease, systemic lupus erythe-

matosus, neurosyphilis, spinocerebellar degenerations, spinal cord following stimulation of the motor cortex or
familial spastic paraplegia, and deciency of vitamin E central motor pathways are referred to as motor evoked
or B12, among other disorders. The diagnostic utility of potentials. For clinical purposes such responses are
the electrophysiologic ndings therefore depends on the recorded most often as the compound muscle action
circumstances in which they are found. Abnormalities potentials elicited by transcutaneous magnetic stimula-
may aid in the localization of lesions to broad areas of tion of the motor cortex. A strong but brief magnetic
the CNS, but attempts at precise localization on electro- eld is produced by passing a current through a coil, and
physiologic grounds are misleading because the genera- this induces stimulating currents in the subjacent neural
tors of many components of the EP are unknown. tissue. The procedure is painless and apparently safe.
The EP ndings are sometimes of prognostic rele- Abnormalities have been described in several neurologic
vance. Bilateral loss of SEP components that are gener- disorders with clinical or subclinical involvement of
ated in the cerebral cortex implies that cognition may central motor pathways, including MS and motor neu-
not be regained in posttraumatic or postanoxic coma, ron disease. In addition to a possible role in the diagnosis
and EP studies may also be useful in evaluating patients of neurologic disorders or in evaluating the extent of
with suspected brain death. In patients who are comatose pathologic involvement, the technique provides infor-
for uncertain reasons, preserved BAEPs suggest either a mation of prognostic relevance (e.g., in suggesting the
metabolic-toxic etiology or bihemispheric disease. In likelihood of recovery of motor function after stroke)
patients with spinal cord injuries, SEPs have been used to and is useful as a means of monitoring intraoperatively
indicate the completeness of the lesion. The presence or the functional integrity of central motor tracts.
early return of a cortically generated response to stimula-
tion of a nerve below the injured segment of the cord ELECTROPHYSIOLOGIC STUDIES
indicates an incomplete lesion and thus a better progno- OF MUSCLE AND NERVE
sis for functional recovery than otherwise. In surgery,
intraoperative EP monitoring of neural structures placed The motor unit is the basic element subserving motor
at risk by the procedure may permit the early recogni- function. It is dened as an anterior horn cell, its axon
tion of dysfunction and thereby permit a neurologic and neuromuscular junctions, and all the muscle bers
complication to be averted or minimized. innervated by the axon.The number of motor units in a
Visual and auditory acuity may be determined using EP muscle ranges from approximately 10 in the extraocular
techniques in patients whose age or mental state precludes muscles to several thousand in the large muscles of the
traditional ophthalmologic or audiologic examinations. legs.There is considerable variation in the average num-
ber of muscle bers within the motor units of an indi-
vidual muscle, i.e., in the innervation ratio of different
Cognitive Evoked Potentials muscles.Thus the innervation ratio is <25 in the human
Certain EP components depend on the mental attention external rectus or platysma muscle and between 1600
of the subject and the setting in which the stimulus occurs, and 1700 in the medial head of the gastrocnemius mus-
rather than simply on the physical characteristics of the cle. The muscle bers of individual motor units are
stimulus. Such event-related potentials (ERPs) or divided into two general types by distinctive contractile
endogenous potentials are related in some manner to properties, histochemical stains, and characteristic
the cognitive aspects of distinguishing an infrequently responses to fatigue. Within each motor unit, all of the
occurring target stimulus from other stimuli occurring muscle bers are of the same type.
more frequently. For clinical purposes, attention has
been directed particularly at the so-called P3 compo-
ELECTROMYOGRAPHY
nent of the ERP, which is also designated the P300
component because of its positive polarity and latency The pattern of electrical activity in muscle [i.e., the
of approximately 300400 ms after onset of an auditory electromyogram (EMG)], both at rest and during activ-
target stimulus. The P3 component is prolonged in ity, may be recorded from a needle electrode inserted
 recorded (Fig. 3-3). The parameters of normal motor 29
A 100 V unit action potentials depend on the muscle under study
10 ms and age of the patient, but their duration is normally

CHAPTER 3
between 5 and 15 ms, amplitude is between 200 V and
B 100 V
2 mV, and most are bi- or triphasic.The number of units
activated depends on the degree of voluntary activity. An
100 ms increase in muscle contraction is associated with an
increase in the number of motor units that are activated
100 V (recruited) and in the frequency with which they dis-

Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG
C D E charge.With a full contraction, so many motor units are
normally activated that individual motor unit action
potentials can no longer be distinguished, and a com-
10 ms plete interference pattern is said to have been produced.
FIGURE 3-3 The incidence of small, short-duration, polyphasic
Activity recorded during EMG. A. Spontaneous brillation motor unit action potentials (i.e., having more than four
potentials and positive sharp waves. B. Complex repetitive phases) is usually increased in myopathic muscle, and an
discharges recorded in partially denervated muscle at rest. excessive number of units is activated for a specied
C. Normal triphasic motor unit action potential. D. Small, degree of voluntary activity. By contrast, the loss of
short-duration, polyphasic motor unit action potential such motor units that occurs in neuropathic disorders leads to
as is commonly encountered in myopathic disorders. E. Long- a reduction in number of units activated during a maxi-
duration polyphasic motor unit action potential such as may mal contraction and an increase in their ring rate, i.e.,
be seen in neuropathic disorders. there is an incomplete or reduced interference pattern.
The conguration and dimensions of the potentials may
also be abnormal, depending on the duration of the
into the muscle.The nature and pattern of abnormalities neuropathic process and on whether reinnervation has
relate to disorders at different levels of the motor unit. occurred.The surviving motor units are initially normal
Relaxed muscle normally is electrically silent except in conguration but, as reinnervation occurs, they
in the end plate region, but abnormal spontaneous increase in amplitude and duration and become
activity (Fig. 3-3) occurs in various neuromuscular dis- polyphasic (Fig. 3-3).
orders, especially those associated with denervation or Action potentials from the same motor unit some-
inammatory changes in affected muscle. Fibrillation times re with a consistent temporal relationship to each
potentials and positive sharp waves (which reect mus- other, so that double, triple, or multiple discharges are
cle ber irritability) and complex repetitive discharges recorded, especially in tetany, hemifacial spasm, or
are most oftenbut not alwaysfound in denervated myokymia.
muscle and may also occur after muscle injury and in Electrical silence characterizes the involuntary, sus-
certain myopathic disorders, especially inammatory dis- tained muscle contraction that occurs in phosphorylase
orders such as polymyositis. After an acute neuropathic deciency, which is designated a contracture.
lesion, they are found earlier in proximal rather than dis- EMG enables disorders of the motor units to be
tal muscles and sometimes do not develop distally in the detected and characterized as either neurogenic or myo-
extremities for 46 weeks; once present, they may persist pathic. In neurogenic disorders, the pattern of affected
indenitely unless reinnervation occurs or the muscle muscles may localize the lesion to the anterior horn
degenerates so completely that no viable tissue remains. cells or to a specic site as the axons traverse a nerve
Fasciculation potentials (which reect the spontaneous root, limb plexus, and peripheral nerve to their terminal
activity of individual motor units) are characteristic of arborizations.The ndings do not enable a specic etio-
slowly progressive neuropathic disorders, especially those logic diagnosis to be made, however, except in conjunc-
with degeneration of anterior horn cells (such as amy- tion with the clinical ndings and results of other labo-
otrophic lateral sclerosis). Myotonic dischargeshigh- ratory studies.
frequency discharges of potentials derived from single The ndings may provide a guide to the severity of
muscle fibers that wax and wane in amplitude and an acute disorder of a peripheral or cranial nerve (by
frequencyare the signature of myotonic disorders such indicating whether denervation has occurred and the
as myotonic dystrophy or myotonia congenita but occur completeness of the lesion) and whether the pathologic
occasionally in polymyositis or other, rarer, disorders. process is active or progressive in chronic or degenera-
Slight voluntary contraction of a muscle leads to acti- tive disorders such as amyotrophic lateral sclerosis. Such
vation of a small number of motor units. The potentials information is important for prognostic purposes.
generated by any muscle bers of these units that are Various quantitative EMG approaches have been
within the pick-up range of the needle electrode will be developed.The most common is to determine the mean
 30 duration and amplitude of 20 motor unit action poten- studies are performed by determining the conduction
tials using a standardized technique. The technique of velocity and amplitude of action potentials in sensory
macro-EMG provides information about the number bers when these bers are stimulated at one point and
SECTION I

and size of muscle bers in a larger volume of the motor the responses are recorded at another point along the
unit territory and has also been used to estimate the course of the nerve. In adults, conduction velocity in the
number of motor units in a muscle. Scanning EMG is a arms is normally between 50 and 70 m/s, and in the legs
computer-based technique that has been used to study is between 40 and 60 m/s.
the topography of motor unit action potentials and, in Nerve conduction studies complement the EMG
particular, the spatial and temporal distribution of activ- examination, enabling the presence and extent of
Introduction to Neurology

ity in individual units. The technique of single-ber peripheral nerve pathology to be determined. They are
EMG is discussed separately later. particularly helpful in determining whether sensory
symptoms are arising from pathology proximal or distal
Nerve Conduction Studies to the dorsal root ganglia (in the former instance,
peripheral sensory conduction studies will be normal)
Recording of the electrical response of a muscle to and whether neuromuscular dysfunction relates to
stimulation of its motor nerve at two or more points peripheral nerve disease. In patients with a mononeu-
along its course (Fig. 3-4) permits conduction velocity ropathy, they are invaluable as a means of localizing a
to be determined in the fastest-conducting motor bers focal lesion, determining the extent and severity of the
between the points of stimulation.The latency and ampli- underlying pathology, providing a guide to prognosis,
tude of the electrical response of muscle (i.e., of the and detecting subclinical involvement of other periph-
compound muscle action potential) to stimulation of its eral nerves. They enable a polyneuropathy to be distin-
motor nerve at a distal site are also compared with values guished from a mononeuropathy multiplex when this is
dened in normal subjects. Sensory nerve conduction not possible clinically, an important distinction because
of the etiologic implications. Nerve conduction studies
provide a means of following the progression and thera-
Recording
electrodes peutic response of peripheral nerve disorders and are
being used increasingly for this purpose in clinical trials.
Reference Ground
They may suggest the underlying pathologic basis in
Active
individual cases. Conduction velocity is often markedly
Cathode
slowed, terminal motor latencies are prolonged, and
Anode compound motor and sensory nerve action potentials
may be dispersed in the demyelinative neuropathies
Stimulating Stimulating (such as in Guillain-Barr syndrome, chronic inamma-
electrodes electrodes
tory polyneuropathy, metachromatic leukodystrophy, or
Stimulation certain hereditary neuropathies); conduction block is
site frequent in acquired varieties of these neuropathies. By
Wrist contrast, conduction velocity is normal or slowed only
mildly, sensory nerve action potentials are small or
absent, and there is EMG evidence of denervation in
axonal neuropathies such as occur in association with
Below
elbow metabolic or toxic disorders.
The utility and complementary role of EMG and
nerve conduction studies are best illustrated by reference
to a common clinical problem. Numbness and paresthe-
Above
elbow sia of the little nger and associated wasting of the
intrinsic muscles of the hand may result from a spinal
cord lesion, C8/T1 radiculopathy, brachial plexopathy
(lower trunk or medial cord), or a lesion of the ulnar
Axilla 5 mV
nerve. If sensory nerve action potentials can be recorded
10 ms normally at the wrist following stimulation of the digital
FIGURE 3-4 bers in the affected nger, the pathology is probably
Arrangement for motor conduction studies of the ulnar nerve. proximal to the dorsal root ganglia, i.e., there is a radicu-
Responses are recorded with a surface electrode from the lopathy or more central lesion; absence of the sensory
abductor digiti minimi muscle to supramaximal stimulation of potentials, by contrast, suggests distal pathology. EMG
the nerve at different sites, and are shown in the lower panel. examination will indicate whether the pattern of
(From Aminoff, 1998.) affected muscles conforms to radicular or ulnar nerve
territory, or is more extensive (thereby favoring a plex- stimulation of a motor nerve at 23 Hz with stimuli 31
opathy). Ulnar motor conduction studies will generally delivered at intervals after voluntary contraction of the
also distinguish between a radiculopathy (normal nd- muscle for about 2030 s, even though preceding activ-

CHAPTER 3
ings) and ulnar neuropathy (abnormal ndings) and will ity in the junctional region inuences the release of
often identify the site of an ulnar nerve lesion: the nerve acetylcholine and thus the size of the end plate poten-
is stimulated at several points along its course to deter- tials elicited by a test stimulus. This is because more
mine whether the compound action potential recorded acetylcholine is normally released than is required to
from a distal muscle that it supplies shows a marked bring the motor end plate potentials to the threshold for
alteration in size or area or a disproportionate change in generating muscle ber action potentials. In disorders of

Electrodiagnostic Studies of Nervous System Disorders: EEG, Evoked Potentials, and EMG
latency, with stimulation at a particular site.The electro- neuromuscular transmission this safety factor is reduced.
physiologic ndings thus permit a denitive diagnosis to Thus in myasthenia gravis, repetitive stimulation, partic-
be made and specic treatment instituted in circum- ularly at a rate of between 2 and 5 Hz, may lead to a
stances where there is clinical ambiguity. depression of neuromuscular transmission, with a decre-
ment in size of the response recorded from affected
muscles. Similarly, immediately after a period of maxi-
F Wave Studies
mal voluntary activity, single or repetitive stimuli of the
Stimulation of a motor nerve causes impulses to travel motor nerve may elicit larger muscle responses than
antidromically (i.e., toward the spinal cord) as well as before, indicating that more muscle bers are respond-
orthodromically (to the nerve terminals). Such antidromic ing. This postactivation facilitation of neuromuscular
impulses cause a few of the anterior horn cells to dis- transmission is followed by a longer-lasting period of
charge, producing a small motor response that occurs depression, maximal between 2 and 4 min after the con-
considerably later than the direct response elicited by nerve ditioning period and lasting for as long as 10 min or so,
stimulation.The F wave so elicited is sometimes abnormal during which responses are reduced in size.
(absent or delayed) with proximal pathology of the periph- Decrementing responses to repetitive stimulation at
eral nervous system, such as a radiculopathy, and may 25 Hz are common in myasthenia gravis but may also
therefore be helpful in detecting abnormalities when occur in the congenital myasthenic syndromes. In
conventional nerve conduction studies are normal. In Lambert-Eaton myasthenic syndrome, in which there is
general, however, the clinical utility of F wave studies has defective release of acetylcholine at the neuromuscular
been disappointing, except perhaps in Guillain-Barr junction, the compound muscle action potential elicited
syndrome, where they are often absent or delayed. by a single stimulus is generally very small. With repeti-
tive stimulation at rates of up to 10 Hz, the rst few
responses may decline in size, but subsequent responses
H Reex Studies
increase. If faster rates of stimulation are used (2050 Hz),
The H reex is easily recorded only from the soleus mus- the increment may be dramatic so that the amplitude of
cle (S1) in normal adults. It is elicited by low-intensity compound muscle action potentials eventually reaches a
stimulation of the tibial nerve and represents a monosy- size that is several times larger than the initial response.
naptic reex in which spindle (Ia) afferent bers consti- In patients with botulism, the response to repetitive
tute the afferent arc and alpha motor axons the efferent stimulation is similar to that in Lambert-Eaton syn-
pathway. The H reexes are often absent bilaterally in drome, although the ndings are somewhat more vari-
elderly patients or with polyneuropathies and may be able and not all muscles are affected.
lost unilaterally in S1 radiculopathies.
Single-Fiber Electromyography
Muscle Response to Repetitive This technique is particularly helpful in detecting disor-
Nerve Stimulation
ders of neuromuscular transmission. A special needle
The size of the electrical response of a muscle to supra- electrode is placed within a muscle and positioned to
maximal electrical stimulation of its motor nerve relates record action potentials from two muscle bers belong-
to the number of muscle bers that are activated. Neu- ing to the same motor unit. The time interval between
romuscular transmission can be tested by several differ- the two potentials will vary in consecutive discharges;
ent protocols, but the most helpful is to record with sur- this is called the neuromuscular jitter. The jitter can be
face electrodes the electrical response of a muscle to quantied as the mean difference between consecutive
supramaximal stimulation of its motor nerve by repeti- interpotential intervals and is normally between 10 and
tive (23 Hz) shocks delivered before and at selected 50 s.This value is increased when neuromuscular trans-
intervals after a maximal voluntary contraction. mission is disturbed for any reason, and in some
There is normally little or no change in size of the instances impulses in individual muscle bers may fail to
compound muscle action potential following repetitive occur because of impulse blocking at the neuromuscular
 32 junction. Single-ber EMG is more sensitive than repet- may lead to uni- or bilateral loss of the response, and the
itive nerve stimulation or determination of acetylcholine ndings may therefore be helpful in identifying or local-
receptor antibody levels in diagnosing myasthenia gravis. izing such pathology.
SECTION I

Single-ber EMG can also be used to determine the

mean ber density of motor units (i.e., mean number of
muscle bers per motor unit within the recording area) FURTHER READINGS
and to estimate the number of motor units in a muscle, AMINOFF MJ: Electromyography in Clinical Practice: Electrodiagnostic
but this is of less immediate clinical relevance. Aspects of Neuromuscular Disease, 3d ed. New York, Churchill
Livingstone, 1998
(ed): Electrodiagnosis in Clinical Neurology, 5th ed. New York,
Introduction to Neurology

Blink Reexes
Churchill Livingstone, 2005
Electrical or mechanical stimulation of the supraorbital BROWN WF et al (eds): Neuromuscular Function and Disease. Philadel-
nerve on one side leads to two separate reex responses phia, Saunders, 2002
of the orbicularis oculian ipsilateral R1 response hav- EBERSOLE JS, PEDLEY TA (eds): Current Practice of Clinical Electroen-
cephalography, 3d ed. Philadelphia, Lippincott Williams & Wilkins,
ing a latency of approximately 10 ms and a bilateral R2
2003
response with a latency in the order of 30 ms. The HOLMES GL et al: Clinical Neurophysiology of Infancy, Childhood, and
trigeminal and facial nerves constitute the afferent and Adolescence. Philadelphia, Butterworth Heinemann, 2006
efferent arcs of the reex, respectively. Abnormalities of KIMURA J: Electrodiagnosis in Diseases of Nerve and Muscle, 3d ed. New
either nerve or intrinsic lesions of the medulla or pons York, Oxford University Press, 2001
 CHAPTER 4

LUMBAR PUNCTURE

Elizabeth Robbins I Stephen L. Hauser

Imaging and Laboratory Studies Prior to LP . . . . . . . . . . . . . . 33

Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Post-LP Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Normal Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

In experienced hands, lumbar puncture (LP) is usually a permanent nerve injury and/or paralysis. If a bleeding
safe procedure. Major complications are extremely disorder is suspected, the platelet count, international
uncommon but can include cerebral herniation, injury normalized ratio (INR), and partial thromboplastin time
to the spinal cord or nerve roots, hemorrhage, or infec- should be checked prior to lumbar puncture. There are
tion. Minor complications occur with greater frequency no data available to assess the safety of LP in patients
and can include backache, post-LP headache, and radic- with low platelet counts; a count of <20,000/L is con-
ular pain or numbness. sidered to be a contraindication to LP. Bleeding compli-
cations rarely occur in patients with platelet counts
>50,000/L and an INR 1.5. Patients receiving low-
IMAGING AND LABORATORY STUDIES
molecular-weight heparin are at increased risk of post-
PRIOR TO LP
LP spinal or epidural hematoma, and doses should be
Patients with an altered level of consciousness, a focal held for 24 h before the procedure.
neurologic decit, new-onset seizure, papilledema, or an LP should not be performed through infected skin as
immunocompromised state are at increased risk for organisms can be introduced into the subarachnoid
potentially fatal cerebellar or tentorial herniation fol- space (SAS).
lowing LP. Neuroimaging should be obtained in these
patients prior to LP to exclude a focal mass lesion or
ANALGESIA
diffuse swelling. Imaging studies should include the spine
in patients with symptoms suggesting cord compression, Anxiety and pain can be minimized prior to beginning the
such as back pain, leg weakness, urinary retention, or procedure. Anxiety can be allayed by the use of lorazepam,
incontinence. In patients with suspected meningitis who 12 mg given PO 30 min prior to the procedure or IV 5
require neuroimaging prior to diagnostic LP, administra- min prior to the procedure. Topical anesthesia can be
tion of antibiotics, preferably following blood culture, achieved by the application of a lidocaine-based cream.
should precede the neuroimaging study. Lidocaine 4% is effective when applied 30 min prior to the
Patients receiving therapeutic anticoagulation or procedure; lidocaine/prilocaine requires 60120 min. The
those with coagulation defects including thrombocy- cream should be applied in a thick layer so that it com-
topenia are at increased risk of post-LP spinal subdural pletely covers the skin; an occlusive dressing is used to keep
or epidural hematomas, either of which can produce the cream in place.

33
 34 POSITIONING After cleansing the skin with povidone-iodine or similar
disinfectant, the area is draped with a sterile cloth; the
Proper positioning of the patient is essential.The proce-
needle insertion site is blotted dry using a sterile gauze
dure should be performed on a rm surface; if the pro-
SECTION I

pad. Proper local disinfection reduces the risk of intro-

cedure is to be performed at the bedside, the patient
ducing skin bacteria into the SAS or other sites. Local
should be positioned at the edge of the bed and not in
anesthetic, typically 1% lidocaine, 35 mL total, is
the middle.The patient is asked to lie on his or her side,
injected into the subcutaneous tissue; in nonemergency
facing away from the examiner, and to roll up into a
situations a topical anesthetic cream can be applied (see
ball. The neck is gently ante-exed and the thighs
above). When time permits, pain associated with the
pulled up toward the abdomen; the shoulders and pelvis
Introduction to Neurology

injection of lidocaine can be minimized by slow, serial

should be vertically aligned without forward or back-
injections, each one progressively deeper than the last,
ward tilt (Fig. 4-1). The spinal cord terminates at
over a period of ~5 min. Approximately 0.51 mL of
approximately the L1 vertebral level in 94% of individ-
lidocaine is injected at a time; the needle is not usually
uals. In the remaining 6%, the conus extends to the L2-
withdrawn between injections. A pause of ~15 s
L3 interspace. LP is therefore performed at or below
between injections helps to minimize the pain of the
the L3-L4 interspace. A useful anatomic guide is a line
subsequent injection. The goal is to inject each mini-
drawn between the posterior superior iliac crests, which
bolus of anesthetic into an area of skin that has become
corresponds closely to the level of the L3-L4 inter-
numb from the preceding injection.Approximately 510
space. The interspace is chosen following gentle palpa-
mini-boluses are injected, using a total of ~5 mL of
tion to identify the spinous processes at each lumbar
lidocaine.
level.
If possible, the LP should be delayed for 1015 min
An alternative to the lateral recumbent position is the
following the completion of the injection of anesthetic;
seated position. The patient sits at the side of the bed,
this signicantly decreases and can even eliminate pain
with feet supported on a chair. The patient is instructed
from the procedure. Even a delay of 5 min will help to
to curl forward, trying to touch the nose to the umbili-
reduce pain.
cus. It is important that the patient not simply lean for-
The LP needle (typically 20- to 22-gauge) is inserted
ward onto a bedside table top, as this is not an optimal
in the midline, midway between two spinous processes,
position for opening up the spinous processes. LP is
and slowly advanced. The bevel of the needle should be
sometimes more easily performed in obese patients if
maintained in a horizontal position, parallel to the direc-
they are sitting. A disadvantage of the seated position is
tion of the dural bers and with the at portion of the
that measurement of opening pressure may not be accu-
bevel pointed upward; this minimizes injury to the bers
rate. In situations in which LP is difcult using palpable
as the dura is penetrated. When lumbar puncture is per-
spinal landmarks, bedside ultrasound to guide needle
formed in patients who are sitting, the bevel should be
placement may be employed.
maintained in the vertical position. In most adults, the
needle is advanced 45 cm (12 in.) before the SAS is
reached; the examiner usually recognizes entry as a sud-
TECHNIQUE
den release of resistance, a pop. If no uid appears
Once the desired target for needle insertion has been despite apparently correct needle placement, then the
identied, the examiner should put on sterile gloves. needle may be rotated 90180. If there is still no uid,
the stylet is reinserted and the needle is advanced slightly.
Some examiners halt needle advancement periodically to
Vertical alignment of remove the stylet and check for ow of cerebrospinal
shoulders and pelvis
uid (CSF). If the needle cannot be advanced because it
hits bone, if the patient experiences sharp radiating pain
down one leg, or if no uid appears (dry tap), the nee-
dle is partially withdrawn and reinserted at a different
angle. If on the second attempt the needle still hits bone
(indicating lack of success in introducing it between the
spinous processes), then the needle should be completely
withdrawn and the patient should be repositioned. The
L3-L4
second attempt is sometimes more successful if the
Inner space patient straightens the spine completely prior to reposi-
FIGURE 4-1 tioning. The needle can then be reinserted at the same
Proper positioning of a patient in the lateral decubitus posi- level or at an adjacent one.
tion. Note that the shoulders and hips are in a vertical plane; Once the SAS is reached, a manometer is attached to
the torso is perpendicular to the bed. (From Straus et al.) the needle and the opening pressure measured. The
examiner should look for normal oscillations in CSF are associated with an increased risk of post-LP 35
pressure associated with pulse and respirations. The headache. Headache usually begins within 48 h but may
upper limit of normal opening pressure with the patient be delayed for up to 12 days. Head pain is dramatically

CHAPTER 4
supine is 180 mm H2O in adults but may be as high as positional; it begins when the patient sits or stands
200250 mm H2O in obese adults. upright; there is relief upon reclining or with abdominal
CSF is allowed to drip into collection tubes; it should compression. The longer the patient is upright, the
not be withdrawn with a syringe. Depending on the longer the latency before head pain subsides.The pain is
clinical indication, uid is then obtained for studies usually a dull ache but may be throbbing; its location is
including: (1) cell count with differential, (2) protein and occipitofrontal. Nausea and stiff neck often accompany

Lumbar Puncture
glucose concentrations, (3) culture (bacterial, fungal, headache, and occasionally, patients report blurred
mycobacterial, viral), (4) smears (e.g., Grams and acid- vision, photophobia, tinnitus, and vertigo. Symptoms
fast stained smears), (5) antigen tests (e.g., latex aggluti- usually resolve over a few days but may on occasion per-
nation) (6) polymerase chain reaction (PCR) amplication sist for weeks to months.
of DNA or RNA of microorganisms (e.g., herpes sim- Post-LP headache is caused by a drop in CSF pressure
plex virus, enteroviruses), (7) antibody levels against related to persistent leakage of CSF at the site where the
microorganisms, (8) immunoelectrophoresis for deter- needle entered the subarachnoid space. Loss of CSF vol-
mination of -globulin level and oligoclonal banding, ume decreases the brains supportive cushion, so that
and (9) cytology. Although 15 mL of CSF is sufcient to when a patient is upright there is probably dilation and
obtain all of the listed studies, the yield of fungal and tension placed on the brains anchoring structures, the
mycobacterial cultures and cytology increases when pain-sensitive dural sinuses, resulting in pain. Although
larger volumes are sampled. In general 2030 mL may intracranial hypotension is the usual explanation for
be safely removed from adults. severe LP headache, the syndrome can occur in patients
A bloody tap due to penetration of a meningeal ves- with normal CSF pressure.
sel (a traumatic tap) may result in confusion with Post-LP headache usually resolves without specic
subarachnoid hemorrhage (SAH). In these situations a treatment, and care is largely supportive with oral anal-
specimen of CSF should be centrifuged immediately gesics [acetaminophen, nonsteroidal anti-inammatory
after it is obtained; clear supernatant following CSF drugs, opioids (Chap. 5)] and antiemetics. Patients may
centrifugation supports the diagnosis of a bloody tap, obtain relief by lying in a comfortable position. For
whereas xanthochromic supernatant suggests SAH. In some patients beverages with caffeine can provide tem-
general, bloody CSF due to the penetration of a porary pain relief.
meningeal vessel clears gradually in successive tubes, For patients with persistent pain, treatment with IV
whereas blood due to SAH does not. In addition to caffeine (500 mg in 500 mL saline administered over 2 h)
SAH, xanthochromic CSF may also be present in may be effective; atrial brillation is an uncommon side
patients with liver disease and when the CSF protein effect. For patients who do not respond to caffeine, an
concentration is markedly elevated [>1.52.0 g/L epidural blood patch accomplished by injection of
(150200 mg/dL)]. 15 mL of autologous whole blood is usually effective.
Prior to removing the LP needle, the stylet is rein- This procedure is usually performed by a pain specialist
serted to avoid the possibility of entrapment of a or anesthesiologist. The mechanism for these treatment
nerve root in the dura as the needle is being with- effects is not straightforward. The blood patch has an
drawn; entrapment could result in a dural CSF leak, immediate effect, making it unlikely that sealing off a
causing headache. Some practitioners question the safety dural hole with blood clot is its sole mechanism of
of this maneuver, with its potential risk of causing a action.
needle-stick injury to the examiner. Injury is unlikely, Strategies to decrease the incidence of post-LP
however, given the exibility of the small-diameter headache are listed in Table 4-1. Use of a smaller cal-
stylet, which tends to bend, rather than penetrate, on iber needle is associated with a lower risk: in one study,
contact. Following LP, the patient is customarily posi- the risk of headache following use of a 20- or 22-gauge
tioned in a comfortable, recumbent position for 1 h standard (Quinke) needle was 2040%, compared to 512%
before rising, although recent data suggest that assum- when a 24- to 27-gauge needle was used. The smallest
ing a recumbent position may be unnecessary as it gauge needles usually require the use of an introducer
does not appear to affect the development of headache needle and are associated with a slower CSF ow rate.
(see below). Use of an atraumatic (Sprotte, pencil point, or non-
cutting) needle also reduces the incidence of moderate
to severe headache compared with standard LP (Quinke,
POST-LP HEADACHE
or traumatic) needles (Fig. 4-2). However, because
The principal complication of LP is headache, occurring atraumatic needles are more difcult to use, more
in 1030% of patients. Younger age and female gender attempts may be required to perform the LP, particularly
 36 TABLE 4-1 TABLE 4-2
REDUCING THE INCIDENCE OF POST-LP HEADACHE CEREBROSPINAL FLUIDa

Effective Strategies CONVENTIONAL

SECTION I

CONSTITUENT SI UNITS UNITS

Use of small-diameter needle (22-gauge or smaller)
Use of atraumatic needle (Sprotte and others) Glucose 2.223.89 mmol/L 4070 mg/dL
Replacement of stylet prior to removal of needle Lactate 12 mmol/L 1020 mg/dL
Insertion of needle with bevel oriented in a cephalad to Total protein
caudad direction (when using standard needle) Lumbar 0.150.5 g/L 1550 mg/dL
Ineffective Strategies Cisternal 0.150.25 g/L 1525 mg/dL
Introduction to Neurology

Ventricular 0.060.15 g/L 615 mg/dL

Bed rest (up to 4 h) following LP Albumin 0.0660.442 g/L 6.644.2 mg/dL
Supplemental uids IgG 0.0090.057 g/L 0.95.7 mg/dL
Minimizing the volume of spinal uid removed IgG indexb 0.290.59
Immediate mobilization following LP Oligoclonal <2 bands not
bands (OGB) present in
matched serum
sample
Ammonia 1547 mol/L 2580 g/dL
in overweight patients. It may also be necessary to use CSF pressure 50180 mm H2O
an introducer with the atraumatic needle, which does CSF volume ~150 mL
not have the customary cutting, beveled tip. There is a (adult)
low risk of needle damage, e.g., breakage, with the Sprotte Red blood cells 0 0
atraumatic needle. Leukocytes
Another strategy to decrease the incidence of headache Total 05 mononuclear
cells per mm3
is to replace the stylet before removing the LP needle. Differential
Studies comparing mobilization immediately following Lymphocytes 6070%
LP with bed rest for up to 4 h show no signicant dif- Monocytes 3050%
ferences in the incidence of headache, suggesting that Neutrophils None
the customary practice of remaining in a recumbent posi-
tion post-LP may be unnecessary. a
Since cerebrospinal uid concentrations are equilibrium values,
measurements of the same parameters in blood plasma obtained at
the same time are recommended. However, there is a time lag in
attainment of equilibrium, and cerebrospinal levels of plasma con-
NORMAL VALUES stituents that can uctuate rapidly (such as plasma glucose) may not
achieve stable values until after a signicant lag phase.
(See Table 4-2) In uninfected CSF, the normal white b
IgG index = CSF IgG(mg/dL) serum albumin(g/dL)/Serum IgG(g/dL)
blood cell count is fewer than five mononuclear cells CSF albumin(mg/dL).
(lymphocytes and monocytes) per L. Polymor-
phonuclear leukocytes (PMNs) are not found in nor-
mal unconcentrated CSF; however, rare PMNs can be
found in centrifuged or concentrated CSF specimens such as those utilized for cytologic examination. Red
blood cells (RBCs) are not normally present in CSF;
if RBCs are present from a traumatic tap, their num-
ber decreases as additional CSF is collected. CSF
glucose concentrations <2.2 mmol/L (<40 mg/dL)
are abnormal.

FURTHER READINGS
ARMON C, EVANS RW: Addendum to assessment: Prevention of
FIGURE 4-2 post-lumbar puncture headaches: Report of the Therapeutics
and Technology Assessment Subcommittee of the American
Comparison of the standard (traumatic or Quinke) LP
Academy of Neurology. Neurology 65:510, 2005
needle with the atraumatic (Sprotte). The atraumatic
ELLENBY MS et al: Lumbar puncture (video). N Engl J Med
needle has its opening on the top surface of the needle, a 355:e12, 2006
design intended to reduce the chance of cutting dural bers EVANS RW et al: Assessment: Prevention of post-lumbar puncture
that, by protruding through the dura, could be responsible headaches: Report of the Therapeutics and Technology Assess-
for subsequent CSF uid leak and post-LP headache. (From ment Subcommittee of the American Academy of Neurology.
Thomas et al.) Neurology 55:909, 2000
FERRE RM, SWEENEY TW: Emergency physicians can easily obtain STRUPP M et al: Incidence of post-lumbar puncture syndrome 37
ultrasound images of anatomical landmarks relevant to lumbar reduced by reinserting the stylet:A randomized prospective study
puncture.Am J Emerg Med 25: 291, 2007 of 600 patients. J Neurol 245:589, 1998
LAVI R et al: Standard vs atraumatic Whitacre needle for diagnostic THOMAS SF et al: Randomised controlled trial of atraumatic versus

CHAPTER 4
lumbar puncture: A randomized trial. Neurology 67:1492, 2006 standard needles for diagnostic lumbar puncture. BMJ 321:986,
RICHMAN JM et al: Bevel direction and postdural puncture 2000
headache:A meta-analysis. Neurologist 12:224, 2006 TURNBULL DK, SHEPHERD DB: Post-dural puncture headache:
STRAUS SE et al: How do I perform a lumbar puncture and analyze Pathogenesis, prevention and treatment. Br J Anaesth 91:718,
the results to diagnose bacterial meningitis? JAMA 296:2012, 2006 2003

Lumbar Puncture
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 SECTION II

CLINICAL
MANIFESTATIONS
OF NEUROLOGIC
DISEASE
 CHAPTER 5

PAIN: PATHOPHYSIOLOGY AND MANAGEMENT

Howard L. Fields Joseph B. Martin

The Pain Sensory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Peripheral Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Central Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Pain Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

The task of medicine is to preserve and restore health stress response consisting of increased blood pressure,
and to relieve suffering. Understanding pain is essential heart rate, pupil diameter, and plasma cortisol levels. In
to both these goals. Because pain is universally under- addition, local muscle contraction (e.g., limb exion,
stood as a signal of disease, it is the most common symp- abdominal wall rigidity) is often present.
tom that brings a patient to a physicians attention. The
function of the pain sensory system is to protect the
body and maintain homeostasis. It does this by detecting, PERIPHERAL MECHANISMS
localizing, and identifying tissue-damaging processes. Since The Primary Afferent Nociceptor
different diseases produce characteristic patterns of tissue
damage, the quality, time course, and location of a patients A peripheral nerve consists of the axons of three different
pain complaint and the location of tenderness provide types of neurons: primary sensory afferents, motor neu-
important diagnostic clues and are used to evaluate the rons, and sympathetic postganglionic neurons (Fig. 5-1).
response to treatment. Once this information is obtained, The cell bodies of primary sensory afferents are located in
it is the obligation of the physician to provide rapid and the dorsal root ganglia in the vertebral foramina.The pri-
effective pain relief. mary afferent axon bifurcates to send one process into the
spinal cord and the other to innervate tissues. Primary affer-
ents are classied by their diameter, degree of myelination,
THE PAIN SENSORY SYSTEM and conduction velocity. The largest-diameter fibers,
A-beta (A), respond maximally to light touch and/or
Pain is an unpleasant sensation localized to a part of the moving stimuli; they are present primarily in nerves that
body. It is often described in terms of a penetrating or innervate the skin. In normal individuals, the activity of
tissue-destructive process (e.g., stabbing, burning, twist- these bers does not produce pain. There are two other
ing, tearing, squeezing) and/or of a bodily or emotional classes of primary afferents: the small-diameter myelinated
reaction (e.g., terrifying, nauseating, sickening). Further- A-delta (A) and the unmyelinated (C fiber) axons
more, any pain of moderate or higher intensity is accom- (Fig. 5-1). These bers are present in nerves to the skin
panied by anxiety and the urge to escape or terminate and to deep somatic and visceral structures. Some tissues,
the feeling.These properties illustrate the duality of pain: such as the cornea, are innervated only by A and C
it is both sensation and emotion. When acute, pain is afferents. Most A and C afferents respond maximally only
characteristically associated with behavioral arousal and a to intense (painful) stimuli and produce the subjective
40
 Dorsal root 41
ganglion
Spinal
Peripheral nerve cord

A
A

CHAPTER 5
C
Sympathetic
Sympathetic preganglionic
postganglionic
FIGURE 5-1
Components of a typical cutaneous nerve. There are two ganglion. Primary afferents include those with large-

Pain: Pathophysiology and Management

distinct functional categories of axons: primary afferents diameter myelinated (A), small-diameter myelinated (A),
with cell bodies in the dorsal root ganglion, and sympa- and unmyelinated (C) axons. All sympathetic postganglionic
thetic postganglionic bers with cell bodies in the sympathetic fibers are unmyelinated.

experience of pain when they are electrically stimulated; noninamed tissue. That is, they cannot be activated by
this denes them as primary afferent nociceptors (pain known mechanical or thermal stimuli and are not sponta-
receptors). The ability to detect painful stimuli is com- neously active. However, in the presence of inammatory
pletely abolished when A and C axons are blocked. mediators, these afferents become sensitive to mechanical
Individual primary afferent nociceptors can respond stimuli. Such afferents have been termed silent nociceptors,
to several different types of noxious stimuli. For exam- and their characteristic properties may explain how under
ple, most nociceptors respond to heating, intense cold, pathologic conditions the relatively insensitive deep struc-
intense mechanical stimuli such as a pinch, and applica- tures can become the source of severe and debilitating pain
tion of irritating chemicals including ATP, serotonin, and tenderness. Low pH, prostaglandins, leukotrienes, and
bradykinin and histamine. other inammatory mediators such as bradykinin play a
signicant role in sensitization.
Sensitization
Nociceptor-Induced Inammation
When intense, repeated, or prolonged stimuli are applied
to damaged or inamed tissues, the threshold for activat- Primary afferent nociceptors also have a neuroeffector func-
ing primary afferent nociceptors is lowered and the fre- tion. Most nociceptors contain polypeptide mediators
quency of ring is higher for all stimulus intensities. that are released from their peripheral terminals when
Inammatory mediators such as bradykinin, nerve growth they are activated (Fig. 5-2). An example is substance P, an
factor, some prostaglandins, and leukotrienes contribute 11-amino-acid peptide. Substance P is released from pri-
to this process, which is called sensitization. In sensitized mary afferent nociceptors and has multiple biologic activi-
tissues, normally innocuous stimuli can produce pain. ties. It is a potent vasodilator, degranulates mast cells, is a
Sensitization is a clinically important process that con- chemoattractant for leukocytes, and increases the produc-
tributes to tenderness, soreness, and hyperalgesia. A strik- tion and release of inammatory mediators. Interestingly,
ing example of sensitization is sunburned skin, in which depletion of substance P from joints reduces the severity
severe pain can be produced by a gentle slap on the of experimental arthritis. Primary afferent nociceptors are
back or a warm shower. not simply passive messengers of threats to tissue injury
Sensitization is of particular importance for pain and but also play an active role in tissue protection through these
tenderness in deep tissues. Viscera are normally relatively neuroeffector functions.
insensitive to noxious mechanical and thermal stimuli,
although hollow viscera do generate signicant discomfort CENTRAL MECHANISMS
when distended. In contrast, when affected by a disease
The Spinal Cord and Referred Pain
process with an inammatory component, deep structures
such as joints or hollow viscera characteristically become The axons of primary afferent nociceptors enter the spinal
exquisitely sensitive to mechanical stimulation. cord via the dorsal root. They terminate in the dorsal
A large proportion of A and C afferents innervating horn of the spinal gray matter (Fig. 5-3). The terminals
viscera are completely insensitive in normal noninjured, of primary afferent axons contact spinal neurons that
 42 Primary activation Skin

K+

PG
BK
H+
SECTION II

Viscus Anterolateral
tract axon
FIGURE 5-3
A The convergence-projection hypothesis of referred pain.
Clinical Manifestations of Neurologic Disease

According to this hypothesis, visceral afferent nociceptors con-

Secondary activation
verge on the same pain-projection neurons as the afferents
from the somatic structures in which the pain is perceived. The
brain has no way of knowing the actual source of input and
mistakenly projects the sensation to the somatic structure.

Mast cell calcitonin gene-related peptide, which produce a slower

SP SP and longer-lasting excitation of the dorsal horn neurons.
H The axon of each primary afferent contacts many spinal
neurons, and each spinal neuron receives convergent
5HT BK inputs from many primary afferents.
Platelet The convergence of sensory inputs to a single spinal
pain-transmission neuron is of great importance because
it underlies the phenomenon of referred pain. All spinal
B neurons that receive input from the viscera and deep
FIGURE 5-2
musculoskeletal structures also receive input from the
Events leading to activation, sensitization, and spread of skin. The convergence patterns are determined by the
sensitization of primary afferent nociceptor terminals. spinal segment of the dorsal root ganglion that supplies
A. Primary activation by intense pressure and consequent cell the afferent innervation of a structure. For example, the
damage. Cell damage induces lower pH (H+) and leads to afferents that supply the central diaphragm are derived
release of potassium (K+) and to synthesis of prostaglandins from the third and fourth cervical dorsal root ganglia.
(PG) and bradykinin (BK). Prostaglandins increase the sensitiv- Primary afferents with cell bodies in these same ganglia
ity of the terminal to bradykinin and other pain-producing sub- supply the skin of the shoulder and lower neck. Thus,
stances. B. Secondary activation. Impulses generated in the sensory inputs from both the shoulder skin and the cen-
stimulated terminal propagate not only to the spinal cord but tral diaphragm converge on pain-transmission neurons in
also into other terminal branches where they induce the release the third and fourth cervical spinal segments. Because of
of peptides, including substance P (SP). Substance P causes this convergence and the fact that the spinal neurons are most
vasodilation and neurogenic edema with further accumulation often activated by inputs from the skin, activity evoked in spinal
of bradykinin. Substance P also causes the release of hista- neurons by input from deep structures is mislocalized by the
mine (H) from mast cells and serotonin (5HT) from platelets. patient to a place that is roughly coextensive with the region of
skin innervated by the same spinal segment. Thus, inamma-
tion near the central diaphragm is usually reported as dis-
comfort near the shoulder. This spatial displacement of
transmit the pain signal to brain sites involved in pain
pain sensation from the site of the injury that produces it
perception.When primary afferents are activated by nox-
is known as referred pain.
ious stimuli, they release neurotransmitters from their
terminals that excite the spinal cord neurons.The major
Ascending Pathways for Pain
neurotransmitter they release is glutamate, which rapidly
excites dorsal horn neurons. Primary afferent nociceptor A majority of spinal neurons contacted by primary
terminals also release peptides, including substance P and afferent nociceptors send their axons to the contralateral
 dimension of pain. This affective dimension of pain pro- 43
F duces suffering and exerts potent control of behavior.
C Because of this dimension, fear is a constant companion
of pain.
SS
Thalamus PAIN MODULATION
Hypothalamus
The pain produced by injuries of similar magnitude is
remarkably variable in different situations and in differ-
ent individuals. For example, athletes have been known

CHAPTER 5
Midbrain to sustain serious fractures with only minor pain, and
Spinothalamic
Beechers classic World War II survey revealed that many
tract soldiers in battle were unbothered by injuries that would
Medulla have produced agonizing pain in civilian patients. Fur-
thermore, even the suggestion of relief can have a signi-
Injury cant analgesic effect (placebo). On the other hand, many

Pain: Pathophysiology and Management

patients nd even minor injuries (such as venipuncture)
frightening and unbearable, and the expectation of pain
has been demonstrated to induce pain without a noxious
stimulus.
Spinal The powerful effect of expectation and other psycho-
cord
A B
logical variables on the perceived intensity of pain implies
FIGURE 5-4 the existence of brain circuits that can modulate the
Pain transmission and modulatory pathways. A. Transmis- activity of the pain-transmission pathways. One of these
sion system for nociceptive messages. Noxious stimuli acti- circuits has links in the hypothalamus, midbrain, and
vate the sensitive peripheral ending of the primary afferent medulla, and it selectively controls spinal pain-transmis-
nociceptor by the process of transduction. The message is sion neurons through a descending pathway (Fig. 5-4).
then transmitted over the peripheral nerve to the spinal cord, Human brain imaging studies have implicated this
where it synapses with cells of origin of the major ascending pain-modulating circuit in the pain-relieving effect of
pain pathway, the spinothalamic tract. The message is relayed attention, suggestion, and opioid analgesic medications.
in the thalamus to the anterior cingulate (C), frontal insular (F), Furthermore, each of the component structures of the
and somatosensory cortex (SS). B. Pain-modulation network. pathway contains opioid receptors and is sensitive to
Inputs from frontal cortex and hypothalamus activate cells in the direct application of opioid drugs. In animals,
the midbrain that control spinal pain-transmission cells via lesions of the system reduce the analgesic effect of sys-
cells in the medulla. temically administered opioids such as morphine. Along
with the opioid receptor, the component nuclei of this
pain-modulating circuit contain endogenous opioid
thalamus.These axons form the contralateral spinothala- peptides such as the enkephalins and -endorphin.
mic tract, which lies in the anterolateral white matter of The most reliable way to activate this endogenous
the spinal cord, the lateral edge of the medulla, and the opioid-mediated modulating system is by prolonged pain
lateral pons and midbrain. The spinothalamic pathway is and/or fear.There is evidence that pain-relieving endoge-
crucial for pain sensation in humans. Interruption of this nous opioids are released following surgical procedures
pathway produces permanent decits in pain and tem- and in patients given a placebo for pain relief.
perature discrimination. Pain-modulating circuits can enhance as well as suppress
Spinothalamic tract axons ascend to several regions of pain. Both pain-inhibiting and pain-facilitating neurons in
the thalamus.There is tremendous divergence of the pain the medulla project to and control spinal pain-transmission
signal from these thalamic sites to broad areas of the neurons. Since pain-transmission neurons can be activated
cerebral cortex that subserve different aspects of the pain by modulatory neurons, it is theoretically possible to gener-
experience (Fig. 5-4). One of the thalamic projections is ate a pain signal with no peripheral noxious stimulus. In
to the somatosensory cortex. This projection mediates fact, human functional imaging studies have demonstrated
the purely sensory aspects of pain, i.e., its location, inten- increased activity in this circuit during migraine headache.
sity, and quality. Other thalamic neurons project to corti- A central circuit that facilitates pain could account for the
cal regions that are linked to emotional responses, such as nding that pain can be induced by suggestion or
the cingulate gyrus and other areas of the frontal lobes, enhanced by expectation, and it could provide a framework
including the insular cortex.These pathways to the frontal for understanding how psychological factors can contribute
cortex subserve the affective or unpleasant emotional to chronic pain.
 44 NEUROPATHIC PAIN rapidly relieved by blocking the sympathetic nervous sys-
tem. This implies that sympathetic activity can activate
Lesions of the peripheral or central nervous pathways for
undamaged nociceptors when inammation is present.
pain typically result in a loss or impairment of pain sen-
Signs of sympathetic hyperactivity should be sought in
sation. Paradoxically, damage to or dysfunction of these
patients with posttraumatic pain and inammation and
pathways can produce pain. For example, damage to
no other obvious explanation.
peripheral nerves, as occurs in diabetic neuropathy, or to
primary afferents, as in herpes zoster, can result in pain
that is referred to the body region innervated by the
damaged nerves.Though rare, pain may also be produced Treatment :
SECTION II

by damage to the central nervous system, particularly the ACUTE PAIN

spinothalamic pathway or thalamus. Such neuropathic The ideal treatment for any pain is to remove the cause;
pains are often severe and are notoriously intractable to thus, diagnosis should always precede treatment plan-
standard treatments for pain. ning. Sometimes treating the underlying condition does
Neuropathic pains typically have an unusual burning, not immediately relieve pain. Furthermore, some condi-
tingling, or electric shocklike quality and may be trig- tions are so painful that rapid and effective analgesia is
Clinical Manifestations of Neurologic Disease

gered by very light touch.These features are rare in other essential (e.g., the postoperative state, burns, trauma,
types of pain. On examination, a sensory decit is char- cancer, sickle cell crisis). Analgesic medications are a rst
acteristically present in the area of the patients pain. line of treatment in these cases, and all practitioners
Hyperpathia is also characteristic of neuropathic pain; should be familiar with their use.
patients often complain that the very lightest moving
stimuli evoke exquisite pain (allodynia). In this regard it ASPIRIN, ACETAMINOPHEN, AND NONS-
is of clinical interest that a topical preparation of 5% TEROIDAL ANTI-INFLAMMATORY AGENTS
lidocaine in patch form is effective for patients with pos- (NSAIDS) These drugs are considered together
therpetic neuralgia who have prominent allodynia. because they are used for similar problems and may have
A variety of mechanisms contribute to neuropathic pain. a similar mechanism of action (Table 5-1). All these com-
As with sensitized primary afferent nociceptors, damaged pounds inhibit cyclooxygenase (COX), and, except for
primary afferents, including nociceptors, become highly acetaminophen, all have anti-inammatory actions, espe-
sensitive to mechanical stimulation and begin to generate cially at higher dosages. They are particularly effective for
impulses in the absence of stimulation.There is evidence mild to moderate headache and for pain of muscu-
that this increased sensitivity and spontaneous activity is loskeletal origin.
due to an increased concentration of sodium channels. Since they are effective for these common types of
Damaged primary afferents may also develop sensitivity to pain and are available without prescription, COX
norepinephrine. Interestingly, spinal cord pain-transmission inhibitors are by far the most commonly used analgesics.
neurons cut off from their normal input may also become They are absorbed well from the gastrointestinal tract
spontaneously active.Thus, both central and peripheral ner- and, with occasional use, have only minimal side effects.
vous system hyperactivity contribute to neuropathic pain. With chronic use, gastric irritation is a common side
effect of aspirin and NSAIDs and is the problem that
most frequently limits the dose that can be given. Gastric
Sympathetically Maintained Pain irritation is most severe with aspirin, which may cause
erosion and ulceration of the gastric mucosa leading to
Patients with peripheral nerve injury can develop a
bleeding or perforation. Because aspirin irreversibly
severe burning pain (causalgia) in the region innervated
acetylates platelets and thereby interferes with coagula-
by the nerve. The pain typically begins after a delay of
tion of the blood, gastrointestinal bleeding is a particular
hours to days or even weeks.The pain is accompanied by
risk. Increased age and history of gastrointestinal disease
swelling of the extremity, periarticular osteoporosis, and
increase the risks of aspirin and NSAIDs. In addition to
arthritic changes in the distal joints.The pain is dramati-
NSAIDs well-known gastrointestinal toxicity, nephrotoxi-
cally and immediately relieved by blocking the sympa-
city is a signicant problem for patients using them on a
thetic innervation of the affected extremity. Damaged
chronic basis, and patients at risk for renal insufciency
primary afferent nociceptors acquire adrenergic sensitiv-
should be monitored closely. NSAIDs also cause an
ity and can be activated by stimulation of the sympa-
increase in blood pressure in a signicant number of
thetic outow.A similar syndrome called reex sympathetic
individuals. Long-term treatment with NSAIDs requires
dystrophy can be produced without obvious nerve dam-
regular blood pressure monitoring and treatment if nec-
age by a variety of injuries, including fractures of bone,
essary. Although toxic to the liver when taken in a high
soft tissue trauma, myocardial infarction, and stroke.
dose, acetaminophen rarely produces gastric irritation
Although the pathophysiology of this condition is poorly
and does not interfere with platelet function.
understood, the pain and the signs of inammation are
TABLE 5-1 45
DRUGS FOR RELIEF OF PAIN

GENERIC NAME DOSE, mg INTERVAL COMMENTS

Nonnarcotic Analgesics: Usual Doses and Intervals

Acetylsalicylic acid 650 PO q4h Enteric-coated preparations available
Acetaminophen 650 PO q4h Side effects uncommon
Ibuprofen 400 PO q 46 h Available without prescription
Naproxen 250500 PO q 12 h Delayed effects may be due to long half-life
Fenoprofen 200 PO q 46 h Contraindicated in renal disease

CHAPTER 5
Indomethacin 2550 PO q8h Gastrointestinal side effects common
Ketorolac 1560 IM/IV q 46 h Available for parenteral use
Celecoxib 100200 PO q 1224 h Useful for arthritis
Valdecoxib 1020 PO q 1224 h Removed from U.S. market in 2005

GENERIC NAME PARENTERAL DOSE, mg PO DOSE, mg COMMENTS

Narcotic Analgesics: Usual Doses and Intervals

Pain: Pathophysiology and Management

Codeine 3060 q 4 h 3060 q 4 h Nausea common
Oxycodone 510 q 46 h Usually available with acetaminophen or aspirin
Morphine 10 q 4 h 60 q 4 h
Morphine sustained 30200 bid Oral slow-release preparation
release to tid
Hydromorphone 12 q 4 h 24 q 4 h Shorter acting than morphine sulfate
Levorphanol 2 q 68 h 4 q 68 h Longer acting than morphine sulfate; absorbed well PO
Methadone 10 q 68 h 20 q 68 h Delayed sedation due to long half-life
Meperidine 75100 q 34 h 300 q 4 h Poorly absorbed PO; normeperidine a toxic metabolite
Butorphanol 12 q 4 h Intranasal spray
Fentanyl 25100 g/h 72-h Transdermal patch
Tramadol 50100 q 46 h Mixed opioid/adrenergic action

UPTAKE BLOCKADE
SEDATIVE ANTICHOLINERGIC ORTHOSTATIC CARDIAC AVE. DOSE, RANGE,
GENERIC NAME 5-HT NE POTENCY POTENCY HYPOTENSION ARRHYTHMIA mg/d mg/d

Antidepressantsa
Doxepin ++ + High Moderate Moderate Less 200 75400
Amitriptyline ++++ ++ High Highest Moderate Yes 150 25300
Imipramine ++++ ++ Moderate Moderate High Yes 200 75400
Nortriptyline +++ ++ Moderate Moderate Low Yes 100 40150
Desipramine +++ ++++ Low Low Low Yes 150 50300
Venlafaxine +++ ++ Low None None No 150 75400
Duloxetine +++ +++ Low None None No 40 3060

GENERIC NAME PO DOSE, mg INTERVAL GENERIC NAME PO DOSE, mg INTERVAL

a
Anticonvulsants and Antiarrhythmics
Phenytoin 300 daily/qhs Clonazepam 1 q6h
Carbamazepine 200300 q6h Gabapentinb 6001200 q8h
Oxcarbazepine 300 bid Pregabalin 150600 bid

a
Antidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treat-
ment of pain.
b
Gabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia.
Note: 5-HT, serotonin; NE, norepinephrine.

The introduction of a parenteral form of NSAID, There are two major classes of COX: COX-1 is constitu-
ketorolac, extends the usefulness of this class of com- tively expressed, and COX-2 is induced in the inamma-
pounds in the management of acute severe pain. tory state. COX-2selective drugs have moderate anal-
Ketorolac is sufciently potent and rapid in onset to gesic potency and produce less gastric irritation than
supplant opioids for many patients with acute severe the nonselective COX inhibitors. It is not yet clear
headache and musculoskeletal pain. whether the use of COX-2selective drugs is associated
 46 with a lower risk of nephrotoxicity compared to nonse- side effects. Because of this, initiation of therapy requires
lective NSAIDs. On the other hand, COX-2selective titration to optimal dose and interval. The most impor-
drugs offer a signicant benet in the management of tant principle is to provide adequate pain relief. This
acute postoperative pain because they do not affect requires determining whether the drug has adequately
blood coagulation. This is a situation in which the nonse- relieved the pain and the duration of the relief. The
lective COX inhibitors would be contraindicated because most common error made by physicians in manag-
they impair platelet-mediated blood clotting and are ing severe pain with opioids is to prescribe an inade-
thus associated with increased bleeding at the operative quate dose. Since many patients are reluctant to
site. COX-2 inhibitors, including celecoxib (Celebrex), and complain, this practice leads to needless suffering. In
SECTION II

valdecoxib (Bextra), are associated with increased cardio- the absence of sedation at the expected time of peak
vascular risk. It is possible that this is a class effect of effect, a physician should not hesitate to repeat the ini-
NSAIDs, excluding aspirin. These drugs are contraindi- tial dose to achieve satisfactory pain relief.
cated in patients in the immediate period after coronary An innovative approach to the problem of achieving
artery bypass surgery and should be used with caution adequate pain relief is the use of patient-controlled anal-
in patients having a history of or signicant risk factors gesia (PCA). PCA requires a device that can deliver a base-
Clinical Manifestations of Neurologic Disease

for cardiovascular disease. line continuous dose of an opioid drug, as well as prepro-
grammed additional doses whenever the patient pushes
OPIOID ANALGESICS Opioids are the most a button. The patient can then titrate the dose to the
potent pain-relieving drugs currently available. Further- optimal level. This approach is used most extensively for
more, of all analgesics, they have the broadest range of the management of postoperative pain, but there is no
efcacy, providing the most reliable and effective reason why it should not be used for any hospitalized
method for rapid pain relief. Although side effects are patient with persistent severe pain. PCA is also used for
common, they are usually not serious except for respi- short-term home care of patients with intractable pain,
ratory depression and can be reversed rapidly with the such as that caused by metastatic cancer.
narcotic antagonist naloxone. The physician should not Because of patient variability in analgesia requirement,
hesitate to use opioid analgesics in patients with acute intravenous PCA is generally begun after the patients
severe pain. Table 5-1 lists the most commonly used pain has been controlled. The bolus dose of the drug
opioid analgesics. (typically 1 mg morphine or 40 g fentanyl) can then be
Opioids produce analgesia by actions in the central delivered repeatedly as needed. To prevent overdosing,
nervous system. They activate pain-inhibitory neurons PCA devices are programmed with a lockout period after
and directly inhibit pain-transmission neurons. Most of each demand dose is delivered (510 min) and a limit on
the commercially available opioid analgesics act at the the total dose delivered per hour.While some have advo-
same opioid receptor (-receptor), differing mainly in cated the use of a simultaneous background infusion of
potency, speed of onset, duration of action, and optimal the PCA drug, this increases the risk of respiratory
route of administration. Although the dose-related side depression and has not been shown to increase the
effects (sedation, respiratory depression, pruritus, con- overall efcacy of the technique.
stipation) are similar among the different opioids, some Many physicians, nurses, and patients have a certain
side effects are due to accumulation of nonopioid trepidation about using opioids that is based on an
metabolites that are unique to individual drugs. One exaggerated fear of addiction. In fact, there is a vanish-
striking example of this is normeperidine, a metabolite ingly small chance of patients becoming addicted to
of meperidine. Normeperidine produces hyperexcitabil- narcotics as a result of their appropriate medical use.
ity and seizures that are not reversible with naloxone. The availability of new routes of administration has
Normeperidine accumulation is increased in patients extended the usefulness of opioid analgesics. Most
with renal failure. important is the availability of spinal administration.
The most rapid relief with opioids is obtained by Opioids can be infused through a spinal catheter placed
intravenous administration; relief with oral administra- either intrathecally or epidurally. By applying opioids
tion is signicantly slower. Common side effects include directly to the spinal cord, regional analgesia can be
nausea, vomiting, constipation, and sedation. The most obtained using a relatively low total dose. In this way,
serious side effect is respiratory depression. Patients with such side effects as sedation, nausea, and respiratory
any form of respiratory compromise must be kept under depression can be minimized. This approach has been
close observation following opioid administration; an used extensively in obstetric procedures and for lower-
oxygen saturation monitor may be useful. The opioid body postoperative pain. Opioids can also be given
antagonist naloxone should be readily available. Opioid intranasally (butorphanol), rectally, and transdermally
effects are dose-related, and there is great variability (fentanyl), thus avoiding the discomfort of frequent
among patients in the doses that relieve pain and produce injections in patients who cannot be given oral medication.
 The fentanyl transdermal patch has the advantage of physical or sexual abuse; and past or present substance 47
providing fairly steady plasma levels, which maximizes abuse.
patient comfort. On examination, special attention should be paid to
whether the patient guards the painful area and whether
OPIOID AND COX INHIBITOR COMBINA- certain movements or postures are avoided because of pain.
TIONS When used in combination, opioids and COX Discovering a mechanical component to the pain can be
inhibitors have additive effects. Because a lower dose of useful both diagnostically and therapeutically. Painful areas
each can be used to achieve the same degree of pain should be examined for deep tenderness, noting whether
relief, and their side effects are nonadditive, such combi- this is localized to muscle, ligamentous structures, or

CHAPTER 5
nations can be used to lower the severity of dose- joints. Chronic myofascial pain is very common, and in
related side effects. Fixed-ratio combinations of an opi- these patients deep palpation may reveal highly localized
oid with acetaminophen carry a special risk. Dose trigger points that are rm bands or knots in muscle.
escalation as a result of increased severity of pain or Relief of the pain following injection of local anesthetic
decreased opioid effect as a result of tolerance may lead into these trigger points supports the diagnosis. A neuro-
to levels of acetaminophen that are toxic to the liver. pathic component to the pain is indicated by evidence of
nerve damage, such as sensory impairment, exquisitely sen-

Pain: Pathophysiology and Management

sitive skin, weakness and muscle atrophy, or loss of deep
tendon reexes. Evidence suggesting sympathetic nervous
system involvement includes the presence of diffuse swelling,
CHRONIC PAIN changes in skin color and temperature, and hypersensitive
skin and joint tenderness compared with the normal side.
Managing patients with chronic pain is intellectually and Relief of the pain with a sympathetic block is diagnostic.
emotionally challenging. The patients problem is often A guiding principle in evaluating patients with chronic
difcult to diagnose; such patients are demanding of the pain is to assess both emotional and organic factors before
physicians time and often appear emotionally distraught. initiating therapy. Addressing these issues together, rather
The traditional medical approach of seeking an obscure than waiting to address emotional issues after organic
organic pathology is usually unhelpful. On the other hand, causes of pain have been ruled out, improves compliance in
psychological evaluation and behaviorally based treatment part because it assures patients that a psychological evalua-
paradigms are frequently helpful, particularly in the setting tion does not mean that the physician is questioning the
of a multidisciplinary pain-management center. validity of their complaint. Even when an organic cause for
There are several factors that can cause, perpetuate, or a patients pain can be found, it is still wise to look for other
exacerbate chronic pain. First, of course, the patient may factors. For example, a cancer patient with painful bony
simply have a disease that is characteristically painful for metastases may have additional pain due to nerve damage
which there is presently no cure. Arthritis, cancer, migraine and may also be depressed. Optimal therapy requires that
headaches, bromyalgia, and diabetic neuropathy are exam- each of these factors be looked for and treated.
ples of this. Second, there may be secondary perpetuating
factors that are initiated by disease and persist after that
disease has resolved. Examples include damaged sensory
nerves, sympathetic efferent activity, and painful reex mus- Treatment:
cle contraction. Finally, a variety of psychological condi- CHRONIC PAIN
tions can exacerbate or even cause pain.
Once the evaluation process has been completed and
There are certain areas to which special attention should
the likely causative and exacerbating factors identied,
be paid in the medical history. Because depression is the
an explicit treatment plan should be developed. An
most common emotional disturbance in patients with chronic
important part of this process is to identify specic and
pain, patients should be questioned about their mood,
realistic functional goals for therapy, such as getting a
appetite, sleep patterns, and daily activity.A simple standard-
good nights sleep, being able to go shopping, or return-
ized questionnaire, such as the Beck Depression Inventory,
ing to work. A multidisciplinary approach that utilizes
can be a useful screening device. It is important to remember
medications, counseling, physical therapy, nerve blocks,
that major depression is a common, treatable, and poten-
and even surgery may be required to improve the
tially fatal illness.
patients quality of life. There are also some newer, rela-
Other clues that a signicant emotional disturbance is
tively invasive procedures that can be helpful for some
contributing to a patients chronic pain complaint include:
patients with intractable pain. These procedures include
pain that occurs in multiple unrelated sites; a pattern of
implanting intraspinal cannulae to deliver morphine or
recurrent, but separate, pain problems beginning in child-
intraspinal electrodes for spinal stimulation. There are
hood or adolescence; pain beginning at a time of emotional
no set criteria for predicting which patients will respond
trauma, such as the loss of a parent or spouse; a history of
 48 to these procedures. They are generally reserved for that block both serotonin and norepinephrine reuptake,
patients who have not responded to conventional phar- appear to retain most of the pain-relieving effect of
macologic approaches. Referral to a multidisciplinary TCAs with a side-effect prole more like that of the sero-
pain clinic for a full evaluation should precede any inva- tonin-selective reuptake inhibitors. These drugs may be
sive procedures. Such referrals are clearly not necessary particularly useful in patients who cannot tolerate the
for all chronic pain patients. For some, pharmacologic side effects of tricyclics.
management alone can provide adequate relief.
ANTICONVULSANTS AND ANTIARRHYTH-
ANTIDEPRESSANT MEDICATIONS The tricyclic
MICS These drugs are useful primarily for patients
anti- depressants [amitriptyline, imipramine, nortripty-
SECTION II

with neuropathic pain. Phenytoin (Dilantin) and carba-

line, desipramine (TCAs; Table 5-1)] are extremely useful
mazepine (Tegretol) were rst shown to relieve the pain
for the management of patients with chronic pain.
of trigeminal neuralgia. This pain has a characteristic
Although developed for the treatment of depression, the
brief, shooting, electric shocklike quality. In fact, anti-
tricyclics have a spectrum of dose-related biologic activi-
convulsants seem to be helpful largely for pains that
ties that include the production of analgesia in a variety
have such a lancinating quality. Newer anticonvulsants,
of clinical conditions. Although the mechanism is
gabapentin (Neurontin) and pregabalin (Lyrica), are
Clinical Manifestations of Neurologic Disease

unknown, the analgesic effect of TCAs has a more rapid

effective for a broad range of neuropathic pains.
onset and occurs at a lower dose than is typically
Antiarrhythmic drugs such as low-dose lidocaine and
required for the treatment of depression. Furthermore,
mexiletine (Mexitil) can also be effective for neuropathic
patients with chronic pain who are not depressed obtain
pain. These drugs block the spontaneous activity of
pain relief with antidepressants. There is evidence that
damaged primary afferent nociceptors.
tricyclic drugs potentiate opioid analgesia, so they may
be useful adjuncts for the treatment of severe persistent CHRONIC OPIOID MEDICATION The long-
pain such as occurs with malignant tumors. Table 5-2 term use of opioids is accepted for patients with pain
lists some of the painful conditions that respond to tri- due to malignant disease. Although opioid use for
cyclics. TCAs are of particular value in the management chronic pain of nonmalignant origin is controversial, it is
of neuropathic pain such as occurs in diabetic neuropa- clear that for many such patients opioid analgesics are
thy and postherpetic neuralgia, for which there are few the best available option. This is understandable since
other therapeutic options. opioids are the most potent and have the broadest
The TCAs that have been shown to relieve pain have range of efcacy of any analgesic medications.
signicant side effects (Table 5-1; Chap. 49). Some of Although addiction is rare in patients who rst use opi-
these side effects, such as orthostatic hypotension, oids for pain relief, some degree of tolerance and physi-
drowsiness, cardiac conduction delay, memory impair- cal dependence are likely with long-term use. Therefore,
ment, constipation, and urinary retention, are particu- before embarking on opioid therapy, other options
larly problematic in elderly patients, and several are should be explored, and the limitations and risks of opi-
additive to the side effects of opioid analgesics. The oids should be explained to the patient. It is also impor-
serotonin-selective reuptake inhibitors such as uoxe- tant to point out that some opioid analgesic medica-
tine (Prozac) have fewer and less serious side effects tions have mixed agonist-antagonist properties (e.g.,
than TCAs, but they are much less effective for relieving pentazocine and butorphanol). From a practical stand-
pain. It is of interest that venlafaxine (Effexor) and dulox- point, this means that they may worsen pain by induc-
etine (Cymbalta), which are nontricyclic antidepressants ing an abstinence syndrome in patients who are physi-
cally dependent on other opioid analgesics.
With long-term outpatient use of orally administered
TABLE 5-2 opioids, it is desirable to use long-acting compounds such
PAINFUL CONDITIONS THAT RESPOND TO as levorphanol, methadone, or sustained-release mor-
TRICYCLIC ANTIDEPRESSANTS phine (Table 5-1). Transdermal fentanyl is another excel-
lent option. The pharmacokinetic prole of these drug
Postherpetic neuralgiaa
Diabetic neuropathya preparations enables prolonged pain relief, minimizes
Tension headachea side effects such as sedation that are associated with high
Migraine headachea peak plasma levels, and reduces the likelihood of rebound
Rheumatoid arthritisa,b pain associated with a rapid fall in plasma opioid concen-
Chronic low back painb tration. Constipation is a virtually universal side effect of
Cancer
opioid use and should be treated expectantly.
Central post-stroke pain

a
TREATMENT OF NEUROPATHIC PAIN It is
Controlled trials demonstrate analgesia.
b
Controlled studies indicate benet but not analgesia.
important to individualize treatment for patients with
neuropathic pain. Several general principles should dependence. Drugs of different classes can be used in 49
guide therapy: the rst is to move quickly to provide combination to optimize pain control.
relief; a second is to minimize drug side effects. For It is worth emphasizing that many patients, espe-
example, in patients with postherpetic neuralgia and cially those with chronic pain, seek medical attention
signicant cutaneous hypersensitivity, topical lidocaine primarily because they are suffering and because only
(Lidoderm patches) can provide immediate relief with- physicians can provide the medications required for
out side effects. Anticonvulsants (gabapentin or prega- pain relief. A primary responsibility of all physicians is to
balin, see earlier) or antidepressants can be used as rst- minimize the physical and emotional discomfort of their
line drugs for patients with neuropathic pain. patients. Familiarity with pain mechanisms and anal-

CHAPTER 5
Antiarrhythmic drugs such as lidocaine and mexiletene gesic medications is an important step toward accom-
can be effective (see earlier). There is no consensus on plishing this aim.
which class of drug should be used as a rst-line treat-
ment for any chronically painful condition. However,
because relatively high doses of anticonvulsants are
required for pain relief, sedation is very common. Seda- FURTHER READINGS

Pain: Pathophysiology and Management

tion is also a problem with the tricyclic antidepressants
but is much less of a problem with serotonin/norepi- CRAIG AD: How do you feel? Interoception: The sense of the
physiological condition of the body. Nat Rev Neurosci 8:655,
nephrine reuptake inhibitors (SNRIs, e.g., venlafaxine
2002
and duloxetine). Thus, in the elderly or in those patients FIELDS HL: Should we be reluctant to prescribe opioids for chronic
whose daily activities require high-level mental activity, nonmalignant pain? Pain 129:233, 2007
these drugs should be considered as the rst line. In KELTNER JR et al: Isolating the modulatory effect of expectation on
contrast, opioid medications should be used as a second- pain transmission: A functional magnetic resonance imaging
or third-line drug class. While highly effective for many study. J Neurosci 26:4437, 2006
painful conditions, opioids are sedating, and their effect MACINTYRE PE: Safety and efcacy of patient-controlled analgesia.
Br J Anaesth 87:36, 2001
tends to lessen over time, leading to dose escalation
WAGER TD et al: Placebo-induced changes in FMRI in the anticipa-
and, occasionally, a worsening of pain due to physical tion and experience of pain. Science 303:1162, 2004
 CHAPTER 6

HEADACHE

Peter J. Goadsby I Neil H. Raskin

I General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 I Primary Headache Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 52

Anatomy and Physiology of Headache . . . . . . . . . . . . . . . . . . 50 Migraine Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Clinical Evaluation of Acute, New-Onset Headache . . . . . . . . . 51 Tension-Type Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
I Secondary Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Trigeminal Autonomic Cephalalgias, Including Cluster
Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Chronic Daily Headache . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Brain Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Other Primary Headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Temporal Arteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Headache is among the most common reasons that patients other factors (Chap. 5). In such situations, pain perception
seek medical attention. Diagnosis and management is based is a normal physiologic response mediated by a healthy
on a careful clinical approach that is augmented by an nervous system. Pain can also result when pain-producing
understanding of the anatomy, physiology, and pharma- pathways of the peripheral or central nervous system
cology of the nervous system pathways that mediate the (CNS) are damaged or activated inappropriately. Headache
various headache syndromes. may originate from either or both mechanisms. Relatively
few cranial structures are pain-producing; these include
the scalp, middle meningeal artery, dural sinuses, falx cere-
GENERAL PRINCIPLES bri, and proximal segments of the large pial arteries. The
A classication system developed by the International ventricular ependyma, choroid plexus, pial veins, and
Headache Society characterizes headache as primary or much of the brain parenchyma are not pain-producing.
secondary (Table 6-1). Primary headaches are those in The key structures involved in primary headache appear
which headache and its associated features are the disor- to be
der in itself, whereas secondary headaches are those caused
by exogenous disorders. Primary headache often results the large intracranial vessels and dura mater
in considerable disability and a decrease in the patients the peripheral terminals of the trigeminal nerve that
quality of life. Mild secondary headache, such as that innervate these structures
seen in association with upper respiratory tract infec- the caudal portion of the trigeminal nucleus, which extends
tions, is common but rarely worrisome. Life-threatening into the dorsal horns of the upper cervical spinal cord and
headache is relatively uncommon, but vigilance is required receives input from the rst and second cervical nerve roots
in order to recognize and appropriately treat patients with (the trigeminocervical complex)
this category of head pain. the pain modulatory systems in the brain that receive
input from trigeminal nociceptors
ANATOMY AND PHYSIOLOGY OF HEADACHE
The innervation of the large intracranial vessels and
Pain usually occurs when peripheral nociceptors are stim- dura mater by the trigeminal nerve is known as the trigemi-
ulated in response to tissue injury, visceral distension, or novascular system. Autonomic symptoms, such as lacrimation
50
TABLE 6-1 TABLE 6-2 51
COMMON CAUSES OF HEADACHE HEADACHE SYMPTOMS THAT SUGGEST A SERIOUS
UNDERLYING DISORDER
PRIMARY HEADACHE SECONDARY HEADACHE
Worst headache ever
TYPE % TYPE % First severe headache
Subacute worsening over days or weeks
Migraine 16 Systemic infection 63
Abnormal neurologic examination
Tension-type 69 Head injury 4
Fever or unexplained systemic signs
Cluster 0.1 Vascular disorders 1
Vomiting that precedes headache
Idiopathic 2 Subarachnoid <1
Pain induced by bending, lifting, cough

CHAPTER 6
stabbing hemorrhage
Pain that disturbs sleep or presents immediately upon
Exertional 1 Brain tumor 0.1
awakening
Known systemic illness
Source: After J Olesen et al: The Headaches. Philadelphia, Lippincott, Onset after age 55
Williams & Wilkins, 2005. Pain associated with local tenderness, e.g., region of
temporal artery

Headache
and nasal congestion, are prominent in the trigeminal auto-
nomic cephalalgias, including cluster headache and parox-
ysmal hemicrania, and may also be seen in migraine.These
autonomic symptoms reect activation of cranial parasym- The psychological state of the patient should also be
pathetic pathways, and functional imaging studies indicate evaluated since a relationship exists between head pain
that vascular changes in migraine and cluster headache, and depression. Many patients in chronic daily pain cycles
when present, are similarly driven by these cranial auto- become depressed, although depression itself is rarely a
nomic systems. Migraine and other primary headache cause of headache. Drugs with antidepressant actions are
types are not vascular headaches; these disorders do not also effective in the prophylactic treatment of both
reliably manifest vascular changes, and treatment outcomes tension-type headache and migraine.
cannot be predicted by vascular effects. Underlying recurrent headache disorders may be acti-
vated by pain that follows otologic or endodontic surgi-
CLINICAL EVALUATION OF ACUTE, cal procedures.Thus, pain about the head as the result of
NEW-ONSET HEADACHE diseased tissue or trauma may reawaken an otherwise qui-
escent migrainous syndrome. Treatment of the headache
The patient who presents with a new, severe headache is largely ineffective until the cause of the primary prob-
has a differential diagnosis that is quite different from the lem is addressed.
patient with recurrent headaches over many years. In Serious underlying conditions that are associated with
new-onset and severe headache, the probability of nd- headache are described below. Brain tumor is a rare cause
ing a potentially serious cause is considerably greater of headache and even less commonly a cause of severe
than in recurrent headache. Patients with recent onset of pain.The vast majority of patients presenting with severe
pain require prompt evaluation and often treatment. headache have a benign cause.
Serious causes to be considered include meningitis, sub-
arachnoid hemorrhage, epidural or subdural hematoma,
glaucoma, and purulent sinusitis. When worrisome SECONDARY HEADACHE
symptoms and signs are present (Table 6-2), rapid diag-
nosis and management is critical. The management of secondary headache focuses on
A complete neurologic examination is an essential rst diagnosis and treatment of the underlying condition.
step in the evaluation. In most cases, patients with an abnor-
mal examination or a history of recent-onset headache MENINGITIS
should be evaluated by a CT or MRI study. As an initial
Acute, severe headache with stiff neck and fever suggests
screening procedure for intracranial pathology in this set-
meningitis. LP is mandatory. Often there is striking accen-
ting, CT and MRI methods appear to be equally sensitive.
tuation of pain with eye movement. Meningitis can be
In some circumstances a lumbar puncture (LP) is also
easily mistaken for migraine in that the cardinal symptoms
required, unless a benign etiology can be otherwise estab-
of pounding headache, photophobia, nausea, and vomiting
lished.A general evaluation of acute headache might include
are present. Meningitis is discussed in Chaps. 35 and 36.
the investigation of cardiovascular and renal status by blood
pressure monitoring and urine examination; eyes by fun-
INTRACRANIAL HEMORRHAGE
doscopy, intraocular pressure measurement, and refraction;
cranial arteries by palpation; and cervical spine by the effect Acute, severe headache with stiff neck but without fever
of passive movement of the head and by imaging. suggests subarachnoid hemorrhage. A ruptured aneurysm,
 52 arteriovenous malformation, or intraparenchymal hem- Most patients can recognize that the origin of their head
orrhage may also present with headache alone. Rarely, if pain is supercial, external to the skull, rather than
the hemorrhage is small or below the foramen magnum, originating deep within the cranium (the pain site for
the head CT scan can be normal. Therefore, LP may be migraineurs). Scalp tenderness is present, often to a
required to denitively diagnose subarachnoid hemorrhage. marked degree; brushing the hair or resting the head on
Intraparenchymal hemorrhage is discussed in Chap. 21 and a pillow may be impossible because of pain. Headache is
subarachnoid hemorrhage in Chap. 22. usually worse at night and often aggravated by exposure
to cold. Additional ndings may include reddened, ten-
BRAIN TUMOR der nodules or red streaking of the skin overlying the
temporal arteries, and tenderness of the temporal or, less
SECTION II

Approximately 30% of patients with brain tumors consider

commonly, the occipital arteries.
headache to be their chief complaint. The head pain is
The erythrocyte sedimentation rate (ESR) is often,
usually nondescriptan intermittent deep, dull aching of
though not always, elevated; a normal ESR does not
moderate intensity, which may worsen with exertion or
exclude giant cell arteritis. A temporal artery biopsy fol-
change in position and may be associated with nausea and
lowed by treatment with prednisone 80 mg daily for the
vomiting.This pattern of symptoms results from migraine
rst 46 weeks should be initiated when clinical suspi-
Clinical Manifestations of Neurologic Disease

far more often than from brain tumor. The headache of

cion is high. The prevalence of migraine among the
brain tumor disturbs sleep in about 10% of patients.Vomit-
ing that precedes the appearance of headache by weeks is elderly is substantial, considerably higher than that of
highly characteristic of posterior fossa brain tumors. A his- giant cell arteritis. Migraineurs often report amelioration
tory of amenorrhea or galactorrhea should lead one to of their headaches with prednisone; thus, caution must
question whether a prolactin-secreting pituitary adenoma be used when interpreting the therapeutic response.
(or the polycystic ovary syndrome) is the source of
headache. Headache arising de novo in a patient with GLAUCOMA
known malignancy suggests either cerebral metastases or Glaucoma may present with a prostrating headache asso-
carcinomatous meningitis, or both. Head pain appearing ciated with nausea and vomiting. The headache often
abruptly after bending, lifting, or coughing can be due to a starts with severe eye pain. On physical examination, the
posterior fossa mass (or a Chiari malformation). Brain eye is often red with a xed, moderately dilated pupil.
tumors are discussed in Chap. 32. Glaucoma is discussed in Chap. 17.
TEMPORAL ARTERITIS
PRIMARY HEADACHE SYNDROMES
Temporal (giant cell) arteritis is an inammatory disorder
of arteries that frequently involves the extracranial carotid Primary headaches are disorders in which headache and
circulation. It is a common disorder of the elderly; its annual associated features occur in the absence of any exoge-
incidence is 77 per 100,000 individuals aged 50 years and nous cause (Table 6-1).The most common are migraine,
older. The average age of onset is 70 years, and women tension-type headache, and cluster headache.
account for 65% of cases. About half of patients with
untreated temporal arteritis develop blindness due to
MIGRAINE HEADACHE
involvement of the ophthalmic artery and its branches;
indeed, the ischemic optic neuropathy induced by giant Migraine, the second most common cause of headache,
cell arteritis is the major cause of rapidly developing bilat- aficts approximately 15% of women and 6% of men. It
eral blindness in patients >60 years. Because treatment is usually an episodic headache that is associated with
with glucocorticoids is effective in preventing this com- certain features such as sensitivity to light, sound, or
plication, prompt recognition of the disorder is important. movement; nausea and vomiting often accompany the
Typical presenting symptoms include headache, poly- headache. A useful description of migraine is a benign
myalgia rheumatica, jaw claudication, fever, and weight and recurring syndrome of headache associated with
loss. Headache is the dominant symptom and often other symptoms of neurologic dysfunction in varying
appears in association with malaise and muscle aches. admixtures (Table 6-3). Migraine can often be recog-
Head pain may be unilateral or bilateral and is located nized by its activators, referred to as triggers.
temporally in 50% of patients but may involve any and The brain of the migraineur is particularly sensitive
all aspects of the cranium. Pain usually appears gradually to environmental and sensory stimuli; migraine-prone
over a few hours before peak intensity is reached; occa- patients do not habituate easily to sensory stimuli. This
sionally, it is explosive in onset. The quality of pain is sensitivity is amplied in females during the menstrual
only seldom throbbing; it is almost invariably described cycle. Headache can be initiated or amplied by various
as dull and boring, with superimposed episodic stabbing triggers, including glare, bright lights, sounds, or other
pains similar to the sharp pains that appear in migraine. afferent stimulation; hunger; excess stress; physical
TABLE 6-3 be useful in management strategies involving lifestyle 53
SYMPTOMS ACCOMPANYING SEVERE MIGRAINE adjustments.
ATTACKS IN 500 PATIENTS

SYMPTOM PATIENTS AFFECTED, % Pathogenesis

Nausea 87 The sensory sensitivity that is characteristic of migraine
Photophobia 82 is probably due to dysfunction of monoaminergic sen-
Lightheadedness 72 sory control systems located in the brainstem and thala-
Scalp tenderness 65 mus (Fig. 6-1).
Vomiting 56 Activation of cells in the trigeminal nucleus results in

CHAPTER 6
Visual disturbances 36
Photopsia 26
the release of vasoactive neuropeptides, particularly cal-
Fortication spectra 10 citonin gene-related peptide (CGRP), at vascular termi-
Paresthesias 33 nations of the trigeminal nerve. Recently, antagonists of
Vertigo 33 CGRP have shown some early promise in the therapy
Alteration of consciousness 18 of migraine. Centrally, the second-order trigeminal neu-
Syncope 10 rons cross the midline and project to ventrobasal and

Headache
Seizure 4 posterior nuclei of the thalamus for further processing.
Confusional state 4
Additionally, there are projections to the periaqueductal
Diarrhea 16
gray and hypothalamus, from which reciprocal descending
systems have established anti-nociceptive effects. Other
Source: From NH Raskin, Headache, 2d ed. New York, Churchill
Livingston, 1988; with permission. brainstem regions likely to be involved in descending
modulation of trigeminal pain include the nucleus locus
coeruleus in the pons and the rostroventromedial medulla.
exertion; stormy weather or barometric pressure changes; Pharmacologic and other data point to the involvement
hormonal uctuations during menses; lack of or excess of the neurotransmitter 5-hydroxytryptamine (5-HT; also
sleep; and alcohol or other chemical stimulation. Knowl- known as serotonin) in migraine. Approximately 50 years
edge of a patients susceptibility to specic triggers can ago, methysergide was found to antagonize certain peripheral

Cortex
Thalamus

Hypothalamus Dorsal raphe

nucleus

Locus
Dura coeruleus
Superior
salivatory nucleus

Magnus raphe
nucleus

Trigeminal
ganglion

Pterygopalatine
ganglion

FIGURE 6-1
Brainstem pathways that modulate sensory input. The project in the quintothalamic tract and, after decussating in
key pathway for pain in migraine is the trigeminovascular the brainstem, synapse on neurons in the thalamus. Impor-
input from the meningeal vessels, which passes through the tant modulation of the trigeminovascular nociceptive input
trigeminal ganglion and synapses on second-order neurons comes from the dorsal raphe nucleus, locus coeruleus, and
in the trigeminocervical complex. These neurons in turn nucleus raphe magnus.
 54
SECTION II
Clinical Manifestations of Neurologic Disease

FIGURE 6-2
Positron emission tomography (PET) activation in migraine. Moreover, lateralization of changes in this region of the brain-
In spontaneous attacks of episodic migraine (A) there is activa- stem correlates with lateralization of the head pain in hemicra-
tion of the region of the dorsolateral pons (intersection of dark nial migraine; the scans shown in panels B and C are of
blue lines); an identical pattern is found in chronic migraine (not patients with acute migraine headache on the right and left
shown). This area, which includes the noradrenergic locus side, respectively. (From S Afridi et al: Arch Neurol 62:1270,
coeruleus, is fundamental to the expression of migraine. 2005; Brain 128:932, 2005.)

actions of 5-HT and was introduced as the rst drug FHM 2, are responsible for about 20% of FHM. Muta-
capable of preventing migraine attacks. The triptans are tions in the neuronal voltage-gated sodium channel
designed to selectively stimulate subpopulations of SCN1A cause FHM 3. Functional neuroimaging has
5-HT receptors; at least 14 different 5-HT receptors exist suggested that brainstem regions in migraine (Fig. 6-2)
in humans. The triptans are potent agonists of 5-HT1B, and the posterior hypothalamic gray matter region close
5-HT1D, and 5-HT1F receptors and are less potent at the to the human circadian pacemaker cells of the suprachi-
5-HT1A receptor. A growing body of data indicates that asmatic nucleus in cluster headache (Fig. 6-3) are good
the antimigraine efcacy of the triptans relates to their candidates for specic involvement in primary headache.
ability to stimulate 5-HT1B/1D receptors, which are located
on both blood vessels and nerve terminals.
Data also support a role for dopamine in the patho-
physiology of certain subtypes of migraine. Most migraine
symptoms can be induced by dopaminergic stimulation.
Moreover, there is dopamine receptor hypersensitivity in
migraineurs, as demonstrated by the induction of yawn-
ing, nausea, vomiting, hypotension, and other symptoms
of a migraine attack by dopaminergic agonists at doses
that do not affect nonmigraineurs. Dopamine receptor
antagonists are effective therapeutic agents in migraine,
especially when given parenterally or concurrently with
other antimigraine agents.
Migraine genes identied by studying families with
familial hemiplegic migraine (FHM) reveal involvement
of ion channels, suggesting that alterations in membrane
excitability can predispose to migraine. Mutations involv-
ing the Cav2.1 (P/Q) type voltage-gated calcium chan- FIGURE 6-3
nel CACNA1A gene are now known to cause FHM 1; Posterior hypothalamic gray matter activation on positron
this mutation is responsible for about 50% of FHM. emission tomography (PET) in a patient with acute cluster
Mutations in the Na+-K+ATPase ATP1A2 gene, designated headache. (From A May et al: Lancet 352:275, 1998.)
TABLE 6-4 migraine (see Chronic Daily Headache, below). Migraine 55
SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE must be differentiated from tension-type headache (dis-
cussed below), the most common primary headache syn-
Repeated attacks of headache lasting 472 h in patients
with a normal physical examination, no other reasonable
drome seen in clinical practice. Migraine at its most basic level
cause for the headache, and: is headache with associated features, and tension-type headache is
At least 2 of the following Plus at least 1 of the headache that is featureless. Most patients with disabling headache
features: following features: probably have migraine.
Unilateral pain Nausea/vomiting Patients with acephalgic migraine experience recur-
Throbbing pain Photophobia and rent neurologic symptoms, often with nausea or vomit-
phonophobia

CHAPTER 6
ing, but with little or no headache.Vertigo can be promi-
Aggravation by movement
Moderate or severe intensity
nent; it has been estimated that one-third of patients
referred for vertigo or dizziness have a primary diagnosis
Source: Adapted from the International Headache Society Classi-
of migraine.
cation (Headache Classication Committee of the International
Headache Society, 2004).
Treatment:

Headache
MIGRAINE HEADACHES
Once a diagnosis of migraine has been established, it is
Diagnosis and Clinical Features important to assess the extent of a patients disease and
disability.The Migraine Disability Assessment Score (MIDAS)
Diagnostic criteria for migraine headache are listed in
is a well-validated, easy-to-use tool (Fig. 6-4).
Table 6-4. A high index of suspicion is required to diag-
Patient education is an important aspect of migraine
nose migraine: the migraine aura, consisting of visual dis-
management. Information for patients is available at
turbances with ashing lights or zigzag lines moving across
www.achenet.org, the website of the American Council
the visual eld or of other neurologic symptoms, is
for Headache Education (ACHE). It is helpful for patients
reported in only 2025% of patients.A headache diary can
to understand that migraine is an inherited tendency to
often be helpful in making the diagnosis; this is also helpful
headache; that migraine can be modied and con-
in assessing disability and the frequency of treatment for
trolled by lifestyle adjustments and medications, but it
acute attacks. Patients with episodes of migraine that
cannot be eradicated; and that, except in some occasions
occur daily or near-daily are considered to have chronic

*MIDAS Questionnaire
INSTRUCTIONS: Please answer the following questions about ALL headaches you have had
over the last 3 months. Write zero if you did not do the activity in the last 3 months.

1. On how many days in the last 3 months did you miss work or school because
of your headaches? ............................................................................................... days
2. How many days in the last 3 months was your productivity at work or school
reduced by half or more because of your headaches (do not include days
you counted in question 1 where you missed work or school)? ............................ days
3. On how many days in the last 3 months did you not do household work
because of your headaches? ................................................................................ days
4. How many days in the last 3 months was your productivity in household work
reduced by half or more because of your headaches (do not include days
you counted in question 3 where you did not do household work)? ..................... days
5. On how many days in the last 3 months did you miss family, social, or leisure
activities because of your headaches? ................................................................. days
A. On how many days in the last 3 months did you have a headache? (If a
headache lasted more than one day, count each day.) ......................................... days
B. On a scale of 010, on average how painful were these headaches? (Where
0 = no pain at all, and 10 = pain as bad as it can be.) ..........................................
*Migraine Disability Assessment Score
(Questions 15 are used to calculate the MIDAS score.)
Grade IMinimal or Infrequent Disability: 05
Grade IIMild or Infrequent Disability: 610
Grade IIIModerate Disability: 1120
Grade IVSevere Disability: > 20
FIGURE 6-4
MIDAS Questionnaire. (From Innovative Medical Research 1997.)
 56 in women on oral estrogens or contraceptives, migraine attack can be reduced signicantly by anti-inammatory
is not associated with serious or life-threatening ill- agents (Table 6-5). Indeed, many undiagnosed migraineurs
nesses. Recent studies have demonstrated an increased are self-treated with nonprescription NSAIDs. A general
number of cerebellar white matter lesions of uncertain consensus is that NSAIDs are most effective when taken
signicance in those with migraine with aura. early in the migraine attack. However, the effectiveness of
anti-inammatory agents in migraine is usually less than
Nonpharmacologic Management Migraine
optimal in moderate or severe migraine attacks. The com-
can often be managed to some degree by a variety of
bination of acetaminophen, aspirin, and caffeine has been
nonpharmacologic approaches. Most patients benet
approved for use by the U.S. Food and Drug Administration
by the identication and avoidance of specic headache
SECTION II

(FDA) for the treatment of mild to moderate migraine. The

triggers. A regulated lifestyle is helpful, including a
combination of aspirin and metoclopramide has been
healthful diet, regular exercise, regular sleep patterns,
shown to be equivalent to a single dose of sumatriptan.
avoidance of excess caffeine and alcohol, and avoidance
Important side effects of NSAIDs include dyspepsia and
of acute changes in stress levels.
gastrointestinal irritation.
The measures that benet a given individual should
be used routinely since they provide a simple, cost- 5-HT1 Agonists
Clinical Manifestations of Neurologic Disease

effective approach to migraine management. Patients Oral Stimulation of 5-HT1B/1D receptors can stop an
with migraine do not encounter more stress than acute migraine attack. Ergotamine and dihydroergota-
headache-free individuals; overresponsiveness to stress mine are nonselective receptor agonists, while the trip-
appears to be the issue. Since the stresses of everyday tans are selective 5-HT1B/1D receptor agonists. A variety
living cannot be eliminated, lessening ones response to of triptans (e.g., naratriptan, rizatriptan, eletriptan, suma-
stress by various techniques is helpful for many triptan, zolmitriptan, almotriptan, frovatriptan) are now
patients. These may include yoga, transcendental medi- available for the treatment of migraine.
tation, hypnosis, and conditioning techniques such as Each drug in the triptan class has similar pharmaco-
biofeedback. For most patients, this approach is, at best, logic properties but varies slightly in terms of clinical
an adjunct to pharmacotherapy. Nonpharmacologic efcacy. Rizatriptan and eletriptan are the most efca-
measures are unlikely to prevent all migraine attacks. cious of the triptans currently available in the United
When these measures fail to prevent an attack, pharma- States. Sumatriptan and zolmitriptan have similar rates
cologic approaches are then needed to abort an attack. of efcacy as well as time to onset, whereas naratriptan
and frovatriptan are the slowest-acting and least efca-
Acute Attack Therapies for Migraine The
cious. Clinical efcacy appears to be related more to
mainstay of pharmacologic therapy is the judicious use
the tmax (time to peak plasma level) than to the potency,
of one or more of the many drugs that are effective in
half-life, or bioavailability. This observation is consistent
migraine (Table 6-5). The selection of the optimal regi-
with a large body of data indicating that faster-acting
men for a given patient depends on a number of factors,
analgesics are more effective than slower-acting agents.
the most important of which is the severity of the
Unfortunately, monotherapy with a selective oral 5-
attack. Mild migraine attacks can usually be managed by
HT1B/1D agonist does not result in rapid, consistent, and
oral agents; the average efcacy rate is 5070%. Severe
complete relief of migraine in all patients. Triptans are
migraine attacks may require parenteral therapy. Most
not effective in migraine with aura unless given after
drugs effective in the treatment of migraine are mem-
the aura is completed and the headache initiated. Side
bers of one of three major pharmacologic classes: anti-
effects are common though often mild and transient.
inammatory agents, 5HT1B/1D receptor agonists, and
Moreover, 5-HT1B/1D agonists are contraindicated in indi-
dopamine receptor antagonists.
viduals with a history of cardiovascular and cerebrovas-
In general, an adequate dose of whichever agent is
cular disease. Recurrence of headache is another impor-
chosen should be used as soon as possible after the
tant limitation of triptan use and occurs at least
onset of an attack. If additional medication is required
occasionally in most patients.
within 60 min because symptoms return or have not
Ergotamine preparations offer a nonselective means
abated, the initial dose should be increased for subse-
of stimulating 5-HT1 receptors. A nonnauseating dose of
quent attacks. Migraine therapy must be individualized;
ergotamine should be sought since a dose that pro-
a standard approach for all patients is not possible. A
vokes nausea is too high and may intensify head pain.
therapeutic regimen may need to be constantly rened
Except for a sublingual formulation of ergotamine, oral
until one is identied that provides the patient with
formulations of ergotamine also contain 100 mg caf-
rapid, complete, and consistent relief with minimal side
feine (theoretically to enhance ergotamine absorption
effects (Table 6-6).
and possibly to add additional analgesic activity). The
Nonsteroidal Anti - Inflammatory Drugs average oral ergotamine dose for a migraine attack is 2 mg.
(NSAIDs) Both the severity and duration of a migraine Since the clinical studies demonstrating the efcacy of
TABLE 6-5 57
TREATMENT OF ACUTE MIGRAINE

DRUG TRADE NAME DOSAGE

Simple Analgesics
Acetaminophen, aspirin, Excedrin Migraine Two tablets or caplets q6h (max 8 per day)
caffeine
NSAIDs
Naproxen Aleve, Anaprox, generic 220550 mg PO bid

CHAPTER 6
Ibuprofen Advil, Motrin, Nuprin, 400 mg PO q34h
generic
Tolfenamic acid Clotam Rapid 200 mg PO. May repeat x 1 after 12 h
5-HT1 Agonists
Oral
Ergotamine Ergomar One 2 mg sublingual tablet at onset and q1/2h (max 3 per day,

Headache
5 per week)
Ergotamine 1 mg, Ercaf, Wigraine One or two tablets at onset, then one tablet q1/2h
caffeine 100 mg (max 6 per day,10 per week)
Naratriptan Amerge 2.5 mg tablet at onset; may repeat once after 4 h
Rizatriptan Maxalt 510 mg tablet at onset; may repeat after 2 h (max 30 mg/d)
Maxalt-MLT
Sumatriptan Imitrex 50100 mg tablet at onset; may repeat after 2 h (max 200 mg/d)
Frovatriptan Frova 2.5 mg tablet at onset, may repeat after 2 h (max 5 mg/d)
Almotriptan Axert 12.5 mg tablet at onset, may repeat after 2 h (max 25 mg/d)
Eletriptan Relpax 40 or 80 mg
Zolmitriptan Zomig 2.5 mg tablet at onset; may repeat after 2 h (max 10 mg/d)
Zomig Rapimelt
Nasal
Dihydroergotamine Migranal Nasal Spray Prior to nasal spray, the pump must be primed 4 times; 1 spray
(0.5 mg) is administered, followed in 15 min by a second spray
Sumatriptan Imitrex Nasal Spray 520 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg
spray (may repeat once after 2 h, not to exceed a dose of 40 mg/d)
Zolmitriptan Zomig 5 mg intranasal spray as one spray (may repeat once after 2 h,
not to exceed a dose of 10 mg/d)
Parenteral
Dihydroergotamine DHE-45 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week)
Sumatriptan Imitrex Injection 6 mg SC at onset (may repeat once after 1 h for max of 2 doses
in 24 h)
Dopamine Antagonists
Oral
Metoclopramide Reglan,a generica 510 mg/d
Prochlorperazine Compazine,a generica 125 mg/d
Parenteral
Chlorpromazine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d
Metoclopramide Reglan,a generic 10 mg IV
Prochlorperazine Compazine,a generica 10 mg IV
Other
Oral
Acetaminophen, 325 mg, plus Midrin, Duradrin, generic Two capsules at onset followed by 1 capsule q1h
dichloralphenazone, 100 mg, (max 5 capsules)
plus isometheptene, 65 mg
Nasal
Butorphanol Stadola 1 mg (1 spray in 1 nostril), may repeat if necessary in 12 h
Parenteral
Narcotics Generica Multiple preparations and dosages; see Table 5-1

a
Not all drugs are specically indicated by the FDA for migraine. Local regulations and guidelines should be consulted.
Note: Antiemetics (e.g., domperidone 10 mg or ondansetron) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts.
NSAIDs, nonsteroidal anti-inammatory drugs; 5-HT, 5-hydroxytryptamine.
 58 TABLE 6-6
the FDA for the rapid relief of a migraine attack. Peak
CLINICAL STRATIFICATION OF ACUTE SPECIFIC plasma levels of dihydroergotamine are achieved 3 min
MIGRAINE TREATMENTS
after intravenous dosing, 30 min after intramuscular
CLINICAL SITUATION TREATMENT OPTIONS dosing, and 45 min after subcutaneous dosing. If an
attack has not already peaked, subcutaneous or intra-
Failed NSAIDS/ First tier
analgesics Sumatriptan 50 mg or 100 mg PO
muscular administration of 1 mg dihydroergotamine
Almotriptan 12.5 mg PO sufces for about 8090% of patients. Sumatriptan, 6 mg
Rizatriptan 10 mg PO subcutaneously, is effective in ~7080% of patients.
Eletriptan 40 mg PO
SECTION II

Zolmitriptan 2.5 mg PO Dopamine Antagonists

Slower effect/better tolerability Oral Oral dopamine antagonists should be consid-
Naratriptan 2.5 mg PO ered as adjunctive therapy in migraine. Drug absorption
Frovatriptan 2.5 mg PO is impaired during migraine because of reduced gas-
Infrequent headache
trointestinal motility. Delayed absorption occurs even in
Ergotamine 12 mg PO
Dihydroergotamine nasal spray
the absence of nausea and is related to the severity of
Clinical Manifestations of Neurologic Disease

2 mg the attack and not its duration. Therefore, when oral

Early nausea or Zolmitriptan 5 mg nasal spray NSAIDs and/or triptan agents fail, the addition of a
difculties taking Sumatriptan 20 mg nasal spray dopamine antagonist such as metoclopramide, 10 mg,
tablets Rizatriptan 10 mg MLT wafer should be considered to enhance gastric absorption. In
Headache recurrence Ergotamine 2 mg (most effective addition, dopamine antagonists decrease nausea/vomit-
PR/usually with caffeine) ing and restore normal gastric motility.
Naratriptan 2.5 mg PO
Almotriptan 12.5 mg PO Parenteral Parenteral dopamine antagonists (e.g.,
Eletriptan 40 mg chlorpromazine, prochlorperazine, metoclopramide) can
Tolerating acute Naratriptan 2.5 mg also provide signicant acute relief of migraine; they can
treatments poorly Almotriptan 12.5 mg
be used in combination with parenteral 5-HT1B/1D ago-
Early vomiting Zolmitriptan 5 mg nasal spray
Sumatriptan 25 mg PR nists. A common intravenous protocol used for the treat-
Sumatriptan 6 mg SC ment of severe migraine is the administration over
Menses-related Prevention 2 min of a mixture of 5 mg of prochlorperazine and
headache Ergotamine PO at night 0.5 mg of dihydroergotamine.
Estrogen patches
Treatment Other Medications for Acute Migraine
Triptans Oral The combination of acetaminophen, dichlo-
Dihydroergotamine nasal spray
ralphenazone, and isometheptene, one to two capsules,
Very rapidly Zolmitriptan 5 mg nasal spray
developing Sumatriptan 6 mg SC has been classied by the FDA as possibly effective in
symptoms Dihydroergotamine 1 mg IM the treatment of migraine. Since the clinical studies
demonstrating the efcacy of this combination anal-
gesic in migraine predated the clinical trial methodolo-
gies used with the triptans, it is difcult to compare the
ergotamine in migraine predated the clinical trial efcacy of this sympathomimetic compound to other
methodologies used with the triptans, it is difcult to agents.
assess the clinical efcacy of ergotamine versus the trip-
tans. In general, ergotamine appears to have a much
Nasal A nasal preparation of butorphanol is available
for the treatment of acute pain. As with all narcotics, the
higher incidence of nausea than triptans, but less
use of nasal butorphanol should be limited to a select
headache recurrence.
group of migraineurs, as described below.
Nasal The fastest-acting nonparenteral antimigraine
therapies that can be self-administered include nasal for-
Parenteral Narcotics are effective in the acute treat-
ment of migraine. For example, intravenous meperidine
mulations of dihydroergotamine (Migranal), zolmitriptan
(50100 mg) is given frequently in the emergency room.
(Zomig nasal), or sumatriptan. The nasal sprays result in
This regimen works in the sense that the pain of
substantial blood levels within 3060 min. Although in
migraine is eliminated. However, this regimen is clearly
theory nasal sprays might provide faster and more effec-
suboptimal for patients with recurrent headache. Nar-
tive relief of a migraine attack than oral formulations,
cotics do not treat the underlying headache mecha-
their reported efcacy is only ~5060%.
nism; rather, they act to alter the pain sensation. More-
Parenteral Parenteral administration of drugs such over, in patients taking oral narcotics such as oxycodone
as dihydroergotamine and sumatriptan is approved by or hydrocodone, narcotic addiction can greatly confuse
the treatment of migraine. Narcotic craving and/or with- adequately with low-dose amitriptyline, propranolol, 59
drawal can aggravate and accentuate migraine. There- topiramate, gabapentin, or valproate. If these agents fail
fore, it is recommended that narcotic use in migraine be or lead to unacceptable side effects, second-line agents
limited to patients with severe, but infrequent, headaches such as methysergide or phenelzine can be used. Once
that are unresponsive to other pharmacologic approaches. effective stabilization is achieved, the drug is continued
for 56 months and then slowly tapered to assess the
Medication-Overuse Headache Acute attack
continued need. Many patients are able to discontinue
medications, particularly codeine or barbiturate-
medication and experience fewer and milder attacks for
containing compound analgesics, have a propensity to
long periods, suggesting that these drugs may alter the

CHAPTER 6
aggravate headache frequency and induce a state of
natural history of migraine.
refractory daily or near-daily headache called medication-
overuse headache. This condition is likely not a separate
headache entity but a reaction of the migraine patient
to a particular medicine. Migraine patients who have
two or more headache days a week should be cautioned TENSION-TYPE HEADACHE
about frequent analgesic use (see Chronic Daily Clinical Features

Headache
Headache, below).
The term tension-type headache (TTH) is commonly used
Preventive Treatments for Migraine Patients to describe a chronic head-pain syndrome characterized
with an increasing frequency of migraine attacks, or by bilateral tight, bandlike discomfort.The pain typically
with attacks that are either unresponsive or poorly builds slowly, uctuates in severity, and may persist more
responsive to abortive treatments, are good candidates or less continuously for many days. The headache may
for preventive agents. In general, a preventive medica- be episodic or chronic (present >15 days per month).
tion should be considered in the subset of patients with A useful clinical approach is to diagnose TTH in patients
ve or more attacks a month. Signicant side effects are whose headaches are completely without accompanying
associated with the use of many of these agents; fur- features such as nausea, vomiting, photophobia, phono-
thermore, determination of dose can be difcult since phobia, osmophobia, throbbing, and aggravation with
the recommended doses have been derived for condi- movement. Such an approach neatly separates migraine,
tions other than migraine. The mechanism of action of which has one or more of these features and is the main
these drugs is unclear; it seems likely that the brain sen- differential diagnosis, from TTH. However, the Interna-
sitivity that underlies migraine is modied. Patients are tional Headache Societys denition of TTH allows an
usually started on a low dose of a chosen treatment; the admixture of nausea, photophobia, or phonophobia in
dose is then gradually increased, up to a reasonable various combinations, illustrating the difculties in distin-
maximum to achieve clinical benet. guishing these two clinical entities. Patients whose headaches
Drugs that have the capacity to stabilize migraine are t the TTH phenotype and who have migraine at other
listed in Table 6-7. Drugs must be taken daily, and there times, along with a family history of migraine, migrain-
is usually a lag of at least 212 weeks before an effect is ous illnesses of childhood, or typical migraine triggers
seen. The drugs that have been approved by the FDA for to their migraine attacks, may be biologically different
the prophylactic treatment of migraine include propra- from those who have TTH headache with none of the
nolol, timolol, sodium valproate, topiramate, and methy- features.
sergide (not available in the United States). In addition, a
number of other drugs appear to display prophylactic
Pathophysiology
efcacy. This group includes amitriptyline, nortriptyline,
unarizine, phenelzine, gabapentin, topiramate, and The pathophysiology of TTH is incompletely understood.
cyproheptadine. Phenelzine and methysergide are usu- It seems likely that TTH is due to a primary disorder of
ally reserved for recalcitrant cases because of their seri- CNS pain modulation alone, unlike migraine, which
ous potential side effects. Phenelzine is a monoamine involves a more generalized disturbance of sensory modu-
oxidase inhibitor (MAOI); therefore, tyramine-containing lation. Data suggest a genetic contribution to TTH, but
foods, decongestants, and meperidine are contraindi- this may not be a valid nding: given the current diagnos-
cated. Methysergide may cause retroperitoneal or car- tic criteria, the studies undoubtedly included many
diac valvular brosis when it is used for >6 months, and migraine patients. The name tension-type headache implies
thus monitoring is required for patients using this drug; that pain is a product of nervous tension, but there is no
the risk of brosis is about 1:1500 and is likely to reverse clear evidence for tension as an etiology. Muscle contrac-
after the drug is stopped. tion has been considered to be a feature that distinguishes
The probability of success with any one of the antimi- TTH from migraine, but there appear to be no differences
graine drugs is 5075%. Many patients are managed in contraction between the two headache types.
 60 TABLE 6-7
PREVENTIVE TREATMENTS IN MIGRAINEa

DRUG DOSE SELECTED SIDE EFFECTS

b
Pizotifen 0.52 mg qd Weight gain
Drowsiness
Beta blocker
Propranolol 40120 mg bid Reduced energy
Tiredness
SECTION II

Postural symptoms
Contraindicated in asthma
Tricyclics
Amitriptyline 1075 mg at night Drowsiness
Dothiepin 2575 mg at night
Nortriptyline 2575 mg at night Note: Some patients may only need a total dose of
Clinical Manifestations of Neurologic Disease

10 mg, although generally 11.5 mg/kg body weight is

required
Anticonvulsants
Topiramate 25200 mg/d Paresthesias
Cognitive symptoms
Weight loss
Glaucoma
Caution with nephrolithiasis
Valproate 400600 mg bid Drowsiness
Weight gain
Tremor
Hair loss
Fetal abnormalities
Hematologic or liver abnormalities
Gabapentin 9003600 mg qd Dizziness
Sedation
Serotonergic drugs
Methysergide 14 mg qd Drowsiness
Leg cramps
Hair loss
Retroperitoneal brosis (1-month drug holiday is required
every 6 months)
Flunarizineb 515 mg qd Drowsiness
Weight gain
Depression
Parkinsonism
No convincing evidence from controlled trials
Verapamil
Controlled trials demonstrate no effect
Nimodipine
Clonidine
SSRIs: uoxetine

a
Commonly used preventives are listed with reasonable doses and common side effects. Not all listed medicines are
approved by the FDA; local regulations and guidelines should be consulted.
b
Not available in the United States.
 Because of the associated nasal congestion or rhinorrhea, 61
Treatment: patients are often misdiagnosed with sinus headache
TENSION-TYPE HEADACHE and treated with decongestants, which are ineffective.
The pain of TTH can generally be managed with simple TACs must be differentiated from short-lasting head-
analgesics such as acetaminophen, aspirin, or NSAIDs. aches that do not have prominent cranial autonomic syn-
Behavioral approaches including relaxation can also be dromes, notably trigeminal neuralgia, primary stabbing
effective. Clinical studies have demonstrated that triptans headache, and hypnic headache.The cycling pattern and
in pure TTH are not helpful, although triptans are effective length, frequency, and timing of attacks are useful in
in TTH when the patient also has migraine. For chronic classifying patients. Patients with TACs should undergo

CHAPTER 6
TTH, amitriptyline is the only proven treatment (Table 6-7); pituitary imaging and pituitary function tests as there is
other tricyclics, selective serotonin reuptake inhibitors, and an excess of TAC presentations in patients with pituitary
the benzodiazepines have not been shown to be effective. tumorrelated headache
There is no evidence for the efcacy of acupuncture.
Placebo controlled trials of botulinum toxin type A in Cluster Headache
chronic TTH have not shown benet.
Cluster headache is a rare form of primary headache

Headache
with a population frequency of 0.1%. The pain is deep,
TRIGEMINAL AUTONOMIC CEPHALALGIAS,
usually retroorbital, often excruciating in intensity, non-
INCLUDING CLUSTER HEADACHE
uctuating, and explosive in quality. A core feature of
The trigeminal autonomic cephalalgias (TACs) are a group cluster headache is periodicity. At least one of the daily
of primary headaches that includes cluster headache, attacks of pain recurs at about the same hour each day
paroxysmal hemicrania, and SUNCT (short-lasting uni- for the duration of a cluster bout. The typical cluster
lateral neuralgiform headache attacks with conjunctival headache patient has daily bouts of one to two attacks of
injection and tearing). TACs are characterized by rela- relatively short-duration unilateral pain for 810 weeks
tively short-lasting attacks of head pain associated with a year; this is usually followed by a pain-free interval that
cranial autonomic symptoms, such as lacrimation, con- averages 1 year. Cluster headache is characterized as
junctival injection, or nasal congestion (Table 6-8). Pain chronic when there is no period of sustained remission.
is usually severe and may occur more than once a day. Patients are generally perfectly well between episodes.

TABLE 6-8
CLINICAL FEATURES OF THE TRIGEMINAL AUTONOMIC CEPHALALGIAS

CLUSTER HEADACHE PAROXYSMAL HEMICRANIA SUNCT

Gender M>F F=M F~M

Pain
Type Stabbing, boring Throbbing, boring, stabbing Burning, stabbing, sharp
Severity Excruciating Excruciating Severe to excruciating
Site Orbit, temple Orbit, temple Periorbital
Attack frequency 1/alternate day8/d 140/d (>5/d for more than 3200/d
half the time)
Duration of attack 15180 min 230 min 5240 s
Autonomic features Yes Yes Yes (prominent conjunctival
injection and lacrimation)a
Migrainous featuresb Yes Yes Yes
Alcohol trigger Yes No No
Cutaneous triggers No No Yes
Indomethacin effect Yesc
Abortive treatment Sumatriptan injection No effective treatment Lidocaine (IV)
or nasal spray
Oxygen
Prophylactic Verapamil Indomethacin Lamotrigine
treatment Methysergide Topiramate
Lithium Gabapentin

a
If conjunctival injection and tearing not present, consider SUNA.
b
Nausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain.
c
Indicates complete response to indomethacin.
Note: SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
 62 Onset is nocturnal in about 50% of patients, and men TABLE 6-9
are affected three times more often than women. PREVENTIVE MANAGEMENT OF CLUSTER HEADACHE
Patients with cluster headache tend to move about dur-
SHORT-TERM PREVENTION LONG-TERM PREVENTION
ing attacks, pacing, rocking, or rubbing their head for
relief; some may even become aggressive during attacks. Episodic Cluster Headache &
This is in sharp contrast to patients with migraine, who Episodic Cluster Prolonged Chronic
prefer to remain motionless during attacks. Headache Cluster Headache
Cluster headache is associated with ipsilateral symp- Prednisone 1 mg/kg up Verapamil 160960 mg/d
toms of cranial parasympathetic autonomic activation: to 60 mg qd, tapering Lithium 400800 mg/d
conjunctival injection or lacrimation, rhinorrhea or nasal
SECTION II

over 21 days Methysergide 312 mg/d

congestion, or cranial sympathetic dysfunction such as Methysergide 312 mg/d Topiramatea 100400 mg/d
ptosis.The sympathetic decit is peripheral and likely to Verapamil 160960 mg/d Gabapentina 12003600 mg/d
be due to parasympathetic activation with injury to ascend- Greater occipital nerve Melatonina 912 mg/d
injection
ing sympathetic bers surrounding a dilated carotid artery
as it passes into the cranial cavity. When present, photo- a
Unproven but of potential benet.
phobia and phonophobia are far more likely to be unilat-
Clinical Manifestations of Neurologic Disease

eral and on the same side of the pain, rather than bilateral,
as is seen in migraine. This phenomenon of unilateral is used, it is most effective when given 12 h before an
photophobia/phonophobia is characteristic of TACs. expected attack. Patients who use ergotamine daily
Cluster headache is likely to be a disorder involving must be educated regarding the early symptoms of
central pacemaker neurons in the region of the posterior ergotism, which may include vomiting, numbness, tin-
hypothalamus (Fig. 6-2). gling, pain, and cyanosis of the limbs; a weekly limit of
14 mg should be adhered to. Lithium (600900 mg qd)
appears to be particularly useful for the chronic form of
Treatment: the disorder.
CLUSTER HEADACHE Many experts favor verapamil as the rst-line preven-
The most satisfactory treatment is the administration of tive treatment for patients with chronic cluster headache
drugs to prevent cluster attacks until the bout is over. or prolonged bouts. While verapamil compares favorably
However, treatment of acute attacks is required for all with lithium in practice, some patients require verapamil
cluster headache patients at some time. doses far in excess of those administered for cardiac disor-
ACUTE ATTACK TREATMENT Cluster headache ders. The initial dose range is 4080 mg twice daily; effec-
attacks peak rapidly, and thus a treatment with quick tive doses may be as high as 960 mg/d. Side effects such
onset is required. Many patients with acute cluster as constipation and leg swelling can be problematic. Of
headache respond very well to oxygen inhalation. This paramount concern, however, is the cardiovascular safety
should be given as 100% oxygen at 1012 L/min for of verapamil, particularly at high doses. Verapamil can
1520 min. It appears that high ow and high oxygen cause heart block by slowing conduction in the atrioven-
content are important. Sumatriptan 6 mg subcuta- tricular node, a condition that can be monitored by fol-
neously is rapid in onset and will usually shorten an lowing the PR interval on a standard ECG. Approximately
attack to 1015 min; there is no evidence of tachyphy- 20% of patients treated with verapamil develop ECG
laxis. Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal abnormalities, which can be observed with doses as low
sprays are both effective in acute cluster headache, as 240 mg/d; these abnormalities can worsen over time in
offering a useful option for patients who may not wish patients on stable doses. A baseline ECG is recommended
to self-inject daily. Oral sumatriptan is not effective for for all patients. The ECG is repeated 10 days after a dose
prevention or for acute treatment of cluster headache. change in those patients whose dose is being increased
above 240 mg daily. Dose increases are usually made in
PREVENTIVE TREATMENTS (Table 6-9) The 80-mg increments. For patients on long-term verapamil,
choice of a preventive treatment in cluster headache ECG monitoring every 6 months is advised.
depends in part on the length of the bout. Patients with
long bouts or those with chronic cluster headache NEUROSTIMULATION THERAPY When med-
require medicines that are safe when taken for long ical therapies fail in chronic cluster headache, neu-
periods. For patients with relatively short bouts, limited rostimulation therapy strategies can be employed.
courses of oral glucocorticoids or methysergide (not Deep-brain stimulation of the region of the posterior
available in the United States) can be very useful. A 10- hypothalamic gray matter has proven successful in a
day course of prednisone, beginning at 60 mg daily for 7 substantial proportion of patients. Favorable results
days and followed by a rapid taper, may interrupt the have also been reported with the less-invasive approach
pain bout for many patients. When ergotamine (12 mg) of occipital nerve stimulation.
Paroxysmal Hemicrania minutes. Each pattern may be seen in the context of an 63
underlying continuous head pain. Characteristics that
Paroxysmal hemicrania (PH) is characterized by frequent
lead to a suspected diagnosis of SUNCT are the cuta-
unilateral, severe, short-lasting episodes of headache. Like
neous (or other) triggerability of attacks, a lack of refrac-
cluster headache, the pain tends to be retroorbital but
tory period to triggering between attacks, and the lack of
may be experienced all over the head and is associated
a response to indomethacin. Apart from trigeminal sen-
with autonomic phenomena such as lacrimation and nasal
sory disturbance, the neurologic examination is normal
congestion. Patients with remissions are said to have
in primary SUNCT.
episodic PH, while those with the nonremitting form are
The diagnosis of SUNCT is often confused with
said to have chronic PH.The essential features of PH are:

CHAPTER 6
trigeminal neuralgia (TN) particularly in rst-division
unilateral, very severe pain; short-lasting attacks (245 min);
TN (Chap. 29). Minimal or no cranial autonomic symp-
very frequent attacks (usually more than ve a day); marked
toms and a clear refractory period to triggering indicate
autonomic features ipsilateral to the pain; rapid course
a diagnosis of TN.
(<72 h); and excellent response to indomethacin. In con-
trast to cluster headache, which predominantly affects
males; the male:female ratio in PH is close to 1:1. Secondary (Symptomatic) SUNCT

Headache
Indomethacin (2575 mg tid), which can completely SUNCT can be seen with posterior fossa or pituitary
suppress attacks of PH, is the treatment of choice. Although lesions. All patients with SUNCT/SUNA should be
therapy may be complicated by indomethacin-induced evaluated with pituitary function tests and a brain MRI
gastrointestinal side effects, currently there are no consis- with pituitary views.
tently effective alternatives. Topiramate is helpful in some
cases. Piroxicam has been used, although it is not as effec-
tive as indomethacin.Verapamil, an effective treatment for Treatment:
cluster headache, does not appear to be useful for PH. In SUNCT/SUNA
occasional patients, PH can coexist with trigeminal neural-
gia (PH-tic syndrome); similar to cluster-tic syndrome, each ABORTIVE THERAPY Therapy of acute attacks is
component may require separate treatment. not a useful concept in SUNCT/SUNA since the attacks
Secondary PH has been reported with lesions in the are of such short duration. However, intravenous lido-
region of the sella turcica, including arteriovenous malfor- caine, which arrests the symptoms, can be used in hospi-
mation, cavernous sinus meningioma, and epidermoid talized patients.
tumors. Secondary PH is more likely if the patient requires PREVENTIVE THERAPY Long-term prevention
high doses (>200 mg/d) of indomethacin. In patients with to minimize disability and hospitalization is the goal of
apparent bilateral PH, raised CSF pressure should be sus- treatment. The most effective treatment for prevention is
pected. It is important to note that indomethacin reduces lamotrigine, 200400 mg/d. Topiramate and gabapentin
CSF pressure.When a diagnosis of PH is considered, MRI may also be effective. Carbamazepine, 400500 mg/d,
is indicated to exclude a pituitary lesion. has been reported by patients to offer modest benet.
Surgical approaches such as microvascular decom-
SUNCT/SUNA pression or destructive trigeminal procedures are sel-
dom useful and often produce long-term complica-
SUNCT is a rare primary headache syndrome charac- tions. Greater occipital nerve injection has produced
terized by severe, unilateral orbital or temporal pain that limited benet in some patients. Mixed success with
is stabbing or throbbing in quality. Diagnosis requires at occipital nerve stimulation has been observed. Com-
least 20 attacks, lasting for 5240 s; ipsilateral conjuncti- plete control with deep-brain stimulation of the poste-
val injection and lacrimation should be present. In some rior hypothalamic region was reported in a single
patients conjunctival injection or lacrimation are miss- patient. For intractable cases, short-term prevention
ing, and the diagnosis of SUNA (short-lasting unilateral with intravenous lidocaine can be effective.
neuralgiform headache attacks with cranial autonomic
symptoms) has been suggested.

Diagnosis
CHRONIC DAILY HEADACHE
The pain of SUNCT/SUNA is unilateral and may be The broad diagnosis of chronic daily headache (CDH)
located anywhere in the head. Three basic patterns can can be applied when a patient experiences headache on
be seen: single stabs, which are usually short-lived; groups 15 days or more per month. CDH is not a single entity;
of stabs; or a longer attack comprising many stabs between it encompasses a number of different headache syn-
which the pain does not completely resolve, thus giving dromes, including chronic TTH as well as headache sec-
a saw-tooth phenomenon with attacks lasting many ondary to trauma, inammation, infection, medication
 64 TABLE 6-10
(see below). Clinical trials using botulinum toxin in
CLASSIFICATION OF CHRONIC DAILY HEADACHE chronic migraine have failed to show any objective
PRIMARY benet.

>4 H DAILY <4 H DAILY SECONDARY

MEDICATION-OVERUSE HEADACHE Overuse
of analgesic medication for headache can aggravate
Chronic migrainea Chronic cluster Posttraumatic head-ache frequency and induce a state of refractory
headacheb Head injury
daily or near-daily headache called medication-overuse
Iatrogenic
Postinfectious headache. A proportion of patients who stop taking
analgesics will experience substantial improvement in
SECTION II

Chronic tension- Chronic

type headachea paroxysmal Inammatory, such as the severity and frequency of their headache. However,
hemicrania Giant cell arteritis even after cessation of analgesic use, many patients
Sarcoidosis continue to have headache, although they may feel
Behets syndrome clinically improved in some way, especially if they have
Hemicrania SUNCT/SUNA Chronic CNS
been using codeine or barbiturates regularly.The resid-
continuaa infection
ual symptoms probably represent the underlying
Clinical Manifestations of Neurologic Disease

New daily Hypnic Medication-overuse

persistent headache headachea headache disorder.
headachea Management of Medication Overuse: Out-
patients For patients who overuse medications, it
a
May be complicated by analgesic overuse.
b
is essential that analgesic use be reduced and elimi-
Some patients may have headache > 4 h per day.
Note: SUNCT, short-lasting unilateral neuralgiform headache attacks nated. One approach is to reduce the medication dose
with conjunctival injection and tearing; SUNA, short-lasting unilateral by 10% every 12 weeks. Immediate cessation of anal-
neuralgiform headache attacks with cranial autonomic symptoms. gesic use is possible for some patients, provided there is
no contraindication. Both approaches are facilitated by
the use of a medication diary maintained during the
overuse, and other causes (Table 6-10). Population-based month or two before cessation; this helps to identify
estimates suggest that about 4% of adults have daily or the scope of the problem. A small dose of an NSAID
near-daily headache. Daily headache may be primary or such as naproxen, 500 mg bid if tolerated, will help
secondary, an important consideration in guiding man- relieve residual pain as analgesic use is reduced. NSAID
agement of this complaint. overuse is not usually a problem for patients with daily
headache when the dose is taken once or twice daily;
however, overuse problems may develop with more
Approach to the Patient: frequent dosing schedules. Once the patient has sub-
CHRONIC DAILY HEADACHE stantially reduced analgesic use, a preventive medica-
The rst step in the management of patients with tion should be introduced. It must be emphasized that
CDH is to diagnose any underlying condition (Table preventives generally do not work in the presence of analgesic
6-10). For patients with primary headaches, diagnosis overuse. The most common cause of unresponsiveness
of the headache type will guide therapy. Preventive to treatment is the use of a preventive when analgesics
treatments such as tricyclics, either amitriptyline or continue to be used regularly. For some patients, dis-
doxepin at doses up to 1 mg/kg, are very useful in continuing analgesics is very difcult; often the best
patients with CDH.Tricyclics are started in low doses approach is to directly inform the patient that some
(1025 mg) daily and may be given 12 h before the degree of pain is inevitable during this initial period.
expected time of awakening in order to avoid excess
morning sleepiness. Anticonvulsants, such as topira- Management of Medication Overuse: Inpa-
mate, valproate, and gabapentin, are also useful in tients Some patients will require hospitalization for
migraineurs. Flunarizine can also be very effective for detoxication. Such patients have typically failed efforts
some patients, as can methysergide or phenelzine. at outpatient withdrawal or have a signicant medical
condition, such as diabetes mellitus, which would com-
MANAGEMENT OF MEDICALLY INTRACTABLE plicate withdrawal as an outpatient. Following admis-
DISABLING CHRONIC DAILY HEADACHE The sion to the hospital, acute medications are withdrawn
management of medically intractable headache is dif- completely on the rst day, in the absence of a con-
cult.At this time, the only promising approach is occip- traindication. Antiemetics and uids are administered as
ital nerve stimulation, which appears to modulate thala- required; clonidine is used for opiate withdrawal symp-
mic processing in migraine and has shown promise in toms. For acute intolerable pain during the waking hours
both chronic cluster headache and hemicrania continua aspirin, 1 g (not approved in United States) intravenously,
TABLE 6-11 65
puncture (LP). Post-LP headache usually begins within
DIFFERENTIAL DIAGNOSIS OF NEW DAILY 48 h but may be delayed for up to 12 days. Its inci-
PERSISTENT HEADACHE dence is between 10 and 30%. Beverages with caffeine
PRIMARY SECONDARY may provide temporary relief. Besides LP, index events
may include epidural injection or a vigorous Valsalva
Migrainous-type Subarachnoid hemorrhage
Featureless (tension-type) Low CSF volume headache
maneuver, such as from lifting, straining, coughing,
Raised CSF pressure clearing the eustachian tubes in an airplane, or multiple
headache orgasms. Spontaneous CSF leaks are well recognized,
Posttraumatic headachea and the diagnosis should be considered whenever the

CHAPTER 6
Chronic meningitis headache history is typical, even when there is no
obvious index event. As time passes from the index
a
Includes postinfectious forms. event, the postural nature may become less apparent;
cases in which the index event occurred several years
before the eventual diagnosis have been recognized.
is useful. Intramuscular chlorpromazine can be helpful Symptoms appear to result from low volume rather

Headache
at night; patients must be adequately hydrated. If the than low pressure: although low CSF pressures, typi-
patient does not improve within 35 days, a course of cally 050 mmH2O, are usually identied, a pressure as
intravenous dihydroergotamine (DHE) can be high as 140 mmH2O has been noted with a docu-
employed. DHE, administered every 8 h for 3 consecu- mented leak. Postural orthostatic tachycardia syndrome
tive days, can induce a signicant remission that allows [POTS (Chap. 28)] can present with orthostatic headache
a preventive treatment to be established. 5-HT3 antago- similar to low CSF volume headache and is a diagnosis
nists, such as ondansetron or granisetron, are often that needs consideration here.
required with DHE to prevent signicant nausea. When imaging is indicated to identify the source of a
presumed leak, an MRI with gadolinium is the initial
NEW DAILY PERSISTENT HEADACHE New
study of choice (Fig. 6-5). A striking pattern of diffuse
daily persistent headache (NDPH) is a clinically dis-
meningeal enhancement is so typical that in the appro-
tinct syndrome; its causes are listed in Table 6-11.
priate clinical context the diagnosis is established. Chiari
Clinical Presentation The patient with NDPH malformations may sometimes be noted on MRI; in
presents with headache on most if not all days; the
onset is recent and clearly recalled by the patient.The
headache usually begins abruptly, but onset may be
more gradual; evolution over 3 days has been pro-
posed as the upper limit for this syndrome. Patients
typically recall the exact day and circumstances of the
onset of headache; the new, persistent head pain does
not remit. The rst priority is to distinguish between
a primary and a secondary cause of this syndrome.
Subarachnoid hemorrhage is the most serious of the
secondary causes and must be excluded either by his-
tory or appropriate investigation (Chap. 22).

SECONDARY NDPH
Low CSF volume headache In these syndromes,
head pain is positional: it begins when the patient sits or
stands upright and resolves upon reclining. The pain,
which is occipitofrontal, is usually a dull ache but may
be throbbing. Patients with chronic low CSF volume
headache typically present with a history of headache
from one day to the next that is generally not present FIGURE 6-5
on waking but worsens during the day. Recumbency Magnetic resonance image showing diffuse meningeal
usually improves the headache within minutes, but it enhancement after gadolinium administration in a patient
takes only minutes to an hour for the pain to return with low CSF volume headache. High-resolution T1 weighted
MRI obtained using voxel-based morphometry demonstrates
when the patient resumes an upright position.
increased gray matter activity, lateralized to the side of pain
The most common cause of headache due to persis-
in a patient with cluster headache. (From A May et al: Nat
tent low CSF volume is CSF leak following lumbar
Med 5:836, 1999.)
 66 such cases surgery to decompress the posterior fossa Initial treatment is with acetazolamide (250500 mg
usually worsens the headache.The source of CSF leak- bid); the headache may improve within weeks. If
age may be identied by spinal MRI, by CT myelo- ineffective, topiramate is the next treatment of choice;
gram, or with 111In-DTPA CSF studies; in the absence it has many actions that may be useful in this setting,
of a directly identied site of leakage, early emptying of including carbonic anhydrase inhibition, weight loss,
111
In-DTPA tracer into the bladder or slow progress of and neuronal membrane stabilization, likely mediated
tracer across the brain suggests a CSF leak. via effects on phosphorylation pathways. Severely dis-
Initial treatment for low CSF volume headache is abled patients who do not respond to medical treat-
bed rest. For patients with persistent pain, intravenous ment require intracranial pressure monitoring and may
SECTION II

caffeine (500 mg in 500 mL saline administered over require shunting.

2 h) is often very effective. An EKG to screen for
arrhythmia should be performed before administra- Post-traumatic headache A traumatic event
tion. It is reasonable to administer at least two infusions can trigger a headache process that lasts for many
of caffeine before embarking on additional tests to months or years after the event. The term trauma is
identify the source of the CSF leak. Since intravenous used in a very broad sense: headache can develop fol-
lowing an injury to the head, but it can also develop
Clinical Manifestations of Neurologic Disease

caffeine is safe and can be curative, it spares many

patients the need for further investigations. If unsuc- after an infectious episode, typically viral meningitis, a
cessful, an abdominal binder may be helpful. If a leak ulike illness, or a parasitic infection. Complaints of
can be identied, an autologous blood patch is usually dizziness, vertigo, and impaired memory can accom-
curative. A blood patch is also effective for post-LP pany the headache. Symptoms may remit after several
headache; in this setting the location is empirically weeks or persist for months and even years after the
determined to be the site of the LP. In patients with injury.Typically the neurologic examination is normal
intractable pain, oral theophylline is a useful alternative; and CT or MRI studies are unrevealing. Chronic sub-
however, its effect is less rapid than caffeine. dural hematoma may on occasion mimic this disorder.
In one series, one-third of patients with NDPH
Raised CSF pressure headache Raised CSF reported headache beginning after a transient ulike
pressure is well recognized as a cause of headache. Brain illness characterized by fever, neck stiffness, photopho-
imaging can often reveal the cause, such as a space- bia, and marked malaise. Evaluation reveals no appar-
occupying lesion. NDPH due to raised CSF pressure ent cause for the headache. There is no convincing
can be the presenting symptom for patients with idio- evidence that persistent Epstein-Barr infection plays a
pathic intracranial hypertension (pseudotumor cerebri) role in this syndrome. A complicating factor is that
without visual problems, particularly when the fundi many patients undergo LP during the acute illness;
are normal. Persistently raised intracranial pressure can iatrogenic low CSF volume headache must be consid-
trigger chronic migraine. These patients typically pre- ered in these cases. Post-traumatic headache may also
sent with a history of generalized headache that is pre- be seen after carotid dissection and subarachnoid
sent on waking and improves as the day goes on. It is hemorrhage, and following intracranial surgery. The
generally worse with recumbency. Visual obscurations underlying theme appears to be that a traumatic event
are frequent. The diagnosis is relatively straightforward involving the pain-producing meninges can trigger a
when papilledema is present, but the possibility must be headache process that lasts for many years.
considered even in patients without fundoscopic Treatment is largely empirical.Tricyclic antidepres-
changes. Formal visual-eld testing should be per- sants, notably amitriptyline, and anticonvulsants such
formed even in the absence of overt ophthalmic as topiramate, valproate, and gabapentin, have been used
involvement. Headache on rising in the morning or with reported benet. The MAOI phenelzine may
nocturnal headache is also characteristic of obstructive also be useful in carefully selected patients.The headache
sleep apnea or poorly controlled hypertension. usually resolves within 35 years, but it can be quite
Evaluation of patients suspected to have raised CSF disabling.
pressure requires brain imaging. It is most efcient to
obtain an MRI, including an MR venogram as the Primary NDPH Primary NDPH occurs in both
initial study. If there are no contraindications, the males and females. It can be of the migrainous type,
CSF pressure should be measured by LP; this should with features of migraine, or it can be featureless,
be done when the patient is symptomatic so that appearing as new-onset TTH (Table 6-11). Migrain-
both the pressure and the response to removal of ous features are common and include unilateral
2030 mL of CSF can be determined. An elevated headache and throbbing pain; each feature is present
opening pressure and improvement in headache fol- in about one-third of patients. Nausea, photophobia,
lowing removal of CSF is diagnostic. and/or phonophobia occur in about half of patients.
 Some patients have a previous history of migraine; 67
Treatment:
however, the proportion of NDPH sufferers with PRIMARY STABBING HEADACHE
preexisting migraine is no greater than the frequency
of migraine in the general population. At 24 months, The response of primary stabbing headache to indo-
~86% of patients are headache-free. Treatment of methacin (2550 mg two to three times daily) is usually
migrainous-type primary NDPH consists of using excellent. As a general rule the symptoms wax and
the preventive therapies effective in migraine (Table wane, and after a period of control on indomethacin, it is
6-7). Featureless NDPH is one of the primary appropriate to withdraw treatment and observe the
headache forms most refractory to treatment. Stan- outcome.

CHAPTER 6
dard preventive therapies can be offered but are often
ineffective.
Primary Cough Headache
Primary cough headache is a generalized headache that
begins suddenly, lasts for several minutes, and is precipi-
OTHER PRIMARY HEADACHES
tated by coughing; it is preventable by avoiding coughing

Headache
Hemicrania Continua or other precipitating events, which can include sneezing,
The essential features of hemicrania continua are moder- straining, laughing, or stooping. In all patients with this
ate and continuous unilateral pain associated with uctu- syndrome serious etiologies must be excluded before a
ations of severe pain; complete resolution of pain with diagnosis of benign primary cough headache can be
indomethacin; and exacerbations that may be associated established. A Chiari malformation or any lesion causing
with autonomic features, including conjunctival injec- obstruction of CSF pathways or displacing cerebral struc-
tion, lacrimation, and photophobia on the affected side. tures can be the cause of the head pain. Other conditions
The age of onset ranges from 11 to 58 years; women are that can present with cough or exertional headache as the
affected twice as often as men.The cause is unknown. initial symptom include cerebral aneurysm, carotid steno-
sis, and vertebrobasilar disease. Benign cough headache
can resemble benign exertional headache (below), but
patients with the former condition are typically older.
Treatment:
HEMICRANIA CONTINUA
Treatment consists of indomethacin; other NSAIDs
appear to be of little or no benet. The intramuscular Treatment:
PRIMARY COUGH HEADACHE
injection of 100 mg indomethacin has been proposed
as a diagnostic tool; administration with a placebo Indomethacin 2550 mg two to three times daily is the
injection has been recommended. Alternatively, a trial of treatment of choice. Some patients with cough headache
oral indomethacin, starting with 25 mg tid, then 50 mg obtain pain relief with LP; this is a simple option when
tid, and then 75 mg tid, can be given. Up to 2 weeks may compared to prolonged use of indomethacin, and it is
be necessary to assess whether a dose has a useful effective in about one-third of patients. The mechanism
effect. Topiramate can be helpful in some patients. of this response is unclear.
Occipital nerve stimulation may have a role in patients
with hemicrania continua who are unable to tolerate
indomethacin.
Primary Exertional Headache
Primary exertional headache has features resembling
both cough headache and migraine. It may be precipi-
Primary Stabbing Headache
tated by any form of exercise; it often has the pulsatile
The essential features of primary stabbing headache are quality of migraine.The pain, which can last from 5 min
stabbing pain conned to the head or, rarely, the face, last- to 24 h, is bilateral and throbbing at onset; migrainous
ing from 1 to many seconds or minutes and occurring as features may develop in patients susceptible to migraine.
a single stab or a series of stabs; absence of associated cra- Primary exertional headache can be prevented by avoid-
nial autonomic features; absence of cutaneous triggering ing excessive exertion, particularly in hot weather or at
of attacks; and a pattern of recurrence at irregular intervals high altitude.
(hours to days). The pains have been variously described The mechanism of primary exertional headache is
as ice-pick pains or jabs and jolts.They are more com- unclear. Acute venous distension likely explains one syn-
mon in patients with other primary headaches, such as drome, the acute onset of headache with straining and
migraine, the TACs, and hemicrania continua. breath holding, as in weightlifters headache. As exertion
 68 can result in headache in a number of serious underlying advice about ceasing sexual activity if a mild, warning
conditions, these must be considered in patients with exer- headache develops. Propranolol can be used to prevent
tional headache. Pain from angina may be referred to the headache that recurs regularly or frequently, but the
head, probably by central connections of vagal afferents, and dosage required varies from 40 to 200 mg/d. An alterna-
may present as exertional headache (cardiac cephalgia).The tive is the calcium channel-blocking agent diltiazem, 60
link to exercise is the main clinical clue that headache is of mg tid. Ergotamine (1 mg) or indomethacin (2550 mg)
cardiac origin. Pheochromocytoma may occasionally cause taken about 3045 min prior to sexual activity can also
exertional headache. Intracranial lesions and stenosis of the be helpful.
carotid arteries are other possible etiologies.
SECTION II

Primary Thunderclap Headache

Treatment:
PRIMARY EXERTIONAL HEADACHE Sudden onset of severe headache may occur in the absence
Exercise regimens should begin modestly and progress of any known provocation. The differential diagnosis
gradually to higher levels of intensity. Indomethacin at includes the sentinel bleed of an intracranial aneurysm, cer-
vicocephalic arterial dissection, and cerebral venous throm-
Clinical Manifestations of Neurologic Disease

daily doses from 25 to 150 mg is generally effective in

benign exertional headache. Indomethacin (50 mg), bosis. Headaches of explosive onset may also be caused by
ergotamine (1 mg orally), dihydroergotamine (2 mg by the ingestion of sympathomimetic drugs or of tyramine-
nasal spray), or methysergide (12 mg orally given 3045 containing foods in a patient who is taking MAOIs, or they
min before exercise) are useful prophylactic measures. may be a symptom of pheochromocytoma.Whether thun-
derclap headache can be the presentation of an unruptured
cerebral aneurysm is uncertain.When neuroimaging studies
Primary Sex Headache and LP exclude subarachnoid hemorrhage, patients with
thunderclap headache usually do very well over the long
Sex headache is precipitated by sexual excitement. The term. In one study of patients whose CT scans and CSF
pain usually begins as a dull bilateral headache which sud- ndings were negative, ~15% had recurrent episodes of
denly becomes intense at orgasm. The headache can be thunderclap headache, and nearly half subsequently devel-
prevented or eased by ceasing sexual activity before orgasm. oped migraine or tension-type headache.
Three types of sex headache are reported: a dull ache in The rst presentation of any sudden-onset severe
the head and neck that intensies as sexual excitement headache should be vigorously investigated with neu-
increases; a sudden, severe, explosive headache occurring at roimaging (CT or, when possible, MRI with MR
orgasm; and a postural headache developing after coitus angiography) and CSF examination. Formal cerebral
that resembles the headache of low CSF pressure.The lat- angiography should be reserved for those cases in which
ter arises from vigorous sexual activity and is a form of low no primary diagnosis is forthcoming and for clinical
CSF pressure headache. Headaches developing at the time situations that are particularly suggestive of intracranial
of orgasm are not always benign; 512% of cases of sub- aneurysm. Reversible segmental cerebral vasoconstric-
arachnoid hemorrhage are precipitated by sexual inter- tion may be seen in primary thunderclap headache
course. Sex headache is reported by men more often than without an intracranial aneurysm. In the presence of
women and may occur at any time during the years of posterior leukoencephalopathy, the differential diagnosis
sexual activity. It may develop on several occasions in suc- includes cerebral angiitis, drug toxicity (cyclosporine,
cession and then not trouble the patient again, even with- intrathecal methotrexate/cytarabine, pseudoephedrine,
out an obvious change in sexual activity. In patients who or cocaine), posttransfusion effects, and postpartum
stop sexual activity when headache is rst noticed, the pain angiopathy. Treatment with nimodipine may be helpful,
may subside within a period of 5 min to 2 h. In about half although by denition the vasoconstriction of primary
of patients, sex headache will subside within 6 months. thunderclap headache resolves spontaneously.
About half of patients with sex headache have a history of
exertional headaches, but there is no excess of cough
Hypnic Headache
headache. Migraine is probably more common in patients
with sex headache. This headache syndrome typically begins a few hours after
sleep onset.The headaches last from 15 to 30 min and are
typically moderately severe and generalized, although
Treatment: they may be unilateral and can be throbbing. Patients may
PRIMARY SEX HEADACHE report falling back to sleep only to be awakened by a fur-
ther attack a few hours later; up to three repetitions of
Benign sex headaches recur irregularly and infrequently.
this pattern occur through the night. Daytime naps can
Management can often be limited to reassurance and
also precipitate head pain. Most patients are women, and
the onset is usually after age 60. Headaches are bilateral in FURTHER READINGS 69
most, but may be unilateral. Photophobia or phonopho- CITTADINI E et al: Paroxysmal hemicrania: A prospective clinical
bia and nausea are usually absent. The major secondary study of 31 cases. Brain 131:1142, 2008
consideration in this headache type is poorly controlled COHEN AS et al:Trigeminal autonomic cephalalgias: Current and future
hypertension; 24-h blood pressure monitoring is recom- treatments. Headache 47:969, 2007
mended to detect this treatable condition. GOADSBY PJ: Is medication-overuse headache a distinct biological
entity? Nat Clin Pract Neurol 2:401, 2006
HAUGE AW et al: Effects of tonabersat on migraine with aura: a ran-
domised, double-blind, placebo-controlled crossover study. Lancet
Treatment: Neurol 8:718, 2009

CHAPTER 6
HYPNIC HEADACHE HEADACHE Classication Committee of the International Headache
Society: The international classication of headache disorders
Patients with hypnic headache generally respond to a
(second edition). Cephalalgia 24:1, 2004
bedtime dose of lithium carbonate (200600 mg). For LANCE JW, Goadsby PJ: Mechanism and Management of Headache. New
those intolerant of lithium, verapamil (160 mg) or York, Elsevier, 2005
methysergide (14 mg at bedtime) may be alternative LEVY M et al:The clinical characteristics of headache in patients with
strategies. One to two cups of coffee or caffeine, 60 mg pituitary tumours. Brain 128:1921, 2005

Headache
orally, at bedtime may be effective in approximately OLESEN J et al: The Headaches. Philadelphia, Lippincott, Williams &
one-third of patients. Case reports suggest that unar- Wilkins, 2005
SCHER AI et al: Migraine Headache in Middle Age and Late-Life
izine, 5 mg nightly, can be effective.
Brain Infarcts. JAMA 301:2563, 2009.
 CHAPTER 7

BACK AND NECK PAIN

John W. Engstrom

I Anatomy of the Spine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Other Causes of Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

I Causes of Back Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 I Pain In the Neck and Shoulder . . . . . . . . . . . . . . . . . . . . . . . . 82
Congenital Anomalies of the Lumbar Spine . . . . . . . . . . . . . . . 74 Trauma to the Cervical Spine . . . . . . . . . . . . . . . . . . . . . . . . . 82
Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cervical Disk Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Lumbar Disk Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Cervical Spondylosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Degenerative Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Other Causes of Neck Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77 Thoracic Outlet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Brachial Plexus and Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Infections/Inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Shoulder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Metabolic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Referred Pain from Visceral Disease . . . . . . . . . . . . . . . . . . . . 78

The importance of back and neck pain in our society is The posterior portion of the spine consists of the ver-
underscored by the following: (1) the cost of back pain tebral arches and seven processes. Each arch consists of
in the United States is ~$100 billion annually, including paired cylindrical pedicles anteriorly and paired laminae
direct health care expenses plus costs due to loss of pro- posteriorly.The vertebral arch gives rise to two transverse
ductivity; (2) back symptoms are the most common processes laterally, one spinous process posteriorly, plus
cause of disability in those <45 years; (3) low back pain two superior and two inferior articular facets.The appo-
is the second most common reason for visiting a physi- sition of a superior and inferior facet constitutes a facet
cian in the United States; and (4) ~1% of the U.S. popu- joint. The functions of the posterior spine are to protect
lation is chronically disabled because of back pain. the spinal cord and nerves within the spinal canal and to
stabilize the spine by providing sites for the attachment
of muscles and ligaments. The contraction of muscles
ANATOMY OF THE SPINE attached to the spinous and transverse processes produces
a system of pulleys and levers that results in exion,
The anterior portion of the spine consists of cylindrical extension, and lateral bending movements of the spine.
vertebral bodies separated by intervertebral disks and Nerve root injury (radiculopathy) is a common cause
held together by the anterior and posterior longitudinal of neck, arm, low back, and leg pain (Figs. 12-2 and 12-3).
ligaments. The intervertebral disks are composed of a The nerve roots exit at a level above their respective
central gelatinous nucleus pulposus surrounded by a vertebral bodies in the cervical region (the C7 nerve root
tough cartilaginous ring, the annulus brosis; disks are exits at the C6-C7 level) and below their respective ver-
responsible for 25% of spinal column length (Figs. 7-1 tebral bodies in the thoracic and lumbar regions (the T1
and 7-2).The disks are largest in the cervical and lumbar nerve root exits at the T1-T2 level). The cervical nerve
regions where movements of the spine are greatest. The roots follow a short intraspinal course before exiting. By
disks are elastic in youth and allow the bony vertebrae contrast, because the spinal cord ends at the vertebral L1
to move easily upon each other. Elasticity is lost with or L2 level, the lumbar nerve roots follow a long
age. The function of the anterior spine is to absorb the intraspinal course and can be injured anywhere from the
shock of body movements such as walking and running. upper lumbar spine to their exit at the intervertebral
70
 Posterior Posterior Anterior 71
Spinous process Superior articular Superior vertebral
process notch
Superior Intervertebral
articular Lamina Transverse foramen
process process

Spinous
process Intervertebral

CHAPTER 7
disk
Transverse Pedicle
process
Body
FIGURE 7-1
Spinal canal Body Vertebral anatomy. (From A
Gauthier Cornuelle, DH Gronefeld:
Inferior articular Inferior vertebral
Radiographic Anatomy Positioning.

Back and Neck Pain

process (facet) notch
New York, McGraw-Hill, 1998; with
A Anterior B permission.)

foramen. For example, disk herniation at the L4-L5 level brosus of the intervertebral disk, epidural veins, and the
commonly produces compression of the traversing S1 posterior longitudinal ligament. Disease of these diverse
nerve root (Fig.7-3). structures may explain many cases of back pain without
Pain-sensitive structures in the spine include the nerve root compression. The nucleus pulposus of the
periosteum of the vertebrae, dura, facet joints, annulus intervertebral disk is not pain-sensitive under normal
circumstances. Pain sensation is conveyed partially by the
sinuvertebral nerve that arises from the spinal nerve at
1
2
each spine segment and reenters the spinal canal
3 Cervical through the intervertebral foramen at the same level.
4
Cervical (7) curvature The lumbar and cervical spine possesses the greatest
5
6
7
potential for movement and injury.
1
2
3
4
5
Thoracic
6
curvature
7
Thoracic (12) 8 4th Lumbar
9 pedicle 4th Lumbar
vertebral body
10
L4 root
11
12
Protruded
1 L4L5 disk
5th Lumbar
2 vertebral body

L5 Root
3
Lumbar
Lumbar (5) curvature Protruded
4 L5S1 disk

5 S1 Root

Sacrum Sacral
S2 Root
curvature
Coccyx

Anterior view Right lateral view

FIGURE 7-2 FIGURE 7-3
Spinal column. (From A Gauthier Cornuelle, DH Gronefeld: Compression of L5 and S1 roots by herniated disks.
Radiographic Anatomy Positioning. New York, McGraw-Hill, (From RD Adams et al: Principles of Neurology, 8th ed. New
1998; with permission.) York, McGraw-Hill, 2005; with permission.)
 72 of abdominal muscles (lifting heavy objects or strain-
Approach to the Patient:
BACK PAIN
ing at stool) may elicit the radiating pain. The pain
may increase in postures that stretch the nerves and
TYPES OF BACK PAIN Understanding the type of nerve roots. Sitting stretches the sciatic nerve (L5 and
pain experienced by the patient is the essential rst step. S1 roots) because the nerve passes posterior to the
Attention is also focused on identication of risk factors hip. The femoral nerve (L2, L3, and L4 roots) passes
for serious underlying diseases; the majority of these are anterior to the hip and is not stretched by sitting.The
due to radiculopathy, fracture, tumor, infection, or description of the pain alone often fails to distinguish
referred pain from visceral structures (Table 7-1). between sclerotomal pain and radiculopathy.
SECTION II

Local pain is caused by stretching of pain-sensitive Pain associated with muscle spasm, although of obscure
structures that compress or irritate sensory nerve origin, is commonly associated with many spine disor-
endings. The site of the pain is near the affected part ders. The spasms are accompanied by abnormal pos-
of the back. ture, taut paraspinal muscles, and dull pain.
Pain referred to the back may arise from abdominal or Knowledge of the circumstances associated with
pelvic viscera. The pain is usually described as pri- the onset of back pain is important when weighing
Clinical Manifestations of Neurologic Disease

marily abdominal or pelvic but is accompanied by possible serious underlying causes for the pain. Some
back pain and usually unaffected by posture. The patients involved in accidents or work-related injuries
patient may occasionally complain of back pain only. may exaggerate their pain for the purpose of com-
Pain of spine origin may be located in the back or pensation or for psychological reasons.
referred to the buttocks or legs. Diseases affecting the EXAMINATION OF THE BACK A physical
upper lumbar spine tend to refer pain to the lumbar examination that includes the abdomen and rectum is
region, groin, or anterior thighs. Diseases affecting the advisable. Back pain referred from visceral organs may
lower lumbar spine tend to produce pain referred to be reproduced during palpation of the abdomen [pan-
the buttocks, posterior thighs, or rarely the calves or creatitis, abdominal aortic aneurysm (AAA)] or per-
feet. Provocative injections into pain-sensitive struc- cussion over the costovertebral angles (pyelonephritis).
tures of the lumbar spine may produce leg pain that The normal spine has cervical and lumbar lordosis,
does not follow a dermatomal distribution.This scle- and a thoracic kyphosis. Exaggeration of these nor-
rotomal pain may explain some cases of back and leg mal alignments may result in hyperkyphosis of the
pain without evidence of nerve root compression. thoracic spine or hyperlordosis of the lumbar spine.
Radicular back pain is typically sharp and radiates Inspection may reveal a lateral curvature of the spine
from the lumbar spine to the leg within the territory (scoliosis) or an asymmetry in the paraspinal muscles,
of a nerve root (see Lumbar Disk Disease, later in the suggesting muscle spasm. Back pain of bony spine
chpater). Coughing, sneezing, or voluntary contraction origin is often reproduced by palpation or percussion
over the spinous process of the affected vertebrae.
Forward bending is often limited by paraspinal
TABLE 7-1
muscle spasm; the latter may atten the usual lumbar
ACUTE LOW BACK PAIN: RISK FACTORS FOR AN lordosis. Flexion of the hips is normal in patients with
IMPORTANT STRUCTURAL CAUSE
lumbar spine disease, but exion of the lumbar spine
History is limited and sometimes painful. Lateral bending to
Pain worse at rest or at night the side opposite the injured spinal element may
Prior history of cancer stretch the damaged tissues, worsen pain, and limit
History of chronic infection (esp. lung, urinary tract, skin) motion. Hyperextension of the spine (with the
History of trauma
Incontinence
patient prone or standing) is limited when nerve root
Age >50 years compression, facet joint pathology, or other bony
Intravenous drug use spine disease is present.
Glucocorticoid use Pain from hip disease may mimic pain of lumbar
History of a rapidly progressive neurologic decit spine disease. Hip pain can be reproduced by internal
Examination and external rotation at the hip with the knee and
Unexplained fever hip in exion (Patrick sign) and by tapping the heel
Unexplained weight loss
with the examiners palm while the leg is extended.
Percussion tenderness over the spine
Abdominal, rectal, or pelvic mass With the patient lying at, passive exion of the
Patricks sign or heel percussion sign extended leg at the hip stretches the L5 and S1 nerve
Straight leg or reverse straight-leg raising signs roots and the sciatic nerve. Passive dorsiflexion of
Progressive focal neurologic decit the foot during the maneuver adds to the stretch.
 While exion to at least 80 is normally possible may be due to pain or a combination of pain and 73
without causing pain, tight hamstring muscles are a underlying true weakness. Breakaway weakness with-
source of pain in some patients. The straight legraising out pain is due to lack of effort. In uncertain cases,
(SLR) test is positive if the maneuver reproduces the electromyography (EMG) can determine whether or
patients usual back or limb pain. Eliciting the SLR not true weakness is present. Findings with specic
sign in the sitting position may help determine if the nerve root lesions are shown in Table 7-2 and are
nding is reproducible.The patient may describe pain discussed below.
in the low back, buttocks, posterior thigh, or lower
leg, but the key feature is reproduction of the patients LABORATORY, IMAGING, AND EMG STUDIES

CHAPTER 7
usual pain. The crossed SLR sign is positive when ex- Routine laboratory studies are rarely needed for the
ion of one leg reproduces the pain in the opposite leg initial evaluation of nonspecic acute (<3 months
or buttocks. The crossed SLR sign is less sensitive but duration) low back pain (ALBP). If risk factors for a
more specic for disk herniation than the SLR sign. serious underlying cause are present, then laboratory
The nerve or nerve root lesion is always on the side studies [complete blood count (CBC), erythrocyte
of the pain.The reverse SLR sign is elicited by standing sedimentation rate (ESR), urinalysis] are indicated.

Back and Neck Pain

the patient next to the examination table and passively CT scanning is superior to routine x-rays for the
extending each leg with the knee fully extended.This detection of fractures involving posterior spine struc-
maneuver, which stretches the L2-L4 nerve roots and tures, craniocervical and craniothoracic junctions, C1
the femoral nerve, is considered positive if the patients and C2 vertebrae, bone fragments within the spinal
usual back or limb pain is reproduced. canal, or malalignment; CT scans are increasingly used
The neurologic examination includes a search for as a primary screening modality for moderate to severe
focal weakness or muscle atrophy, focal reex changes, trauma. In the absence of risk factors, these imaging
diminished sensation in the legs, and signs of spinal studies are rarely helpful in nonspecic ALBP. MRI
cord injury.The examiner should be alert to the pos- and CT-myelography are the radiologic tests of choice
sibility of breakaway weakness, dened as uctuating for evaluation of most serious diseases involving the
strength during muscle testing. Breakaway weakness spine. MRI is superior for the denition of soft tissue

TABLE 7-2
LUMBOSACRAL RADICULOPATHYNEUROLOGIC FEATURES
EXAMINATION FINDINGS
LUMBOSACRAL PAIN
NERVE ROOTS REFLEX SENSORY MOTOR DISTRIBUTION

L2a Upper anterior thigh Psoas (hip exion) Anterior thigh

L3a Lower anterior thigh Psoas (hip exion) Anterior thigh, knee
Anterior knee Quadriceps (knee extension)
Thigh adduction
L4a Quadriceps Medial calf Quadriceps (knee extension)b Knee, medial calf
(knee) Thigh adduction
Tibialis anterior (foot Anterolateral thigh
dorsiexion)
L5c Dorsal surfacefoot Peroneii (foot eversion)b Lateral calf, dorsal foot,
Lateral calf Tibialis anterior (foot posterolateral thigh, buttocks
dorsiexion)
Gluteus medius (hip
abduction)
Toe dorsiexors
S1c Gastrocnemius/ Plantar surfacefoot Gastrocnemius/soleus (foot Bottom foot, posterior calf,
soleus (ankle) plantar exion)b posterior thigh, buttocks
Lateral aspectfoot Abductor hallucis (toe
exors)b
Gluteus maximus (hip
extension)

a
Reverse straight legraising sign presentsee Examination of the Back.
b
These muscles receive the majority of innervation from this root.
c
Straight legraising sign presentsee Examination of the Back.
 74 structures, whereas CT-myelography provides optimal TABLE 7-3
imaging of the lateral recess of the spinal canal and CAUSES OF BACK AND NECK PAIN
bony lesions and is tolerated by claustrophobic Congenital/developmental
patients.While the added diagnostic value of modern Spondylolysis and spondylolisthesisa
neuroimaging is signicant, there is concern that Kyphoscoliosisa
these studies may be overutilized in patients with Spina bida occultaa
ALBP. Tethered spinal corda
Minor trauma
Electrodiagnostic studies can be used to assess the Strain or sprain
functional integrity of the peripheral nervous system Whiplash injuryb
SECTION II

(Chap. 3). Sensory nerve conduction studies are nor- Fractures

mal when focal sensory loss is due to nerve root Traumaticfalls, motor vehicle accidents
damage because the nerve roots are proximal to the Atraumaticosteoporosis, neoplastic inltration,
nerve cell bodies in the dorsal root ganglia.The diag- exogenous steroids
nostic yield of needle EMG is higher than that of Intervertebral disk herniation
Degenerative
nerve conduction studies for radiculopathy. Denerva-
Disk-osteophyte complex
Clinical Manifestations of Neurologic Disease

tion changes in a myotomal (segmental) distribution Internal disk disruption

are detected by sampling multiple muscles supplied Spinal stenosis with neurogenic claudicationa
by different nerve roots and nerves; the pattern of Uncovertebral joint diseaseb
muscle involvement indicates the nerve root(s) Atlantoaxial joint disease (e.g., rheumatoid arthritis)a
responsible for the injury. Needle EMG provides Arthritis
objective information about motor nerve ber injury Spondylosis
Facet or sacroiliac arthropathy
when the clinical evaluation of weakness is limited by
Autoimmune (e.g., anklyosing spondylitis, Reiters
pain or poor effort. EMG and nerve conduction syndrome)
studies will be normal when only limb pain or sen- Neoplasmsmetastatic, hematologic, primary bone
sory nerve root injury or irritation is present. tumors
Infection/inammation
Vertebral osteomyelitis
Spinal epidural abscess
Septic disk
CAUSES OF BACK PAIN (Table 7-3) Meningitis
Lumbar arachnoiditisa
CONGENITAL ANOMALIES OF THE Metabolic
LUMBAR SPINE Osteoporosishyperparathyroidism, immobility
Osteosclerosis (e.g., Pagets disease)
Spondylolysis is a bony defect in the pars interarticularis
Vascular
(a segment near the junction of the pedicle with the Abdominal aortic aneurysm
lamina) of the vertebra; the etiology may be a stress frac- Vertebral artery dissectionb
ture in a congenitally abnormal segment. The defect Other
(usually bilateral) is best visualized on oblique projec- Referred pain from visceral disease
tions in plain x-rays, CT scan, or single photon emission Postural
CT (SPECT) bone scan and occurs in the setting of a Psychiatric, malingering, chronic pain syndromes
single injury, repeated minor injuries, or growth.
a
Although frequently asymptomatic, it is the most com- Low back pain only.
b
Neck pain only.
mon cause of persistent low back pain in adolescents
and is often activity-related.
Spondylolisthesis is the anterior slippage of the verte-
bral body, pedicles, and superior articular facets, leaving may be present on deep palpation of the posterior ele-
the posterior elements behind. Spondylolisthesis can be ments of the segment above the spondylolisthetic joint.
associated with spondylolysis, congenital anomalies of The trunk may be shortened and the abdomen protu-
the lumbosacral junction, infection, osteoporosis, tumor, berant as a result of extreme forward displacement of L4
trauma, prior surgery, or degenerative spine disease. It on L5; in severe cases cauda equina syndrome (CES)
occurs more frequently in women. The slippage may be may occur (see later). Surgery is considered for symp-
asymptomatic or may cause low back pain and ham- toms persisting for >1 year that do not respond to con-
string tightness, nerve root injury (the L5 root most fre- servative measures (e.g., rest, physical therapy). Surgery is
quently), or symptomatic spinal stenosis.Tenderness may usually indicated for cases with progressive neurologic
be elicited near the segment that has slipped forward decit, abnormal gait or postural deformity, slippage
(most often L4 on L5 or occasionally L5 on S1).A step >50%, or scoliosis.
 Spina bida occulta is a failure of closure of one or sev- 75
eral vertebral arches posteriorly; the meninges and spinal
cord are normal. A dimple or small lipoma may overlie
the defect. Most cases are asymptomatic and discovered
incidentally during evaluation for back pain.
Tethered cord syndrome usually presents as a progressive
cauda equina disorder (see later), although myelopathy
may also be the initial manifestation.The patient is often
a young adult who complains of perineal or perianal

CHAPTER 7
pain, sometimes following minor trauma. Neuroimaging
studies reveal a low-lying conus (below L1-L2) and a
short and thickened lum terminale.

TRAUMA
A patient with a complaint of back pain and inability to

Back and Neck Pain

move the legs may have a spinal fracture or dislocation,
FIGURE 7-4
and, with fractures above L1, spinal cord compression.
MRI of lumbar herniated disk; left S1 radiculopathy. Sagit-
Care must be taken to avoid further damage to the
tal T1-weighted image on the left with arrows outlining disk
spinal cord or nerve roots by immobilizing the back
margins. Sagittal T2 image on the right reveals a protruding
pending results of x-rays. disk at the L5S1 level (arrows), which displaces the central
thecal sac.
Sprains and Strains
The terms low back sprain, strain, or mechanically induced
muscle spasm refer to minor, self-limited injuries associ- individuals. Disk herniation is unusual prior to age 20
ated with lifting a heavy object, a fall, or a sudden decel- and is rare in the brotic disks of the elderly. Degenera-
eration such as in an automobile accident. These terms tion of the nucleus pulposus and the annulus brosus
are used loosely and do not clearly describe a specic increases with age and may be asymptomatic or painful.
anatomic lesion. The pain is usually conned to the Genetic factors may play a role in predisposing some
lower back, and there is no radiation to the buttocks or patients to disk degeneration. The pain may be located
legs. Patients with paraspinal muscle spasm often assume in the low back only or referred to the leg, buttock, or
unusual postures. hip. A sneeze, cough, or trivial movement may cause the
nucleus pulposus to prolapse, pushing the frayed and
Traumatic Vertebral Fractures weakened annulus posteriorly. With severe disk disease,
the nucleus may protrude through the annulus (hernia-
Most traumatic fractures of the lumbar vertebral bodies tion) or become extruded to lie as a free fragment in the
result from injuries producing anterior wedging or spinal canal.
compression.With severe trauma, the patient may sustain The mechanism by which intervertebral disk injury
a fracture-dislocation or a burst fracture involving the causes back pain is controversial. The inner annulus
vertebral body and posterior elements. Traumatic verte- brosus and nucleus pulposus are normally devoid of
bral fractures are caused by falls from a height (a pars innervation. Inammation and production of proinam-
interarticularis fracture of the L5 vertebra is common), matory cytokines within the protruding or ruptured
sudden deceleration in an automobile accident, or direct disk may trigger or perpetuate back pain. Ingrowth of
injury. Neurologic impairment is common, and early nociceptive (pain) nerve bers into inner portions of a
surgical treatment is indicated. In victims of blunt diseased disk may be responsible for chronic disko-
trauma, CT scans of the chest, abdomen, or pelvis can genic pain. Nerve root injury (radiculopathy) from disk
be reformatted to detect associated vertebral fractures. herniation may be due to compression, inammation, or
both; pathologically, demyelination and axonal loss are
usually present.
LUMBAR DISK DISEASE
Symptoms of a ruptured disk include back pain,
This is a common cause of chronic or recurrent low abnormal posture, limitation of spine motion (particu-
back and leg pain (Figs. 7-3 and 7-4). Disk disease is larly exion), or radicular pain. A dermatomal pattern of
most likely to occur at the L4-L5 and L5-S1 levels, but sensory loss or a reduced or absent deep tendon reex is
upper lumbar levels are involved occasionally. The cause more suggestive of a specic root lesion than is the pat-
is often unknown; the risk is increased in overweight tern of pain. Motor ndings (focal weakness, muscle
 76 atrophy, or fasciculations) occur less frequently than treatment should also be considered if steady pain
focal sensory or reex changes. Symptoms and signs are and/or neurologic ndings do not substantially improve
usually unilateral, but bilateral involvement does occur over 412 weeks.
with large central disk herniations that compress multi- The usual surgical procedure is a partial hemil-
ple descending nerve roots within the spinal canal. Clin- aminectomy with excision of the prolapsed disk. Fusion
ical manifestations of specic nerve root lesions are of the involved lumbar segments should be considered
summarized in Table 7-2. There is suggestive evidence only if signicant spinal instability is present (i.e., degen-
that lumbar disk herniation with a nonprogressive nerve erative spondylolisthesis or isthmic spondylolysis). Over
root decit can be managed nonsurgically. The size of a recent 5-year period, the number of lumbar fusion
the disk protrusion may naturally decrease over time. procedures performed in the United States more than
SECTION II

The differential diagnosis covers a variety of serious doubled, for uncertain reasons. There are no large
and treatable conditions, including epidural abscess, prospective, randomized trials comparing fusion to other
hematoma, or tumor. Fever, constant pain uninuenced types of surgical intervention. In one study, patients with
by position, sphincter abnormalities, or signs of spinal persistent low back pain despite an initial diskectomy
cord disease suggests an etiology other than lumbar disk fared no better with spine fusion than with a conserva-
disease. Bilateral absence of ankle reexes can be a nor- tive regimen of cognitive intervention and exercise.
Clinical Manifestations of Neurologic Disease

mal nding in old age or a sign of bilateral S1 radicu- Cauda equina syndrome (CES) signies an injury of
lopathy. An absent deep tendon reex or focal sensory multiple lumbosacral nerve roots within the spinal canal.
loss may indicate injury to a nerve root, but other sites Low back pain, weakness and areexia in the legs, saddle
of injury along the nerve must also be considered. For anesthesia, and loss of bladder function may occur. The
example, an absent knee reex may be due to a femoral problem must be distinguished from disorders of the lower
neuropathy or an L4 nerve root injury. A loss of sensa- spinal cord (conus medullaris syndrome), acute transverse
tion over the foot and lateral lower calf may result from myelitis (Chap. 30), and Guillain-Barr syndrome (Chap. 41).
a peroneal or lateral sciatic neuropathy or an L5 nerve Combined involvement of the conus medullaris and
root injury. Focal muscle atrophy may reect a nerve cauda equina can occur. CES is commonly due to a
root or peripheral nerve injury, an anterior horn cell ruptured lumbosacral intervertebral disk, lumbosacral
disease, or disuse. spine fracture, hematoma within the spinal canal (e.g.,
An MRI scan or CT-myelogram is necessary to estab- following lumbar puncture in patients with coagulopa-
lish the location and type of pathology. Spinal MRI yields thy), compressive tumor, or other mass lesion.Treatment
exquisite views of intraspinal and adjacent soft tissue options include surgical decompression, sometimes
anatomy. Bony lesions of the lateral recess or interverte- urgently in an attempt to restore or preserve motor or
bral foramen are optimally visualized by CT-myelography. sphincter function, or radiotherapy for metastatic tumors
The correlation of neuroradiologic ndings to symptoms, (Chap. 32).
particularly pain, is not simple. Contrast-enhancing tears
in the annulus brosus or disk protrusions are widely
DEGENERATIVE CONDITIONS
accepted as common sources of back pain; however,
many studies have found that most asymptomatic adults Lumbar spinal stenosis describes a narrowed lumbar spinal
have similar ndings. Asymptomatic disk protrusions are canal. Neurogenic claudication is the usual symptom, con-
also common and may enhance with contrast. Further- sisting of back and buttock or leg pain induced by walk-
more, in patients with known disk herniation treated ing or standing and relieved by sitting. Symptoms in the
either medically or surgically, persistence of the hernia- legs are usually bilateral. Lumbar stenosis, by itself, is fre-
tion 10 years later had no relationship to the clinical quently asymptomatic, and the correlation between the
outcome. In summary, MRI ndings of disk protrusion, severity of symptoms and degree of stenosis of the spinal
tears in the annulus brosus, or contrast enhancement canal is poor. Unlike vascular claudication, symptoms are
are common incidental ndings that, by themselves, often provoked by standing without walking. Unlike lum-
should not dictate management decisions for patients bar disk disease, symptoms are usually relieved by sitting.
with back pain. Focal weakness, sensory loss, or reex changes may occur
There are four indications for intervertebral disk when spinal stenosis is associated with radiculopathy.
surgery: (1) progressive motor weakness from nerve root Severe neurologic decits, including paralysis and uri-
injury demonstrated on clinical examination or EMG, nary incontinence, occur rarely. Spinal stenosis can be
(2) bowel or bladder disturbance or other signs of spinal acquired (75%), congenital, or due to a combination of
cord compression, (3) incapacitating nerve root pain these factors. Congenital forms (achondroplasia, idio-
despite conservative treatment for 4 weeks at a mini- pathic) are characterized by short, thick pedicles that pro-
mum, and (4) recurrent incapacitating pain despite con- duce both spinal canal and lateral recess stenosis.Acquired
servative treatment.The latter two criteria are more sub- factors that contribute to spinal stenosis include degenera-
jective and less well established than the others. Surgical tive diseases (spondylosis, spondylolisthesis, scoliosis), trauma,
 with stiffness. The relationship between clinical symp- 77
toms and radiologic ndings is usually not straightfor-
ward. Pain may be prominent when x-ray, CT, or MRI
ndings are minimal, and large osteophytes can be seen
in asymptomatic patients. Radiculopathy occurs when
hypertrophied facets and osteophytes compress nerve
roots in the lateral recess or intervertebral foramen.
Osteophytes arising from the vertebral body may cause
or contribute to central spinal canal stenosis. Disc

CHAPTER 7
degeneration may also play a role in reducing the cross-
sectional area of the intervertebral foramen; the
descending pedicle may compress the exiting nerve
root. Rarely, osteoarthritic changes in the lumbar spine
A B are sufcient to compress the cauda equina.
FIGURE 7-5
Spinal stenosis. Sagittal T2 fast spin echo magnetic reso-

Back and Neck Pain

Ankylosing Spondylitis
nance imaging of a normal (A) and stenotic (B) lumbar spine,
revealing multifocal narrowing (arrows) of the cerebrospinal This distinctive arthritic spine disease typically presents
uid spaces surrounding the nerve roots within the thecal sac. with the insidious onset of low back and buttock pain.
Patients are often males below age 40. Associated fea-
tures include morning back stiffness, nocturnal pain,
spine surgery, metabolic or endocrine disorders (epidural pain unrelieved by rest, an elevated ESR, and the histo-
lipomatosis, osteoporosis, acromegaly, renal osteodystro- compatibility antigen HLA-B27. Onset at a young age
phy, hypoparathyroidism), and Pagets disease. MRI and back pain improving with exercise are characteristic.
provides the best denition of the abnormal anatomy Loss of the normal lumbar lordosis and exaggeration of
(Fig. 7-5). thoracic kyphosis develop as the disease progresses.
Conservative treatment of symptomatic spinal steno- Inammation and erosion of the outer bers of the
sis includes nonsteroidal anti-inammatory drugs annulus brosus at the point of contact with the verte-
(NSAIDs), exercise programs, and symptomatic treat- bral body are followed by ossication and bony growth
ment of acute pain episodes. Surgical therapy is consid- that bridges adjacent vertebral bodies and reduces spine
ered when medical therapy does not relieve symptoms mobility in all planes. Radiologic hallmarks are periar-
sufciently to allow for activities of daily living or when ticular destructive changes, sclerosis of the sacroiliac
signicant focal neurologic signs are present. Most joints, and bridging of vertebral bodies to produce the
patients with neurogenic claudication treated surgically fused bamboo spine.
experience at least 75% relief of back and leg pain. Up Stress fractures through the spontaneously ankylosed
to 25% develop recurrent stenosis at the same spinal posterior bony elements of the rigid, osteoporotic spine
level or an adjacent level 5 years after the initial surgery; may produce focal pain, spinal instability, spinal cord
recurrent symptoms usually respond to a second surgical compression, or CES. Atlantoaxial subluxation with
decompression. spinal cord compression occasionally occurs. Ankylosis
Facet joint hypertrophy can produce unilateral radicular of the ribs to the spine and a decrease in the height of
symptoms or signs due to bony compression; symptoms the thoracic spine may compromise respiratory func-
are often indistinguishable from disk-related radiculopa- tion. For many patients, therapy with anti-tumor necro-
thy. Stretch signs, focal motor weakness, hyporeexia, or sis factor agents is effective in reducing disease activity.
dermatomal sensory loss may be present. Hypertrophic Similar to ankylosing spondylitis, restricted movements
superior or inferior facets can be visualized by x-rays, may accompany Reiters syndrome, psoriatic arthritis,
CT, or MRI. Surgical foraminotomy results in long- and chronic inammatory bowel disease.
term relief of leg and back pain in 8090% of these
patients. The usefulness of therapeutic facet joint blocks NEOPLASMS
for pain has not been rigorously studied.
(See Chap. 32) Back pain is the most common neuro-
logic symptom in patients with systemic cancer and
ARTHRITIS may be the presenting symptom. The cause is usually
Spondylosis, or osteoarthritic spine disease, typically vertebral metastases. Metastatic carcinoma (breast, lung,
occurs in later life and primarily involves the cervical prostate, thyroid, kidney, gastrointestinal tract), multiple
and lumbosacral spine. Patients often complain of back myeloma, and non-Hodgkins and Hodgkins lymphomas
pain that is increased with movement and associated frequently involve the spine. Cancer-related back pain
 78 tends to be constant, dull, unrelieved by rest, and worse METABOLIC CAUSES
at night. By contrast, mechanical low back pain usually
Osteoporosis and Osteosclerosis
improves with rest. Plain x-rays may or may not show
destructive lesions in one or several vertebral bodies Immobilization or underlying conditions such as osteo-
without disk space involvement. MRI, CT, and CT- malacia, hyperparathyroidism, hyperthyroidism, multiple
myelography are the studies of choice when spinal myeloma, metastatic carcinoma, or glucocorticoid use may
metastasis is suspected. MRI is preferred, but the most accelerate osteoporosis and weaken the vertebral body, lead-
rapidly available procedure is best because the patients ing to compression fractures and pain. The most common
condition may worsen quickly. Less than 5% of patients causes of nontraumatic vertebral body fractures are post-
who are nonambulatory at the time of diagnosis ever menopausal (type 1) or senile (type 2) osteoporosis. Com-
SECTION II

regain the ability to walk, thus early diagnosis is crucial. pression fractures occur in up to half of patients with severe
osteoporosis, and those who sustain a fracture have a 4.5-
INFECTIONS/INFLAMMATION fold increased risk for recurrence.The sole manifestation of
a compression fracture may be localized back pain or radic-
Vertebral osteomyelitis is usually caused by staphylococci, ular pain exacerbated by movement and often reproduced
but other bacteria or tuberculosis (Potts disease) may be by palpation over the spinous process of the affected verte-
Clinical Manifestations of Neurologic Disease

responsible. The primary source of infection is usually bra.The clinical context, neurologic signs, and x-ray appear-
the urinary tract, skin, or lungs. Intravenous drug use is a ance of the spine establish the diagnosis. Antiresorptive
well-recognized risk factor. Whenever pyogenic drugs including bisphosphonates (e.g., alendronate), trans-
osteomyelitis is found, the possibility of bacterial endo- dermal estrogen, and tamoxifen have been shown to reduce
carditis should be considered. Back pain exacerbated by the risk of osteoporotic fractures. Fewer than one-third of
motion and unrelieved by rest, spine tenderness over the patients with prior compression fractures are adequately
involved spine segment, and an elevated ESR are the treated for osteoporosis despite the increased risk for future
most common ndings in vertebral osteomyelitis. Fever fractures; rates of primary prevention among individuals at
or an elevated white blood cell count is found in a risk, but without a history of fracture, are even less. Com-
minority of patients. Plain radiographs may show a nar- pression fractures above the midthoracic region suggest
rowed disk space with erosion of adjacent vertebrae; malignancy; if tumor is suspected, a bone biopsy or diagnos-
however, these diagnostic changes may take weeks or tic search for a primary tumor is indicated.
months to appear. MRI and CT are sensitive and spe- Interventions [percutaneous vertebroplasty (PVP),
cic for osteomyelitis; CT may be more readily available kyphoplasty] exist for osteoporotic compression fractures
in emergency settings and better tolerated by some associated with debilitating pain. Candidates for PVP have
patients with severe back pain. midline back pain, palpation tenderness over the spinous
Spinal epidural abscess (Chap. 30) presents with back process of the affected vertebral body, <80% loss of ver-
pain (aggravated by movement or palpation) and fever. tebral body height, and onset of symptoms within the
Signs of nerve root injury or spinal cord compression prior 4 months.The PVP technique consists of injection
may be present. The abscess may track over multiple of polymethylmethacrylate, under uoroscopic guidance,
spinal levels and is best delineated by spine MRI. into the affected vertebral body. Kyphoplasty adds the
Lumbar adhesive arachnoiditis with radiculopathy is due inflation of a balloon in the vertebral body prior to
to brosis following inammation within the subarach- the injection of cement. Rare complications can include
noid space. The brosis results in nerve root adhesions, extravasation of cement into the epidural space (resulting
and presents as back and leg pain associated with motor, in myelopathy) or fatal pulmonary embolism from migra-
sensory, or reex changes. Causes of arachnoiditis include tion of cement into paraspinal veins.Approximately three-
multiple lumbar operations, chronic spinal infections, quarters of patients who meet selection criteria have
spinal cord injury, intrathecal hemorrhage, myelography reported enhanced quality of life. Relief of pain follow-
(rare), intrathecal injection of glucocorticoids or anes- ing PVP has also been reported in patients with vertebral
thetics, and foreign bodies. The MRI shows clumped metastases, myeloma, or hemangiomas.
nerve roots located centrally or adherent to the dura Osteosclerosis, an abnormally increased bone density
peripherally, or loculations of cerebrospinal uid within often due to Pagets disease, is readily identiable on
the thecal sac. Clumped nerve roots may also occur with routine x-ray studies and may or may not produce back
demyelinating polyneuropathy or neoplastic inltration. pain. Spinal cord or nerve root compression may result
Treatment is usually unsatisfactory. Microsurgical lysis of from bony encroachment.
adhesions, dorsal rhizotomy, and dorsal root ganglionec-
tomy have been tried, but outcomes have been poor.
Dorsal column stimulation for pain relief has produced
REFERRED PAIN FROM VISCERAL DISEASE
varying results. Epidural injections of glucocorticoids Diseases of the thorax, abdomen, or pelvis may refer pain to
have been of limited value. the posterior portion of the spinal segment that innervates
the diseased organ. Occasionally, back pain may be the rst The pain is referred to the sacral region. Endometriosis 79
and only manifestation. Upper abdominal diseases gener- or uterine cancers may invade the uterosacral ligaments.
ally refer pain to the lower thoracic or upper lumbar region Pain associated with endometriosis is typically premen-
(eighth thoracic to the rst and second lumbar vertebrae), strual and often continues until it merges with men-
lower abdominal diseases to the mid-lumbar region (sec- strual pain. Uterine malposition may cause uterosacral
ond to fourth lumbar vertebrae), and pelvic diseases to ligament traction (retroversion, descensus, and prolapse)
the sacral region. Local signs (pain with spine palpation, or produce sacral pain after prolonged standing.
paraspinal muscle spasm) are absent, and little or no pain Menstrual pain may be felt in the sacral region. The
accompanies routine movements of the spine. poorly localized, cramping pain can radiate down the

CHAPTER 7
legs. Pain due to neoplastic inltration of nerves is typi-
cally continuous, progressive in severity, and unrelieved
Low Thoracic or Lumbar Pain with by rest at night. Less commonly, radiation therapy of
Abdominal Disease
pelvic tumors may produce sacral pain from late radia-
Peptic ulcers or tumors of the posterior wall of the tion necrosis of tissue or nerves. Low back pain that
stomach or duodenum typically produce epigastric pain, radiates into one or both thighs is common in the last
but midline back or paraspinal pain may occur if weeks of pregnancy.

Back and Neck Pain

retroperitoneal extension is present. Fatty foods are Urologic sources of lumbosacral back pain include
more likely to induce back pain associated with biliary chronic prostatitis, prostate cancer with spinal metastasis
disease. Diseases of the pancreas produce back pain to (Chap. 32), and diseases of the kidney and ureter. Lesions
the right of the spine (head of the pancreas involved) or of the bladder and testes do not usually produce back
to the left (body or tail involved). Pathology in retroperi- pain. Infectious, inammatory, or neoplastic renal dis-
toneal structures (hemorrhage, tumors, pyelonephritis) eases may produce ipsilateral lumbosacral pain, as can
produces paraspinal pain that radiates to the lower renal artery or vein thrombosis. Paraspinal lumbar pain
abdomen, groin, or anterior thighs. A mass in the iliop- may be a symptom of ureteral obstruction due to
soas region often produces unilateral lumbar pain with nephrolithiasis.
radiation toward the groin, labia, or testicles.The sudden
appearance of lumbar pain in a patient receiving antico-
OTHER CAUSES OF BACK PAIN
agulants suggests retroperitoneal hemorrhage.
Isolated low back pain occurs in 1520% of patients Postural Back Pain
with a contained rupture of an AAA. The classic clinical There is a group of patients with nonspecic chronic
triad of abdominal pain, shock, and back pain occurs in low back pain (CLBP) in whom no anatomic lesion can
<20% of patients.Two of these three features are present be found despite exhaustive investigation.These individ-
in two-thirds of patients, and hypotension is present in uals complain of vague, diffuse back pain with pro-
half. The typical patient is an elderly male smoker with longed sitting or standing that is relieved by rest. The
back pain. Frequently, the diagnosis is initially missed physical examination is unrevealing except for poor
because the symptoms and signs can be nonspecic. posture. Imaging studies and laboratory evaluations do
Common misdiagnoses include nonspecic back pain, not identify a specic cause. Exercises to strengthen the
diverticulitis, renal colic, sepsis, and myocardial infarction. paraspinal and abdominal muscles are sometimes helpful.
A careful abdominal examination revealing a pulsatile
mass (present in 5075% of patients) is an important
physical nding. Patients with suspected AAA should be Psychiatric Disease
evaluated with abdominal ultrasound, CT, or MRI. CLBP may be encountered in patients who seek nan-
Inammatory bowel disorders (colitis, diverticulitis) or cial compensation; in malingerers; or in those with con-
cancers of the colon may produce lower abdominal pain, current substance abuse, chronic anxiety states, or
midlumbar back pain, or both.The pain may have a belt- depression. Many patients with CLBP have a history of
line distribution around the body. A lesion in the trans- psychiatric illness (depression, anxiety, substance abuse)
verse or proximal descending colon may refer pain to the or childhood trauma (physical or sexual abuse) that
mid or left back at the L2-L3 level. Lesions of the sigmoid antedates the onset of back pain. Preoperative psycho-
colon may refer pain to the upper sacral or midline supra- logical assessment has been used to exclude patients
pubic regions or left lower quadrant of the abdomen. with marked psychological impairments that predict a
poor surgical outcome.
Sacral Pain with Gynecologic
and Urologic Disease Unidentied
Pelvic organs rarely cause low back pain, except for gyne- The cause of low back pain occasionally remains unclear.
cologic disorders involving the uterosacral ligaments. Some patients have had multiple operations for disk
 80 disease but have persistent pain and disability.The origi- collars can be modestly helpful by limiting spontaneous
nal indications for surgery may have been questionable, and reex neck movements that exacerbate pain. Evi-
with back pain only, no denite neurologic signs, or a dence regarding the efcacy of ice is lacking; heat may
minor disk bulge noted on CT or MRI. Scoring sys- provide a short-term reduction in pain and disability.
tems based upon neurologic signs, psychological factors, These interventions are optional given the lack of nega-
physiologic studies, and imaging studies have been devised tive evidence, low cost, and low risk. Biofeedback has
to minimize the likelihood of unsuccessful surgery. not been studied rigorously. Facet joint, trigger point,
and ligament injections are not recommended for acute
treatment.
SECTION II

Treatment: A role for modication of posture has not been vali-

BACK PAIN dated by rigorous clinical studies. As a practical matter,
temporary suspension of activity known to increase
ACUTE LOW BACK PAIN (ALBP) ALBP is mechanical stress on the spine (heavy lifting, prolonged
dened as pain of <3 months duration. Full recovery can sitting, bending or twisting, straining at stool) may be
be expected in 85% of adults with ALBP without leg helpful.
Clinical Manifestations of Neurologic Disease

pain. Most have purely mechanical symptoms (i.e., pain Education is an important part of treatment. Satisfac-
that is aggravated by motion and relieved by rest). tion and the likelihood of follow-up increase when
Observational studies have been used to justify a patients are educated about prognosis, treatment
minimalist approach to this problem. These studies methods, activity modications, and strategies to pre-
share a number of limitations: (1) a true placebo control vent future exacerbations. In one study, patients who
group is often lacking; (2) patients who consult different felt they did not receive an adequate explanation for
provider groups (generalists, orthopedists, neurologists) their symptoms wanted further diagnostic tests. Evi-
are assumed to have similar etiologies for their back dence for the efcacy of structured education programs
pain; (3) no information is provided about the details of (back school) is inconclusive; there is modest evidence
treatment; and (4) no attempt to tabulate structural for a short-term benet, but evidence for a long-term
causes of ALBP is made. benet is lacking. Randomized studies of back school
The algorithms for the treatment of back pain for primary prevention of low back injury and pain have
(Fig. 7-6) draw from published clinical practice guide- failed to demonstrate any benet.
lines (CPGs). However, since CPGs are based on incom- NSAIDs and acetaminophen (Table 5-1) are effective
plete evidence, guidelines should not substitute for clin- over-the-counter agents for ALBP. Muscle relaxants
ical judgment. (cyclobenzaprine, 10 mg PO qhs as initial dose, up to
The initial assessment excludes serious causes of 10 mg PO tid) provide short-term (47 days) benet,
spine pathology that require urgent intervention, includ- particularly at night if sleep is affected, but drowsiness
ing infection, cancer, and trauma. Risk factors for a seri- limits daytime use. Opioid analgesics are no more effec-
ous cause of ALBP are shown in Table 7-1. Laboratory tive than NSAIDs or acetaminophen for initial treatment
studies are unnecessary if risk factors are absent. Plain of ALBP, nor do they increase the likelihood of return to
spine lms or CT are rarely indicated in the rst month of work. Short-term use of opioids may be necessary in
symptoms unless a spine fracture is suspected. patients unresponsive to or intolerant of acetaminophen
Clinical trials have shown no benet of >2 days of or NSAIDs. There is no evidence to support the use of
bed rest for uncomplicated ALBP. There is evidence that oral glucocorticoids or tricyclic antidepressants for
bed rest is also ineffective for patients with sciatica or ALBP.
for acute back pain with signs of nerve root injury. Simi- Epidural glucocorticoids may occasionally produce
larly, traction is not effective for ALBP. Possible advan- short-term pain relief in ALBP with radiculopathy, but
tages of early ambulation for ALBP include maintenance proof is lacking for pain relief beyond 1 month. Epidural
of cardiovascular conditioning, improved disk and carti- glucocorticoids, anesthetics, or opioids are not indicated
lage nutrition, improved bone and muscle strength, and in the initial treatment of ALBP without radiculopathy.
increased endorphin levels. One trial of early vigorous Diagnostic nerve root blocks have been advocated to
exercise was negative, but the value of less vigorous determine if pain originates from a specic nerve root.
exercise or other exercise programs are unknown. Early However, improvement may result even when the nerve
resumption of normal physical activity (without heavy root is not responsible for the pain; this may occur as a
manual labor) is likely to be benecial. placebo effect, from a pain-generating lesion located
Proof is lacking to support the treatment of acute distally along the peripheral nerve, or from anesthesia
back and neck pain with acupuncture, transcutaneous of the sinuvertebral nerve. Therapeutic nerve root
electrical nerve stimulation, massage, ultrasound, blocks with injection of glucocorticoids and a local
diathermy, magnets, or electrical stimulation. Cervical anesthetic should be considered only after conservative
 81
Acute low back pain Not improving over 4 weeks
Acute low back +/ leg symptoms Leg symptoms?

Yes No
Medical history and examination
Risk factors for serious etiology? Consult specialist;
EMG/NCV Risk factors for
neurologic examination No
Radiculopathy? serious etiology?
Yes No
Clear nerve root signs?

No diagnostic tests Yes Yes No No Present

Reassurance
Table 7-1 and 7-3
Patient education

CHAPTER 7
Pain relief necessary? Imaging study (MRI, or Specialist Evaluate
CT-myelography) follow-up; nerve and treat
No
No Yes Are imaging and neurologic root, plexus,
evaluations concordant? or CNS problem?

Follow-up at 2 weeks Yes Yes Absent

Return to normal activity?

Consult spine surgeon Appropriate

No
Algorithm C intervention

Back and Neck Pain

Symptomatic treatment options
Encourage early return to usual activity, excluding 1
heavy manual labor Reconsider symptomatic treatment options
Activity alterations to minimize symptoms Exercise program optional
Yes
Acetaminophen or NSAIDs Symptoms improving?
Short duration muscle relaxants or opioids optional
Bed rest optional no more than 2 days
No Yes
Spinal manipulation optional
Physical therapy optional
By 12 weeks: Address psychosocial issues Resume
Consider long-term management options normal
Resume normal activity Consider re-evaluation activity

Follow-up at 2 weeks
Return to activity tolerance? Back and leg pain managed > 4 weeks
Focal neurologic deficit by examination or EMG
Focal pathology by spine imaging study
No Yes
Patient symptoms worse or not improving
Will patient consider surgery?
Review response to initial treatment Resume normal activity
Review risk factors Yes No
Modify symptomatic treatment
Spine surgery consultation to discuss:
Surgical procedure
Risks/benefits No Algorithm B at 1
Short-term and long-term outcomes
Follow-up 2 weeks later Yes Availability of second opinion
Return to normal activity? Does the patient choose surgery?

No Yes

Algorithm B Enter Algorithm B at 1 postoperatively

A C

FIGURE 7-6
Algorithms for management of acute low back pain, age blood count; ESR, erythrocyte sedimentation rate; UA, urinal-
18 years. A. Symptoms <3 months, rst 4 weeks. B. Man- ysis; EMG, electromyography; NCV, nerve conduction velocity
agement weeks 412.  1 , entry point from Algorithm C post- studies; MRI, magnetic resonance imaging; CT, computed
operatively or if patient declines surgery. C. Surgical options. tomography; CNS, central nervous system.)
(NSAIDs, nonsteroidal anti-inammatory drugs; CBC, complete

measures fail, particularly when temporary relief of pain adequate placebo control. Specic PT or chiropractic
is necessary. protocols that may provide benet have not been fully
A short course of lumbar spinal manipulation or dened.
physical therapy (PT) for symptomatic relief of uncom-
plicated ALBP is a reasonable option. Prospective, ran- CHRONIC LOW BACK PAIN CLBP, dened as
domized studies are difcult to perform in part because pain lasting >12 weeks, accounts for 50% of total back
there is no consensus about what constitutes an pain costs. Risk factors include obesity, female gender,
 82 older age, prior history of back pain, restricted spinal good evidence to suggest that one NSAID is more
mobility, pain radiating into a leg, high levels of psycho- effective than another. Bed rest should not exceed
logical distress, poor self-rated health, minimal physical 2 days. Activity tolerance is the primary goal, while
activity, smoking, job dissatisfaction, and widespread pain relief is secondary. Exercise programs can reverse
pain. Combinations of these premorbid factors have atrophy in paraspinal muscles and strengthen exten-
been used to predict which individuals with ALBP are sors of the trunk. Intensive physical exercise or work
likely to develop CLBP. The initial approach to these hardening regimens (under the guidance of a physical
patients is similar to that for ALBP. Treatment of this het- therapist) have been effective in returning some patients
erogeneous group of patients is directed toward the to work, improving walking distances, and diminishing
SECTION II

underlying cause when known; the ultimate goal is to pain. The benefit can be sustained with home exercise
restore function to the maximum extent possible. regimens. It is difficult to endorse one specific exercise
Many conditions that produce CLBP can be identied or PT regimen given the heterogeneous nature of this
by a combination of neuroimaging and electrophysio- patient group. The role of manipulation, back school,
logic studies. Spine MRI and CT-myelography are almost or epidural steroid injections in the treatment of CLBP
always the imaging techniques of choice. Imaging stud- is unproven. There is no strong evidence to support
Clinical Manifestations of Neurologic Disease

ies should be performed only in circumstances when the use of acupuncture or traction. A reduction in sick
the results are likely to inuence management. leave days, long-term health care utilization, and pen-
Injection studies can be used diagnostically to sion expenditures may offset the initial expense of
help determine the anatomic source of back pain. multidisciplinary treatment programs. Studies of
Reproduction of the patients typical pain with hydrotherapy for CLBP have yielded mixed results;
diskography has been used as evidence that a spe- however, given its low risk and cost, hydrotherapy can
cific disk is the pain generator. Pain relief following a be considered as a treatment option. Transcutaneous
foraminal nerve root block or glucocorticoid injection electrical nerve stimulation (TENS) has not been ade-
into a facet has been similarly used as evidence that quately studied in CLBP.
the facet joint or nerve root is the source. However,
the possibility that the injection response was a
placebo effect or due to systemic absorption of the
glucocorticoids is usually not considered. The value of
these procedures in the treatment of CLBP or in the PAIN IN THE NECK AND SHOULDER
selection of candidates for surgery is largely unknown (Table 7-4)
despite their widespread use. The value of thermog-
raphy in the assessment of radiculopathy also has not Neck pain, which usually arises from diseases of the cer-
been rigorously studied. vical spine and soft tissues of the neck, is common (4.6%
The diagnosis of nerve root injury is most secure of adults in one study). Neck pain arising from the cer-
when the history, examination, results of imaging vical spine is typically precipitated by movement and
studies, and the EMG are concordant. The correlation may be accompanied by focal tenderness and limitation
between CT and EMG for localization of nerve root injury of motion. Pain arising from the brachial plexus, shoul-
is between 65 and 73%. Up to one-third of asympto- der, or peripheral nerves can be confused with cervical
matic adults have a disk protrusion detected by CT or spine disease, but the history and examination usually
MRI scans. Thus, surgical intervention based solely upon identify a more distal origin for the pain. Cervical spine
radiologic ndings increases the likelihood of an unsuc- trauma, disk disease, or spondylosis may be asympto-
cessful outcome. matic or painful and can produce a myelopathy, radicu-
An unblinded study in patients with chronic sciatica lopathy, or both. The nerve roots most commonly
found that surgery could hasten relief of symptoms by affected are C7 and C6.
~2 months; however, at 1 year there was no advantage
of surgery over conservative medical therapy, and
nearly all patients (95%) in both groups made a full TRAUMA TO THE CERVICAL SPINE
recovery regardless of the treatment approach. A large
Trauma to the cervical spine (fractures, subluxation)
observational cohort study of patients with lumbar
places the spinal cord at risk for compression. Motor
spinal stenosis showed surgery to be relatively safe,
vehicle accidents, violent crimes, or falls account for 87%
likely reducing pain at 2 years with little effect on func-
of spinal cord injuries (Chap. 30). Immediate immobi-
tion or disability.
lization of the neck is essential to minimize further spinal
CLBP can be treated with a variety of conservative
cord injury from movement of unstable cervical spine
measures. Acute and subacute exacerbations are man-
segments. A CT scan is the diagnostic procedure of
aged with NSAIDs and comfort measures. There is no
choice for detection of acute fractures. Following major
TABLE 7-4 83
CERVICAL RADICULOPATHYNEUROLOGIC FEATURES
EXAMINATION FINDINGS
CERVICAL PAIN
NERVE ROOTS REFLEX SENSORY MOTOR DISTRIBUTION

C5 Biceps Over lateral deltoid Supraspinatusa (initial arm abduction) Lateral arm, medial scapula
Infraspinatusa (arm external rotation)
Deltoida (arm abduction)
Biceps (arm exion)
C6 Biceps Thumb, index ngers Biceps (arm exion) Lateral forearm, thumb,

CHAPTER 7
Radial hand/forearm Pronator teres (internal forearm index nger
rotation)
C7 Triceps Middle ngers Tricepsa (arm extension) Posterior arm, dorsal
Dorsum forearm Wrist extensorsa forearm, lateral hand
Extensor digitoruma (nger extension)
C8 Finger Little nger Abductor pollicis brevis (abduction D1) 4th and 5th ngers, medial
exors Medial hand First dorsal interosseous (abduction D2) forearm

Back and Neck Pain

and forearm Abductor digiti minimi (abduction D5)
T1 Finger Axilla and Abductor pollicis brevis (abduction D1) Medial arm, axilla
exors medial arm First dorsal interosseous (abduction D2)
Abductor digiti minimi (abduction D5)

a
These muscles receive the majority of innervation from this root.

trauma to the cervical spine, injury to the vertebral nerve root territory, and (3) the location of pain is the
arteries is common; most lesions are asymptomatic and most variable of the clinical features.
can be visualized by MRI and angiography.
Whiplash injury is due to trauma (usually automobile CERVICAL SPONDYLOSIS
accidents) causing cervical musculoligamental sprain or
strain due to hyperexion or hyperextension. This diag- Osteoarthritis of the cervical spine may produce neck
nosis should not be applied to patients with fractures, pain that radiates into the back of the head, shoulders, or
disk herniation, head injury, focal neurologic ndings, or arms, or may be the source of headaches in the posterior
altered consciousness. Imaging of the cervical spine is occipital region (supplied by the C2-C4 nerve roots).
not cost-effective acutely but is useful to detect disk Osteophytes, disk protrusions, and hypertrophic facet or
herniations when symptoms persist for >6 weeks fol- uncovertebral joints may compress one or several nerve
lowing the injury. Severe initial symptoms have been roots at the intervertebral foramina (Fig. 7-7); this com-
associated with a poor long-term outcome. pression accounts for 75% of cervical radiculopathies.
The roots most commonly affected are C7 and C6.
Narrowing of the spinal canal by osteophytes, ossica-
CERVICAL DISK DISEASE
tion of the posterior longitudinal ligament (OPLL), or a
Herniation of a lower cervical disk is a common cause of large central disk may compress the cervical spinal cord.
neck, shoulder, arm, or hand pain or tingling. Neck pain, Combinations of radiculopathy and myelopathy may
stiffness, and a range of motion limited by pain are the also be present. Spinal cord involvement is suggested by
usual manifestations. A herniated cervical disk is respon- Lhermitts symptom, an electrical sensation elicited by
sible for ~25% of cervical radiculopathies. Extension and neck exion and radiating down the spine from the
lateral rotation of the neck narrows the ipsilateral inter- neck. When little or no neck pain accompanies cord
vertebral foramen and may reproduce radicular symp- compression, the diagnosis may be confused with amy-
toms (Spurlings sign). In young persons, acute nerve root otrophic lateral sclerosis (Chap. 27), multiple sclerosis
compression from a ruptured cervical disk is often due to (Chap. 34), spinal cord tumors, or syringomyelia (Chap. 30).
trauma. Cervical disk herniations are usually posterolat- The possibility of cervical spondylosis should be consid-
eral near the lateral recess and intervertebral foramen. ered even when the patient presents with symptoms or
Typical patterns of reex, sensory, and motor changes signs in the legs only. MRI is the study of choice to
that accompany specic cervical nerve root lesions are dene the anatomic abnormalities, but plain CT is ade-
summarized in Table 7-4; however, (1) overlap in func- quate to assess bony spurs, foraminal narrowing, or
tion between adjacent nerve roots is common, (2) symp- OPLL. EMG and nerve conduction studies can localize
toms and signs may be evident in only part of the injured and assess the severity of the nerve root injury.
 84
SECTION II

FIGURE 7-7
Cervical spondylosis; left C6 radiculopathy. A. Sagittal T2 fast spin echo
Clinical Manifestations of Neurologic Disease

magnetic resonance imaging reveals a hypointense osteophyte that pro-

trudes from the C5C6 level into the thecal sac, displacing the spinal cord
posteriorly (white arrow). B. Axial 2-mm section from a 3-D volume gradient
echo sequence of the cervical spine. The high signal of the right C5C6
intervertebral foramen contrasts with the narrow high signal of the left
C5C6 intervertebral foramen produced by osteophytic spurring (arrows).

OTHER CAUSES OF NECK PAIN lung apex. Injury to these structures may result in pos-
tural or movement-induced pain around the shoulder
Rheumatoid arthritis (RA) of the cervical apophyseal and supraclavicular region. True neurogenic thoracic outlet
joints produces neck pain, stiffness, and limitation of syndrome (TOS) results from compression of the lower
motion. In advanced RA, synovitis of the atlantoaxial trunk of the brachial plexus or ventral rami of the C8 or
joint (C1-C2; Fig. 7-2) may damage the transverse liga- T1 nerve roots by an anomalous band of tissue connect-
ment of the atlas, producing forward displacement of the ing an elongate transverse process at C7 with the rst
atlas on the axis (atlantoaxial subluxation). Radiologic rib. Signs include weakness of intrinsic muscles of the
evidence of atlantoaxial subluxation occurs in 30% of hand and diminished sensation on the palmar aspect of
patients with RA. Not surprisingly, the degree of sub- the fourth and fth digits. EMG and nerve conduction
luxation correlates with the severity of erosive disease. studies conrm the diagnosis. Treatment consists of sur-
When subluxation is present, careful assessment is gical resection of the anomalous band. The weakness
important to identify early signs of myelopathy. Occa- and wasting of intrinsic hand muscles typically does not
sional patients develop high spinal cord compression improve, but surgery halts the insidious progression of
leading to quadriparesis, respiratory insufciency, and weakness. Arterial TOS results from compression of the
death. Surgery should be considered when myelopathy subclavian artery by a cervical rib; the compression
or spinal instability is present. results in poststenotic dilatation of the artery and throm-
Ankylosing spondylitis can cause neck pain and less com- bus formation. Blood pressure is reduced in the affected
monly atlantoaxial subluxation; surgery may be required limb, and signs of emboli may be present in the hand.
to prevent spinal cord compression. Acute herpes zoster Neurologic signs are absent. Ultrasound can conrm the
presents as acute posterior occipital or neck pain prior to diagnosis noninvasively. Treatment is with thrombolysis
the outbreak of vesicles. Neoplasms metastatic to the cervi- or anticoagulation (with or without embolectomy) and
cal spine, infections (osteomyelitis and epidural abscess), and surgical excision of the cervical rib compressing the
metabolic bone diseases may be the cause of neck pain. Neck subclavian artery or vein. Disputed TOS includes a large
pain may also be referred from the heart with coronary number of patients with chronic arm and shoulder pain
artery ischemia (cervical angina syndrome). of unclear cause. The lack of sensitive and specic nd-
ings on physical examination or laboratory markers for
this condition frequently results in diagnostic uncer-
THORACIC OUTLET
tainty.The role of surgery in disputed TOS is controver-
The thoracic outlet contains the rst rib, the subclavian sial. Multidisciplinary pain management is a conservative
artery and vein, the brachial plexus, the clavicle, and the approach, although treatment is often unsuccessful.
BRACHIAL PLEXUS AND NERVES improved neurologic function are reasonable goals. 85
Pain from injury to the brachial plexus or peripheral Symptomatic treatment includes the use of analgesic
nerves of the arm can occasionally mimic pain of cervi- medications and/or a soft cervical collar. Most treatment
cal spine origin. Neoplastic inltration of the lower recommendations reect anecdotal experience, case
trunk of the brachial plexus may produce shoulder pain series, or conclusions derived from studies of the lumbar
radiating down the arm, numbness of the fourth and spine. Controlled studies of oral prednisone or trans-
fth ngers, and weakness of intrinsic hand muscles foraminal glucocorticoid injections have not been per-
innervated by the ulnar and median nerves. Postradia- formed. Reasonable indications for cervical disk surgery
tion brosis (most commonly from treatment of breast include a progressive radicular motor decit, pain that

CHAPTER 7
cancer) may produce similar ndings, although pain is fails to respond to conservative management and limits
less often present. A Pancoast tumor of the lung is activities of daily living, or cervical spinal cord compres-
another cause and should be considered, especially when sion. Surgical management of herniated cervical disks
a Horners syndrome is present. Suprascapular neuropathy usually consists of an anterior approach with diskec-
may produce severe shoulder pain, weakness, and wast- tomy followed by anterior interbody fusion. A simple
ing of the supraspinatous and infraspinatous muscles. posterior partial laminectomy with diskectomy is an

Back and Neck Pain

Acute brachial neuritis is often confused with radiculopa- acceptable alternative approach. Another surgical
thy; the acute onset of severe shoulder or scapular pain is approach involves implantation of an articial disk; in
followed over days to weeks by weakness of the proxi- one prospective trial, outcomes after 2 years favored the
mal arm and shoulder girdle muscles innervated by the implant over a traditional anterior cervical discectomy
upper brachial plexus.The onset is often preceded by an with fusion. The articial disk is not yet approved for
infection.The suprascapular and long thoracic nerves are general use in the United States. The risk of subsequent
most often affected; the latter results in a winged radiculopathy or myelopathy at cervical segments adja-
scapula. Brachial neuritis may also present as an isolated cent to the fusion is ~3% per year and 26% per decade.
paralysis of the diaphragm. Complete recovery occurs in Although this risk is sometimes portrayed as a late com-
75% of patients after 2 years and in 89% after 3 years. plication of surgery, it may also reect the natural his-
Occasional cases of carpal tunnel syndrome produce tory of degenerative cervical disk disease.
pain and paresthesias extending into the forearm, arm, Nonprogressive cervical radiculopathy due to a her-
and shoulder resembling a C5 or C6 root lesion. Lesions niated cervical disk may be treated conservatively, even
of the radial or ulnar nerve can mimic a radiculopathy at if a focal neurologic decit is present, with a high rate of
C7 or C8, respectively. EMG and nerve conduction success. However, if the cervical radiculopathy is due to
studies can accurately localize lesions to the nerve roots, bony compression from cervical spondylosis, then surgi-
brachial plexus, or peripheral nerves. For further discus- cal decompression is generally indicated to forestall the
sion of peripheral nerve disorders, see Chap. 40. progression of neurologic signs.
Cervical spondylotic myelopathy is typically man-
SHOULDER aged with either anterior decompression and fusion or
laminectomy in order to forestall progression of the
Pain arising from the shoulder can on occasion mimic pain myelopathy known to occur in 2030% of untreated
from the spine. If symptoms and signs of radiculopathy are patients. However, one prospective study comparing
absent, then the differential diagnosis includes mechanical surgery vs. conservative treatment for mild cervical
shoulder pain (tendonitis, bursitis, rotator cuff tear, disloca- spondylotic myelopathy showed no difference in out-
tion, adhesive capsulitis, and cuff impingement under the come after 2 years of follow-up.
acromion) and referred pain (subdiaphragmatic irritation,
angina, Pancoast tumor). Mechanical pain is often worse at
night, associated with local shoulder tenderness and aggra-
vated by abduction, internal rotation, or extension of the
FURTHER READINGS
arm. Pain from shoulder disease may radiate into the arm
or hand, but sensory, motor, and reex changes are absent. BAGLEY LJ: Imaging of spinal trauma. Radiol Clin North Am 44:1, 2006
BHANGLE SD et al: Back pain made simple: an approach based on
principles and evidence. Cleve Clin J Med 76:393, 2009
CASSIDY JD et al: Effect of eliminating compensation for pain and
suffering on the outcome of insurance claims for whiplash
Treatment:
injury. N Engl J Med 342:1179, 2000
NECK PAIN
CAVALIER R et al: Spondylolysis and spondylolisthesis in children and
There are few well-designed clinical trials that address adolescents: Diagnosis, natural history, and non-surgical manage-
optimal treatment of neck pain or cervical radiculopa- ment. J Am Acad Orthop Surg 14:417, 2006
thy. Relief of pain, prevention of recurrence, and COWAN JA JR et al: Changes in the utilization of spinal fusion in the
United States. Neurosurgery 59:1, 2006
 86 DATTA S et al: Systematic assessment of diagnostic accuray and thera- VAN ALFEN N,VAN ENGELEN BG:The clinical spectrum of neuralgic
peutic utility of lumbar facet joint interventions. Pain Physician amyotrophy in 246 cases. Brain 129:438, 2006
12:437, 2009 WEINSTEIN JN et al: Surgical versus nonsurgical therapy for lumbar
MUMMANENI PV et al: Clinical and radiographic analysis of cervi- spinal stenosis. N Engl J Med 358:794, 2008
cal disk arthroplasty compared with allograft fusion: A ran- __________ et al: Surgical versus nonsurgical treatment for lumbar
domized controlled clinical trial. J Neurosurg Spine 6:198, degenerative spondylolisthesis. N Engl J Med 356:2257, 2007
2007 __________ et al: Surgical vs nonoperative treatment for lumbar disc
PEUL WC et al: Surgery versus prolonged conservative treatment for herniation. The spine patient outcomes research trial (SPORT):
sciatica. N Engl J Med 356:2245, 2007 A randomized trial. JAMA 296:2441, 2006
SECTION II
Clinical Manifestations of Neurologic Disease
 CHAPTER 8

SYNCOPE

Mark D. Carlson

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
I Causes of Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Disorders of Vascular Tone or Blood Volume . . . . . . . . . . . . . . 88
I Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Cerebrovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
I Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Anxiety Attacks and Hyperventilation Syndrome . . . . . . . . . . . 91
Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Hysterical Fainting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Syncope, a transient loss of consciousness and postural tone renin-aldosterone-angiotensin system. Knowledge of
due to reduced cerebral blood ow, is associated with spon- the processes is important to understanding the patho-
taneous recovery. It may occur suddenly, without warning, physiology of syncope. Approximately three-fourths of
or may be preceded by symptoms of faintness (presyn- the systemic blood volume is contained in the venous
cope).These symptoms include lightheadedness, dizziness, bed, and any interference in venous return may lead to
a feeling of warmth, diaphoresis, nausea, and visual blurring a reduction in cardiac output. Cerebral blood flow can
occasionally proceeding to transient blindness. Presyncopal be maintained if cardiac output and systemic arterial
symptoms vary in duration and may increase in severity vasoconstriction compensate, but when these adjust-
until loss of consciousness occurs, or they may resolve prior ments fail, hypotension with resultant cerebral under-
to loss of consciousness if the cerebral ischemia is cor- perfusion to less than half of normal results in syncope.
rected. The differentiation of syncope from seizure is an Normally, the pooling of blood in the lower parts of
important, sometimes difcult, diagnostic problem. the body is prevented by (1) pressor reflexes that
Syncope may be benign when it occurs as a result of induce constriction of peripheral arterioles and venules,
normal cardiovascular reex effects on heart rate and (2) reflex acceleration of the heart by means of aortic
vascular tone, or serious when due to a life-threatening and carotid reflexes, and (3) improvement of venous
cardiac arrhythmia. Syncope may occur as a single event return to the heart by activity of the muscles of the
or may be recurrent. Recurrent, unexplained syncope, limbs. Tilting a normal person upright on a tilt table
particularly in an individual with structural heart disease, causes some blood to accumulate in the lower limbs
is associated with a high risk of death (40% mortality and diminishes cardiac output slightly; this may be fol-
within 2 years). lowed by a slight transitory fall in systolic blood pres-
sure. However, in a patient with defective vasomotor
reexes, upright tilt may produce an abrupt and sustained
PATHOPHYSIOLOGY
fall in blood pressure, precipitating a faint. A recent
Under normal circumstances systemic blood pressure is study suggests that susceptibility to neurally-mediated
regulated by a complex process that includes the mus- syncope is driven partly by an enhanced vascular response
culature, venous valves, autonomic nervous system, and to hypocapnia.
87
 88 CAUSES OF SYNCOPE TABLE 8-1
CAUSES OF SYNCOPE
Transiently decreased cerebral blood ow is usually due I. Disorders of Vascular Tone or Blood Volume
to one of three general mechanisms: disorders of vascu- A. Reex syncopes
lar tone or blood volume, cardiovascular disorders 1. Neurocardiogenic
including obstructive lesions and cardiac arrhythmias, or 2. Situational
Cough
cerebrovascular disease (Table 8-1). Not infrequently,
Micturition
however, the cause of syncope is multifactorial. Defecation
Valsalva
SECTION II

Deglutition
DISORDERS OF VASCULAR TONE OR 3. Carotid sinus hypersensitivity
BLOOD VOLUME B. Orthostatic hypotension
1. Drug-induced (antihypertensive or vasodilator
Disorders of vascular tone or blood volume that can drugs)
cause syncope include the reex syncopes and a number 2. Pure autonomic failure (idiopathic orthostatic
of conditions resulting in orthostatic intolerance. The hypotension)
Clinical Manifestations of Neurologic Disease

reex syncopesincluding neurocardiogenic syncope, 3. Multisystem atrophies

4. Peripheral neuropathy (diabetic, alcoholic,
situational syncope, and carotid sinus hypersensitivity nutritional, amyloid)
share common autonomic nervous system pathophysio- 5. Physical deconditioning
logic mechanisms: a cardioinhibitory component (e.g., 6. Sympathectomy
bradycardia due to increased vagal activity), a vasodepres- 7. Decreased blood volume
sor component (e.g., inappropriate vasodilatation due to II. Cardiovascular Disorders
sympathetic withdrawal), or both. A. Structural and obstructive causes
1. Pulmonary embolism
2. Pulmonary hypertension
3. Atrial myxoma
Neurocardiogenic (Vasovagal and 4. Mitral valvular stenosis
Vasodepressor) Syncope 5. Myocardial disease (massive acute myocardial
infarction)
The term neurocardiogenic is generally used to encompass
6. Left ventricular myocardial restriction or
both vasovagal and vasodepressor syncope. Strictly speak- constriction
ing, vasovagal syncope is associated with both sympathetic 7. Pericardial constriction or tamponade
withdrawal (vasodilatation) and increased parasympa- 8. Aortic outow tract obstruction
thetic activity (bradycardia), whereas vasodepressor syn- 9. Aortic valvular stenosis
cope is associated with sympathetic withdrawal alone. 10. Hypertrophic obstructive cardiomyopathy
B. Cardiac arrhythmias
These forms of syncope are the common faint that
1. Bradyarrhythmias
may be experienced by normal persons; they account for a. Sinus bradycardia, sinoatrial block, sinus
approximately half of all episodes of syncope. Neurocar- arrest, sick-sinus syndrome
diogenic syncope is frequently recurrent and commonly b. Atrioventricular block
precipitated by a hot or crowded environment, alcohol, 2. Tachyarrhythmias
extreme fatigue, severe pain, hunger, prolonged standing, a. Supraventricular tachycardia with structural
cardiovascular disease
and emotional or stressful situations. Episodes are often
b. Atrial brillation with the Wolff-Parkinson-White
preceded by a presyncopal prodrome lasting seconds to syndrome
minutes, and rarely occur in the supine position. The c. Atrial utter with 1:1 atrioventricular
individual is usually sitting or standing and experiences conduction
weakness, nausea, diaphoresis, lightheadedness, blurred d. Ventricular tachycardia
vision, and often a forceful heartbeat with tachycardia III. Cerebrovascular Disease
A. Vertebrobasilar insufciency
followed by cardiac slowing and decreasing blood pres-
B. Basilar artery migraine
sure prior to loss of consciousness.The individual appears IV. Other Disorders that May Resemble Syncope
pale or ashen; in dark-skinned individuals, the pallor may A. Metabolic
only be notable in the conjunctivae and lips. Patients 1. Hypoxia
with a gradual onset of presyncopal symptoms have time 2. Anemia
to protect themselves against injury; in others, syncope 3. Diminished carbon dioxide due to hyperventilation
4. Hypoglycemia
occurs suddenly, without warning.
B. Psychogenic
The depth and duration of unconsciousness vary. 1. Anxiety attacks
Sometimes the patient remains partly aware of the sur- 2. Hysterical fainting
roundings, or there may be complete unresponsiveness. C. Seizures
The unconscious patient usually lies motionless, with
skeletal muscles relaxed, but a few clonic jerks of the and defecation are associated with maneuvers (such as 89
limbs and face may occur. Sphincter control is usually Valsalvas, straining, and coughing) that may contribute
maintained, in contrast to a seizure. The pulse may be to hypotension and syncope by decreasing venous
feeble or apparently absent, the blood pressure low or return. Increased intracranial pressure secondary to the
undetectable, and breathing may be almost impercepti- increased intrathoracic pressure may also contribute by
ble. The duration of unconsciousness is rarely longer decreasing cerebral blood ow.
than a few minutes if the conditions that provoke the Cough syncope typically occurs in men with chronic
episode are reversed. Once the patient is placed in a bronchitis or chronic obstructive lung disease during or
horizontal position, the strength of the pulse improves, after prolonged coughing ts. Micturition syncope

CHAPTER 8
color begins to return to the face, breathing becomes occurs predominantly in middle-aged and older men,
quicker and deeper, and consciousness is restored. Some particularly those with prostatic hypertrophy and
patients may experience a sense of residual weakness obstruction of the bladder neck; loss of consciousness
after regaining consciousness, and rising too soon may usually occurs at night during or immediately after
precipitate another faint. Unconsciousness may be pro- voiding. Deglutition syncope and defecation syncope
longed if an individual remains upright; thus, it is essen- occur in men and women. Deglutition syncope may be
tial that individuals with vasovagal syncope assume a associated with esophageal disorders, particularly

Syncope
recumbent position as soon as possible. Although usually esophageal spasm. In some individuals, particular foods
benign, neurocardiogenic syncope can be associated and carbonated or cold beverages initiate episodes by
with prolonged asystole and hypotension, resulting in activating esophageal sensory receptors that trigger
hypoxic-ischemic injury. reex sinus bradycardia or atrioventricular (AV) block.
Neurocardiogenic syncope often occurs in the setting Defecation syncope is probably secondary to Valsalvas
of increased peripheral sympathetic activity and venous maneuver in older individuals with constipation.
pooling. Under these conditions, vigorous myocardial
contraction of a relatively empty left ventricle is thought
to activate myocardial mechanoreceptors and vagal affer- Carotid Sinus Hypersensitivity
ent nerve bers that inhibit sympathetic activity and Syncope due to carotid sinus hypersensitivity is precipi-
increase parasympathetic activity.The resultant vasodilata- tated by pressure on the carotid sinus baroreceptors,
tion and bradycardia induce hypotension and syncope. which are located just cephalad to the bifurcation of the
Although the reex involving myocardial mechanore- common carotid artery.This typically occurs in the setting
ceptors is the mechanism usually accepted as responsible of shaving, a tight collar, or turning the head to one side.
for neurocardiogenic syncope, other reexes may also be Carotid sinus hypersensitivity occurs predominantly in
operative. Patients with transplanted (denervated) hearts men 50 years. Activation of carotid sinus baroreceptors
have experienced cardiovascular responses identical to gives rise to impulses carried via the nerve of Hering, a
those present during neurocardiogenic syncope. This branch of the glossopharyngeal nerve, to the medulla in
should not be possible if the response depends solely on the brainstem. These afferent impulses activate efferent
the reex mechanisms described above, unless the trans- sympathetic nerve bers to the heart and blood vessels,
planted heart has become reinnervated. Moreover, neu- cardiac vagal efferent nerve bers, or both. In patients
rocardiogenic syncope often occurs in response to stimuli with carotid sinus hypersensitivity, these responses may
(fear, emotional stress, or pain) that may not be associated cause sinus arrest or AV block (a cardioinhibitory response),
with venous pooling in the lower extremities, which vasodilatation (a vasodepressor response), or both (a mixed
suggests a cerebral component to the reex. response).The underlying mechanisms responsible for the
As distinct from the peripheral mechanisms, the cen- carotid sinus hypersensitivity are not clear, and validated
tral nervous system (CNS) mechanisms responsible for diagnostic criteria do not exist.
neurocardiogenic syncope are uncertain, but a sudden
surge in central serotonin levels may contribute to the
sympathetic withdrawal. Endogenous opiates (endor- Postural (Orthostatic) Hypotension
phins) and adenosine are also putative participants in the
pathogenesis. Orthostatic intolerance can result from hypovolemia or
from disturbances in vascular control. The latter may
occur due to agents that affect the vasculature or due to
Situational Syncope primary or secondary abnormalities of autonomic con-
A variety of activities, including cough, deglutition, mic- trol. Sudden rising from a recumbent position or stand-
turition, and defecation, are associated with syncope in ing quietly are precipitating circumstances. Orthostatic
susceptible individuals. Like neurocardiogenic syncope, hypotension may be the cause of syncope in up to 30% of the
these syndromes may involve a cardioinhibitory response, elderly; polypharmacy with antihypertensive or antidepressant
a vasodepressor response, or both. Cough, micturition, drugs is often a contributor in these patients.
 90 Postural syncope may occur in otherwise normal per- especially if the person is in the supine position. As the
sons with defective postural reexes. Pure autonomic heart rate decreases, ventricular lling time and stroke
failure (formerly called idiopathic postural hypotension) is volume increase to maintain normal cardiac output. At
characterized by orthostatic hypotension, syncope and rates <30 beats/min, stroke volume can no longer
near syncope, neurocardiogenic bladder, constipation, increase to compensate adequately for the decreased
heat intolerance, inability to sweat, and erectile dysfunc- heart rate. At rates greater than ~180 beats/min, ventric-
tion (Chap. 28). The disorder is more common in men ular lling time is inadequate to maintain adequate
than women and typically begins between 50 and 75 years stroke volume. In either case, cerebral hypoperfusion and
of age. syncope may occur. Upright posture; cerebrovascular
Orthostatic hypotension, often accompanied by distur- disease; anemia; loss of atrioventricular synchrony; and
SECTION II

bances in sweating, impotence, and sphincter difculties, coronary, myocardial, or valvular disease all reduce the
is also a primary feature of a variety or other autonomic tolerance to alterations in rate.
nervous system disorders (Chap. 28). Among the most Bradyarrhythmias may occur as a result of an abnor-
common causes of neurogenic orthostatic hypotension mality of impulse generation (e.g., sinoatrial arrest) or
are chronic diseases of the peripheral nervous system impulse conduction (e.g., AV block). Either may cause
that involve postganglionic unmyelinated bers (e.g., syncope if the escape pacemaker rate is insufcient to
Clinical Manifestations of Neurologic Disease

diabetic, nutritional, and amyloid polyneuropathy). maintain cardiac output. Syncope due to bradyarrhyth-
Much less common are the multiple system atrophies; mias may occur abruptly, without presyncopal symp-
these are CNS disorders in which orthostatic hypoten- toms, and recur several times daily. Patients with sick
sion is associated with (1) parkinsonism (Shy-Drager sinus syndrome may have sinus pauses (>3 s), and those
syndrome), (2) progressive cerebellar degeneration, or (3) with syncope due to high-degree AV block (Stokes-
a more variable parkinsonian and cerebellar syndrome Adams-Morgagni syndrome) may have evidence of con-
(Chap. 28).A rare, acute postganglionic dysautonomia may duction system disease (e.g., prolonged PR interval,
represent a variant of Guillain-Barr syndrome (Chaps. 28 bundle branch block). However, the arrhythmia is often
and 41); a related disorder, autoimmune autonomic neu- transitory, and the surface electrocardiogram or continu-
ropathy, is associated with autoantibodies to the ganglionic ous electrocardiographic monitor (Holter monitor) taken
acetylcholine receptor. later may not reveal the abnormality. The bradycardia-
There are several additional causes of postural syn- tachycardia syndrome is a common form of sinus node
cope: (1) after physical deconditioning (such as after dysfunction in which syncope generally occurs as a
prolonged illness with recumbency, especially in elderly result of marked sinus pauses, some following termina-
individuals with reduced muscle tone) or after pro- tion of paroxysms of atrial tachyarrhythmias. Drugs
longed weightlessness, as in space ight; (2) after sympa- are a common cause for bradyarrhythmias, particularly
thectomy that has abolished vasopressor reexes; and (3) in patients with underlying structural heart disease.
in patients receiving antihypertensive or vasodilator drugs Digoxin, -adrenergic receptor antagonists, calcium chan-
and those who are hypovolemic because of diuretics, nel blockers, and many antiarrhythmic drugs may sup-
excessive sweating, diarrhea, vomiting, hemorrhage, or press sinoatrial node impulse generation or slow AV nodal
adrenal insufciency. conduction.
Syncope due to a tachyarrhythmia is usually preceded
Glossopharyngeal Neuralgia by palpitation or lightheadedness but may occur abruptly
with no warning symptoms. Supraventricular tach-
Syncope due to glossopharyngeal neuralgia (Chap. 29) is yarrhythmias are unlikely to cause syncope in individu-
preceded by pain in the oropharynx, tonsillar fossa, or als with structurally normal hearts but may do so if
tongue. Loss of consciousness is usually associated with they occur in patients with (1) heart disease that also
asystole rather than vasodilatation. The mechanism is compromises cardiac output, (2) cerebrovascular dis-
thought to involve activation of afferent impulses in the ease, (3) a disorder of vascular tone or blood volume,
glossopharyngeal nerve that terminate in the nucleus or (4) a rapid ventricular rate. These tachycardias result
solitarius of the medulla and, via collaterals, activate the most commonly from paroxysmal atrial flutter, atrial
dorsal motor nucleus of the vagus nerve. fibrillation, or reentry involving the AV node or acces-
sory pathways that bypass part or all of the AV conduc-
tion system. Patients with Wolff-Parkinson-White syndrome
CARDIOVASCULAR DISORDERS may experience syncope when a very rapid ventricular
rate occurs due to reentry across an accessory AV
Cardiac syncope results from a sudden reduction in car- connection.
diac output, caused most commonly by a cardiac arrhyth- In patients with structural heart disease, ventricular
mia. In normal individuals, heart rates between 30 and tachycardia is a common cause of syncope, particularly
180 beats/min do not reduce cerebral blood flow, in those with a prior myocardial infarction. Patients with
aortic valvular stenosis and hypertrophic obstructive car- 91
diomyopathy are also at risk for ventricular tachycardia.
DIFFERENTIAL DIAGNOSIS
Individuals with abnormalities of ventricular repolariza- ANXIETY ATTACKS AND
tion (prolongation of the QT interval) are at risk to HYPERVENTILATION SYNDROME
develop polymorphic ventricular tachycardia (torsades
des pointes). Those with the inherited form of this syn- Anxiety, such as occurs in panic attacks, is frequently
drome often have a family history of sudden death in interpreted as a feeling of faintness or dizziness resem-
young individuals. Genetic markers can identify some bling presyncope. However, the symptoms are not
patients with familial long-QT syndrome, but the clini- accompanied by facial pallor and are not relieved by
recumbency. The diagnosis is made on the basis of the

CHAPTER 8
cal utility of these markers remains unproven. Drugs
(i.e., certain antiarrhythmics and erythromycin) and associated symptoms such as a feeling of impending
electrolyte disorders (i.e., hypokalemia, hypocalcemia, doom, air hunger, palpitations, and tingling of the ngers
hypomagnesemia) can prolong the QT interval and pre- and perioral region. Attacks can often be reproduced
dispose to torsades des pointes. Antiarrhythmic medica- by hyperventilation, resulting in hypocapnia, alkalosis,
tions may precipitate ventricular tachycardia, particularly increased cerebrovascular resistance, and decreased cere-
in patients with structural heart disease. bral blood ow. The release of epinephrine also con-

Syncope
In addition to arrhythmias, syncope may also occur tributes to the symptoms.
with a variety of structural cardiovascular disorders.
Episodes are usually precipitated when the cardiac out-
put cannot increase to compensate adequately for SEIZURES
peripheral vasodilatation. Peripheral vasodilatation may A seizure may be heralded by an aura, which is caused
be appropriate, such as following exercise, or may occur by a focal seizure discharge and hence has localizing
due to inappropriate activation of left ventricular significance (Chap. 20). The aura is usually followed by
mechanoreceptor reexes, as occurs in aortic outow a rapid return to normal or by a loss of consciousness.
tract obstruction (aortic valvular stenosis or hyper- Injury from falling is frequent in a seizure and rare in
trophic obstructive cardiomyopathy). Obstruction to syncope, since only in generalized seizures are protective
forward ow is the most common reason that cardiac reexes abolished instantaneously. Sustained tonic-clonic
output cannot increase. Pericardial tamponade is a rare movements are characteristic of convulsive seizures, but
cause of syncope. Syncope occurs in up to 10% of brief clonic, or tonic-clonic, seizure-like activity can
patients with massive pulmonary embolism and may accompany fainting episodes. The period of uncon-
occur with exertion in patients with severe primary pul- sciousness in seizures tends to be longer than in syn-
monary hypertension. The cause is an inability of the cope. Urinary incontinence is frequent in seizures and
right ventricle to provide appropriate cardiac output in rare in syncope. The return of consciousness is prompt
the presence of obstruction or increased pulmonary vascu- in syncope and slow after a seizure. Mental confusion,
lar resistance. Loss of consciousness is usually accompanied headache, and drowsiness are common sequelae of seizures,
by other symptoms such as chest pain and dyspnea. Atrial whereas physical weakness with a clear sensorium char-
myxoma, a prosthetic valve thrombus, and, rarely, mitral acterizes the postsyncopal state. Repeated spells of uncon-
stenosis may impair left ventricular lling, decrease cardiac sciousness in a young person at a rate of several per
output, and cause syncope. day or month are more suggestive of epilepsy than
syncope. See Table 20-7 for a comparison of seizures
CEREBROVASCULAR DISEASE and syncope.
Cerebrovascular disease alone rarely causes syncope but
may lower the threshold for syncope in patients with HYPOGLYCEMIA
other causes. The vertebrobasilar arteries, which supply
brainstem structures responsible for maintaining con- Severe hypoglycemia is usually due to a serious disease
sciousness, are usually involved when cerebrovascular such as a tumor of the islets of Langerhans or advanced
diseases causes or contributes to syncope. An exception adrenal, pituitary, or hepatic disease; or to excessive
is the rare patient with tight bilateral carotid stenosis and administration of insulin.
recurrent syncope, often precipitated by standing or
walking. Most patients who experience lightheadedness
HYSTERICAL FAINTING
or syncope due to cerebrovascular disease also have
symptoms of focal neurologic ischemia, such as arm or The attack is usually unattended by an outward display
leg weakness, diplopia, ataxia, dysarthria, or sensory dis- of anxiety. Lack of change in pulse and blood pressure or
turbances. Basilar artery migraine is a rare disorder that color of the skin and mucous membranes distinguish it
causes syncope in adolescents. from the vasodepressor faint.
 92 The physical examination should include evalua-
Approach to the Patient:
SYNCOPE
tion of heart rate and blood pressure in the supine,
sitting, and standing positions. In patients with unex-
The diagnosis of syncope is often challenging. The plained recurrent syncope, an attempt to reproduce
cause may be apparent only at the time of the event, an attack may assist in diagnosis. Anxiety attacks
leaving few, if any, clues when the patient is seen later induced by hyperventilation can be reproduced read-
by the physician. The physician should think rst of ily by having the patient breathe rapidly and deeply
those causes that constitute a therapeutic emergency, for 23 min. Cough syncope may be reproduced by
including massive internal hemorrhage or myocardial inducing the Valsalvas maneuver. Carotid sinus mas-
infarction, which may be painless, and cardiac arrhyth-
SECTION II

sage should generally be avoided, unless carotid ultra-

mias. In elderly persons, a sudden faint, without obvi- sound is negative for atheroma, because its diagnostic
ous cause, should arouse the suspicion of complete specicity is unknown and it may provoke a transient
heart block or a tachyarrhythmia, even though all ischemic attack (TIA) or stroke in individuals with
ndings are negative when the patient is seen. carotid atheromas.
Figure 8-1 depicts an algorithmic approach to syn-
cope. A careful history is the most important diagnos-
Clinical Manifestations of Neurologic Disease

DIAGNOSTIC TESTS The choice of diagnostic

tic tool, both to suggest the correct cause and to tests should be guided by the history and the physical
exclude important potential causes (Table 8-1). The examination. Measurements of serum electrolytes,
nature of the events and their time course immedi- glucose, and the hematocrit are usually indicated.
ately prior to, during, and after an episode of syncope Cardiac enzymes should be evaluated if myocardial
often provide valuable etiologic clues. Loss of con- ischemia is suspected. Blood and urine toxicology
sciousness in particular situations, such as during screens may reveal the presence of alcohol or other
venipuncture or micturition or with volume deple- drugs. In patients with possible adrenocortical insuf-
tion, suggests an abnormality of vascular tone. The ciency, plasma aldosterone and mineralocorticoid
position of the patient at the time of the syncopal levels should be obtained.
episode is important; syncope in the supine position is Although the surface electrocardiogram is unlikely
unlikely to be vasovagal and suggests an arrhythmia or to provide a denitive diagnosis, it may provide clues
a seizure. Syncope due to carotid sinus syndrome may to the cause of syncope and should be performed in
occur when the individual is wearing a shirt with a almost all patients. The presence of conduction abnor-
tight collar, turning the head (turning to look while malities (PR prolongation and bundle branch block)
driving in reverse), or manipulating the neck (as in suggests a bradyarrhythmia, whereas pathologic Q
shaving). The patients medications must be noted, waves or prolongation of the QT interval suggests a
including nonprescription drugs or health store sup- ventricular tachyarrhythmia. Inpatients should undergo
plements, with particular attention to recent changes. continuous electrocardiographic monitoring; outpa-
tients should wear a Holter monitor for 2448 h.
Whenever possible, symptoms should be correlated
with the occurrence of arrhythmias. Continuous elec-
Syncope trocardiographic monitoring may establish the cause
of syncope in as many as 15% of patients. Cardiac
Normal history History, physical Examination Review event monitors may be useful in patients with infre-
and physical exam, ECG reveals medication
examination suggest cardiac orthostatic quent symptoms, particularly in patients with presyn-
disease hypotension
cope. An implantable event monitor may be necessary
for patients with extremely infrequent episodes. The
Reflex Echocardiogram, Normal Abnormal
syncope 24-h Holter neurologic neurologic presence of a late potential on a signal-averaged elec-
monitor, stress test,
other cardiac
exam exam trocardiogram is associated with increased risk for
Tilt testing if
testing as indicated
Consider Peripheral
ventricular tachyarrhythmias in patients with a prior
severe or postganglionic neuropathy myocardial infarction. Low-voltage (visually inapparent)
recurrent autonomic (consider diabetic,
insufficiency nutritional, T wave alternans is also associated with development
amyloid, etc.) of sustained ventricular arrhythmias.
Central nervous Invasive cardiac electrophysiologic testing provides diag-
sytem findings
Consider multiple
nostic and prognostic information regarding sinus
system atrophy node function, AV conduction, and supraventricular
and ventricular arrhythmias. Prolongation of the sinus
FIGURE 8-1 node recovery time (>1500 ms) is a specic nding
Approach to the patient with syncope.
(85100%) for diagnosis of sinus node dysfunction arrhythmias. In some patients, cardiac catheterization 93
but has a low sensitivity; continuous electrocardio- may be necessary to diagnose the presence or severity
graphic monitoring is usually more effective for diag- of coronary artery disease or valvular abnormalities.
nosing this abnormality. Prolongation of the HV Ultrafast CT scan, ventilation-perfusion scan, or pul-
interval and conduction block below the His bundle monary angiography is indicated in patients in whom
indicate that His-Purkinje disease may be responsible syncope may be due to pulmonary embolus.
for syncope. Programmed stimulation for ventricular In cases of possible cerebrovascular syncope, neu-
arrhythmias is most useful in patients who have expe- roimaging tests may be indicated, including Doppler
rienced a myocardial infarction; the sensitivity and ultrasound studies of the carotid and vertebrobasilar

CHAPTER 8
specicity of this technique is lower in patients with systems, MRI, magnetic resonance angiography, and
normal hearts or those with heart disease other than x-ray angiography of the cerebral vasculature (Chap. 2).
coronary artery disease. Electroencephalography is indicated if seizures are
Upright tilt table testing is indicated for recurrent syn- suspected.
cope, a single syncopal episode that caused injury, or a
single syncopal event in a high-risk setting (pilot,

Syncope
commercial vehicle driver, etc.), whether or not there
is a history of preexisting heart disease or prior vaso-
vagal episodes. In susceptible patients, upright tilt at an
angle between 60 and 80 for 3060 min induces a Treatment:
vasovagal episode. The protocol can be shortened if SYNCOPE
upright tilt is combined with administration of drugs The treatment of syncope is directed at the underlying
that cause venous pooling or increase adrenergic stim- cause. This discussion will focus on disorders of auto-
ulation (isoproterenol, nitroglycerin, edrophonium, or nomic control. Cerebrovascular disorders are discussed
adenosine). The sensitivity and specicity of tilt-table in Chap. 21.
testing is difcult to ascertain because of the lack of Certain precautions should be taken regardless of
validated criteria. Moreover, the reexes responsible the cause of syncope. At the rst sign of symptoms,
for vasovagal syncope can be elicited in most, if not patients should make every effort to avoid injury should
all, individuals given the appropriate stimulus. The they lose consciousness. Patients with frequent
specicity of tilt-table testing has been reported to be episodes, or those who have experienced syncope with-
near 90%, but it is lower when pharmacologic provo- out warning symptoms, should avoid situations in
cation is employed.The reported sensitivity of the test which sudden loss of consciousness might result in
ranges between 20 and 74%, the variability due to dif- injury (e.g., climbing ladders, swimming alone, operat-
ferences in populations studied, techniques used, and ing heavy machinery, driving). Patients should lower
the absence of a true gold standard against which to their head to the extent possible and preferably should
compare test results. The reproducibility (in a time lie down. Lowering the head by bending at the waist
ranging from several hours to weeks) is 8090% for an should be avoided because it may further compromise
initially positive response, but may be less for an ini- venous return to the heart. When appropriate, family
tially negative response (ranging from 30 to 90%). members or other close contacts should be educated as
A variety of other tests may be useful to determine to the problem. This will ensure appropriate therapy
the presence of structural heart disease that may cause and may prevent delivery of inappropriate therapy
syncope. The echocardiogram with Doppler examina- (chest compressions associated with cardiopulmonary
tion detects valvular, myocardial, and pericardial abnor- resuscitation) that may inict trauma.
malities.The echocardiogram is the gold standard for Patients who have lost consciousness should be
the diagnosis of hypertrophic cardiomyopathy and placed in a position that maximizes cerebral blood ow,
atrial myxoma. Cardiac cine MRI provides an alterna- offers protection from trauma, and secures the airway.
tive noninvasive modality that may be useful for Whenever possible, the patient should be placed supine
patients in whom diagnostic-quality echocardiographic with the head turned to the side to prevent aspiration
images cannot be obtained. This test is also indicated and the tongue from blocking the airway. Assessment
for patients suspected of having arrhythmogenic right of the pulse and direct cardiac auscultation may assist
ventricular dysplasia or right ventricular outow tract in determining if the episode is associated with a brad-
ventricular tachycardia. Both are associated with right yarrhythmia or a tachyarrhythmia. Clothing that ts
ventricular structural abnormalities that are better visu- tightly around the neck or waist should be loosened.
alized on MR imaging than by echocardiogram. Exer- Peripheral stimulation, such as sprinkling cold water on
cise testing may detect ischemia or exercise-induced the face, may be helpful. Patients should not be given
 94 anything by mouth or be permitted to rise until the Although several clinical trials have suggested that
sense of physical weakness has passed. pharmacologic therapy for neurocardiogenic syncope is
Patients with vasovagal syncope should be instructed effective, the few long-term prospective randomized
to avoid situations or stimuli that have caused them to controlled trials have yielded mixed results. In the Pre-
lose consciousness and to assume a recumbent position vention of Syncope Trial (POST), metoprolol was ineffec-
when premonitory symptoms occur. These behavioral tive in patients <42 years but decreased the incidence
modications alone may be sufcient for patients with of syncope in patients >42 years, raising the possibility
infrequent and relatively benign episodes of vasovagal that there may be signicant age-related differences in
syncope, particularly when loss of consciousness occurs response to pharmacologic therapy.
SECTION II

in response to a specic stimulus. Tilt training (standing Studies of permanent pacing for neurocardiogenic
and leaning against a wall for progressively longer peri- syncope have also yielded mixed results. Dual-chamber
ods each day) has been used with limited success, par- cardiac pacing may be effective for patients with fre-
ticularly for patients with orthostatic intolerance. quent episodes of vasovagal syncope, particularly for
Episodes associated with intravascular volume deple- those with prolonged asystole associated with vasova-
tion may be prevented by salt and uid loading prior to gal episodes. Pacemakers that can be programmed to
Clinical Manifestations of Neurologic Disease

provocative events. transiently pace at a high rate (90100 beats/min) after

Drug therapy may be necessary when vasovagal syn- a profound drop in the patients intrinsic heart rate are
cope is resistant to the above measures, when episodes most effective.
occur frequently, or when syncope is associated with a Patients with orthostatic hypotension should be
signicant risk for injury. -Adrenergic receptor antago- instructed to rise slowly and systematically (supine to
nists (metoprolol, 2550 mg bid; atenolol, 2550 mg qd; seated, seated to standing) from the bed or a chair.
or nadolol, 1020 mg bid; all starting doses), the most Movement of the legs prior to rising facilitates venous
widely used agents, mitigate the increase in myocardial return from the lower extremities. Whenever possible,
contractility that stimulates left ventricular mechanore- medications that aggravate the problem (vasodilators,
ceptors and also block central serotonin receptors. Sero- diuretics, etc.) should be discontinued. Elevation of the
tonin reuptake inhibitors (paroxetine, 2040 mg qd; or head of the bed [2030 cm (812 in.)] and use of com-
sertraline, 2550 mg qd), appear to be effective for
pression stockings may help.
some patients. Bupropion SR (150 mg qd), another anti-
Additional therapeutic modalities include salt load-
depressant, has also been used with success. -Adrener-
ing and a variety of pharmacologic agents including
gic receptor antagonists and serotonin reuptake
sympathomimetic amines, monamine oxidase inhibitors,
inhibitors are well tolerated and are often used as rst-
beta blockers, and levodopa. The treatment of orthosta-
line agents for younger patients. Hydroudrocortisone
tic hypotension secondary to central or peripheral
(0.10.2 mg qd), a mineralocorticoid, promotes sodium
disorders of the autonomic nervous system is discussed
retention, volume expansion, and peripheral vasocon-
in Chap. 28.
striction by increasing -receptor sensitivity to endoge-
nous catecholamines. Hydroudrocortisone is useful for Glossopharyngeal neuralgia is treated with carba-
patients with intravascular volume depletion and for mazepine, which is effective for syncope as well as for
those who also have postural hypotension. Proamatine pain. Patients with carotid sinus hypersensitivity should
(2.510 mg bid or tid), an -agonist, has been used as a be instructed to avoid clothing and situations that
rst-line agent for some patients. In a randomized con- stimulate carotid sinus baroreceptors. They should turn
trolled trial, proamatine was more effective than their entire body, rather than just their head, when look-
placebo in preventing syncope during an upright tilt- ing to the side. Those with intractable syncope due
test. However, in some patients, proamatine and to the cardioinhibitory response to carotid sinus
hydroudrocortisone may increase resting supine sys- stimulation should undergo permanent pacemaker
temic blood pressure, which may be problematic for implantation.
those with hypertension. Patients with syncope should be hospitalized when
Disopyramide (150 mg bid), a vagolytic antiarrhyth- there is a possibility that the episode may have resulted
mic drug with negative inotropic properties, and trans- from a life-threatening abnormality or if recurrence with
dermal scopolamine, another vagolytic, have been used signicant injury seems likely. These individuals should
to treat vasovagal syncope, as have theophylline and be admitted to a bed with continuous electrocardio-
ephedrine. Side effects associated with these drugs graphic monitoring. Patients who are known to have a
have limited their use for this indication. Disopyramide normal heart and for whom the history strongly sug-
is a type 1A antiarrhythmic drug and should be used gests vasovagal or situational syncope may be treated
with great caution, if at all, in patients who are at risk for as outpatients if the episodes are neither frequent nor
ventricular arrhythmias. severe.
FURTHER READINGS NORCLIFFE-KAUFMANN LJ et al: Enhanced vascular responses to 95
hypocapnia in neurally mediated syncope.Ann Neurol 63:288, 2008
BENDITT DG, NGUYEN JT: Syncope:Therapeutic approaches. J Am Coll SOTERIADES E et al: Incidence and prognosis of syncope. N Engl J
Cardiol. 53:1741, 2009 Med 347:878, 2002
GRUBB BP: Neurocardiogenic syncope and related disorders of STRICKBERGER SA et al: AHA/ACCF scientic statement on the
orthostatic intolerance. Circulation 111:2997, 2005 evaluation of syncope: From the American Heart Association
, OLSHANSKY B (eds): Syncope: Mechanisms and Management, Councils on Clinical Cardiology, Cardiovascular Nursing, Car-
2d ed. Malden, Mass., Blackwell Futura, 2005 diovascular Disease in the Young, and Stroke, and the Quality of
KAPOOR WN: Current evaluation in management of syncope. Circu- Care and Outcomes Research Interdisciplinary Working Group;
lation 106:1606, 2002 and the American College of Cardiology Foundation: In collab-
KERR SRJ et al: Carotid sinus hypersensitivity in asymptomatic older oration with the Heart Rhythm Society: Endorsed by the Amer-

CHAPTER 8
persons: Implications for diagnosis of syncope and falls. Arch ican Autonomic Society. Circulation 113(2):316, 2006
Intern Med 166:515, 2006 VAN DIJK N et al: Quality of life within one year following presenta-
MAISEL W, STEBENSON W: Syncopegetting to the heart of the matter. tion after transient loss of consciousness. Am J Cardiol 100:672,
N Engl J Med 347:931, 2002 2007

Syncope
 CHAPTER 9

DIZZINESS AND VERTIGO

Robert B. Daroff

Faintness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Vertigo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Miscellaneous Head Sensations . . . . . . . . . . . . . . . . . . . . . . . 99
Global Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Dizziness is a common and often vexing symptom. FAINTNESS

Patients use the term to encompass a variety of sensa-
Prior to an actual faint (syncope), there are often pro-
tions, including those that seem semantically appropriate
dromal presyncopal symptoms (faintness) reecting
(e.g., lightheadedness, faintness, spinning, giddiness) and
ischemia to a degree insufcient to impair conscious-
those that are misleadingly inappropriate, such as mental
ness. These include lightheadedness, dizziness without
confusion, blurred vision, headache, or tingling. More-
true vertigo, a feeling of warmth, diaphoresis, nausea,
over, some individuals with gait disorders caused by
and visual blurring occasionally proceeding to blindness.
peripheral neuropathy, myelopathy, spasticity, parkinson-
Presyncopal symptoms vary in duration and may
ism, or cerebellar ataxia have complaint of dizziness
increase in severity until loss of consciousness occurs or
despite the absence of vertigo or other abnormal
may resolve prior to loss of consciousness if the cerebral
cephalic sensations. In this context, the term dizziness is
ischemia is corrected. Faintness and syncope are dis-
being used to describe disturbed ambulation.There may
cussed in detail in Chap. 8.
be mild associated lightheadedness, particularly with
impaired sensation from the feet or poor vision; this is
known as multiple-sensory-defect dizziness and occurs in
VERTIGO
elderly individuals who complain of dizziness only
when walking. Decreased position sense (secondary to Vertigo is usually due to a disturbance in the vestibular
neuropathy or myelopathy) and poor vision (from system. The end organs of this system, situated in the
cataracts or retinal degeneration) create an overreliance bony labyrinths of the inner ears, consist of the three
on the aging vestibular apparatus. A less precise but semicircular canals and the otolithic apparatus (utricle
sometimes comforting designation to patients is benign and saccule) on each side. The canals transduce angular
dysequilibrium of aging.Thus, a careful history is necessary acceleration, while the otoliths transduce linear accelera-
to determine exactly what a patient who states,Doctor, tion and the static gravitational forces that provide a
Im dizzy, is experiencing. After eliminating the mis- sense of head position in space.The neural output of the
leading symptoms or gait disturbance, dizziness usually end organs is conveyed to the vestibular nuclei in the
means either faintness (presyncope) or vertigo (an illusory brainstem via the eighth cranial nerves. The principal
or hallucinatory sense of movement of the body or projections from the vestibular nuclei are to the nuclei of
environment, most often a feeling of spinning). Opera- cranial nerves III, IV, and VI; spinal cord; cerebral cortex;
tionally, after obtaining the history, dizziness may be and cerebellum.The vestibuloocular reex (VOR) serves
classied into three categories: (1) faintness, (2) vertigo, to maintain visual stability during head movement and
and (3) miscellaneous head sensations. depends on direct projections from the vestibular nuclei
96
to the sixth cranial nerve (abducens) nuclei in the pons associated with jerk nystagmus and is frequently accom- 97
and, via the medial longitudinal fasciculus, to the third panied by nausea, postural unsteadiness, and gait ataxia.
(oculomotor) and fourth (trochlear) cranial nerve nuclei Since vertigo increases with rapid head movements,
in the midbrain. These connections account for the nys- patients tend to hold their heads still.
tagmus (to-and-fro oscillation of the eyes) that is an almost
invariable accompaniment of vestibular dysfunction. The
vestibular nerves and nuclei project to areas of the cerebel- Labyrinthine Dysfunction
lum (primarily the occulus and nodulus) that modulate This causes severe rotational or linear vertigo.When rota-
the VOR. The vestibulospinal pathways assist in the tional, the hallucination of movement, whether of envi-
ronment or self, is directed away from the side of the

CHAPTER 9
maintenance of postural stability. Projections to the cere-
bral cortex, via the thalamus, provide conscious awareness lesion. The fast phases of nystagmus beat away from the
of head position and movement. lesion side, and the tendency to fall is toward the side of
The vestibular system is one of three sensory systems the lesion, particularly in darkness or with the eyes closed.
subserving spatial orientation and posture; the other two Under normal circumstances, when the head is straight
are the visual system (retina to occipital cortex) and the and immobile, the vestibular end organs generate a tonic
somatosensory system that conveys peripheral informa- resting ring frequency that is equal from the two sides.

Dizziness and Vertigo

tion from skin, joint, and muscle receptors.The three sta- With any rotational acceleration, the anatomic positions
bilizing systems overlap sufciently to compensate (partially of the semicircular canals on each side necessitate an
or completely) for each others deciencies.Vertigo may increased ring rate from one and a commensurate
represent either physiologic stimulation or pathologic decrease from the other.This change in neural activity is
dysfunction in any of the three sensory systems. ultimately projected to the cerebral cortex, where it is
summed with inputs from the visual and somatosensory
systems to produce the appropriate conscious sense of
Physiologic Vertigo rotational movement. After cessation of prolonged rota-
tion, the ring frequencies of the two end organs
This occurs in normal individuals when (1) the brain is reverse; the side with the initially increased rate decreases,
confronted with an intersensory mismatch among the and the other side increases. A sense of rotation in the
three stabilizing sensory systems; (2) the vestibular sys- opposite direction is experienced; since there is no
tem is subjected to unfamiliar head movements to actual head movement, this hallucinatory sensation is
which it is unadapted, such as in seasickness; (3) unusual physiologic postrotational vertigo.
head/neck positions, such as the extreme extension Any disease state that changes the ring frequency of
when painting a ceiling; or (4) following a spin. Inter- an end organ, producing unequal neural input to the
sensory mismatch explains carsickness, height vertigo, brainstem and ultimately the cerebral cortex, causes ver-
and the visual vertigo most commonly experienced dur- tigo. The symptom can be conceptualized as the cortex
ing motion picture chase scenes; in the latter, the visual inappropriately interpreting the abnormal neural input
sensation of environmental movement is unaccompa- as indicating actual head rotation. Transient abnormali-
nied by concomitant vestibular and somatosensory ties produce short-lived symptoms. With a xed unilat-
movement cues. Space sickness, a frequent transient effect eral decit, central compensatory mechanisms ultimately
of active head movement in the weightless zero-gravity diminish the vertigo. Since compensation depends on
environment, is another example of physiologic vertigo. the plasticity of connections between the vestibular
nuclei and the cerebellum, patients with brainstem or
cerebellar disease have diminished adaptive capacity, and
Pathologic Vertigo
symptoms may persist indenitely. Compensation is
This results from lesions of the visual, somatosensory, or always inadequate for severe xed bilateral lesions
vestibular systems. Visual vertigo is caused by new or despite normal cerebellar connections; these patients are
incorrect eyeglasses or by the sudden onset of an permanently symptomatic when they move their heads.
extraocular muscle paresis with diplopia; in either Acute unilateral labyrinthine dysfunction is caused by
instance, central nervous system (CNS) compensation infection, trauma, and ischemia. Often, no specic etiol-
rapidly counteracts the vertigo. Somatosensory vertigo, ogy is uncovered, and the nonspecic terms acute
rare in isolation, is usually due to a peripheral neuropa- labyrinthitis, acute peripheral vestibulopathy, or vestibular neu-
thy or myelopathy that reduces the sensory input neces- ritis are used to describe the event. The vertiginous
sary for central compensation when there is dysfunction attacks are brief and leave the patient with mild vertigo
of the vestibular or visual systems. for several days. Infection with herpes simplex virus type
The most common cause of pathologic vertigo is 1 has been implicated. It is impossible to predict
vestibular dysfunction involving either its end organ whether a patient recovering from the rst bout of ver-
(labyrinth), nerve, or central connections. The vertigo is tigo will have recurrent episodes.
 98 Labyrinthine ischemia, presumably due to occlusion the vertical nystagmus in the upper eye increases in
of the labyrinthine branch of the internal auditory amplitude. Mild dysequilibrium when upright may also
artery, may be the sole manifestation of vertebrobasilar be present.
insufciency (Chap. 21); patients with this syndrome A perilymphatic stula should be suspected when
present with the abrupt onset of severe vertigo, nausea, episodic vertigo is precipitated by Valsalva or exertion,
and vomiting, but without tinnitus or hearing loss. particularly upon a background of a stepwise progressive
Acute bilateral labyrinthine dysfunction is usually the sensory-neural hearing loss. The condition is usually
result of toxins such as drugs or alcohol.The most com- caused by head trauma or barotrauma or occurs after
mon offending drugs are the aminoglycoside antibiotics middle ear surgery.
that damage the hair cells of the vestibular end organs
SECTION II

and may cause a permanent disorder of equilibrium. Vertigo of Vestibular Nerve Origin
Recurrent unilateral labyrinthine dysfunction, in associa- This occurs with diseases that involve the nerve in the
tion with signs and symptoms of cochlear disease (pro- petrous bone or the cerebellopontine angle. Although
gressive hearing loss and tinnitus), is usually due to less severe and less frequently paroxysmal, it has many of
Mnires disease (Chap. 18). When auditory manifesta- the characteristics of labyrinthine vertigo. The adjacent
tions are absent, the term vestibular neuronitis denotes
Clinical Manifestations of Neurologic Disease

auditory division of the eighth cranial nerve is usually

recurrent monosymptomatic vertigo. Transient ischemic affected, which explains the frequent association of ver-
attacks of the posterior cerebral circulation (verte- tigo with unilateral tinnitus and hearing loss. The most
brobasilar insufciency) only infrequently cause recur- common cause of eighth cranial nerve dysfunction is a
rent vertigo without concomitant motor, sensory, visual, tumor, usually a schwannoma (acoustic neuroma) or a
cranial nerve, or cerebellar signs (Chap. 21). meningioma. These tumors grow slowly and produce
Positional vertigo is precipitated by a recumbent head such a gradual reduction of labyrinthine output that
position, either to the right or to the left. Benign parox- central compensatory mechanisms can prevent or mini-
ysmal positional (or positioning) vertigo (BPPV) of the mize the vertigo; auditory symptoms are the most com-
posterior semicircular canal is particularly common. mon manifestations.
Although the condition may be due to head trauma,
usually no precipitating factors are identied. It generally
Central Vertigo
abates spontaneously after weeks or months. The vertigo
Lesions of the brainstem or cerebellum can cause acute
and accompanying nystagmus have a distinct pattern of
vertigo, but associated signs and symptoms usually permit
latency, fatigability, and habituation that differs from the
distinction from a labyrinthine etiology (Table 9-2).
less common central positional vertigo (Table 9-1) due
Occasionally, an acute lesion of the vestibulocerebellum
to lesions in and around the fourth ventricle. Moreover,
may present with monosymptomatic vertigo indistin-
the pattern of nystagmus in posterior canal BPPV is dis-
guishable from a labyrinthopathy.
tinctive. When supine, with the head turned to the side
Vertigo may be a manifestation of a migraine aura
of the offending ear (bad ear down), the lower eye dis-
(Chap. 6), but some patients with migraine have
plays a large-amplitude torsional nystagmus, and the upper
episodes of vertigo unassociated with their headaches.
eye has a lesser degree of torsion combined with upbeat-
Antimigrainous treatment should be considered in such
ing nystagmus. If the eyes are directed to the upper ear,
patients with otherwise enigmatic vertiginous episodes.
Vestibular epilepsy, vertigo secondary to temporal lobe
epileptic activity, is rare and almost always intermixed
TABLE 9-1 with other epileptic manifestations.
BENIGN PAROXYSMAL POSITIONAL VERTIGO AND
CENTRAL POSITIONAL VERTIGO
Psychogenic Vertigo
FEATURES BPPV CENTRAL This is sometimes called phobic postural vertigo and is
Latencya 340 s None: immediate
usually a concomitant of panic attacks (Chap. 49) or
vertigo and nystagmus agoraphobia (fear of large open spaces, crowds, or leav-
Fatigabilityb Yes No ing the safety of home). It should be suspected in
Habituationc Yes No patients so incapacitated by their symptoms that they
Intensity of vertigo Severe Mild adopt a prolonged housebound status. Most patients
Reproducibilityd Variable Good with organic vertigo attempt to function despite their
discomfort. Organic vertigo is accompanied by nystag-
a
Time between attaining head position and onset of symptoms. mus; a psychogenic etiology is almost certain when nys-
b
Disappearance of symptoms with maintenance of offending posi-
tion.
tagmus is absent during a vertiginous episode. The
c
Lessening of symptoms with repeated trials. symptoms often develop after an episode of acute
d
Likelihood of symptom production during any examination session. labyrinthine dysfunction.
TABLE 9-2 99
FEATURES OF PERIPHERAL AND CENTRAL VERTIGO

CENTRAL (BRAINSTEM
SIGN OR SYMPTOM PERIPHERAL (LABYRINTH) OR CEREBELLUM)

Direction of associated nystagmus Unidirectional; fast phase opposite lesiona Bidirectional or unidirectional
Purely horizontal nystagmus without Uncommon Common
torsional component
Vertical or purely torsional Never present May be present
nystagmus

CHAPTER 9
Visual xation Inhibits nystagmus and vertigo No inhibition
Severity of vertigo Marked Often mild
Direction of spin Toward fast phase Variable
Direction of fall Toward slow phase Variable
Duration of symptoms Finite (minutes, days, weeks) but recurrent May be chronic
Tinnitus and/or Often present Usually absent
deafness

Dizziness and Vertigo

Associated CNS None Extremely common (e.g., diplopia,
abnormalities hiccups, cranial neuropathies,
dysarthria)
Common causes BPPV, infection (labyrinthitis), Mnires, Vascular, demyelinating,
neuronitis, ischemia, trauma, toxin neoplasm

a
In Mnires disease, the direction of the fast phase is variable.

MISCELLANEOUS HEAD SENSATIONS simulate either cephalic ischemia or vestibular dys-

This designation is used, primarily for purposes of initial function. Cephalic ischemia is obvious if the dizziness
classication, to describe dizziness that is neither faint- is duplicated during maneuvers that produce ortho-
ness nor vertigo. Cephalic ischemia or vestibular dys- static hypotension. Further provocation involves the
function may be of such low intensity that the usual Valsalva maneuver, which decreases cerebral blood
symptomatology is not clearly identied. For example, a ow and should reproduce ischemic symptoms.
small decrease in blood pressure or a slight vestibular Hyperventilation is the cause of dizziness in many
imbalance may cause sensations different from distinct anxious individuals; tingling of the hands and face
faintness or vertigo but that may be identied properly may be absent. Forced hyperventilation for 1 min is
by provocative testing techniques (see below). Other indicated for patients with enigmatic dizziness and
causes of dizziness in this category are hyperventilation normal neurologic examinations.
syndrome, hypoglycemia, and the somatic symptoms of a The simplest provocative test for vestibular dys-
clinical depression; these patients should all have normal function is rapid rotation and abrupt cessation of
neurologic examinations and vestibular function tests. movement in a swivel chair. This always induces ver-
Depressed patients often insist that the depression is tigo that the patients can compare with their sympto-
secondary to the dizziness. matic dizziness. The intense induced vertigo may be
unlike the spontaneous symptoms, but shortly there-
after, when the vertigo has all but subsided, a light-
headedness supervenes that may be identied as my
Approach to the Patient: dizziness. When this occurs, the dizzy patient, origi-
DIZZINESS AND VERTIGO
nally classied as suffering from miscellaneous head
The most important diagnostic tool is a detailed history sensations, is now properly diagnosed as having mild
focused on the meaning of dizziness to the patient. Is vertigo secondary to a vestibulopathy.
it faintness (presyncope)? Is there a sensation of spin- Patients with symptoms of positional vertigo should
ning? If either of these is afrmed and the neurologic be appropriately tested (Table 9-1). A nal provoca-
examination is normal, appropriate investigations for tive and diagnostic vestibular test, requiring the use of
the multiple causes of cephalic ischemia, presyncope Frenzel eyeglasses (self-illuminated goggles with con-
(Chap. 8), or vestibular dysfunction are undertaken. vex lenses that blur out the patients vision, but allow
When the meaning of dizziness is uncertain, the examiner to see the eyes greatly magnied), is
provocative tests may be helpful.These ofce procedures vigorous head shaking in the horizontal plane for
 100 about 10 s. If nystagmus develops after the shaking TABLE 9-3
stops, even in the absence of vertigo, vestibular dys- TREATMENT OF VERTIGO
function is demonstrated. The maneuver can then be AGENTa DOSEb
repeated in the vertical plane. If the provocative tests
establish the dizziness as a vestibular symptom, an Antihistamines
Meclizine 2550 mg 3 times/day
evaluation of vestibular vertigo is undertaken. Dimenhydrinate 50 mg 12 times/day
Promethazinec 2550-mg suppository
EVALUATION OF PATIENTS WITH PATHO- or IM
LOGIC VESTIBULAR VERTIGO The evaluation Benzodiazepines
SECTION II

depends on whether a central etiology is suspected Diazepam 2.5 mg 13 times/day

(Table 9-2). If so, MRI of the head is mandatory. Such Clonazepam 0.25 mg 13 times/day
an examination is rarely helpful in cases of recurrent Phenothiazines
Prochlorperazinec 5 mg IM or 25 mg
monosymptomatic vertigo with a normal neurologic
suppository
examination. Typical BPPV requires no investigation Anticholinergicd
after the diagnosis is made (Table 9-1). Scopolamine transdermal Patch
Clinical Manifestations of Neurologic Disease

Vestibular function tests serve to (1) demonstrate an Sympathomimeticsd

abnormality when the distinction between organic Ephedrine 25 mg/d
and psychogenic is uncertain, (2) establish the side of Combination preparationsd
the abnormality, and (3) distinguish between peripheral Ephedrine and promethazine 25 mg/d of each
and central etiologies. The standard test is electronys- Exercise therapy
Repositioning maneuverse
tagmography (calorics), where warm and cold water Vestibular rehabilitationf
(or air) are applied, in a prescribed fashion, to the Other
tympanic membranes, and the slow-phase velocities Diuretics or low-salt (1 g/d) dietg
of the resultant nystagmus from the two are com- Antimigrainous drugsh
pared. A velocity decrease from one side indicates Inner ear surgeryi
hypofunction (canal paresis). An inability to induce Prednisonec 100 mg/d for 3 days,
nystagmus with ice water denotes a dead labyrinth. tapered by 20 mg
every 3 days
Some institutions have the capability of quantitatively
determining various aspects of the VOR using com- a
All listed drugs are U.S. Food and Drug Administration approved,
puter-driven rotational chairs and precise oculo- but most are not approved for the treatment of vertigo.
graphic recording of the eye movements. b
Usual oral (unless otherwise stated) starting dose in adults; mainte-
CNS disease can produce dizzy sensations of all nance dose can be reached by a gradual increase.
c
types. Consequently, a neurologic examination is always For acute vertigo only.
d
For motion sickness only.
required even if the history or provocative tests suggest e
For benign paroxysmal positional vertigo.
a cardiac, peripheral vestibular, or psychogenic etiology. f
For vertigo other than Mnires and positional.
Any abnormality on the neurologic examination g
For Mnires disease.
h
should prompt appropriate neurodiagnostic studies. For migraine-associated vertigo (see Chap. 6 for a listing of prophy-
lactic antimigrainous drugs).
i
For perilymphatic stula and refractory cases of Mnires disease.

Treatment: Posterior semicircular canal BPPV, the most common

VERTIGO type, is often self-limited but, when persistent, may
Treatment of acute vertigo consists of bed rest (12 days respond dramatically to specic repositioning exercise
maximum) and vestibular suppressant drugs such as programs designed to empty particulate debris from
antihistaminics (meclizine, dimenhydrinate, promet- the canal. One of these exercises, the Epley procedure, is
hazine), tranquilizers with GABA-ergic effects (diazepam, graphically demonstrated, in four languages, on a website
clonazepam), phenothiazines (prochlorperazine), or glu- for use in both physicians ofces and self-treatment:
cocorticoids (Table 9-3). If the vertigo persists beyond a www.charite.de/ch/neuro/vertigo.html
few days, most authorities advise ambulation in an Prophylactic measures to prevent recurrent vertigo
attempt to induce central compensatory mechanisms, are variably effective. Antihistamines are commonly uti-
despite the short-term discomfort to the patient. lized but are of limited value. Mnires disease may
Chronic vertigo of labyrinthine origin may be treated respond to a diuretic or, more effectively, to a very low
with a systematized vestibular rehabilitation program to salt diet (1 g/d). Recurrent episodes of migraine-associ-
facilitate central compensation. ated vertigo should be treated with antimigrainous
 therapy (Chap. 6). There are a variety of inner ear surgi- number of reports of horizontal (lateral) BPPV from 101
cal procedures for refractory Mnires disease, but Italy and Korea.
these are only rarely necessary.
Psychogenic (phobic postural) vertigo is best FURTHER READINGS
treated with cognitive-behavioral therapy. FIFE TD et al: Practice parameter: Therapies for benign paroxysmal
Helpful websites for both physicians and vertigo positional vertigo (an evidence-based review). Neurology
patients: www.iVertigo.net and www.tchain.com. 70:2067, 2008
HALMAGI GM: Diagnosis and management of vertigo. Clin Med
5:159, 2005

CHAPTER 9
LEIGH RJ, ZEE DS: Neurology of Eye Movement, 4th ed. New York,
Oxford, 2006, 7679; 559597
GLOBAL CONSIDERATIONS SAJJADI H, PAPARELLA MM: Menieres disease. Lancet 372:406, 2008
There are no epidemiologic studies indicating an STRUPP M et al: Methylprednisolone, valacyclovir, or the combina-
tion for vestibular neuritis. N Engl J Med 351:354, 2004
increased frequency of specic types of vertigo
, BRANDT T: Pharmacological advances in the treatment of
in different geographical areas. However, whereas neuro-otological and eye movement disorders. Curr Opin Neu-
BPPV of the posterior semicircular canal is overwhelm-

Dizziness and Vertigo

rol 19:33, 2006
ingly the most common form of positional vertigo in ZINGLER VC et al: Causative factors and epidemiology of bilateral
most countries, there seems to be an unusually large vestibulopathy in 255 patients.Ann Neurol 61:524, 2007
 CHAPTER 10

WEAKNESS AND PARALYSIS

Michael J. Aminoff

Normal motor function involves integrated muscle weakness generally produce spasticity, an increase in tone
activity that is modulated by the activity of the cerebral associated with disease of upper motor neurons. Spastic-
cortex, basal ganglia, cerebellum, and spinal cord. Motor ity is velocity-dependent, has a sudden release after
system dysfunction leads to weakness or paralysis, which reaching a maximum (the clasp-knife phenomenon),
is discussed in this chapter, or to ataxia (Chap. 26) or and predominantly affects the antigravity muscles (i.e.,
abnormal movements (Chaps. 24 and 25). The mode of upper-limb exors and lower-limb extensors). Spasticity
onset, distribution, and accompaniments of weakness is distinct from rigidity and paratonia, two other types of
help to suggest its cause. hypertonia. Rigidity is increased tone that is present
Weakness is a reduction in the power that can be throughout the range of motion (a lead pipe or plas-
exerted by one or more muscles. Increased fatigability tic stiffness) and affects exors and extensors equally; it
or limitation in function due to pain or articular stiff- sometimes has a cogwheel quality that is enhanced by
ness is often confused with weakness by patients. voluntary movement of the contralateral limb (rein-
Increased fatigability is the inability to sustain the perfor- forcement). Rigidity occurs with certain extrapyramidal
mance of an activity that should be normal for a person disorders such as Parkinsons disease. Paratonia (or gegen-
of the same age, gender, and size. Increased time is halten) is increased tone that varies irregularly in a man-
sometimes required for full power to be exerted, and ner that may seem related to the degree of relaxation, is
this bradykinesia may be misinterpreted as weakness. present throughout the range of motion, and affects
Severe proprioceptive sensory loss may also lead to exors and extensors equally; it usually results from dis-
complaints of weakness because adequate feedback ease of the frontal lobes. Weakness with decreased tone
information about the direction and power of move- (accidity) or normal tone occurs with disorders of motor
ments is lacking. Finally, apraxia, a disorder of planning units. A motor unit consists of a single lower motor neu-
and initiating a skilled or learned movement unrelated ron and all of the muscle bers that it innervates.
to a signicant motor or sensory decit (Chap. 15), is Muscle bulk is generally unaffected in patients with
sometimes mistaken for weakness by inexperienced upper motor neuron lesions, although mild disuse atro-
medical staff. phy may eventually occur. By contrast, atrophy is often
Paralysis indicates weakness that is so severe that the conspicuous when a lower motor neuron lesion is
muscle cannot be contracted at all, whereas paresis refers responsible for weakness and may also occur with
to weakness that is mild or moderate.The prex hemi- advanced muscle disease.
refers to one half of the body, para- to both legs, and Muscle stretch (tendon) reexes are usually increased
quadri- to all four limbs. The sufx -plegia signies with upper motor neuron lesions, although they may be
severe weakness or paralysis. decreased or absent for a variable period immediately
Weakness or paralysis is typically accompanied by after onset of an acute lesion. This is usuallybut not
other neurologic abnormalities that help to indicate the invariablyaccompanied by abnormalities of cutaneous
site of the responsible lesion. These include changes in reexes (such as supercial abdominals; Chap. 1) and, in
tone, muscle bulk, muscle stretch reexes, and cutaneous particular, by an extensor plantar (Babinski) response.
reexes (Table 10-1). The muscle stretch reexes are depressed in patients
Tone is the resistance of a muscle to passive stretch. with lower motor neuron lesions when there is direct
Central nervous system (CNS) abnormalities that cause involvement of specic reex arcs. The stretch reexes

102
 TABLE 10-1 103
SIGNS THAT DISTINGUISH ORIGIN OF WEAKNESS

SIGN UPPER MOTOR NEURON LOWER MOTOR NEURON MYOPATHIC

Atrophy None Severe Mild

Fasciculations None Common None
Tone Spastic Decreased Normal/decreased
Distribution of Pyramidal/regional Distal/segmental Proximal
weakness
Tendon reexes Hyperactive Hypoactive/absent Normal/hypoactive

CHAPTER 10
Babinskis sign Present Absent Absent

are generally preserved in patients with myopathic Lower Motor Neuron Weakness
weakness except in advanced stages, when they are
This pattern results from disorders of cell bodies of

Weakness and Paralysis

sometimes attenuated. In disorders of the neuromuscular
lower motor neurons in the brainstem motor nuclei and
junction, the intensity of the reexes may be affected by
the anterior horn of the spinal cord, or from dysfunction
preceding voluntary activity of affected musclessuch
of the axons of these neurons as they pass to skeletal
activity may lead to enhancement of initially depressed
muscle (Fig. 10-2).Weakness is due to a decrease in the
reexes in Lambert-Eaton myasthenic syndrome and,
number of muscle bers that can be activated, through a
conversely, to depression of initially normal reexes in
loss of motor neurons or disruption of their connec-
myasthenia gravis (Chap. 42).
tions to muscle. Loss of motor neurons does not cause
The distinction of neuropathic (lower motor neuron)
weakness but decreases tension on the muscle spindles,
from myopathic weakness is sometimes difcult clinically,
which decreases muscle tone and attenuates the stretch
although distal weakness is likely to be neuropathic and
reexes elicited on examination. An absent stretch reex
symmetric proximal weakness myopathic. Fasciculations
suggests involvement of spindle afferent bers.
(visible or palpable twitch within a muscle due to the
When a motor unit becomes diseased, especially in
spontaneous discharge of a motor unit) and early atro-
anterior horn cell diseases, it may spontaneously dis-
phy indicate that weakness is neuropathic.
charge, producing fasciculations that may be seen or felt
clinically or recorded by electromyography (EMG).
PATHOGENESIS When motor neurons or their axons degenerate, the
Upper Motor Neuron Weakness denervated muscle bers may also discharge sponta-
neously. These single muscle ber discharges, or brilla-
This pattern of weakness results from disorders that affect tion potentials, cannot be seen or felt but can be recorded
the upper motor neurons or their axons in the cerebral with EMG. If lower motor neuron weakness is present,
cortex, subcortical white matter, internal capsule, brain- recruitment of motor units is delayed or reduced, with
stem, or spinal cord (Fig. 10-1). Such lesions produce fewer than normal activated at a given discharge fre-
weakness through decreased activation of the lower quency. This contrasts with weakness of upper motor
motor neurons. In general, distal muscle groups are neuron type, in which a normal number of motor units
affected more severely than proximal ones, and axial is activated at a given frequency but with a diminished
movements are spared unless the lesion is severe and maximal discharge frequency.
bilateral. With corticobulbar involvement, weakness is
usually observed only in the lower face and tongue;
Myopathic Weakness
extraocular, upper facial, pharyngeal, and jaw muscles are
almost always spared.With bilateral corticobulbar lesions, Myopathic weakness is produced by disorders of the
pseudobulbar palsy often develops: dysarthria, dysphagia, muscle bers. Disorders of the neuromuscular junctions
dysphonia, and emotional lability accompany bilateral also produce weakness, but this is variable in degree and
facial weakness and a brisk jaw jerk. Spasticity accompa- distribution and is inuenced by preceding activity of
nies upper motor neuron weakness but may not be pre- the affected muscle.At a muscle ber, if the nerve termi-
sent in the acute phase. Upper motor neuron lesions also nal releases a normal number of acetylcholine molecules
affect the ability to perform rapid repetitive movements. presynaptically and a sufcient number of postsynaptic
Such movements are slow and coarse, but normal rhyth- acetylcholine receptors are opened, the end plate
micity is maintained. Finger-nose-nger and heel-knee- reaches threshold and thereby generates an action
shin maneuvers are performed slowly but adequately. potential that spreads across the muscle ber membrane
 104 Corticospinal

Sh Trunk
Hip

d er

Wr ow
tract

oul

Fin ist
El b

um s
Th ger
Knee

b
ck
Ankle Ne
B w
ro
Toes
Eyelid
Nares
Lips
Tongue
Larynx
SECTION II

Red nucleus
Reticular nuclei
Vestibular nuclei
Clinical Manifestations of Neurologic Disease

Vestibulospinal tract Rubrospinal tract

Lateral corticospinal
Reticulospinal tract tract

Lateral
corticospinal tract

Rubrospinal
(ventrolateral)
tract
Ventromedial
bulbospinal
tracts
FIGURE10-1
The corticospinal and bulbospinal upper motor neuron are involved in the execution of learned, ne movements.
pathways. Upper motor neurons have their cell bodies in Corticobulbar neurons are similar to corticospinal neurons
layer V of the primary motor cortex (the precentral gyrus, or but innervate brainstem motor nuclei.
Brodmanns area 4) and in the premotor and supplemental Bulbospinal upper motor neurons influence strength and
motor cortex (area 6). The upper motor neurons in the primary tone but are not part of the pyramidal system. The
motor cortex are somatotopically organized as illustrated on descending ventromedial bulbospinal pathways originate in
the right side of the gure. the tectum of the midbrain (tectospinal pathway), the
Axons of the upper motor neurons descend through the vestibular nuclei (vestibulospinal pathway), and the reticular
subcortical white matter and the posterior limb of the internal formation (reticulospinal pathway). These pathways influ-
capsule. Axons of the pyramidal or corticospinal system ence axial and proximal muscles and are involved in the
descend through the brainstem in the cerebral peduncle of maintenance of posture and integrated movements of the
the midbrain, the basis pontis, and the medullary pyramids. limbs and trunk. The descending ventrolateral bulbospinal
At the cervicomedullary junction, most pyramidal axons pathways, which originate predominantly in the red nucleus
decussate into the contralateral corticospinal tract of the lat- (rubrospinal pathway), facilitate distal limb muscles. The
eral spinal cord, but 1030% remains ipsilateral in the ante- bulbospinal system is sometimes referred to as the
rior spinal cord. Pyramidal neurons make direct monosynap- extrapyramidal upper motor neuron system. In all figures,
tic connections with lower motor neurons. They innervate nerve cell bodies and axon terminals are shown, respec-
most densely the lower motor neurons of hand muscles and tively, as closed circles and forks.

and into the transverse tubular system. This electrical within motor units.With muscular dystrophies, inamma-
excitation activates intracellular events that produce an tory myopathies, or myopathies with muscle ber necrosis,
energy-dependent contraction of the muscle ber (exci- the number of muscle bers is reduced within many
tation-contraction coupling). motor units. On EMG, the size of each motor unit action
Myopathic weakness is produced by a decrease in the potential is decreased, and motor units must be recruited
number or contractile force of muscle bers activated more rapidly than normal to produce the desired power.
 Hemiparesis 105
Afferent
neuron Hemiparesis results from an upper motor neuron lesion
above the midcervical spinal cord; most such lesions are
above the foramen magnum. The presence of other neu-
rologic decits helps to localize the lesion.Thus, language
disorders, cortical sensory disturbances, cognitive abnor-
malities, disorders of visual-spatial integration, apraxia, or
seizures point to a cortical lesion. Homonymous visual
eld defects reect either a cortical or a subcortical hemi-

CHAPTER 10
Alpha and gamma
motor neurons spheric lesion. A pure motor hemiparesis of the face,
arm, or leg is often due to a small, discrete lesion in the
posterior limb of the internal capsule, cerebral peduncle,
or upper pons. Some brainstem lesions produce crossed
Motor end plates on paralyses, consisting of ipsilateral cranial nerve signs and
voluntary muscle
(extrafusal fibers) contralateral hemiparesis. The absence of cranial nerve

Weakness and Paralysis

signs or facial weakness suggests that a hemiparesis is due
Muscle spindle
to a lesion in the high cervical spinal cord, especially if
(intrafusal fibers) associated with ipsilateral loss of proprioception and con-
FIGURE 10-2 tralateral loss of pain and temperature sense (the Brown-
Lower motor neurons are divided into and types. The Squard syndrome).
larger motor neurons are more numerous and innervate the Acute or episodic hemiparesis usually results from ischemic
extrafusal muscle bers of the motor unit. Loss of motor or hemorrhagic stroke, but may also relate to hemor-
neurons or disruption of their axons produces lower motor rhage occurring into brain tumors or as a result of
neuron weakness. The smaller, less numerous motor neu- trauma; other causes include a focal structural lesion or
rons innervate the intrafusal muscle bers of the muscle spin- inammatory process as in multiple sclerosis, abscess, or
dle and contribute to normal tone and stretch reexes. The sarcoidosis. Evaluation begins immediately with a CT
motor neuron receives direct excitatory input from corticomo- scan of the brain (Fig. 10-3) and laboratory studies. If
toneurons and primary muscle spindle afferents. The and the CT is normal and an ischemic stroke is unlikely,
motor neurons also receive excitatory input from other MRI of the brain or cervical spine is performed.
descending upper motor neuron pathways, segmental sen- Subacute hemiparesis that evolves over days or weeks
sory inputs, and interneurons. The motor neurons receive has an extensive differential diagnosis. A common cause
direct inhibition from Renshaw cell interneurons, and other is subdural hematoma, especially in elderly or anticoagu-
interneurons indirectly inhibit the and motor neurons. lated patients, even when there is no history of trauma.
A tendon reex requires the function of all illustrated struc- Infectious possibilities include cerebral abscess, fungal
tures. A tap on a tendon stretches muscle spindles (which granuloma or meningitis, and parasitic infection. Weak-
are tonically activated by motor neurons) and activates the
ness from primary and metastatic neoplasms may evolve
primary spindle afferent neurons. These stimulate the
over days to weeks. AIDS may present with subacute
motor neurons in the spinal cord, producing a brief muscle
hemiparesis due to toxoplasmosis or primary CNS lym-
contraction, which is the familiar tendon reex.
phoma. Noninfectious inammatory processes, such as
multiple sclerosis or, less commonly, sarcoidosis, merit
consideration. If the brain MRI is normal and there are
Some myopathies produce weakness through loss of con- no cortical and hemispheric signs, MRI of the cervical
tractile force of muscle bers or through relatively selec- spine should be undertaken.
tive involvement of the type II (fast) bers.These may not Chronic hemiparesis that evolves over months is usually
affect the size of individual motor unit action potentials due to a neoplasm or vascular malformation, a chronic
and are detected by a discrepancy between the electrical subdural hematoma, or a degenerative disease. If an
activity and force of a muscle. MRI of the brain is normal, the possibility of a foramen
Diseases of the neuromuscular junction, such as myas- magnum or high cervical spinal cord lesion should be
thenia gravis, produce weakness in a similar manner, but considered.
the loss of muscle bers is functional (due to inability to
activate them) rather than related to muscle ber loss.The
Paraparesis
number of muscle bers that are activated varies over time,
depending on the state of rest of the neuromuscular junc- An intraspinal lesion at or below the upper thoracic
tions. Thus, fatigable weakness is suggestive of myasthenia spinal cord level is most commonly responsible, but a
gravis or other disorders of the neuromuscular junction. paraparesis may also result from lesions at other locations
 106
DISTRIBUTION OF WEAKNESS

Hemiparesis Paraparesis Quadriparesis Monoparesis Distal Proximal Restricted

Alert

UMN signs LMN signs* Yes No UMN signs LMN signs*

SECTION II

Cerebral signs

Yes No
UMN signs LMN signs*

EMG and NCS

Clinical Manifestations of Neurologic Disease

UMN pattern LMN pattern Myopathic pattern

Anterior horn, Muscle or

Brain CT
Spinal MRI root, or peripheral neuromuscular
or MRI nerve disease junction disease

* or signs of myopathy

If no abnormality detected, consider spinal MRI.

If no abnormality detected, consider myelogram or brain MRI.

FIGURE 10-3
An algorithm for the initial workup of a patient with neuron; NCS, nerve conduction studies; UMN, upper motor
weakness. EMG, electromyography; LMN, lower motor neuron.

that disturb upper motor neurons (especially parasagittal confusion, seizures, or other hemispheric signs, MRI of
intracranial lesions) and lower motor neurons [anterior the brain should be undertaken.
horn cell disorders, cauda equina syndromes due to Paraparesis may result from a cauda equina syndrome,
involvement of nerve roots derived from the lower spinal for example, following trauma to the low back, a mid-
cord (Chap. 30), and peripheral neuropathies]. line disk herniation, or an intraspinal tumor; although
Acute paraparesis may not be recognized as due to sphincters are affected, hip exion is often spared, as is
spinal cord disease at an early stage if the legs are accid sensation over the anterolateral thighs. Rarely, paraparesis
and areexic. Usually, however, there is sensory loss in is caused by a rapidly evolving anterior horn cell disease
the legs with an upper level on the trunk; a dissociated (such as poliovirus or West Nile virus infection), periph-
sensory loss suggestive of a central cord syndrome; or eral neuropathy (such as Guillain-Barr syndrome;
exaggerated stretch reexes in the legs with normal Chap. 41) or myopathy (Chap. 43). In such cases, elec-
reexes in the arms. It is important to image the spinal trophysiologic studies are diagnostically helpful and
cord (Fig. 10-3). Compressive lesions (particularly epidural refocus the subsequent evaluation.
tumor, abscess, or hematoma, but also a prolapsed inter- Subacute or chronic paraparesis with spasticity is caused
vertebral disk and vertebral involvement by malignancy by upper motor neuron disease. When there is associ-
or infection), spinal cord infarction (proprioception is ated lower-limb sensory loss and sphincter involvement,
usually spared), an arteriovenous stula or other vascular a chronic spinal cord disorder is likely (Chap. 30). If an
anomaly, and transverse myelitis, are among the possible MRI of the spinal cord is normal, MRI of the brain
causes (Chap. 30). may be indicated. If hemispheric signs are present, a
Diseases of the cerebral hemispheres that produce parasagittal meningioma or chronic hydrocephalus is
acute paraparesis include anterior cerebral artery ischemia likely and MRI of the brain is the initial test. In the
(shoulder shrug is also affected), superior sagittal sinus or rare situation in which a longstanding paraparesis has a
cortical venous thrombosis, and acute hydrocephalus. If lower motor neuron or myopathic etiology, the local-
upper motor neuron signs are associated with drowsiness, ization is usually suspected on clinical grounds by the
absence of spasticity and conrmed by EMG and nerve but the patient is alert, the initial test is usually an MRI 107
conduction tests. of the cervical cord. If weakness is lower motor neuron,
myopathic, or uncertain in origin, the clinical approach
Quadriparesis or Generalized Weakness begins with blood studies to determine the level of
muscle enzymes and electrolytes and an EMG and nerve
Generalized weakness may be due to disorders of the conduction study.
CNS or of the motor unit.Although the terms quadripare-
sis and generalized weakness are often used interchangeably, Subacute or Chronic Quadriparesis
quadriparesis is commonly used when an upper motor When quadriparesis due to upper motor neuron disease

CHAPTER 10
neuron cause is suspected, and generalized weakness develops over weeks, months, or years, the distinction
when a disease of the motor unit is likely.Weakness from between disorders of the cerebral hemispheres, brain-
CNS disorders is usually associated with changes in con- stem, and cervical spinal cord is usually possible clinically.
sciousness or cognition, with spasticity and brisk stretch An MRI is obtained of the clinically suspected site of
reexes, and with alterations of sensation. Most neuro- pathology. EMG and nerve conduction studies help to
muscular causes of generalized weakness are associated distinguish lower motor neuron disease (which usually
with normal mental function, hypotonia, and hypoactive presents with weakness that is most profound distally)

Weakness and Paralysis

muscle stretch reexes. The major causes of intermittent from myopathic weakness, which is typically proximal.
weakness are listed in Table 10-2.A patient with general-
ized fatigability without objective weakness may have the
chronic fatigue syndrome (Chap. 47). Monoparesis
This is usually due to lower motor neuron disease, with
Acute Quadriparesis or without associated sensory involvement. Upper
Acute quadriparesis with onset over minutes may result motor neuron weakness occasionally presents as a
from disorders of upper motor neurons (e.g., anoxia, monoparesis of distal and nonantigravity muscles. Myo-
hypotension, brainstem or cervical cord ischemia, trauma, pathic weakness is rarely limited to one limb.
and systemic metabolic abnormalities) or muscle (elec-
trolyte disturbances, certain inborn errors of muscle Acute Monoparesis
energy metabolism, toxins, or periodic paralyses). Onset If the weakness is predominantly in distal and nonanti-
over hours to weeks may, in addition to the above, be due gravity muscles and not associated with sensory impair-
to lower motor neuron disorders. Guillain-Barr syn- ment or pain, focal cortical ischemia is likely (Chap. 21);
drome (Chap. 41) is the most common lower motor neu- diagnostic possibilities are similar to those for acute hemi-
ron weakness that progresses over days to 4 weeks; the paresis. Sensory loss and pain usually accompany acute
nding of an elevated protein level in the cerebrospinal lower motor neuron weakness; the weakness is commonly
uid is helpful but may be absent early in the course. localized to a single nerve root or peripheral nerve within
In obtunded patients, evaluation begins with a CT the limb but occasionally reects plexus involvement. If
scan of the brain. If upper motor neuron signs are present lower motor neuron weakness is suspected, or the pattern
of weakness is uncertain, the clinical approach begins
with an EMG and nerve conduction study.
TABLE 10-2
CAUSES OF EPISODIC GENERALIZED WEAKNESS Subacute or Chronic Monoparesis
Weakness and atrophy that develop over weeks or
1. Electrolyte disturbances, e.g., hypokalemia,
hyperkalemia, hypercalcemia, hypernatremia,
months are usually of lower motor neuron origin. If
hyponatremia, hypophosphatemia, hypermagnesemia they are associated with sensory symptoms, a peripheral
2. Muscle disorders cause (nerve, root, or plexus) is likely; in the absence of
a. Channelopathies (periodic paralyses) such symptoms, anterior horn cell disease should be
b. Metabolic defects of muscle (impaired carbohydrate considered. In either case, an electrodiagnostic study is
or fatty acid utilization; abnormal mitochondrial indicated. If weakness is of upper motor neuron type, a
function) discrete cortical (precentral gyrus) or cord lesion may be
3. Neuromuscular junction disorders
a. Myasthenia gravis
responsible, and an imaging study is performed of the
b. Lambert-Eaton myasthenic syndrome appropriate site.
4. Central nervous system disorders
a. Transient ischemic attacks of the brainstem Distal Weakness
b. Transient global cerebral ischemia
c. Multiple sclerosis Involvement of two or more limbs distally suggests
lower motor neuron or peripheral nerve disease. Acute
 108 distal lower limb weakness occurs occasionally from an Weakness in a Restricted Distribution
acute toxic polyneuropathy or cauda equina syndrome.
Weakness may not t any of the above patterns, being
Distal symmetric weakness usually develops over weeks,
limited, for example, to the extraocular, hemifacial, bul-
months, or years and, when associated with numbness, is
bar, or respiratory muscles. If unilateral, restricted weak-
due to metabolic, toxic, hereditary, degenerative, or
ness is usually due to lower motor neuron or peripheral
inammatory diseases of peripheral nerves (Chap. 40).
nerve disease, such as in a facial palsy (Chap. 29) or an
Anterior horn cell disease may begin distally but is typi-
isolated superior oblique muscle paresis (Chap. 17).
cally asymmetric and without accompanying numbness
Weakness of part of a limb is usually due to a peripheral
(Chap. 27). Rarely, myopathies present with distal weak-
nerve lesion such as carpal tunnel syndrome or another
ness (Chap. 43). Electrodiagnostic studies help to localize
SECTION II

entrapment neuropathy. Relatively symmetric weakness

the disorder (Fig. 10-3).
of extraocular or bulbar muscles is usually due to a
Proximal Weakness myopathy (Chap. 43) or neuromuscular junction disor-
der (Chap. 42). Bilateral facial palsy with areexia sug-
Myopathy often produces symmetric weakness of the gests Guillain-Barr syndrome (Chap. 41). Worsening of
pelvic or shoulder girdle muscles (Chap. 43). Diseases of relatively symmetric weakness with fatigue is character-
Clinical Manifestations of Neurologic Disease

the neuromuscular junction [such as myasthenia gravis istic of neuromuscular junction disorders. Asymmetric
(Chap. 42)], may present with symmetric proximal bulbar weakness is usually due to motor neuron disease.
weakness often associated with ptosis, diplopia, or bulbar Weakness limited to respiratory muscles is uncommon
weakness and uctuating in severity during the day. and is usually due to motor neuron disease, myasthenia
Extreme fatigability present in some cases of myasthenia gravis, or polymyositis/dermatomyositis (Chap. 44).
gravis may even suggest episodic weakness, but strength
rarely returns fully to normal. In anterior horn cell dis- ACKNOWLEDGMENT
ease proximal weakness is usually asymmetric, but may
be symmetric if familial. Numbness does not occur with Richard K. Olney, MD, was the author of this chapter
any of these diseases.The evaluation usually begins with in previous editions, and his contributions in the last three
determination of the serum creatine kinase level and editions of Harrisons Principles of Internal Medicine are
electrophysiologic studies. appreciated.
 CHAPTER 11

GAIT AND BALANCE DISORDERS

Lewis Sudarsky

Prevalence, Morbidity, and Mortality . . . . . . . . . . . . . . . . . . . 109

Anatomy and Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Disorders of Gait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Disorders of Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

PREVALENCE, MORBIDITY, AND are widely distributed in the central nervous system.The
MORTALITY biomechanics of bipedal walking are complex, and the
performance is easily compromised by injury at any
Gait and balance problems are common in the elderly
level. Command and control centers in the brainstem,
and contribute to the risk of falls and injury. Gait disor-
cerebellum, and forebrain modify the action of spinal
ders have been described in 15% of individuals older than
pattern generators to promote stepping.While a form of
65 years. By 80 years, one person in four will use a
ctive locomotion can be elicited from quadrupedal
mechanical aid to assist ambulation.Among those 85 years
animals after spinal transection, this capacity is limited in
and older, the prevalence of gait abnormality approaches
primates. Step generation in primates is dependent on
40%. In epidemiologic studies, gait disorders are consis-
tently identied as a major risk factor for falls and injury. locomotor centers in the pontine tegmentum, midbrain,
A substantial number of older persons report insecure and subthalamic region. Locomotor synergies are exe-
balance and experience falls and fear of falling. Prospec- cuted through the reticular formation and descending
tive studies indicate that 2030% of individuals >65 years pathways in the ventromedial spinal cord. Cerebral con-
fall each year, and the proportion is even higher in hos- trol provides a goal and purpose for walking and is involved
pitalized elderly and nursing home patients. Each year in avoidance of obstacles and adaptation of locomotor
8% of individuals >75 years suffer a serious fall-related programs to context and terrain.
injury. Hip fractures often result in hospitalization and Postural control requires the maintenance of the cen-
nursing home admission. For each person who is physi- ter of mass over the base of support through the gait
cally disabled, there are others whose functional inde- cycle. Unconscious postural adjustments maintain stand-
pendence is constrained by anxiety and fear of falling. ing balance: long latency responses are measurable in the
Nearly one in ve of elderly individuals voluntarily leg muscles, beginning 110 ms after a perturbation. For-
limit their activity because of fear of falling.With loss of ward motion of the center of mass provides propulsive
ambulation, there is a diminished quality of life and force for stepping, but failure to maintain the center of
increased morbidity and mortality. mass within stability limits results in falls. The anatomic
substrate for dynamic balance has not been well dened,
but the vestibular nucleus and midline cerebellum con-
ANATOMY AND PHYSIOLOGY
tribute to balance control in animals. Human patients
Upright bipedal gait depends on the successful integra- with damage to these structures have impaired balance
tion of postural control and locomotion.These functions with standing and walking.
109
 110 Standing balance depends on good quality sensory TABLE 11-1
information about the position of the body center with ETIOLOGY OF GAIT DISORDER
respect to the environment, support surface, and gravita-
CASES PERCENT
tional forces. Sensory information for postural control is
primarily generated by the visual system, the vestibular Sensory decits 22 18.3
system, and by proprioceptive receptors in the muscle Myelopathy 20 16.7
spindles and joints. A healthy redundancy of sensory Multiple infarcts 18 15.0
afferent information is generally available, but loss of Parkinsonism 14 11.7
Cerebellar degeneration 8 6.7
two of the three pathways is sufcient to compromise Hydrocephalus 8 6.7
standing balance. Balance disorders in older individuals
SECTION II

Toxic/metabolic 3 2.5
sometimes result from multiple insults in the peripheral Psychogenic 4 3.3
sensory systems (e.g., visual loss, vestibular decit, Other 6 5.0
peripheral neuropathy), critically degrading the quality Unknown cause 17 14.2
of afferent information needed for balance stability. Total 120 100%
Older patients with mental status abnormalities and
dementia from neurodegenerative diseases appear to be
Clinical Manifestations of Neurologic Disease

Source: Reproduced with permission from Masdeu et al.

particularly prone to falls and injury. Frailty, muscle weak-
ness, and deconditioning undoubtedly contribute to the
risk.There is a growing literature on the use of attentional
resources to manage locomotion. The ability to walk level gait disturbance. Physical therapy often improves
while attending to a cognitive task (dual tasking) may be walking to the degree that follow-up observation may
particularly compromised in older adults with a history of reveal a more specic underlying disorder.
falls. Walking is generally considered to be unconscious
and automatic, but older patients with decits in execu- Stiff-Legged Gait
tive function may be unable to manage the attention
needed for dynamic balance when distracted. Spastic gait is characterized by stiffness in the legs, an
imbalance of muscle tone, and a tendency to circumduct
and scuff the feet. The disorder reects compromise of
DISORDERS OF GAIT corticospinal command and overactivity of spinal
The heterogeneity of gait disorders observed in clinical reexes. The patient may walk on his or her toes. In
practice reects the large network of neural systems extreme instances, the legs cross due to increased tone in
involved in the task. There is the potential for abnor- the adductors. Upper motor neuron signs are present on
malities to develop, and walking is vulnerable to neuro- physical examination. Shoes often reect an uneven pat-
logic disease at every level. Gait disorders have been tern of wear across the outside. The disorder may be
classied descriptively, based on the abnormal physiol- cerebral or spinal in origin.
ogy and biomechanics. One problem with this approach Myelopathy from cervical spondylosis is a common
is that many failing gaits look fundamentally similar. cause of spastic or spastic-ataxic gait. Demyelinating dis-
This overlap reects common patterns of adaptation to ease and trauma are the leading causes of myelopathy in
threatened balance stability and declining performance. younger patients. In a chronic progressive myelopathy of
The gait disorder observed clinically must be viewed as the unknown cause, workup with laboratory and imaging
product of a neurologic decit and a functional adaptation. tests may establish a diagnosis of multiple sclerosis. A
Unique features of the failing gait are often over- family history should suggest hereditary spastic paraple-
whelmed by the adaptive response. Some of the com- gia (HSP). Genetic testing is now available for some of
mon patterns of abnormal gait are summarized below. the common HSP mutations.Tropical spastic paraparesis
Gait disorders can also be classied by etiology, as listed related to the retrovirus HTLV-I is endemic in parts of
in Table 11-1. the Caribbean and South America. A structural lesion,
such as tumor or spinal vascular malformation, should
be excluded with appropriate testing. Spinal cord disor-
Cautious Gait
ders are discussed in detail in Chap. 30.
The term cautious gait is used to describe the patient With cerebral spasticity asymmetry is common, involve-
who walks with an abbreviated stride and lowered center ment of the upper extremities is usually observed, and
of mass, as if walking on a slippery surface.This disorder dysarthria is often an associated feature. Common causes
is both common and nonspecic. It is, in essence, an include vascular disease (stroke), multiple sclerosis, and
adaptation to a perceived postural threat. A fear of falling perinatal injury to the nervous system (cerebral palsy).
may be associated. In one study, this disorder was observed Other stiff-legged gaits include dystonia (Chap. 25) and
in more than one-third of older patients with a higher stiff-person syndrome. Dystonia is a disorder characterized
by sustained muscle contractions, resulting in repetitive disease). The clinical syndrome includes mental change 111
twisting movements and abnormal posture. It often has a (variable in degree), dysarthria, pseudobulbar affect (emo-
genetic basis. Dystonic spasms produce plantar exion tional disinhibition), increased tone, and hyperreexia in
and inversion of the feet, sometimes with torsion of the the lower limbs.
trunk. In autoimmune stiff-person syndrome, there is Communicating hydrocephalus in the adult also pre-
exaggerated lordosis of the lumbar spine and overactiva- sents with a gait disorder of this type. Other features of
tion of antagonist muscles, which restricts trunk and the diagnostic triad (mental change, incontinence) may
lower limb movement and results in a wooden or xed be absent in the initial stages. MRI demonstrates ven-
posture. tricular enlargement, an enlarged ow void about the

CHAPTER 11
aqueduct, and a variable degree of periventricular white
Parkinsonism and Freezing Gait matter change. A lumbar puncture or dynamic test is
necessary to conrm the presence of hydrocephalus.
Parkinsons disease (Chap. 24) is common, affecting 1%
of the population >55 years. The stooped posture and
Cerebellar Gait Ataxia
shufing gait are characteristic and distinctive features.
Patients sometimes accelerate (festinate) with walking or Disorders of the cerebellum have a dramatic impact on

Gait and Balance Disorders

display retropulsion. There may be difculty with gait gait and balance. Cerebellar gait ataxia is characterized
initiation (freezing) and a tendency to turn en bloc. by a wide base of support, lateral instability of the trunk,
Imbalance and falls may develop as the disease progresses erratic foot placement, and decompensation of balance
over years. Other progressive neurodegenerative disorders when attempting to walk tandem. Difculty maintain-
may also involve a freezing gait; these include progressive ing balance when turning is often an early feature.
supranuclear palsy, multiple system atrophy, corticobasal Patients are unable to walk tandem heel to toe, and dis-
degeneration, and primary pallidal degeneration. Such play truncal sway in narrow-based or tandem stance.
patients with atypical parkinsonian syndromes frequently They show considerable variation in their tendency to
present with axial stiffness, postural instability, and a fall in daily life.
shufing gait but tend to lack the characteristic pill-rolling Causes of cerebellar ataxia in older patients include
tremor of Parkinsons disease. Falls within the rst year stroke, trauma, tumor, and neurodegenerative disease,
suggest the possibility of progressive supranuclear palsy. including multiple system atrophy (Chaps. 24 and 26)
Hyperkinetic movement disorders also produce char- and various forms of hereditary cerebellar degeneration
acteristic and recognizable disturbances in gait. In Hunt- (Chap. 24). MRI demonstrates the extent and topogra-
ingtons disease (Chap. 25), the unpredictable occurrence phy of cerebellar atrophy. A short expansion at the site
of choreic movements gives the gait a dancing quality. of the fragile X mutation (fragile X pre-mutation) has
Tardive dyskinesia is the cause of many odd, stereotypic been associated with gait ataxia in older men. Alcoholic
gait disorders seen in chronic psychiatric patients. cerebellar degeneration can be screened by history and
often conrmed by MRI.
Frontal Gait Disorder
Sensory Ataxia
Frontal gait disorder, sometimes known as gait apraxia,
is common in the elderly and has a variety of causes. As reviewed above, balance depends on high-quality
Typical features include a wide base of support, short afferent information from the visual and the vestibular
stride, shufing along the oor, and difculty with starts systems and proprioception. When this information is
and turns. Many patients exhibit difculty with gait ini- lost or degraded, balance during locomotion is impaired
tiation, descriptively characterized as the slipping and instability results. The sensory ataxia of tabetic neu-
clutch syndrome or gait ignition failure. The term rosyphilis is a classic example.The contemporary equiva-
lower body parkinsonism is also used to describe such lent is the patient with neuropathy affecting large bers.
patients. Strength is generally preserved, and patients are Vitamin B12 deciency is a treatable cause of large-ber
able to make stepping movements when not standing sensory loss in the spinal cord and peripheral nervous
and maintaining balance at the same time. This disorder system. Joint position and vibration sense are diminished
is a higher level motor control disorder, as opposed to an in the lower limbs.The stance in such patients is destabi-
apraxia. lized by eye closure; they often look down at their feet
The most common cause of frontal gait disorder is when walking and do poorly in the dark. Patients have
vascular disease, particularly subcortical small-vessel dis- been described with imbalance from bilateral vestibular
ease. Lesions are frequently found in the deep frontal loss, caused by disease or by exposure to ototoxic drugs.
white matter and centrum ovale. Gait disorder may be Table 11-2 compares sensory ataxia with cerebellar ataxia
the salient feature in hypertensive patients with ischemic and frontal gait disorder. Some patients exhibit a syndrome
lesions of the deep hemisphere white matter (Binswangers of imbalance from the combined effect of multiple sensory
 112 TABLE 11-2
FEATURES OF CEREBELLAR ATAXIA, SENSORY ATAXIA, AND FRONTAL GAIT DISORDERS

CEREBELLAR ATAXIA SENSORY ATAXIA FRONTAL GAIT

Base of support Wide-based Narrow base, looks down Wide-based

Velocity Variable Slow Very slow
Stride Irregular, lurching Regular with path Short, shufing
deviation
Romberg +/ Unsteady, falls +/
Heel shin Abnormal +/ Normal
SECTION II

Initiation Normal Normal Hesitant

Turns Unsteady +/ Hesitant, multistep
Postural instability + +++ ++++
Poor postural synergies
getting up from a chair
Falls Late event Frequent Frequent
Clinical Manifestations of Neurologic Disease

decits. Such patients, often elderly and diabetic, have patients with extreme anxiety or phobia walk with
disturbances in proprioception, vision, and vestibular exaggerated caution with abduction of the arms, as if
sense that impair postural support. walking on ice. This inappropriately overcautious gait
differs in degree from the gait of the patient who is
Neuromuscular Disease insecure and making adjustments for imbalance.
Depressed patients exhibit primarily slowness, a manifes-
Patients with neuromuscular disease often have an abnor- tation of psychomotor retardation, and lack of purpose
mal gait, occasionally as a presenting feature. With distal in their stride. Hysterical gait disorders are among the
weakness (peripheral neuropathy) the step height is most spectacular encountered. Odd gyrations of posture
increased to compensate for foot drop, and the sole of with wastage of muscular energy (astasia-abasia),
the foot may slap on the oor during weight acceptance. extreme slow motion, and dramatic uctuations over
Neuropathy may be associated with a degree of sensory time may be observed in patients with somatoform dis-
imbalance, as described earlier. Patients with myopathy or orders and conversion reaction.
muscular dystrophy more typically exhibit proximal
weakness. Weakness of the hip girdle may result in a
degree of excess pelvic sway during locomotion.

Toxic and Metabolic Disorders

Approach to the Patient:
Alcohol intoxication is the most common cause of acute SLOWLY PROGRESSIVE DISORDER OF GAIT
walking difculty. Chronic toxicity from medications When reviewing the history it is helpful to inquire
and metabolic disturbances can impair motor function about the onset and progression of disability. Initial
and gait. Mental status changes may be present, and awareness of an unsteady gait often follows a fall.
examination may reveal asterixis or myoclonus. Static Stepwise evolution or sudden progression suggest vas-
equilibrium is disturbed, and such patients are easily cular disease. Gait disorder may be associated with
thrown off balance. Disequilibrium is particularly evi- urinary urgency and incontinence, particularly in
dent in patients with chronic renal disease and those patients with cervical spine disease or hydrocephalus.
with hepatic failure, in whom asterixis may impair pos- It is always important to review the use of alcohol
tural support. Sedative drugs, especially neuroleptics and and medications that affect gait and balance. Informa-
long-acting benzodiazepines, affect postural control and tion on localization derived from the neurologic
increase the risk for falls. These disorders are important examination can be helpful to narrow the list of pos-
to recognize because they are often treatable. sible diagnoses.
Gait observation provides an immediate sense of
Psychogenic Gait Disorder the patients degree of disability. Characteristic pat-
terns of abnormality are sometimes observed, though
Psychogenic disorders are common in outpatient prac-
failing gaits often look fundamentally similar. Cadence
tice, and the presentation often involves gait. Some
 (steps/min), velocity, and stride length can be recorded Somatosensory decits also produce imbalance and 113
by timing a patient over a xed distance. Watching falls.There is often a subjective sense of insecure balance
the patient get out of a chair provides a good func- and fear of falling. Postural control is compromised by
tional assessment of balance. eye closure (Rombergs sign); these patients also have dif-
Brain imaging studies may be informative in patients culty navigating in the dark. A dramatic example is the
with an undiagnosed disorder of gait. MRI is sensitive patient with autoimmune subacute sensory neuropathy,
for cerebral lesions of vascular or demyelinating disease sometimes a paraneoplastic disorder (Chap. 39). Com-
and is a good screening test for occult hydrocephalus. pensatory strategies enable such patients to walk in the
Patients with recurrent falls are at risk for subdural virtual absence of proprioception, but the task requires

CHAPTER 11
hematoma. Many elderly patients with gait and balance active visual monitoring. Patients with higher level disor-
difculty have white matter abnormalities in the ders of equilibrium have difculty maintaining balance
periventricular region and centrum semiovale. While in daily life and may present with falls. There may be
these lesions may be an incidental nding, a substantial reduced awareness of balance impairment. Classic exam-
burden of white matter disease will ultimately impact ples include patients with progressive supranuclear palsy
cerebral control of locomotion. and normal pressure hydrocephalus. Patients on sedating
medications are also in this category. In prospective stud-

Gait and Balance Disorders

ies, cognitive impairment and the use of sedative medica-
tions substantially increase the risk for falls.
DISORDERS OF BALANCE
Balance is the ability to maintain equilibrium: a state in
FALLS
which opposing physical forces cancel. In physiology, Falls are a common event, particularly among the
this is taken to mean the ability of the organism to con- elderly. Modest changes in balance function have been
trol the center of mass with respect to gravity and the described in t older subjects as a result of normal
support surface. In reality, no one is aware of what or aging. Subtle decits in sensory systems, attention, and
where the center of mass is, but everyone, including motor reaction time contribute to the risk, and environ-
gymnasts, gure skaters, and platform divers, move so as mental hazards abound. Epidemiologic studies have
to manage it. Imbalance implies a disturbance of equi- identied a number of risk factors for falls, summarized
librium. Disorders of balance present with difculty in Table 11-3. A fall is not a neurologic problem, nor
maintaining posture standing and walking and with a reason for referral to a specialist, but there are circum-
subjective sense of disequilibrium, a form of dizziness. stances in which neurologic evaluation is appropriate. In
The cerebellum and vestibular system organize anti- a classic study, 90% of fall events occurred among 10%
gravity responses needed to maintain the upright pos- of individuals, a group known as recurrent fallers. Some of
ture. As reviewed earlier, these responses are physiologi- these are frail older persons with chronic diseases.
cally complex, and the anatomic representation is not Recurrent falls sometimes indicate the presence of seri-
well understood. Failure, resulting in disequilibrium, can ous balance impairment. Syncope, seizure, or falls related
occur at several levels: cerebellar, vestibular, somatosen- to loss of consciousness require appropriate evaluation
sory, and higher level disequilibrium. Patients with and treatment (Chaps. 8 and 20).
hereditary ataxia or alcoholic cerebellar degeneration do
not generally complain of dizziness, but balance is visi-
bly impaired. Neurologic examination will reveal a vari- TABLE 11-3
ety of cerebellar signs. Postural compensation may pre-
RISK FACTORS FOR FALLS, A META-ANALYSIS:
vent falls early on, but falls inevitably occur with disease SUMMARY OF SIXTEEN CONTROLLED STUDIES
progression. The progression of a neurodegenerative
ataxia is often measured by the number of years to loss RISK FACTOR MEAN RR (OR) RANGE
of stable ambulation.Vestibular disorders have symptoms Weakness 4.9 1.910.3
and signs in three categories: vertigo, the subjective Balance decit 3.2 1.65.4
appreciation or illusion of movement; nystagmus, a Gait disorder 3.0 1.74.8
vestibulo-oculomotor sign; and poor balance, an impair- Visual decit 2.8 1.17.4
ment of vestibulospinal function. Not every patient has Mobility limitation 2.5 1.05.3
all manifestations. Patients with vestibular decits related Cognitive impairment 2.4 2.04.7
Impaired functional status 2.0 1.03.1
to ototoxic drugs may lack vertigo or obvious nystag- Postural hypotension 1.9 1.03.4
mus, but balance is impaired on standing and walking,
and the patient cannot navigate in the dark. Laboratory Note: RR, relative risks from prospective studies; OR, odds ratios
testing is available to explore vestibulo-oculomotor and from retrospective studies.
vestibulospinal decits. Source: Reprinted from Masdeu et al, with permission.
 114 The descriptive classication of falls is as difcult as Falls of this nature occur in patients with advanced
the classication of gait disorders, for many of the same Parkinsons disease once postural instability has developed.
reasons. Postural control systems are widely distributed,
and a number of disease-related abnormalities occur. Gait Freezing
Unlike gait problems that are apparent on observation,
falls are rarely observed in the ofce. The patient and Another fall pattern in Parkinsons disease and related
family may have limited information about what trig- disorders is the fall due to freezing of gait.The feet stick
gered the fall. Injuries can complicate the physical to the oor and the center of mass keeps moving, result-
examination. Although there is no standard nosology of ing in a disequilibrium from which the patient cannot
falls, common patterns can be identied. recover. This can result in a forward fall. Gait freezing
SECTION II

can also occur as the patient attempts to turn and

Slipping, Tripping, and Mechanical Falls change direction. Similarly, the patient with Parkinsons
disease and festinating gait may nd his feet unable to
Slipping on icy pavement, tripping on obstacles, and falls keep up, resulting in a forward fall.
related to obvious environmental factors are often
termed mechanical falls. They occasionally occur in
Falls Related to Sensory Decit
Clinical Manifestations of Neurologic Disease

healthy individuals with good balance compensation.

Frequent tripping falls raise suspicion about an underly- Patients with somatosensory, visual, or vestibular decits
ing neurologic decit. Patients with spasticity, leg weak- are prone to falls. These patients have particular difculty
ness, or foot drop experience tripping falls. dealing with poor illumination or walking on uneven
ground.These patients often express subjective imbalance,
Weakness and Frailty apprehension, and fear of falling. Decits in joint position
and vibration sense are apparent on physical examination.
Patients who lack strength in antigravity muscles have
difculty rising from a chair, fatigue easily when walk-
ing, and have difculty maintaining their balance after a
perturbation. These patients are often unable to get up
after a fall and may be on the oor for an hour or more Treatment:
before help arrives. Deconditioning of this sort is often INTERVENTIONS TO REDUCE
treatable. Resistance strength training can increase mus- THE RISK OF FALLS AND INJURY
cle mass and leg strength in people in their 80s and 90s. Efforts should be made to dene the etiology of the gait
disorder and mechanism of the falls. Standing blood
Drop Attacks and Collapsing Falls pressure should be recorded. Specic treatment may be
possible, once a diagnosis is established. Therapeutic
Drop attacks are sudden collapsing falls without loss of intervention is often recommended for older patients at
consciousness. Patients who collapse from lack of pos- substantial risk for falls, even if no neurologic disease is
tural tone present a diagnostic challenge.The patient may identied. A home visit to look for environmental hazards
report that his or her legs just gave out underneath; the can be helpful. A variety of modications may be recom-
family may describe the patient as collapsing in a heap. mended to improve safety, including improved lighting
Orthostatic hypotension may be a factor in some such and the installation of grab bars and nonslip surfaces.
falls. Asterixis or epilepsy may impair postural support. Rehabilitation interventions attempt to improve muscle
A colloid cyst of the third ventricle can present with inter- strength and balance stability and to make the patient
mittent obstruction of the foramen of Monroe, resulting in more resistant to injury. High-intensity resistance strength
a drop attack. While collapsing falls are more common in training with weights and machines is useful to improve
older patients with vascular risk factors, they should not be muscle mass, even in frail older patients. Improvements
confused with vertebrobasilar ischemic attacks. are realized in posture and gait, which should translate to
reduced risk of falls and injury. The goal of sensory bal-
Toppling Falls ance training is to improve balance stability. Measurable
gains can be achieved in a few weeks of training, and
Some patients maintain tone in antigravity muscles but benets can be maintained over 6 months by a 10- to
fall over like a tree trunk, as if postural defenses had disen- 20-min home exercise program.This strategy is particularly
gaged. There may be a consistent direction to such falls. successful in patients with vestibular and somatosensory
The patient with cerebellar pathology may lean and top- balance disorders. The Yale Health and Aging study used
ple over toward the side of the lesion. Patients with a strategy of targeted, multiple risk factor abatement to
lesions of the vestibular system or its central pathways reduce falls in the elderly. Prescription medications were
may experience lateral pulsion and toppling falls. Patients adjusted, and home-based exercise programs were
with progressive supranuclear palsy often fall over backwards.
 BRONSTEIN A et al: Clinical Disorders of Balance, Posture and Gait. 115
tailored to the patients need, based on an initial geriatric London,Arnold Press, 2003
assessment. The program realized a 44% reduction in GANZ DA et al:Will my patient fall? JAMA 297:77, 2007
falls, in comparison with a control group of patients who Horlings CG et al: A weak balance: the contribution of muscle
had periodic social visits. weakness to postural instability and falls. Nat Clin Pract Neurol
4:504, 2008
MASDEU J et al: Gait Disorders of Aging:With Special Reference to Falls.
Boston, Little Brown, 1995
FURTHER READINGS
SNIJDERS AH et al: Neurological gait disorders in elderly people:
BISCHOFF-FERRARI HA et al: Fall prevention with supplemental and Clinical approach and classication. Lancet Neurol 6:63, 2007

CHAPTER 11
active forms of vitamin D: a meta-analysis of randomised controlled TINETTI ME: Preventing falls in elderly persons. N Engl J Med
trials. BMJ 339:3692, 2009 348:42, 2003

Gait and Balance Disorders

 CHAPTER 12

NUMBNESS, TINGLING, AND SENSORY LOSS

Michael J. Aminoff I Arthur K. Asbury

Positive and Negative Symptoms . . . . . . . . . . . . . . . . . . . . . 116

Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Anatomy of Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
I Examination of Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
I Localization of Sensory Abnormalities . . . . . . . . . . . . . . . . . . 120

Normal somatic sensation reects a continuous moni- Negative phenomena represent loss of sensory func-
toring process, little of which reaches consciousness tion and are characterized by diminished or absent feel-
under ordinary conditions. By contrast, disordered sen- ing, often experienced as numbness, and by abnormal
sation, particularly when experienced as painful, is ndings on sensory examination. In disorders affecting
alarming and dominates the sufferers attention. Physi- peripheral sensation, it is estimated that at least half the
cians should be able to recognize abnormal sensations by afferent axons innervating a given site are lost or func-
how they are described, know their type and likely site tionless before a sensory decit can be demonstrated by
of origin, and understand their implications. Pain is con- clinical examination. This threshold varies according to
sidered separately in Chap. 5. how rapidly function is lost in sensory nerve bers. If the
rate of loss is slow, lack of cutaneous feeling may be
unnoticed by the patient and difcult to demonstrate on
POSITIVE AND NEGATIVE SYMPTOMS
examination, even though few sensory bers are func-
Abnormal sensory symptoms may be divided into two tioning; if rapid, both positive and negative phenomena
categories, positive and negative. The prototypical posi- are usually conspicuous. Subclinical degrees of sensory
tive symptom is tingling (pins-and-needles); other posi- dysfunction may be revealed by sensory nerve conduction
tive sensory phenomena include altered sensations that studies or somatosensory evoked potentials (Chap. 3).
are described as pricking, bandlike, lightning-like shoot- Whereas sensory symptoms may be either positive or
ing feelings (lancinations), aching, knifelike, twisting, negative, sensory signs on examination are always a mea-
drawing, pulling, tightening, burning, searing, electrical, sure of negative phenomena.
or raw feelings. Such symptoms are often painful.
Positive phenomena usually result from trains of
TERMINOLOGY
impulses generated at sites of lowered threshold or
heightened excitability along a peripheral or central Words used to characterize sensory disturbance are
sensory pathway. The nature and severity of the abnor- descriptive and based on convention. Paresthesias and
mal sensation depend on the number, rate, timing, and dysesthesias are general terms used to denote positive sen-
distribution of ectopic impulses and the type and func- sory symptoms. The term paresthesias typically refers to
tion of nervous tissue in which they arise. Because posi- tingling or pins-and-needles sensations but may include a
tive phenomena represent excessive activity in sensory wide variety of other abnormal sensations, except pain; it
pathways, they are not necessarily associated with a sen- sometimes implies that the abnormal sensations are per-
sory decit (loss) on examination. ceived spontaneously. The more general term dysesthesias

116
denotes all types of abnormal sensations, including painful spinal cord (Fig.12-1). From there the smaller bers 117
ones, regardless of whether a stimulus is evident. take a different route to the parietal cortex than the
Another set of terms refers to sensory abnormalities larger bers. The polysynaptic projections of the smaller
found on examination. Hypesthesia or hypoesthesia refers to bers (unmyelinated and small myelinated), which sub-
a reduction of cutaneous sensation to a specic type of serve mainly nociception, temperature sensibility, and
testing such as pressure, light touch, and warm or cold touch, cross and ascend in the opposite anterior and lat-
stimuli; anesthesia, to a complete absence of skin sensation eral columns of the spinal cord, through the brainstem,
to the same stimuli plus pinprick; and hypalgesia or analge- to the ventral posterolateral (VPL) nucleus of the thala-
sia to reduced or absent pain perception (nociception), mus, and ultimately project to the postcentral gyrus of the

CHAPTER 12
such as perception of the pricking quality elicited by a parietal cortex. This is the spinothalamic pathway or antero-
pin. Hyperesthesia means pain or increased sensitivity in lateral system.The larger bers, which subserve tactile and
response to touch. Similarly, allodynia describes the situa- position sense and kinesthesia, project rostrally in the
tion in which a nonpainful stimulus, once perceived, is posterior column on the same side of the spinal cord
experienced as painful, even excruciating. An example is
elicitation of a painful sensation by application of a vibrat-
ing tuning fork. Hyperalgesia denotes severe pain in

Numbness, Tingling, and Sensory Loss

response to a mildly noxious stimulus, and hyperpathia, a Leg
Trunk Post-central
broad term, encompasses all the phenomena described by cortex
hyperesthesia, allodynia, and hyperalgesia. With hyper-
Arm
pathia, the threshold for a sensory stimulus is increased Thalamus
and perception is delayed, but once felt, is unduly painful.
Disorders of deep sensation, arising from muscle spin-
dles, tendons, and joints, affect proprioception (position Face

sense). Manifestations include imbalance (particularly

with eyes closed or in the dark), clumsiness of precision
movements, and unsteadiness of gait, which are referred Internal
capsule
to collectively as sensory ataxia. Other ndings on exami- Ventral
nation usually, but not invariably, include reduced or posterolateral
nucleus of
absent joint position and vibratory sensibility and absent thalamus
deep tendon reexes in the affected limbs. Rombergs MIDBRAIN
sign is positive, which means that the patient sways
markedly or topples when asked to stand with feet close Reticulothalamic pathway
together and eyes closed. In severe states of deafferenta-
tion involving deep sensation, the patient cannot walk or Principal sensory PONS
nucleus of V
stand unaided or even sit unsupported. Continuous invol- Medial lemniscus

untary movements (pseudoathetosis) of the outstretched

hands and ngers occur, particularly with eyes closed. Nucleus of
funiculus gracilis
Nucleus of
funiculus cuneatus MEDULLA
ANATOMY OF SENSATION Spinothalamic tract
Nucleus of
spinal tract V
Cutaneous afferent innervation is conveyed by a rich variety
of receptors, both naked nerve endings (nociceptors and
thermoreceptors) and encapsulated terminals (mechanore-
ceptors). Each type of receptor has its own set of sensitivities SPINAL CORD
to specic stimuli, size and distinctness of receptive elds, Spinothalamic tract
and adaptational qualities. Much of the knowledge about
these receptors has come from the development of tech- FIGURE12-1
niques to study single intact nerve bers intraneurally in The main somatosensory pathways. The spinothalamic tract
awake, unanesthetized human subjects. It is possible not only (pain, thermal sense) and the posterior columnlemniscal sys-
to record from but also to stimulate single bers in isolation. tem (touch, pressure, joint position) are shown. Offshoots from
A single impulse, whether elicited by a natural stimulus or the ascending anterolateral fasciculus (spinothalamic tract) to
evoked by electrical microstimulation in a large myelinated nuclei in the medulla, pons, and mesencephalon and nuclear
afferent ber may be both perceived and localized. terminations of the tract are indicated. (From AH Ropper, RH
Afferent bers of all sizes in peripheral nerve trunks Brown, in Adams and Victors Principles of Neurology, 8th ed.
traverse the dorsal roots and enter the dorsal horn of the New York, McGraw-Hill, 2007.)
 118 and make their rst synapse in the gracile or cuneate sensation, but some idea of proprioceptive function may
nucleus of the lower medulla. Axons of the second- be gained by noting the patients best performance of
order neuron decussate and ascend in the medial lem- movements requiring balance and precision. Frequently,
niscus located medially in the medulla and in the patients present with sensory symptoms that do not t an
tegmentum of the pons and midbrain and synapse in the anatomic localization and that are accompanied by either
VPL nucleus; the third-order neurons project to parietal no abnormalities or gross inconsistencies on examination.
cortex.This large-ber system is referred to as the poste- The examiner should then consider whether the sensory
rior columnmedial lemniscal pathway (lemniscal, for short). symptoms are a disguised request for help with psycholog-
Note that although the lemniscal and the anterolateral ical or situational problems. Discretion must be used in
pathways both project up the spinal cord to the thala- pursuing this possibility. Finally, sensory examination of a
SECTION II

mus, it is the (crossed) anterolateral pathway that is patient who has no neurologic complaints can be brief
referred to as the spinothalamic tract, by convention. and consist of pinprick, touch, and vibration testing in the
Although the ber types and functions that make up hands and feet plus evaluation of stance and gait, including
the spinothalamic and lemniscal systems are relatively the Romberg maneuver. Evaluation of stance and gait also
well known, many other bers, particularly those associ- tests the integrity of motor and cerebellar systems.
ated with touch, pressure, and position sense, ascend in a
Clinical Manifestations of Neurologic Disease

diffusely distributed pattern both ipsilaterally and con-

tralaterally in the anterolateral quadrants of the spinal Primary Sensation
cord. This explains why a complete lesion of the poste- (See Table 12-1) The sense of pain is usually tested with
rior columns of the spinal cord may be associated with a clean pin, asking the patient to focus on the pricking
little sensory decit on examination. or unpleasant quality of the stimulus and not just the
pressure or touch sensation elicited. Areas of hypalgesia
should be mapped by proceeding radially from the most
EXAMINATION OF SENSATION hypalgesic site (Figs. 12-2 and 12-3).
Temperature sensation, to both hot and cold, is best
The main components of the sensory examination are tested with small containers lled with water of the
tests of primary sensation (pain, touch, vibration, joint desired temperature. This is impractical in most settings.
position, and thermal sensation; Table 12-1). An alternative way to test cold sensation is to touch a
Some general principles pertain. The examiner must metal object, such as a tuning fork at room temperature,
depend on patient responses, particularly when testing to the skin. For testing warm temperatures, the tuning
cutaneous sensation (pin, touch, warm, or cold), which fork or other metal object may be held under warm
complicates interpretation. Further, examination may be water of the desired temperature and then used. The
limited in some patients. In a stuporous patient, for exam- appreciation of both cold and warmth should be tested
ple, sensory examination is reduced to observing the brisk- because different receptors respond to each.
ness of withdrawal in response to a pinch or other noxious Touch is usually tested with a wisp of cotton or a ne
stimulus. Comparison of response on one side of the body camelhair brush. In general, it is better to avoid testing
to the other is essential. In the alert but uncooperative touch on hairy skin because of the profusion of sensory
patient, it may not be possible to examine cutaneous endings that surround each hair follicle.

TABLE 12-1
TESTING PRIMARY SENSATION

FIBER SIZE
SENSE TEST DEVICE ENDINGS ACTIVATED MEDIATING CENTRAL PATHWAY

Pain Pinprick Cutaneous nociceptors Small SpTh, also D

Temperature, heat Warm metal object Cutaneous thermoreceptors for hot Small SpTh
Temperature, cold Cold metal object Cutaneous thermoreceptors for cold Small SpTh
Touch Cotton wisp, Cutaneous mechanoreceptors, Large and Lem, also D and SpTh
ne brush also naked endings small
Vibration Tuning fork, 128 Hz Mechanoreceptors, especially Large Lem, also D
pacinian corpuscles
Joint position Passive movement Joint capsule and tendon endings, Large Lem, also D
of specic joints muscle spindles

Note: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; SpTh, spinothalamic projection, contralateral; Lem,
posterior column and lemniscal projection, ipsilateral.
 Ophthalmic n.
Greater occipital n. 119
Greater auricular n. C2 Lesser occipital n.
Maxillary n. Greater auricular n.
Transverse colli n.
C2 Mandibular n.
Cutaneous branches of
C3 Great auricular n.
C3 dorsal rami of spinal nn.
Transverse colli n.
C4 Supraclavicular n.
C4 Supraclavicular nn. Lat. cutaneous branches
Intercostal nn. C5 T2 of intercostal n.
T2 1. Ant cutaneous rami T4 Axillary n.
C5
2. Lat cutaneous rami T6 Post. brachial cutaneous n.

CHAPTER 12
T4
Axillary n. T8 Med. brachial cutaneous
T6
and intercostobrachial nn.
T8 Med. brachial cutaneous T10
T1 Post. antebrachial
and intercostobrachial nn. T1
C6 T10 T12 cutaneous n.
T12 Med. antebrachial L1 Lat. antebrachial
C7 cutaneous n. L2 cutaneous n.
S4 Med antebrachial
L1 Lat. antebrachial cutaneous n.
cutaneous n. C6
S3 Radial n.

Numbness, Tingling, and Sensory Loss

Radial n. C7 Ulnar n.
Median n. S2 Median n.
C8
C8 L2 Ulnar n. L2 Iliohypogastric n.
Iliohypogastric n. Cluneal nn.
Ilioinguinal n. Obturator n.
Genitofemoral n. Ant. femoral cutaneous n.
L3 L3
Lat femoral cutaneous n. Lat. femoral cutaneous n.
Obturator n.
L5 L4 Post. femoral cutaneous n.
Ant femoral cutaneous n. L4
Saphenous n. Lat. sural cutaneous n.
L5
Lat. sural cutaneous n. Sural n.
Saphenous n.
Superficial peroneal n. S1
Calcaneal nn.
S1 Sural n. Saphenous n.
Medial plantar n. L5 Plantar branches of tibial n.
Deep peroneal n.
FIGURE 12-2 FIGURE 12-3
Anterior view of dermatomes (left) and cutaneous areas Posterior view of dermatomes (left) and cutaneous areas
(right) supplied by individual peripheral nerves. (Modied (right) supplied by individual peripheral nerves. (Modied
from MB Carpenter and J Sutin, in Human Neuroanatomy, from MB Carpenter and J Sutin, in Human Neuroanatomy,
8th ed. Baltimore, Williams & Wilkins, 1983.) 8th ed. Baltimore, Williams & Wilkins, 1983.)

Joint position testing is a measure of proprioception, Vibratory thresholds at the same site in the patient and
one of the most important functions of the sensory sys- the examiner may be compared for control purposes.
tem.With the patients eyes closed, joint position is tested
in the distal interphalangeal joint of the great toe and n- Quantitative Sensory Testing
gers. If errors are made in recognizing the direction of
passive movements, more proximal joints are tested. A test Effective sensory testing devices are now available com-
of proximal joint position sense, primarily at the shoulder, mercially. Quantitative sensory testing is particularly use-
is performed by asking the patient to bring the two index ful for serial evaluation of cutaneous sensation in clinical
ngers together with arms extended and eyes closed. trials. Threshold testing for touch and vibratory and
Normal individuals can do this accurately, with errors of thermal sensation is the most widely used application.
1 cm or less.
The sense of vibration is tested with a tuning fork
Cortical Sensation
that vibrates at 128 Hz. Vibration is usually tested over
bony points, beginning distally; in the feet, it is tested The most commonly used tests of cortical function are
over the dorsal surface of the distal phalanx of the big two-point discrimination, touch localization, and bilat-
toes and at the malleoli of the ankles, and in the hands eral simultaneous stimulation and tests for graphesthesia
dorsally at the distal phalanx of the ngers. If abnormali- and stereognosis. Abnormalities of these sensory tests, in
ties are found, more proximal sites can be examined. the presence of normal primary sensation in an alert
 120 cooperative patient, signify a lesion of the parietal cortex dysesthesias can also be an early event in an evolving
or thalamocortical projections to the parietal lobe. If polyneuropathy or may herald a myelopathy, such as from
primary sensation is altered, these cortical discriminative vitamin B12 deciency. Sometimes distal dysesthesias have
functions will usually be abnormal also. Comparisons no denable basis. In contrast, dysesthesias that corre-
should always be made between analogous sites on the spond to a particular peripheral nerve territory denote a
two sides of the body because the decit with a specic lesion of that nerve trunk. For instance, dysesthesias
parietal lesion is likely to be unilateral. Interside com- restricted to the fth digit and the adjacent one-half of
parisons are important for all cortical sensory testing. the fourth nger on one hand reliably point to disorder
Two-point discrimination is tested by special calipers, the of the ulnar nerve, most commonly at the elbow.
points of which may be set from 2 mm to several cen-
SECTION II

timeters apart and then applied simultaneously to the Nerve and Root
site to be tested.The pulp of the ngertips is a common
site to test; a normal individual can distinguish about In focal nerve trunk lesions severe enough to cause a
3-mm separation of points there. decit, sensory abnormalities are readily mapped and gen-
Touch localization is performed by light pressure for an erally have discrete boundaries (Figs. 12-2 and 12-3).
instant with the examiners ngertip or a wisp of cotton- Root (radicular) lesions are frequently accompanied by
Clinical Manifestations of Neurologic Disease

wool; the patient, whose eyes are closed, is required to deep, aching pain along the course of the related nerve
identify the site of touch with the ngertip. Bilateral simul- trunk. With compression of a fth lumbar (L5) or rst
taneous stimulation at analogous sites (e.g., the dorsum of sacral (S1) root, as from a ruptured intervertebral disc, sci-
both hands) can be carried out to determine whether the atica (radicular pain relating to the sciatic nerve trunk) is a
perception of touch is extinguished consistently on one frequent manifestation (Chap. 7).With a lesion affecting a
side or the other. The phenomenon is referred to as single root, sensory decits may be minimal or absent
extinction. Graphesthesia means the capacity to recognize because adjacent root territories overlap extensively.
with eyes closed letters or numbers drawn by the exam- With polyneuropathies, sensory decits are generally
iners ngertip on the palm of the hand. Once again, graded, distal, and symmetric in distribution (Chap. 40).
interside comparison is of prime importance. Inability to Dysesthesias, followed by numbness, begin in the toes
recognize numbers or letters is termed agraphesthesia. and ascend symmetrically. When dysesthesias reach the
Stereognosis refers to the ability to identify common knees, they have usually also appeared in the ngertips.
objects by palpation, recognizing their shape, texture, The process appears to be nerve lengthdependent, and
and size. Common standard objects, such as a key, paper the decit is often described as stocking-glove in type.
clip, or coins, are best used. Patients with normal stere- Involvement of both hands and feet also occurs with
ognosis should be able to distinguish a dime from a lesions of the upper cervical cord or the brainstem, but
penny and a nickel from a quarter without looking. an upper level of the sensory disturbance may then be
Patients should only be allowed to feel the object with found on the trunk and other evidence of a central
one hand at a time. If they are unable to identify it in lesion may be present, such as sphincter involvement or
one hand, it should be placed in the other for compari- signs of an upper motor neuron lesion (Chap. 10).
son. Individuals unable to identify common objects and Although most polyneuropathies are pansensory and
coins in one hand and who can do so in the other are affect all modalities of sensation, selective sensory dys-
said to have astereognosis of the abnormal hand. function according to nerve ber size may occur. Small-
ber polyneuropathies are characterized by burning,
painful dysesthesias with reduced pinprick and thermal
LOCALIZATION OF SENSORY sensation but sparing of proprioception, motor function,
ABNORMALITIES and deep tendon reexes. Touch is involved variably;
when spared, the sensory pattern is referred to as exhibit-
Sensory symptoms and signs can result from lesions at ing sensory dissociation. Sensory dissociation may occur
almost any level of the nervous system from parietal with spinal cord lesions as well as small-ber neu-
cortex to the peripheral sensory receptor. Noting the ropathies. Large-ber polyneuropathies are characterized
distribution and nature of sensory symptoms and signs is by vibration and position sense decits, imbalance, absent
the most important way to localize their source. Their tendon reexes, and variable motor dysfunction but
extent, conguration, symmetry, quality, and severity are preservation of most cutaneous sensation. Dysesthesias, if
the key observations. present at all, tend to be tingling or bandlike in quality.
Dysesthesias without sensory ndings by examina-
tion may be difcult to interpret. To illustrate, tingling
Spinal Cord
dysesthesias in an acral distribution (hands and feet) can
be systemic in origin, e.g., secondary to hyperventilation, (See Chap. 30) If the spinal cord is transected, all sensation
or induced by a medication such as acetazolamide. Distal is lost below the level of transection. Bladder and bowel
function are also lost, as is motor function. Hemisection Thalamus 121
of the spinal cord produces the Brown-Squard syn-
Hemisensory disturbance with tingling numbness from
drome, with absent pain and temperature sensation con-
head to foot is often thalamic in origin but can also arise
tralaterally and loss of proprioceptive sensation and power
from the anterior parietal region. If abrupt in onset, the
ipsilaterally below the lesion (see Figs. 12-1 and 30-1).
lesion is likely to be due to a small stroke (lacunar
Numbness or paresthesias in both feet may arise from a
infarction), particularly if localized to the thalamus.
spinal cord lesion; this is especially likely when the upper
Occasionally, with lesions affecting the VPL nucleus or
level of the sensory loss extends to the trunk. When all
adjacent white matter, a syndrome of thalamic pain, also
extremities are affected, the lesion is probably in the cer-
called Djerine-Roussy syndrome, may ensue. The persis-

CHAPTER 12
vical region or brainstem unless a peripheral neuropathy
tent, unrelenting unilateral pain is often described in
is responsible. The presence of upper motor neuron signs
dramatic terms.
(Chap. 10) supports a central lesion; a hyperesthetic band
on the trunk may suggest the level of involvement.
A dissociated sensory loss can reect spinothalamic Cortex
tract involvement in the spinal cord, especially if the
decit is unilateral and has an upper level on the torso. With lesions of the parietal lobe involving either the

Numbness, Tingling, and Sensory Loss

Bilateral spinothalamic tract involvement occurs with cortex or subjacent white matter, the most prominent
lesions affecting the center of the spinal cord, such as in symptoms are contralateral hemineglect, hemi-inatten-
syringomyelia. There is a dissociated sensory loss with tion, and a tendency not to use the affected hand and
impairment of pinprick and temperature appreciation arm. On cortical sensory testing (e.g., two-point dis-
but relative preservation of light touch, position sense, crimination, graphesthesia), abnormalities are often
and vibration appreciation. found but primary sensation is usually intact. Anterior
Dysfunction of the posterior columns in the spinal parietal infarction may present as a pseudothalamic syn-
cord or of the posterior root entry zone may lead to a drome with contralateral loss of primary sensation from
bandlike sensation around the trunk or a feeling of tight head to toe. Dysesthesias or a sense of numbness may
pressure in one or more limbs. Flexion of the neck also occur, and rarely, a painful state.
sometimes leads to an electric shocklike sensation that
radiates down the back and into the legs (Lhermittes Focal Sensory Seizures
sign) in patients with a cervical lesion affecting the pos-
terior columns, such as from multiple sclerosis, cervical These are generally due to lesions in the area of the
spondylosis, or recent irradiation to the cervical region. postcentral or precentral gyrus. The principal symptom
of focal sensory seizures is tingling, but additional, more
complex sensations may occur, such as a rushing feeling,
Brainstem
a sense of warmth, or a sense of movement without
Crossed patterns of sensory disturbance, in which one side detectable motion. Symptoms typically are unilateral;
of the face and the opposite side of the body are affected, commonly begin in the arm or hand, face, or foot; and
localize to the lateral medulla. Here a small lesion may often spread in a manner that reects the cortical repre-
damage both the ipsilateral descending trigeminal tract sentation of different bodily parts, as in a Jacksonian
and ascending spinothalamic bers subserving the oppo- march. Duration of seizures is variable; they may be
site arm, leg, and hemitorso (see Lateral medullary syn- transient, lasting only for seconds, or persist for an hour
drome in Fig. 21-10). A lesion in the tegmentum of the or more. Focal motor features may supervene, often
pons and midbrain, where the lemniscal and spinothalamic becoming generalized with loss of consciousness and
tracts merge, causes pansensory loss contralaterally. tonic-clonic jerking.
 CHAPTER 13

CONFUSION AND DELIRIUM

Scott Andrew Josephson I Bruce L. Miller

Clinical Features of Delirium . . . . . . . . . . . . . . . . . . . . . . . . . 122

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Confusion, a mental and behavioral state of reduced Delirium is a clinical diagnosis that can only be made
comprehension, coherence, and capacity to reason, is at the bedside. Two broad clinical categories of delirium
one of the most common problems encountered in have been described, hyperactive and hypoactive sub-
medicine, accounting for a large number of emergency types, based on differential psychomotor features. The
department visits, hospital admissions, and inpatient con- cognitive syndrome associated with severe alcohol with-
sultations. Delirium, a term used to describe an acute drawal remains the classic example of the hyperactive
confusional state, remains a major cause of morbidity subtype, featuring prominent hallucinations, agitation,
and mortality, contributing billions of dollars yearly to and hyperarousal, often accompanied by life-threatening
health care costs in the United States alone. Delirium autonomic instability. In striking contrast is the hypoac-
often goes unrecognized despite clear evidence that it is tive subtype of delirium, exemplied by opiate intoxica-
usually the cognitive manifestation of serious underlying tion, in which patients are withdrawn and quiet, with
medical or neurologic illness. prominent apathy and psychomotor slowing.
This dichotomy between subtypes of delirium is a
useful construct, but patients often fall somewhere along
CLINICAL FEATURES OF DELIRIUM a spectrum between the hyperactive and hypoactive
A multitude of terms are used to describe delirium, extremes, sometimes uctuating from one to the other
including encephalopathy, acute brain failure, acute con- within minutes. Therefore, clinicians must recognize the
fusional state, and postoperative or intensive care unit broad range of presentations of delirium in order to
(ICU) psychosis. Delirium has many clinical manifesta- identify all patients with this potentially reversible cog-
tions, but essentially it is dened as a relatively acute nitive disturbance. Hyperactive patients, such as those
decline in cognition that uctuates over hours or days. with delirium tremens, are easily recognized by their
The hallmark of delirium is a decit of attention, characteristic severe agitation, tremor, hallucinations, and
although all cognitive domainsincluding memory, autonomic instability. Patients who are quietly disturbed
executive function, visuospatial tasks, and languageare are more often overlooked on the medical wards and in
variably involved. Associated symptoms may include the ICU, yet multiple studies suggest that this under-
altered sleep-wake cycles, perceptual disturbances such recognized hypoactive subtype is associated with worse
as hallucinations or delusions, affect changes, and auto- outcomes.
nomic ndings including heart rate and blood pressure The reversibility of delirium is emphasized because
instability. many etiologies, such as systemic infection and medication

122
effects, can be easily treated. However, the long-term prominent visual hallucinations, parkinsonism, and an 123
cognitive effects of delirium remain largely unknown and attentional decit that clinically resembles hyperactive
understudied. Some episodes of delirium continue for delirium. Delirium in the elderly often reects an insult
weeks, months, or even years. The persistence of delir- to the brain that is vulnerable due to an underlying
ium in some patients and its high recurrence rate may neurodegenerative condition. Therefore, the develop-
be due to inadequate treatment of the underlying etiol- ment of delirium sometimes heralds the onset of a pre-
ogy for the syndrome. In some instances, delirium does viously unrecognized brain disorder.
not disappear because there is underlying permanent
neuronal damage. Even after an episode of delirium

CHAPTER 13
resolves, there may still be lingering effects of the disor- EPIDEMIOLOGY
der. A patients recall of events after delirium varies Delirium is a common disease, but its reported inci-
widely, ranging from complete amnesia to repeated dence has varied widely based on the criteria used to
reexperiencing of the frightening period of confusion in dene the disorder. Estimates of delirium in hospitalized
a disturbing manner, similar to what is seen in patients patients range from 14 to 56%, with higher rates
with posttraumatic stress disorder. reported for elderly patients and patients undergoing hip

Confusion and Delirium

surgery. Older patients in the ICU have especially high
RISK FACTORS rates of delirium ranging from 70 to 87%.The condition
An effective primary prevention strategy for delirium is not recognized in up to one-third of delirious inpa-
begins with identication of patients at highest risk, includ- tients, and the diagnosis is especially problematic in the
ing those preparing for elective surgery or being admitted ICU environment where cognitive dysfunction is often
to the hospital.Although no single validated scoring system difcult to appreciate in the setting of serious systemic
has been widely accepted as a screen for asymptomatic illness and sedation. Delirium in the ICU should be
patients, there are multiple well-established risk factors for viewed as an important manifestation of organ dysfunc-
delirium. tion not unlike liver, kidney, or heart failure. Outside
The two most consistently identied risks are older age of the acute hospital setting, delirium occurs in nearly
and baseline cognitive dysfunction. Individuals who are two-thirds of patients in nursing homes and in over 80%
older than 65 years or exhibit low scores on standardized of those at the end of life.These estimates emphasize the
tests of cognition develop delirium upon hospitalization at remarkably high frequency of this cognitive syndrome in
a rate approaching 50%. Whether age and baseline cogni- older patients, a population expected to grow in the
tive dysfunction are truly independent risk factors is upcoming decade with the aging of the baby boom
uncertain. Other predisposing factors include sensory generation.
deprivation, such as preexisting hearing and visual impair- In previous decades an episode of delirium was viewed
ment, as well as indices for poor overall health, including as a transient condition that carried a benign prognosis.
baseline immobility, malnutrition, and underlying medical Delirium has now been clearly associated with substan-
or neurologic illness. tial morbidity and increased mortality, and is increasingly
In-hospital risks for delirium include the use of blad- recognized as a sign of serious underlying illness. Recent
der catheterization, physical restraints, sleep and sensory estimates of in-hospital mortality among delirious patients
deprivation, and the addition of three or more new have ranged from 2533%, a rate that is similar to patients
medications. Avoiding such risks remains a key compo- with sepsis. Patients with an in-hospital episode of delir-
nent of delirium prevention as well as treatment. Surgi- ium have a higher mortality in the months and years
cal and anesthetic risk factors for the development of following their illness compared with age-matched non-
postoperative delirium include specic procedures such delirious hospitalized patients. Delirious hospitalized
as those involving cardiopulmonary bypass and inade- patients have a longer length of stay, are more likely to
quate or excessive treatment of pain in the immediate be discharged to a nursing home, and are more likely to
postoperative period. experience subsequent episodes of delirium; as a result,
The relationship between delirium and dementia this condition has enormous economic implications.
(Chap. 23) is complicated by signicant overlap between
these two conditions, and it is not always simple to dis-
PATHOGENESIS
tinguish between the two. Dementia and preexisting
cognitive dysfunction serve as major risk factors for The pathogenesis and anatomy of delirium are incom-
delirium, and at least two-thirds of cases of delirium pletely understood. The attentional decit that serves as
occur in patients with coexisting underlying dementia. the neuropsychological hallmark of delirium appears to
A form of dementia with parkinsonism, termed dementia have a diffuse localization with the brainstem, thalamus,
with Lewy bodies, is characterized by a uctuating course, prefrontal cortex, thalamus, and parietal lobes. Rarely,
 124 focal lesions such as ischemic strokes have led to delir-
ium in otherwise healthy persons; right parietal and Approach to the Patient:
medial dorsal thalamic lesions have been reported most DELIRIUM
commonly, stressing the relevance of these areas to delir- As the diagnosis of delirium is clinical and made at
ium pathogenesis. In most cases, delirium results from the bedside, a careful history and physical examina-
widespread disturbances in cortical and subcortical tion is necessary when evaluating patients with possi-
regions, rather than a focal neuroanatomic cause. Elec- ble confusional states. Screening tools can aid physi-
troencephalogram (EEG) data in persons with delirium cians and nurses in identifying patients with delirium,
usually show symmetric slowing, a nonspecic nding including the Confusion Assessment Method (CAM)
supporting diffuse cerebral dysfunction. (Table 13-1); the Organic Brain Syndrome Scale; the
SECTION II

Deciency of acetylcholine often plays a key role in Delirium Rating Scale; and, in the ICU, the Delirium
delirium pathogenesis. Medications with anticholinergic Detection Score and the ICU version of the CAM.
properties can precipitate delirium in susceptible indi- These scales are based on criteria from the American
viduals, and therapies designed to boost cholinergic tone Psychiatric Associations Diagnostic and Statistical Man-
such as cholinesterase inhibitors have, in small trials, ual of Mental Disorders (DSM) or the World Health
been shown to relieve symptoms of delirium. Dementia Organizations International Classication of Diseases
Clinical Manifestations of Neurologic Disease

patients are susceptible to episodes of delirium, and (ICD). Unfortunately, these scales themselves do not
those with Alzheimers pathology are known to have a identify the full spectrum of patients with delirium.
chronic cholinergic deciency state due to degeneration All patients who are acutely confused should be pre-
of acetylcholine-producing neurons in the basal fore- sumed delirious regardless of their presentation due
brain. Another common dementia associated with to the wide variety of possible clinical features.A course
decreased acetylcholine levels, dementia with Lewy bod-
ies, clinically mimics delirium in some patients. Other
neurotransmitters are also likely involved in this diffuse TABLE 13-1
cerebral disorder. For example, increases in dopamine THE CONFUSION ASSESSMENT METHOD (CAM)
can also lead to delirium. Patients with Parkinsons dis- DIAGNOSTIC ALGORITHM
ease treated with dopaminergic medications can develop
a delirious-like state that features visual hallucinations, The diagnosis of delirium requires the presence of
features 1 and 2 and of either 3 or 4.a
uctuations, and confusion. In contrast, reducing dopamin- Feature 1: Acute onset and uctuating course
ergic tone with dopamine antagonists such as typical and This feature is satised by positive responses to
atypical antipsychotic medications has long been recog- these questions: Is there evidence of an acute
nized as effective symptomatic treatment in patients with change in mental status from the patients baseline?
delirium. Did the (abnormal) behavior uctuate during the
Not all individuals exposed to the same insult will daythat is, tend to come and goor did it
develop signs of delirium. A low dose of an anticholin- increase and decrease in severity?
Feature 2: Inattention
ergic medication may have no cognitive effects on a
This feature is satised by a positive response to this
healthy young adult but may produce a orid delirium question: Did the patient have difculty focusing
in an elderly person with known underlying dementia. attentionfor example, was easily distractibleor
However, an extremely high dose of the same anti- have difculty keeping track of what was being
cholinergic medication may lead to delirium even in said?
healthy young persons. This concept of delirium devel- Feature 3: Disorganized thinking
oping as the result of an insult in predisposed individu- This feature is satised by a positive response to this
als is currently the most widely accepted pathogenic question: Was the patients thinking disorganized
or incoherent, such as rambling or irrelevant
construct. Therefore, if a previously healthy individual
conversation, unclear or illogical ow of ideas, or
with no known history of cognitive illness develops unpredictable switching from subject to subject?
delirium in the setting of a relatively minor insult such Feature 4: Altered level of consciousness
as elective surgery or hospitalization, then an unrecog- This feature is satised by any answer other than
nized underlying neurologic illness such as a neurode- alert to this question: Overall, how would you rate
generative disease, multiple previous strokes, or another this patients level of consciousness: alert (normal),
diffuse cerebral cause should be considered. In this con- vigilant (hyperalert), lethargic (drowsy, easily
text, delirium can be viewed as the symptom resulting aroused), stupor (difcult to arouse), or coma
(unarousable)?
from a stress test for the brain induced by the insult.
Exposure to known inciting factors such as systemic a
Information is usually obtained from a reliable reporter, such as a
infection or offending drugs can unmask a decreased cere- family member, caregiver, or nurse.
bral reserve and herald a serious underlying and poten- Source: Modied from Inouye SK et al: Ann Intern Med 113:941,
tially treatable illness. 1990.
that uctuates over hours or days and may worsen at Other important elements of the history include 125
night (termed sundowning) is typical but not essential screening for symptoms of organ failure or systemic
for the diagnosis. Observation of the patient will usu- infection, which often contributes to delirium in the
ally reveal an altered level of consciousness or a decit elderly. A history of illicit drug use, alcoholism, or
of attention. Other hallmark features that may be pre- toxin exposure is common in younger delirious
sent in the delirious patient include alteration of patients. Finally, asking the patient and collateral
sleep-wake cycles, thought disturbances such as hallu- source about other symptoms that may accompany
cinations or delusions, autonomic instability, and delirium, such as depression or hallucinations, may
changes in affect. help identify potential therapeutic targets.

CHAPTER 13
HISTORY It may be difcult to elicit an accurate PHYSICAL EXAMINATION The general physical
history in delirious patients who have altered levels of examination in a delirious patient should include a
consciousness or impaired attention. Information careful screening for signs of infection such as fever,
from a collateral source such as a spouse or other tachypnea, pulmonary consolidation, heart murmur,
family member is therefore invaluable.The three most or stiff neck. The patients uid status should be

Confusion and Delirium

important pieces of history include the patients base- assessed; both dehydration and uid overload with
line cognitive function, the time course of the present resultant hypoxia have been associated with delirium,
illness, and current medications. and each is usually easily rectied. The appearance of
Premorbid cognitive function can be assessed the skin can be helpful, showing jaundice in hepatic
through the collateral source or, if needed, via a encephalopathy, cyanosis in hypoxia, or needle tracks
review of outpatient records. Delirium by denition in patients using intravenous drugs.
represents a change that is relatively acute, usually over The neurologic examination requires a careful
hours to days, from a cognitive baseline. As a result, an assessment of mental status. Patients with delirium
acute confusional state is nearly impossible to diagnose often present with a uctuating course; therefore the
without some knowledge of baseline cognitive func- diagnosis can be missed when relying on a single
tion. Without this information, many patients with time point of evaluation. Some but not all patients
dementia or depression may be mistaken as delirious exhibit the characteristic pattern of sundowning, a
during a single initial evaluation. Patients with a more worsening of their condition in the evening. In these
hypoactive, apathetic presentation with psychomotor cases, assessment only during morning rounds may be
slowing may only be identied as being different from falsely reassuring.
baseline through conversations with family members. An altered level of consciousness ranging from
A number of validated instruments have been shown hyperarousal to lethargy to coma is present in most
to accurately diagnose cognitive dysfunction using a patients with delirium and can be easily assessed at
collateral source including the modied Blessed the bedside. In the patient with a relatively normal
Dementia Rating Scale and Clinical Dementia Rating level of consciousness, a screen for an attentional
(CDR). Baseline cognitive impairment is common in decit is in order, as this decit is the classic neu-
patients with delirium. Even when no such history of ropsychological hallmark of delirium. Attention can
cognitive impairment is elicited, there should still be a be assessed while taking a history from the patient.
high suspicion for previously unrecognized underlying Tangential speech, a fragmentary ow of ideas, or
neurologic disorder. inability to follow complex commands often signies
Establishing the time course of cognitive change is an attentional problem. Formal neuropsychological
important not only to make a diagnosis of delirium tests to assess attention exist, but a simple bedside test
but also to correlate the onset of the illness with of digit span forward is quick and fairly sensitive. In
potentially treatable etiologies such as recent medica- this task, patients are asked to repeat successively
tion changes or symptoms of systemic infection. longer random strings of digits beginning with two
Medications remain a common cause of delirium, digits in a row. Average adults can repeat a string of
especially those compounds with anticholinergic or between ve to seven digits before faltering; a digit
sedative properties. It is estimated that nearly one- span of four or less usually indicates an attentional
third of all cases of delirium are secondary to medica- decit unless hearing or language barriers are present.
tions, especially in the elderly. Medication histories More formal neuropsychological testing can be
should include all prescription as well as over-the- extraordinarily helpful in assessing the delirious
counter and herbal substances taken by the patient patient, but it is usually too cumbersome and time-
and any recent changes in dosing or formulation, consuming in the inpatient setting. A simple Mini
including substitution of generics for brand-name Mental Status Examination (MMSE) (Table 23-5) can
medications. provide some information regarding orientation,
 126 language, and visuospatial skills; however, perfor- TABLE 13-2
mance of some tasks on the MMSE such as spelling COMMON ETIOLOGIES OF DELIRIUM
world backwards or serial subtraction of digits will Toxins
be impaired by delirious patients attentional decits Prescription medications: especially those with
alone and are therefore unreliable. anticholinergic properties, narcotics and
The remainder of the screening neurologic exami- benzodiazepines
nation should focus on identifying new focal neuro- Drugs of abuse: alcohol intoxication and alcohol
withdrawal, opiates, ecstasy, LSD, GHB, PCP,
logic decits. Focal strokes or mass lesions in isolation ketamine, cocaine
are rarely the cause of delirium, but patients with Poisons: inhalants, carbon monoxide, ethylene glycol,
SECTION II

underlying extensive cerebrovascular disease or neu- pesticides

rodegenerative conditions may not be able to cogni- Metabolic conditions
tively tolerate even relatively small new insults. Electrolyte disturbances: hypoglycemia, hyperglycemia,
Patients should also be screened for additional signs hyponatremia, hypernatremia, hypercalcemia,
of neurodegenerative conditions such as parkinson- hypocalcemia, hypomagnesemia
Hypothermia and hyperthermia
ism, which is seen not only in idiopathic Parkinsons
Pulmonary failure: hypoxemia and hypercarbia
Clinical Manifestations of Neurologic Disease

disease but also in other dementing conditions such Liver failure/hepatic encephalopathy
as Alzheimers disease, dementia with Lewy bodies, Renal failure/uremia
and progressive supranuclear palsy. The presence of Cardiac failure
multifocal myoclonus or asterixis on the motor Vitamin deciencies: B12, thiamine, folate, niacin
examination is nonspecic but usually indicates a Dehydration and malnutrition
metabolic or toxic etiology of the delirium. Anemia
Infections
ETIOLOGY Some etiologies can be easily dis- Systemic infections: urinary tract infections,
cerned through a careful history and physical exami- pneumonia, skin and soft tissue infections, sepsis
nation, while others require conrmation with labo- CNS infections: meningitis, encephalitis, brain abscess
ratory studies, imaging, or other ancillary tests. A Endocrinologic conditions
Hyperthyroidism, hypothyroidism
large, diverse group of insults can lead to delirium, Hyperparathyroidism
and the cause in many patients is often multifactorial. Adrenal insufciency
Common etiologies are listed in Table 13-2. Cerebrovascular disorders
Prescribed, over-the-counter, and herbal medica- Global hypoperfusion states
tions are common precipitants of delirium. Drugs Hypertensive encephalopathy
with anticholinergic properties, narcotics, and benzo- Focal ischemic strokes and hemorrhages, especially
diazepines are especially frequent offenders, but nondominant parietal and thalamic lesions
Autoimmune disorders
nearly any compound can lead to cognitive dysfunc-
CNS vasculitis
tion in a predisposed patient.While an elderly patient Cerebral lupus
with baseline dementia may become delirious upon Seizure-related disorders
exposure to a relatively low dose of a medication, Nonconvulsive status epilepticus
other less-susceptible individuals may only become Intermittent seizures with prolonged post-ictal states
delirious with very high doses of the same medica- Neoplastic disorders
tion. This observation emphasizes the importance of Diffuse metastases to the brain
Gliomatosis cerebri
correlating the timing of recent medication changes,
Carcinomatous meningitis
including dose and formulation, with the onset of Hospitalization
cognitive dysfunction. Terminal end of life delirium
In younger patients especially, illicit drugs and
toxins are common causes of delirium. In addition Note: LSD, lysergic acid diethylamide; GHB, -hydroxybutyrate;
to more classic drugs of abuse, the recent rise in PCP, phencyclidine; CNS, central nervous system.
availability of so-called club drugs, such as methyl-
enedioxymethamphetamine (MDMA, ecstasy), -
hydroxybutyrate (GHB), and the PCP-like agent
ketamine, has led to an increase in delirious young it is withdrawal from alcohol that leads to a classic
persons presenting to acute care settings. Many com- hyperactive delirium. Alcohol and benzodiazepine
mon prescription drugs such as oral narcotics and withdrawal should be considered in all cases of delir-
benzodiazepines are now often abused and readily ium as even patients who drink only a few servings
available on the street. Alcohol intoxication with high of alcohol every day can experience relatively severe
serum levels can cause confusion, but more commonly withdrawal symptoms upon hospitalization.
 Metabolic abnormalities such as electrolyte distur- It is very common for patients to experience delir- 127
bances of sodium, calcium, magnesium, or glucose can ium at the end of life in palliative care settings. This
cause delirium, and mild derangements can lead to condition, sometimes described as terminal restlessness,
substantial cognitive disturbances in susceptible indi- must be identied and treated aggressively as it is an
viduals. Other common metabolic etiologies include important cause of patient and family discomfort at
liver and renal failure, hypercarbia and hypoxia, vitamin the end of life. It should be remembered that these
deciencies of thiamine and B12, autoimmune disor- patients may also be suffering from more common
ders including CNS vasculitis, and endocrinopathies etiologies of delirium such as systemic infection.
such as thyroid and adrenal disorders.

CHAPTER 13
LABORATORY AND DIAGNOSTIC EVALUA-
Systemic infections often cause delirium, especially
TION A cost-effective approach to the diagnostic
in the elderly. A common scenario involves the devel-
evaluation of delirium allows the history and physical
opment of an acute cognitive decline in the setting of
examination to guide tests. No established algorithm
a urinary tract infection in a patient with baseline
for workup will t all delirious patients due to the
dementia. Pneumonia, skin infections such as celluli-
staggering number of potential etiologies, but one
tis, and frank sepsis can also lead to delirium.This so- step-wise approach is detailed in Table 13-3. If a

Confusion and Delirium

called septic encephalopathy, often seen in the ICU, is clear precipitant is identied early, such as an offend-
likely due to the release of proinammatory cytokines ing medication, then little further workup is required.
and their diffuse cerebral effects. CNS infections such If, however, no likely etiology is uncovered with ini-
as meningitis, encephalitis, and abscess are less-com- tial evaluation, an aggressive search for an underlying
mon etiologies of delirium; however, given the high cause should be initiated.
mortality associated with these conditions when not Basic screening labs, including a complete blood
treated quickly, clinicians must always maintain a high count, electrolyte panel, and tests of liver and renal
index of suspicion. function, should be obtained in all patients with delir-
In some susceptible individuals, exposure to the ium. In elderly patients, screening for systemic infection,
unfamiliar environment of a hospital can lead to delir- including chest radiography, urinalysis and culture, and
ium.This etiology usually occurs as part of a multifac- possibly blood cultures, is important. In younger indi-
torial delirium and should be considered a diagnosis of viduals, serum and urine drug and toxicology screen-
exclusion after all other causes have been thoroughly ing may be appropriate early in the workup. Addi-
investigated. Many primary prevention and treatment tional laboratory tests addressing other autoimmune,
strategies for delirium involve relatively simple meth- endocrinologic, metabolic, and infectious etiologies
ods to address those aspects of the inpatient setting that should be reserved for patients in whom the diagnosis
are most confusing. remains unclear after initial testing.
Cerebrovascular etiologies are usually due to global Multiple studies have demonstrated that brain
hypoperfusion in the setting of systemic hypotension imaging in patients with delirium is often unhelpful.
from heart failure, septic shock, dehydration, or ane- However, if the initial workup is unrevealing, most
mia. Focal strokes in the right parietal lobe and clinicians quickly move toward imaging of the brain
medial dorsal thalamus can rarely lead to a delirious in order to exclude structural causes. A noncontrast
state. A more common scenario involves a new focal CT scan can identify large masses and hemorrhages
stroke or hemorrhage causing confusion in a patient but is otherwise relatively insensitive for discovering
who has decreased cerebral reserve. In these individu- an etiology of delirium. The ability of MRI to iden-
als, it is sometimes difcult to distinguish between tify most acute ischemic strokes as well as to provide
cognitive dysfunction resulting from the new neu- neuroanatomic detail that gives clues to possible
rovascular insult itself and delirium due to the infec- infectious, inammatory, neurodegenerative, and neo-
tious, metabolic, and pharmacologic complications plastic conditions makes it the test of choice. Since
that can accompany hospitalization after stroke. MRI techniques are limited by availability, speed of
Because a uctuating course is often seen in delir- imaging, patient cooperation, and contraindications
ium, intermittent seizures may be overlooked when to magnetic exposure, many clinicians begin with CT
considering potential etiologies. Both nonconvulsive scanning and proceed to MRI if the etiology of delir-
status epilepticus as well as recurrent focal or general- ium remains elusive.
ized seizures followed by post-ictal confusion can Lumbar puncture (LP) must be obtained immedi-
cause delirium; EEG remains essential for this diag- ately, after appropriate neuroimaging, in all patients in
nosis. Seizure activity spreading from an electrical whom CNS infection is suspected. Spinal uid exam-
focus in a mass or infarct can explain global cognitive ination can also be useful in identifying inammatory
dysfunction caused by relatively small lesions. and neoplastic conditions as well as in the diagnosis
 128 TABLE 13-3
infections should be given appropriate antibiotics and
STEP-WISE EVALUATION OF A PATIENT WITH underlying electrolyte disturbances judiciously cor-
DELIRIUM
rected). These treatments often lead to prompt resolu-
Initial evaluation tion of delirium. Blindly targeting the symptoms of delir-
History with special attention to medications (including ium pharmacologically only serves to prolong the time
over-the-counter and herbals) patients remain in the confused state and may mask
General physical examination and neurologic
examination
important diagnostic information. Recent trials of med-
Complete blood count ications used to boost cholinergic tone in delirious
Electrolyte panel including calcium, magnesium, patients have led to mixed results, and this strategy is
SECTION II

phosphorus not currently recommended.

Liver function tests including albumin Relatively simple methods of supportive care can be
Renal function tests highly effective in treating patients with delirium. Reori-
First-tier further evaluation guided by initial evaluation
entation by the nursing staff and family combined with
Systemic infection screen
Urinalysis and culture visible clocks, calendars, and outside-facing windows
Chest radiograph can reduce confusion. Sensory isolation should be pre-
Clinical Manifestations of Neurologic Disease

Blood cultures vented by providing glasses and hearing aids to those

Electrocardiogram patients who need them. Sundowning can be
Arterial blood gas addressed to a large extent through vigilance to appro-
Serum and/or urine toxicology screen (perform earlier in
priate sleep-wake cycles. During the day, a well-lit room
young persons)
Brain imaging with MRI with diffusion and gadolinium should be accompanied by activities or exercises to pre-
(preferred) or CT vent napping. At night, a quiet, dark environment with
Suspected CNS infection: lumbar puncture following limited interruptions by staff can assure proper rest.
brain imaging These sleep-wake cycle interventions are especially
Suspected seizure-related etiology: electroencephalogram important in the ICU setting as the usual constant 24-h
(EEG) (if high suspicion should be performed activity commonly provokes delirium. Attempting to
immediately)
mimic the home environment as much as possible has
Second-tier further evaluation
Vitamin levels: B12, folate, thiamine also been shown to help treat and even prevent delir-
Endocrinologic laboratories: thyroid-stimulating ium. Visits from friends and family throughout the day
hormone (TSH) and free T4; cortisol minimize the anxiety associated with the constant ow
Serum ammonia of new faces of staff and physicians. Allowing hospital-
Sedimentation rate ized patients to have access to home bedding, clothing,
Autoimmune serologies: antinuclear antibodies (ANA),
and nightstand objects makes the hospital environment
complement levels; p-ANCA, c-ANCA
Infectious serologies: rapid plasmin reagin (RPR); fungal less foreign and therefore less confusing. Simple stan-
and viral serologies if high suspicion; HIV antibody dard nursing practices such as maintaining proper
Lumbar puncture (if not already performed) nutrition and volume status as well as managing incon-
Brain MRI with and without gadolinium (if not already tinence and skin breakdown also help to alleviate dis-
performed) comfort and resulting confusion.
In some instances, patients pose a threat to their own
Note: p-ANCA, perinuclear antineutrophil cytoplasmic antibody; safety or to the safety of staff members, and acute man-
c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody.
agement is required. Bed alarms and personal sitters are
more effective and much less disorienting than physical
restraints. Chemical restraints should be avoided, but,
of hepatic encephalopathy through elevated CSF glu- when necessary, very-low-dose typical or atypical
tamine levels. As a result, LP should be considered in antipsychotic medications administered on an as-
any delirious patient with a negative workup. EEG needed basis are effective. The recent association of
does not have a routine role in the workup of delir- atypical antipsychotic use in the elderly with increased
ium, but it remains invaluable if seizure-related eti- mortality underscores the importance of using these
ologies are considered. medications judiciously and only as a last resort. Benzo-
diazepines are not as effective as antipsychotics and
often worsen confusion via their sedative properties.
Treatment: Although many clinicians still use benzodiazepines to
DELIRIUM treat acute confusion, their use should be limited only
Management of delirium begins with treatment of the to cases in which delirium is caused by alcohol or ben-
underlying inciting factor (e.g., patients with systemic zodiazepine withdrawal.
PREVENTION standardized protocols to address common risk factors 129
with the goal of decreasing the incidence of delirium.
Given the high morbidity associated with delirium and
the tremendously increased health care costs that ACKNOWLEDGMENT
accompany it, development of an effective strategy to
prevent delirium in hospitalized patients is extremely In the previous edition, Allan H. Ropper contributed to a sec-
important. Successful identication of high-risk patients tion on acute confusional states that was incorporated into this
is the rst step, followed by initiation of appropriate current chapter.
interventions. One trial randomized more than 850
elderly inpatients to simple standardized protocols used FURTHER READINGS

CHAPTER 13
to manage risk factors for delirium, including cognitive FONG TG et al: Delirium in elderly adults: diagnosis, prevention, and
impairment, immobility, visual impairment, hearing treatment. Nat Rev Neurol 5:210, 2009
impairment, sleep deprivation, and dehydration. Signi- GIRARD TD et al: Delirium in the intensive care unit. Crit Care 12
cant reductions in the number and duration of episodes Suppl 3:S3, 2008
of delirium were observed in the treatment group, but INOUYE SK et al: A multicomponent intervention to prevent delir-
unfortunately delirium recurrence rates were unchanged. ium in hospitalized older patients. N Engl J Med 340:669, 1999

Confusion and Delirium

LAT I et al:The impact of delirium on clinical outcomes in mechani-
Recent trials in the ICU have focused on identifying
cally ventilated surgical and trauma patients. Crit Care Med
sedatives, such as dexmedetomidine, that are less likely 37:1898, 2009
to lead to delirium in critically ill patients. All hospitals RIKER RR et al: Dexmedetomidine vs midazolam for sedation of
and health care systems should work toward developing critically ill patients: a randomized trial. JAMA 301:489, 2009
 CHAPTER 14

COMA

Allan H. Ropper

The Anatomy and Physiology of Coma . . . . . . . . . . . . . . . . . 131

Laboratory Studies and Imaging . . . . . . . . . . . . . . . . . . . . . . 136
Differential Diagnosis of Coma . . . . . . . . . . . . . . . . . . . . . . . 137
Brain Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

Coma is among the most common and striking prob- Yawning, coughing, swallowing, as well as limb and head
lems in general medicine. It accounts for a substantial movements persist, but there are few, if any, meaningful
portion of admissions to emergency departments and responses to the external and internal environmentin
occurs on all hospital services. Because coma demands essence, an awake coma. Respiratory and autonomic
immediate attention, the physician must employ an orga- functions are retained. The term vegetative is unfortu-
nized approach. nate as it is subject to misinterpretation by laypersons.
There is a continuum of states of reduced alertness, The possibility of incorrectly attributing meaningful
the severest form being coma, a deep sleeplike state from behavior to these patients has created inordinate prob-
which the patient cannot be aroused. Stupor refers to a lems. There are always accompanying signs that indicate
higher degree of arousability in which the patient can extensive damage in both cerebral hemispheres, e.g.,
be awakened only by vigorous stimuli, accompanied by decerebrate or decorticate limb posturing and absent
motor behavior that leads to avoidance of uncomfort- responses to visual stimuli (see later). In the closely
able or aggravating stimuli. Drowsiness, which is familiar related but less severe minimally conscious state the patient
to all persons, simulates light sleep and is characterized may make intermittent rudimentary vocal or motor
by easy arousal and the persistence of alertness for brief responses. Cardiac arrest with cerebral hypoperfusion and
periods. Drowsiness and stupor are usually attended by head injuries are the most common causes of the vegeta-
some degree of confusion (Chap. 13).A narrative descrip- tive and minimally conscious states (Chaps. 22 and 31).
tion of the level of arousal and of the type of responses The prognosis for regaining mental faculties once the
evoked by various stimuli, precisely as observed at the vegetative state has supervened for several months is very
bedside, is preferable to ambiguous terms such as lethargy, poor, and after a year, almost nil, hence the term persistent
semicoma, or obtundation. vegetative state. Most reports of dramatic recovery, when
Several other neurologic conditions render patients investigated carefully, are found to yield to the usual rules
apparently unresponsive and thereby simulate coma, and for prognosis, but there have been rare instances in which
certain subsyndromes of coma must be considered sepa- recovery has occurred to a demented condition and, in
rately because of their special signicance. Among the rare childhood cases, to an even better state.
latter, the vegetative state signies an awake but nonre- Quite apart from the above conditions, certain syn-
sponsive state. These patients have emerged from coma dromes that affect alertness are prone to be misinterpreted
after a period of days or weeks to a state in which the as stupor or coma. Akinetic mutism refers to a partially or
eyelids are open, giving the appearance of wakefulness. fully awake state in which the patient is able to form

130
impressions and think but remains virtually immobile and damage the RAS or its projections; (2) destruction of 131
mute. The condition results from damage in the regions large portions of both cerebral hemispheres; and (3) sup-
of the medial thalamic nuclei or the frontal lobes (partic- pression of reticulo-cerebral function by drugs, toxins, or
ularly lesions situated deeply or on the orbitofrontal sur- metabolic derangements such as hypoglycemia, anoxia,
faces), or from hydrocephalus. The term abulia is in uremia, and hepatic failure.
essence a milder form of akinetic mutism, used to The proximity of the RAS to structures that control
describe mental and physical slowness and diminished pupillary function and eye movements permits clinical
ability to initiate activity. It is also generally the result of localization of the cause of coma in many cases. Pupillary
damage to the frontal lobe network (Chap. 15). Catatonia enlargement with loss of light reaction and loss of verti-

CHAPTER 14
is a curious hypomobile and mute syndrome that arises as cal and adduction movements of the eyes suggests that
part of a major psychosis, usually schizophrenia or major the likely location of the lesion is in the upper brainstem.
depression. Catatonic patients make few voluntary or Conversely, preservation of pupillary reactivity and eye
responsive movements, although they blink, swallow, and movements absolves the upper brainstem and indicates
may not appear distressed.There are nonetheless signs that that widespread structural lesions or metabolic suppres-
the patient is responsive, although it may take some inge- sion of the cerebral hemispheres is responsible.
nuity on the part of the examiner to demonstrate them.

Coma
For example, eyelid elevation is actively resisted, blinking
occurs in response to a visual threat, and the eyes move Coma Due to Cerebral Mass Lesions
and Herniations
concomitantly with head rotation, all of which are incon-
sistent with the presence of a brain lesion. It is character- The cranial cavity is separated into compartments by
istic but not invariable in catatonia for the limbs to retain infoldings of the dura.The two cerebral hemispheres are
the postures in which they have been placed by the separated by the falx, and the anterior and posterior fos-
examiner (waxy exibility, or catalepsy). Upon recovery, sae by the tentorium. Herniation refers to displacement
such patients have some memory of events that occurred of brain tissue into a compartment that it normally does
during their catatonic stupor. The appearance is super- not occupy. Many of the signs associated with coma, and
cially similar to akinetic mutism, but clinical evidence of indeed coma itself, can be attributed to these tissue
cerebral damage such as Babinski signs and hypertonicity shifts, and certain clinical congurations are characteristic
of the limbs is lacking. The singular problem of brain of specic herniations (Fig. 14-1). They are in essence
death is discussed later. false localizing signs since they derive from compres-
The locked-in state describes yet another type of sion of brain structures at a distance from the mass.
pseudocoma in which an awake patient has no means of
producing speech or volitional movement, but retains
voluntary vertical eye movements and lid elevation, thus
allowing the patient to signal with a clear mind. The
pupils are normally reactive. Such individuals have writ-
ten entire treatises using Morse code. The usual cause is
an infarction or hemorrhage of the ventral pons, which
transects all descending corticospinal and corticobulbar C
pathways. A similar awake but de-efferented state occurs
as a result of total paralysis of the musculature in severe
B
cases of Guillain-Barr syndrome (Chap. 41), critical ill-
ness neuropathy (Chap. 22), and pharmacologic neuro- A
muscular blockade.

THE ANATOMY AND PHYSIOLOGY

OF COMA
D
Almost all instances of diminished alertness can be traced
to widespread abnormalities of the cerebral hemispheres
or to reduced activity of a special thalamocortical alert-
ing system termed the reticular activating system. The
proper functioning of this system, its ascending projec-
tions to the cortex, and the cortex itself are required to FIGURE 14-1
maintain alertness and coherence of thought. It follows Types of cerebral herniation. (A) uncal; (B) central;
that the principal causes of coma are (1) lesions that (C) transfalcial; (D) foraminal.
 132 The most common herniations are from the supra- drowsiness are the heralding signs. Both temporal and
tentorial to the infratentorial compartments through central herniations have classically been considered to
the tentorial opening, hence transtentorial. Uncal transten- cause a progressive compression of the brainstem from
torial herniation refers to impaction of the anterior above in an orderly manner: rst the midbrain, then the
medial temporal gyrus (the uncus) into the tentorial pons, and nally the medulla.The result is a sequence of
opening just anterior to and adjacent to the midbrain neurologic signs that corresponds to each affected level.
(Fig. 14-1, A).The displaced brain tissue compresses the Other forms of herniation are transfalcial herniation (dis-
third nerve as it traverses the subarachnoid space, and placement of the cingulate gyrus under the falx and
results in enlargement of the ipsilateral pupil (putatively across the midline, Fig. 14-1, C), and foraminal herniation
because the bers subserving parasympathetic pupillary (downward forcing of the cerebellar tonsils into the
SECTION II

function are located peripherally in the nerve). The foramen magnum, Fig. 14-1, D), which causes compres-
coma that follows is due to compression of the mid- sion of the medulla and respiratory arrest.
brain against the opposite tentorial edge by the dis- A direct relationship between the various congura-
placed parahippocampal gyrus (Fig. 14-2). In some tions of transtentorial herniations and coma is not
cases, the lateral displacement of the midbrain causes always found. Drowsiness and stupor typically occur
compression of the opposite cerebral peduncle, produc- with moderate horizontal shifts at the level of the dien-
Clinical Manifestations of Neurologic Disease

ing a Babinski sign and hemiparesis contralateral to the cephalon (thalami) well before transtentorial or other
original hemiparesis (the Kernohan-Woltman sign). In herniations are evident. Lateral shift may be quantied
addition to compressing the upper brainstem, tissue on axial images of CT and MRI scans (Fig. 14-2). In
shifts, including herniations, may compress major blood cases of acutely appearing masses, horizontal displacement
vessels, particularly the anterior and posterior cerebral of the pineal calcication of 35 mm is generally associ-
arteries as they pass over the tentorial reections, thus ated with drowsiness, 68 mm with stupor, and >9 mm
producing brain infarctions. The distortions may also with coma. Intrusion of the medial temporal lobe into
entrap portions of the ventricular system, resulting in the tentorial opening may be apparent on MRI and CT
regional hydrocephalus. scans by an obliteration of the cisterns that surround the
Central transtentorial herniation denotes a symmetric upper brainstem.
downward movement of the thalamic medial structures
through the tentorial opening with compression of Coma Due to Metabolic Disorders
the upper midbrain (Fig. 14-1, B). Miotic pupils and
Many systemic metabolic abnormalities cause coma by
interrupting the delivery of energy substrates (hypoxia,
ischemia, hypoglycemia) or by altering neuronal excitabil-
ity (drug and alcohol intoxication, anesthesia, and epilepsy).
The same metabolic abnormalities that produce coma
may in milder form induce widespread cortical dysfunc-
tion and an acute confusional state. Thus, in metabolic
encephalopathies, clouded consciousness and coma are in
a continuum.
Cerebral neurons are fully dependent on cerebral
blood ow (CBF) and the related delivery of oxygen
and glucose. CBF is ~75 mL per 100 g/min in gray mat-
ter and 30 mL per 100 g/min in white matter (mean =
55 mL per 100 g/min); oxygen consumption is 3.5 mL per
100 g/min, and glucose utilization is 5 mg per 100 g/min.
Brain stores of glucose provide energy for ~2 min after
A B blood ow is interrupted, and oxygen stores last 810 s
FIGURE 14-2 after the cessation of blood ow. Simultaneous hypoxia
Coronal (A) and axial (B) magnetic resonance images from and ischemia exhaust glucose more rapidly. The elec-
a stuporous patient with a left third nerve palsy as a result of troencephalogram (EEG) rhythm in these circum-
a large left-sided subdural hematoma (seen as a gray-white rim). stances becomes diffusely slowed, typical of metabolic
The upper midbrain and lower thalamic regions are com- encephalopathies, and as conditions of substrate delivery
pressed and displaced horizontally away from the mass, and worsen, eventually all recordable brain electrical activity
there is transtentorial herniation of the medial temporal lobe ceases. In almost all instances of metabolic encephalo-
structures, including the uncus anteriorly. The lateral ventricle pathy, the global metabolic activity of the brain is
opposite to the hematoma has become enlarged as a result of reduced in proportion to the degree of diminished
compression of the third ventricle. consciousness.
 Conditions such as hypoglycemia, hyponatremia, The postictal state produces a pattern of continuous, gen- 133
hyperosmolarity, hypercapnia, hypercalcemia, and hepatic eralized slowing of the background EEG activity similar
and renal failure are associated with a variety of alter- to that of other metabolic encephalopathies.
ations in neurons and astrocytes. Unlike hypoxia-ischemia,
which causes neuronal destruction, metabolic disorders Toxic DrugInduced Coma
generally cause only minor neuropathologic changes.
The reversible effects of these conditions on the brain This common class of encephalopathy is in large mea-
are not understood but may result from impaired energy sure reversible and leaves no residual damage providing
supplies, changes in ion uxes across neuronal mem- hypoxia does not supervene. Many drugs and toxins are

CHAPTER 14
branes, and neurotransmitter abnormalities. For example, capable of depressing nervous system function. Some
the high brain ammonia concentration of hepatic coma produce coma by affecting both the brainstem nuclei,
interferes with cerebral energy metabolism and with the including the RAS, and the cerebral cortex.The combi-
Na+, K+-ATPase pump, increases the number and size of nation of cortical and brainstem signs, which occurs in
astrocytes, alters nerve cell function, and causes increased certain drug overdoses, may lead to an incorrect diagno-
concentrations of potentially toxic products of ammonia sis of structural brainstem disease. Overdose of medica-
metabolism; it may also result in abnormalities of neuro- tions that have atropinic actions produces physical signs

Coma
transmitters, including putative false neurotransmitters such as dilated pupils, tachycardia, and dry skin.
that are active at receptor sites.Apart from hyperammone-
mia, which of these mechanisms is of critical impor- Coma Due to Widespread Damage to the
tance is not clear.The mechanism of the encephalopathy Cerebral Hemispheres
of renal failure is also not known. Unlike ammonia, urea
itself does not produce central nervous system (CNS) This special category, comprising a number of unrelated
toxicity. A multifactorial causation has been proposed, disorders, results from widespread structural cerebral
including increased permeability of the blood-brain bar- damage, thereby simulating a metabolic disorder of the
rier to toxic substances such as organic acids and an increase cortex.The effect of prolonged hypoxia-ischemia is per-
in brain calcium or cerebrospinal uid (CSF) phosphate haps the best known and one in which it is not possible
content. to distinguish the acute effects of hypoperfusion of the
Coma and seizures are a common accompaniment of brain from the further effects of generalized neuronal
any large shifts in sodium and water balance in the brain. damage. Similar bihemispheral damage is produced by
These changes in osmolarity arise from systemic medical disorders that occlude small blood vessels throughout
disorders including diabetic ketoacidosis, the nonketotic the brain; examples include cerebral malaria, thrombotic
hyperosmolar state, and hyponatremia from any cause thrombocytopenic purpura, and hyperviscosity.The pres-
(e.g., water intoxication, excessive secretion of antidi- ence of seizures and the bihemispheral damage are some-
uretic hormone or atrial natriuretic peptides). Sodium times an indication of this class of disorder.
levels <125 mmol/L induce confusion, and <115 mmol/L
are associated with coma and convulsions. In hyperosmo-
lar coma the serum osmolarity is generally >350
mosmol/L. Hypercapnia depresses the level of conscious-
Approach to the Patient:
ness in proportion to the rise in CO2 tension in the
COMA
blood. In all of these metabolic encephalopathies, the degree of
neurologic change depends to a large extent on the rapidity with Acute respiratory and cardiovascular problems should
which the serum changes occur. The pathophysiology of be attended to prior to neurologic assessment. In
other metabolic encephalopathies such as hypercalcemia, most instances, a complete medical evaluation, except
hypothyroidism, vitamin B12 deciency, and hypothermia for vital signs, funduscopy, and examination for
are incompletely understood but must also reect nuchal rigidity, may be deferred until the neurologic
derangements of CNS biochemistry and membrane evaluation has established the severity and nature of
function. coma. The approach to the patient with cranial
trauma is discussed in Chap. 31.
Epileptic Coma HISTORY In many cases, the cause of coma is
immediately evident (e.g., trauma, cardiac arrest, or
Continuous, generalized electrical discharges of the cor- known drug ingestion). In the remainder, certain
tex (seizures) are associated with coma even in the absence points are especially useful: (1) the circumstances and
of epileptic motor activity (convulsions). The self-limited rapidity with which neurologic symptoms developed;
coma that follows seizures, termed the postictal state, may (2) the antecedent symptoms (confusion, weakness,
be due to exhaustion of energy reserves or effects of headache, fever, seizures, dizziness, double vision, or
locally toxic molecules that are the byproduct of seizures.
 134 vomiting); (3) the use of medications, illicit drugs, or patient bilateral asterixis is a certain sign of metabolic
alcohol; and (4) chronic liver, kidney, lung, heart, or encephalopathy or drug intoxication.
other medical disease. Direct interrogation of family The terms decorticate rigidity and decerebrate rigidity,
and observers on the scene, in person or by tele- or posturing, describe stereotyped arm and leg
phone, is an important part of the initial evaluation. movements occurring spontaneously or elicited by
Ambulance technicians often provide the most useful sensory stimulation. Flexion of the elbows and wrists
information. and supination of the arm (decortication) suggests
bilateral damage rostral to the midbrain, whereas
GENERAL PHYSICAL EXAMINATION The
extension of the elbows and wrists with pronation
temperature, pulse, respiratory rate and pattern, and
SECTION II

(decerebration) indicates damage to motor tracts in

blood pressure should be measured quickly. Fever
the midbrain or caudal diencephalon. The less fre-
suggests a systemic infection, bacterial meningitis, or
quent combination of arm extension with leg exion
encephalitis; only rarely is it attributable to a brain
or accid legs is associated with lesions in the pons.
lesion that has disturbed hypothalamic temperature-
These concepts have been adapted from animal work
regulating centers (central fever). A slight elevation in
and cannot be applied with the same precision to
temperature may follow vigorous convulsions. High
Clinical Manifestations of Neurologic Disease

coma in humans. In fact, acute and widespread disor-

body temperature, 4244C, associated with dry skin
ders of any type, regardless of location, frequently
should arouse the suspicion of heat stroke or anti-
cause limb extension, and almost all such extensor
cholinergic drug intoxication. Hypothermia is observed
posturing becomes predominantly exor as time
with alcoholic, barbiturate, sedative, or phenothiazine
passes. Posturing may also be unilateral and may
intoxication; hypoglycemia; peripheral circulatory
coexist with purposeful limb movements, usually
failure; or hypothyroidism. Hypothermia itself causes
reecting incomplete damage to the motor system.
coma only when the temperature is <31C. Tachyp-
nea may indicate systemic acidosis or pneumonia. LEVEL OF AROUSAL A sequence of increasingly
Aberrant respiratory patterns that reect brainstem intense stimuli is used to determine the threshold for
disorders are discussed later. Marked hypertension arousal and the optimal motor response of each side
either indicates hypertensive encephalopathy or is the of the body. The results of testing may vary from
result of a rapid rise in intracranial pressure (ICP; the minute to minute and serial examinations are most
Cushing response) most often after cerebral hemor- useful. Tickling the nostrils with a cotton wisp is a
rhage or head injury. Hypotension is characteristic of moderate stimulus to arousalall but deeply stu-
coma from alcohol or barbiturate intoxication, inter- porous and comatose patients will move the head
nal hemorrhage, myocardial infarction, sepsis, pro- away and rouse to some degree. Using the hand to
found hypothyroidism, or Addisonian crisis. remove the offending stimulus represents an even
The funduscopic examination can detect subarachnoid greater degree of responsiveness. Stereotyped postur-
hemorrhage (subhyaloid hemorrhages), hypertensive ing in response to noxious stimuli indicates severe
encephalopathy (exudates, hemorrhages, vessel-crossing dysfunction of the corticospinal system. Abduction-
changes, papilledema), and increased ICP (papilledema). avoidance movement of a limb is usually purposeful
Cutaneous petechiae suggest thrombotic thrombocy- and denotes an intact corticospinal system. Pressure
topenic purpura, meningococcemia, or a bleeding on the knuckles or bony prominences and pinprick
diathesis from which an intracerebral hemorrhage has stimulation are humane forms of noxious stimuli;
arisen. pinching the skin causes unsightly ecchymoses and is
generally not necessary but may be useful in eliciting
NEUROLOGIC EXAMINATION First, the patient
abduction withdrawal movements of the limbs.
should be observed without intervention by the exam-
iner. Tossing about in the bed, reaching up toward the BRAINSTEM REFLEXES Assessment of brainstem
face, crossing legs, yawning, swallowing, coughing, or function is essential to localization of the lesion in coma
moaning denotes a state close to normal awakeness. (Fig. 14-3). The brainstem reexes that are conve-
Lack of restless movements on one side or an out- niently examined are pupillary responses to light, spon-
turned leg suggests a hemiplegia. Intermittent twitch- taneous and elicited eye movements, corneal responses,
ing movements of a foot, nger, or facial muscle may and the respiratory pattern.As a rule, when these brain-
be the only sign of seizures. Multifocal myoclonus stem activities are preserved, particularly the pupil reac-
almost always indicates a metabolic disorder, particu- tions and eye movements, coma must be ascribed to
larly uremia, anoxia, or drug intoxication (lithium and bilateral hemispheral disease. The converse, however, is
haloperidol are particularly likely to cause this sign), or not always true, as a mass in the hemispheres may be
the rare conditions of a prion disease (Chap. 38) or the underlying cause of coma but nonetheless produce
Hashimoto encephalopathy. In a drowsy and confused brainstem signs by inducing transtentorial herniation.
 Pupillary light reflex
pupil is a transitional sign that accompanies early 135
midbrainthird nerve compression. The most extreme
pupillary sign, bilaterally dilated and unreactive pupils,
indicates severe midbrain damage, usually from com-
pression by a supratentorial mass. Ingestion of drugs
with anticholinergic activity, the use of mydriatic eye
drops, and direct ocular trauma are among the causes
of misleading pupillary enlargement.
Unilateral miosis in coma has been attributed to

CHAPTER 14
dysfunction of sympathetic efferents originating in
III III
the posterior hypothalamus and descending in the
M tegmentum of the brainstem to the cervical cord. It is
V L Pons
F an occasional nding with a large cerebral hemor-
Vl rhage that affects the thalamus. Reactive and bilater-
Vll
Vlll ally small (12.5 mm) but not pinpoint pupils are

Coma
seen in metabolic encephalopathies or in deep bilat-
Medulla eral hemispheral lesions such as hydrocephalus or
Corneal-blink Reflex conjugate
reflex eye movements thalamic hemorrhage. Very small but reactive pupils
(<1 mm) characterize narcotic or barbiturate over-
Respiratory
doses but also occur with extensive pontine hemor-
neurons rhage. The response to naloxone and the presence of
reex eye movements (see below) distinguish these.

Ocular Movements The eyes are rst observed

by elevating the lids and noting the resting position
and spontaneous movements of the globes. Lid tone,
FIGURE 14-3
tested by lifting the eyelids and noting their resistance
Examination of brainstem reexes in coma. Midbrain and to opening and the speed of closure, is reduced pro-
third nerve function are tested by pupillary reaction to light, gressively as coma deepens. Horizontal divergence of
pontine function by spontaneous and reex eye movements the eyes at rest is normal in drowsiness. As coma
and corneal responses, and medullary function by respiratory deepens, the ocular axes may become parallel again.
and pharyngeal responses. Reex conjugate, horizontal eye Spontaneous eye movements in coma often take
movements are dependent on the medial longitudinal fasci- the form of conjugate horizontal roving.This nding
culus (MLF) interconnecting the sixth and contralateral third alone exonerates the midbrain and pons and has the
nerve nuclei. Head rotation (oculocephalic reex) or caloric same signicance as normal reex eye movements
stimulation of the labyrinths (oculovestibular reex) elicits (see below). Conjugate horizontal ocular deviation to
contraversive eye movements (for details see text). one side indicates damage to the pons on the oppo-
site side or alternatively, to the frontal lobe on the
same side. This phenomenon is summarized by the
following maxim: The eyes look toward a hemispheral
lesion and away from a brainstem lesion. Seizures also
Pupillary Signs Pupillary reactions are examined drive the eyes to one side. On rare occasions, the eyes
with a bright, diffuse light (not an ophthalmoscope); if may turn paradoxically away from the side of a deep
the response is absent, this should be conrmed by hemispheral lesion (wrong-way eyes). The eyes
observation through a magnifying lens. Normally turn down and inward as a result of thalamic and
reactive and round pupils of midsize (2.55 mm) upper midbrain lesions, typically with thalamic hem-
essentially exclude midbrain damage, either primary orrhage. Ocular bobbing describes brisk downward
or secondary to compression. Reaction to light is and slow upward movements of the eyes associated
often difcult to appreciate in pupils <2 mm in diam- with loss of horizontal eye movements and is diag-
eter, and bright room lighting mutes pupillary reactiv- nostic of bilateral pontine damage, usually from
ity. One unreactive and enlarged pupil (>6 mm) or thrombosis of the basilar artery. Ocular dipping is a
one that is poorly reactive signies compression of the slower, arrhythmic downward movement followed by
third nerve from the effects of a mass above. Enlarge- a faster upward movement in patients with normal
ment of the pupil contralateral to a mass may occur reex horizontal gaze; it indicates diffuse cortical
rst but is infrequent. An oval and slightly eccentric anoxic damage. Many other complex eye movements
 136 are known but do not have the same clinical impor- Shallow, slow, but regular breathing suggests metabolic
tance as those mentioned earlier. or drug depression. Cheyne-Stokes respiration in its
The oculocephalic reexes depend on the integrity classic cyclic form, ending with a brief apneic period,
of the ocular motor nuclei and their interconnecting signies bihemispheral damage or metabolic suppres-
tracts that extend from the midbrain to the pons and sion and commonly accompanies light coma. Rapid,
medulla. These reexes are elicited by moving the deep (Kussmaul) breathing usually implies metabolic
head from side to side or vertically and observing acidosis but may also occur with pontomesencephalic
evoked eye movements in the direction opposite to lesions. Agonal gasps are the result of lower brainstem
the head movement (Fig. 14-3). The movements, (medullary) damage and are well known as the termi-
SECTION II

called somewhat inappropriately dolls eyes (which nal respiratory pattern of severe brain damage.A num-
refers more accurately to the reex elevation of the ber of other cyclic breathing variations have been
eyelids with exion of the neck), are normally sup- described but are of lesser signicance.
pressed in the awake patient.The ability to elicit them
therefore indicates a reduced cortical inuence on the
brainstem. Furthermore, preservation of evoked reex
Clinical Manifestations of Neurologic Disease

eye movements signies the integrity of the brainstem LABORATORY STUDIES AND IMAGING
and implies that the origin of unconsciousness lies in The studies that are most useful in the diagnosis of coma
the cerebral hemispheres. The opposite, an absence of are: chemical-toxicologic analysis of blood and urine,
reex eye movements, usually signies damage within cranial CT or MRI, EEG, and CSF examination. Arter-
the brainstem but can be produced infrequently by ial blood-gas analysis is helpful in patients with lung dis-
profound overdoses of certain drugs. Normal pupillary ease and acid-base disorders. The metabolic aberrations
size and light reaction distinguishes most drug- commonly encountered in clinical practice require mea-
induced comas from structural brainstem damage. surements of electrolytes, glucose, calcium, osmolarity,
Thermal, or caloric, stimulation of the vestibular and renal (blood urea nitrogen) and hepatic (NH3) func-
apparatus (oculovestibular response) provides a more tion. Toxicologic analysis is necessary in any case of
intense stimulus for the oculocephalic reex but gives coma where the diagnosis is not immediately clear.
fundamentally the same information. The test is per- However, the presence of exogenous drugs or toxins,
formed by irrigating the external auditory canal with especially alcohol, does not exclude the possibility that
cool water in order to induce convection currents in other factors, particularly head trauma, are also contribut-
the labyrinths. After a brief latency, the result is tonic ing to the clinical state. An ethanol level of 43 mmol/L
deviation of both eyes to the side of cool-water irriga- (0.2 g/dL) in nonhabituated patients generally causes
tion and nystagmus in the opposite direction. (The impaired mental activity and of >65 mmol/L (0.3 g/dL)
acronym COWS has been used to remind generations is associated with stupor. The development of tolerance
of medical students of the direction of nystagmus may allow the chronic alcoholic to remain awake at levels
cold water opposite, warm water same.) The loss of >87 mmol/L (0.4 g/dL).
conjugate ocular movements indicates brainstem dam- The availability of CT and MRI has focused attention
age.The absence of nystagmus despite conjugate devia- on causes of coma that are radiologically detectable (e.g.,
tion of the globes indicates that the cerebral hemispheres hemorrhages, tumors, or hydrocephalus). Resorting pri-
are damaged or metabolically suppressed. marily to this approach, although at times expedient, is
By touching the cornea with a wisp of cotton, a imprudent because most cases of coma (and confusion)
response consisting of brief bilateral lid closure is nor- are metabolic or toxic in origin.The notion that a normal
mally observed. The corneal reexes depend on the CT scan excludes anatomic lesions as the cause of coma is
integrity of pontine pathways between the fth also erroneous. Bilateral hemisphere infarction, acute
(afferent) and both seventh (efferent) cranial nerves; brainstem infarction, encephalitis, meningitis, mechanical
although rarely useful alone, in conjunction with shearing of axons as a result of closed head trauma, sagittal
reex eye movements they are important clinical tests sinus thrombosis, and subdural hematomas that are iso-
of pontine function. CNS depressant drugs diminish dense to adjacent brain are some of the disorders that may
or eliminate the corneal responses soon after reex not be detected. Nevertheless, if the source of coma
eye movements are paralyzed but before the pupils remains unknown, a scan should be obtained.
become unreactive to light.The corneal (and pharyn- The EEG is useful in metabolic or drug-induced states
geal) response may be lost for a time on the side of an but is rarely diagnostic, except when coma is due to clini-
acute hemiplegia. cally unrecognized seizures, to herpesvirus encephalitis, or
to prion (Creutzfeldt-Jakob) disease.The amount of back-
Respiratory Patterns These are of less localiz-
ground slowing of the EEG is a reection of the severity
ing value in comparison to other brainstem signs.
of any diffuse encephalopathy. Predominant high-voltage
slowing ( or triphasic waves) in the frontal regions is Lumbar puncture should therefore not be deferred if 137
typical of metabolic coma, as from hepatic failure, and meningitis is a possibility.
widespread fast () activity implicates sedative drugs (e.g.,
diazepines, barbiturates).A special pattern of alpha coma, DIFFERENTIAL DIAGNOSIS OF COMA
dened by widespread, variable 8- to 12-Hz activity,
supercially resembles the normal rhythm of waking (Table 14-1) The causes of coma can be divided into
but is unresponsive to environmental stimuli. It results three broad categories: those without focal neurologic
from pontine or diffuse cortical damage and is associated signs (e.g., metabolic encephalopathies); meningitis syn-
with a poor prognosis. Most importantly, EEG recordings dromes, characterized by fever or stiff neck and an

CHAPTER 14
may reveal clinically inapparent epileptic discharges in a excess of cells in the spinal uid (e.g., bacterial meningi-
patient with coma. Normal activity on the EEG, which tis, subarachnoid hemorrhage); and conditions associated
is suppressed by stimulating the patient, also alerts the with prominent focal signs (e.g., stroke, cerebral hemor-
clinician to the locked-in syndrome or to hysteria or rhage). In most instances coma is part of an obvious
catatonia. medical problem such as drug ingestion, hypoxia, stroke,
Lumbar puncture is performed less frequently than in the trauma, or liver or kidney failure. Conditions that cause
past for coma diagnosis because neuroimaging effectively sudden coma include drug ingestion, cerebral hemorrhage,

Coma
excludes intracerebral and extensive subarachnoid hemor- trauma, cardiac arrest, epilepsy, or basilar artery embolism.
rhage. However, examination of the CSF remains indis- Coma that appears subacutely is usually related to a
pensable in the diagnosis of meningitis and encephalitis. preceding medical or neurologic problem, including the

TABLE 14-1
DIFFERENTIAL DIAGNOSIS OF COMA
1. Diseases that cause no focal or lateralizing neurologic signs, usually with normal brainstem functions; CT scan and cellular
content of the CSF are normal
a. Intoxications: alcohol, sedative drugs, opiates, etc.
b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia, hypercalcemia, diabetic acidosis, nonketotic
hyperosmolar hyperglycemia, hypoglycemia, uremia, hepatic coma, hypercarbia, addisonian crisis, hypo- and
hyperthyroid states, profound nutritional deciency
c. Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome
d. Shock from any cause
e. Postseizure states, status epilepticus, subclinical epilepsy
f. Hypertensive encephalopathy, eclampsia
g. Severe hyperthermia, hypothermia
h. Concussion
i. Acute hydrocephalus
2. Diseases that cause meningeal irritation with or without fever, and with an excess of WBCs or RBCs in the CSF, usually
without focal or lateralizing cerebral or brainstem signs; CT or MRI shows no mass lesion
a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, trauma
b. Acute bacterial meningitis
c. Viral encephalitis
d. Miscellaneous: Fat embolism, cholesterol embolism, carcinomatous and lymphomatous meningitis, etc.
3. Diseases that cause focal brainstem or lateralizing cerebral signs, with or without changes in the CSF; CT and MRI are
abnormal
a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large middle cerebral artery territory) with secondary
brainstem compression
b. Brainstem infarction due to basilar artery thrombosis or embolism
c. Brain abscess, subdural empyema
d. Epidural and subdural hemorrhage, brain contusion
e. Brain tumor with surrounding edema
f. Cerebellar and pontine hemorrhage and infarction
g. Widespread traumatic brain injury
h. Metabolic coma (see above) with preexisting focal damage
i. Miscellaneous: cortical vein thrombosis, herpes simplex encephalitis, multiple cerebral emboli due to bacterial
endocarditis, acute hemorrhagic leukoencephalitis, acute disseminated (postinfectious) encephalomyelitis, thrombotic
thrombocytopenic purpura, cerebral vasculitis, gliomatosis cerebri, pituitary apoplexy, intravascular lymphoma, etc.

Note: CSF, cerebrospinal uid; WBCs, white blood cells; RBCs, red blood cells.
 138 secondary brain swelling of a mass lesion such as tumor Demonstration that apnea is due to irreversible
or cerebral infarction. medullary damage requires that the PCO2 be high
Cerebrovascular diseases cause the greatest difculty in enough to stimulate respiration during a test of sponta-
coma diagnosis (Chap. 21). The most common categories neous breathing. Apnea testing can be done safely by the
are: (1) basal ganglia and thalamic hemorrhage (acute but use of diffusion oxygenation prior to removing the ven-
not instantaneous onset, vomiting, headache, hemiplegia, tilator. This is accomplished by preoxygenation with
and characteristic eye signs); (2) pontine hemorrhage (sud- 100% oxygen, which is then sustained during the test by
den onset, pinpoint pupils, loss of reex eye movements and oxygen administered through a tracheal cannula. CO2
corneal responses, ocular bobbing, posturing, hyperventila- tension increases ~0.30.4 kPa/min (23 mm Hg/min)
tion, and excessive sweating); (3) cerebellar hemorrhage during apnea. At the end of the period of observation,
SECTION II

(occipital headache, vomiting, gaze paresis, and inability to typically several minutes, arterial PCO2 should be at least
stand); (4) basilar artery thrombosis (neurologic prodrome or >6.68.0 kPa (5060 mm Hg) for the test to be valid.
warning spells, diplopia, dysarthria, vomiting, eye movement Apnea is conrmed if no respiratory effort is observed
and corneal response abnormalities, and asymmetric limb in the presence of a sufciently elevated PCO2.
paresis); and (5) subarachnoid hemorrhage (precipitous The possibility of profound drug-induced or hypother-
coma after headache and vomiting). The most common mic depression of the nervous system should be excluded,
Clinical Manifestations of Neurologic Disease

stroke, infarction in the territory of the middle cerebral and some period of observation, usually 624 h, is desir-
artery, does not generally cause coma, but edema surround- able during which the signs of brain death are sustained. It
ing large infarcts may expand during the rst few days and is advisable to delay clinical testing for at least 24 h if a car-
act as a mass.The syndrome of acute hydrocephalus accom- diac arrest has caused brain death or if the inciting disease
panies many intracranial diseases, particularly subarachnoid is not known.An isoelectric EEG may be used as a conr-
hemorrhage. It is characterized by headache and sometimes matory test for total cerebral damage. Radionuclide brain
vomiting that may progress quickly to coma, with extensor scanning, cerebral angiography, or transcranial Doppler
posturing of the limbs, bilateral Babinski signs, small unreac- measurements may also be used to demonstrate the
tive pupils, and impaired oculocephalic movements in the absence of cerebral blood ow but they have not been
vertical direction. extensively correlated with pathologic changes.
If the history and examination do not indicate the Although it is largely accepted in western society that
cause of coma, then information obtained from CT or the respirator can be disconnected from a brain-dead
MRI may be needed.The majority of medical causes of patient, problems frequently arise because of poor com-
coma can be established without a neuroimaging study. munication and inadequate preparation of the family by
the physician. Reasonable medical practice allows the
BRAIN DEATH removal of support or transfer out of an intensive care
unit of patients who are not brain dead but whose con-
This is a state of cessation of cerebral function while dition is nonetheless hopeless and are likely to live for
somatic function is maintained by articial means and only a brief time.
the heart continues to pump. It is the only type of brain
damage that is recognized as equivalent to death. Several
similar criteria have been advanced for the diagnosis of
brain death, and it is essential to adhere to those standards
endorsed by the local medical community. Ideal criteria Treatment:
are simple, can be assessed at the bedside, and allow no COMA
chance of diagnostic error. They contain three essential
The immediate goal in a comatose patient is prevention
elements of clinical evidence: (1) widespread cortical
of further nervous system damage. Hypotension, hypo-
destruction that is reected by deep coma and unrespon-
glycemia, hypercalcemia, hypoxia, hypercapnia, and
siveness to all forms of stimulation; (2) global brainstem
hyperthermia should be corrected rapidly. An oropha-
damage demonstrated by absent pupillary light reaction
ryngeal airway is adequate to keep the pharynx open in
and by the loss of oculovestibular and corneal reexes;
drowsy patients who are breathing normally. Tracheal
and (3) destruction of the medulla manifested by com-
intubation is indicated if there is apnea, upper airway
plete apnea. The pulse rate is invariant and unresponsive
obstruction, hypoventilation, or emesis, or if the patient
to atropine. Diabetes insipidus is often present but may
is liable to aspirate because of coma. Mechanical ventila-
develop hours or days after the other clinical signs of
tion is required if there is hypoventilation or a need to
brain death. The pupils are often enlarged but may be
induce hypocapnia in order to lower ICP as described
mid-sized; they should not, however, be constricted. The
below. IV access is established, and naloxone and dextrose
absence of deep tendon reexes is not required because
are administered if narcotic overdose or hypoglycemia are
the spinal cord remains functional.There may or may not
even remote possibilities; thiamine is given along with
be Babinski signs.
 glucose to avoid provoking Wernicke disease in malnour- vegetative. The uniformly poor outcome of the persis- 139
ished patients. In cases of suspected basilar thrombosis tent vegetative state has already been mentioned. Chil-
with brainstem ischemia, IV heparin or a thrombolytic dren and young adults may have ominous early clinical
agent is often utilized, after cerebral hemorrhage has ndings such as abnormal brainstem reexes and yet
been excluded by a neuroimaging study. Physostigmine recover, so that temporization in offering a prognosis in
may awaken patients with anticholinergic-type drug this group of patients is wise. Metabolic comas have a far
overdose but should be used only by experienced better prognosis than traumatic ones.All systems for esti-
physicians and with careful monitoring; many physi- mating prognosis in adults should be taken as approxi-
cians believe that it should only be used to treat anti- mations, and medical judgments must be tempered by

CHAPTER 14
cholinergic overdose-associated cardiac arrhythmias. factors such as age, underlying systemic disease, and gen-
The use of benzodiazepine antagonists offers some eral medical condition. In an attempt to collect prognos-
prospect of improvement after overdoses of soporic tic information from large numbers of patients with
drugs and has transient benet in hepatic encephalopa- head injury, the Glasgow Coma Scale was devised;
thy. IV administration of hypotonic solutions should be empirically it has predictive value in cases of brain
monitored carefully in any serious acute brain illness trauma (Table 31-2). For anoxic and metabolic coma,
clinical signs such as the pupillary and motor responses

Coma
because of the potential for exacerbating brain swelling.
Cervical spine injuries must not be overlooked, particu- after 1 day, 3 days, and 1 week have been shown to have
larly prior to attempting intubation or evaluating of ocu- predictive value (Fig. 22-4). The absence of the cortical
locephalic responses. Fever and meningismus indicate waves of the somatosensory evoked potentials has also
an urgent need for examination of the CSF to diagnose proved a strong indicator of poor outcome in coma
meningitis. If the lumbar puncture in a case of sus- from any cause.
pected meningitis is delayed for any reason, an antibi-
otic such as a third-generation cephalosporin should be FURTHER READINGS
administered as soon as possible, preferably after LAUREYS S et al: Brain function in coma, vegetative state, and related
obtaining blood cultures. The management of raised ICP disorders. Lancet Neurol 3:537, 2004
is discussed in Chap. 22. POSNER JB et al: Plum and Posners Diagnosis of Stupor and Coma, 4th ed.
New York and London, Oxford Univ Press, 2007
ROPPER AH: Neurological and Neurosurgical Intensive Care, 4th ed. New
York, Lippincott Williams & Wilkins, 2004
PROGNOSIS WIJDICKS EF et al: Neuropathology of brain death in the modern
transplant era. Neurology 70:1234, 2008
One hopes to avoid the emotionally painful, hopeless YOUNG GB: Clinical Practice. Neurologic prognosis after cardiac
outcome of a patient who is left severely disabled or arrest. N Engl J Med 361:605, 2009
 CHAPTER 15
APHASIA, MEMORY LOSS, AND OTHER
FOCAL CEREBRAL DISORDERS
M. -Marsel Mesulam

I The Left Perisylvian Network for Language: I The Occipitotemporal Network for Face and Object
Aphasias and Related Conditions . . . . . . . . . . . . . . . . . . . . 140 Recognition: Prosopagnosia and Object Agnosia . . . . . . . . 150
Clinical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 I The Limbic Network for Memory: Amnesias . . . . . . . . . . . . . 150
I The Parietofrontal Network for Spatial Orientation: I The Prefrontal Network for Attention and Behavior . . . . . . . . 152
Neglect and Related Conditions . . . . . . . . . . . . . . . . . . . . . 147 I Caring for the Patient with Decits of Higher
Hemispatial Neglect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 Cerebral Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Blints Syndrome, Simultanagnosia, Dressing Apraxia, I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
and Construction Apraxia . . . . . . . . . . . . . . . . . . . . . . . . . . 148

The cerebral cortex of the human brain contains ~20 other parts of the network undergo compensatory reor-
billion neurons spread over an area of 2.5 m2.The primary ganization; and (4) individual anatomic sites within a
sensory areas provide an obligatory portal for the entry of network display a relative (but not absolute) specializa-
sensory information into cortical circuitry, whereas the tion for different behavioral aspects of the relevant func-
primary motor areas provide nal common pathways for tion. Five anatomically dened large-scale networks are
coordinating complex motor acts. The primary sensory most relevant to clinical practice: a perisylvian network
and motor areas constitute 10% of the cerebral cortex. for language; a parietofrontal network for spatial cogni-
The rest is subsumed by unimodal, heteromodal, paral- tion; an occipitotemporal network for face and object
imbic, and limbic areas, collectively known as the associa- recognition; a limbic network for retentive memory; and
tion cortex (Fig. 15-1). The association cortex mediates a prefrontal network for attention and behavior.
the integrative processes that subserve cognition, emo-
tion, and behavior. A systematic testing of these mental
functions is necessary for the effective clinical assessment THE LEFT PERISYLVIAN NETWORK FOR
of the association cortex and its diseases. LANGUAGE: APHASIAS AND RELATED
According to current thinking, there are no centers CONDITIONS
for hearing words,perceiving space, or storing mem-
ories. Cognitive and behavioral functions (domains) are Language allows the communication and elaboration of
coordinated by intersecting large-scale neural networks that thoughts and experiences by linking them to arbitrary
contain interconnected cortical and subcortical compo- symbols known as words. The neural substrate of lan-
nents.The network approach to higher cerebral function guage is composed of a distributed network centered in
has at least four implications of clinical relevance: (1) a the perisylvian region of the left hemisphere. The poste-
single domain such as language or memory can be dis- rior pole of this network is located at the temporopari-
rupted by damage to any one of several areas, as long as etal junction and includes a region known as Wernickes
these areas belong to the same network; (2) damage area. An essential function of Wernickes area is to trans-
conned to a single area can give rise to multiple form sensory inputs into their lexical representations so
decits, involving the functions of all networks that that these can establish the distributed associations that
intersect in that region; (3) damage to a network com- give the word its meaning.The anterior pole of the lan-
ponent may give rise to minimal or transient decits if guage network is located in the inferior frontal gyrus
140
 and Brocas areas are interconnected with each other 141
and with additional perisylvian, temporal, prefrontal, and
posterior parietal regions, making up a neural network
subserving the various aspects of language function.
Damage to any one of these components or to their
interconnections can give rise to language disturbances
(aphasia). Aphasia should be diagnosed only when there
are decits in the formal aspects of language such as
naming, word choice, comprehension, spelling, and syn-

CHAPTER 15
tax. Dysarthria and mutism do not, by themselves, lead
to a diagnosis of aphasia.The language network shows a
left hemisphere dominance pattern in the vast majority
of the population. In ~90% of right handers and 60% of
A left handers, aphasia occurs only after lesions of the left
hemisphere. In some individuals no hemispheric domi-
nance for language can be discerned, and in some others

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

(including a small minority of right handers) there is a
right hemisphere dominance for language. A language
disturbance occurring after a right hemisphere lesion in
a right hander is called crossed aphasia.

CLINICAL EXAMINATION
The clinical examination of language should include the
assessment of naming, spontaneous speech, comprehen-
sion, repetition, reading, and writing.A decit of naming
(anomia) is the single most common nding in aphasic
patients. When asked to name common objects (pencil
B or wristwatch), the patient may fail to come up with the
FIGURE 15-1 appropriate word, may provide a circumlocutious
Lateral (A) and medial (B) views of the cerebral hemi- description of the object (the thing for writing), or
spheres. The numbers refer to the Brodmann cytoarchitec- may come up with the wrong word (paraphasia). If the
tonic designations. Area 17 corresponds to the primary patient offers an incorrect but legitimate word (pen
visual cortex, 4142 to the primary auditory cortex, 13 to for pencil), the naming error is known as a semantic
the primary somatosensory cortex, and 4 to the primary paraphasia; if the word approximates the correct answer
motor cortex. The rest of the cerebral cortex contains associ- but is phonetically inaccurate (plentil for pencil), it
ation areas. AG, angular gyrus; B, Brocas area; CC, corpus is known as a phonemic paraphasia. Asking the patient to
callosum; CG, cingulate gyrus; DLPFC, dorsolateral pre- name body parts, geometric shapes, and component
frontal cortex; FEF, frontal eye elds (premotor cortex); FG, parts of objects (lapel of coat, cap of pen) can elicit mild
fusiform gyrus; IPL, inferior parietal lobule; ITG, inferior tem- forms of anomia in patients who can otherwise name
poral gyrus; LG, lingual gyrus; MPFC, medial prefrontal cor-
common objects. In most anomias, the patient cannot
tex; MTG, middle temporal gyrus; OFC, orbitofrontal cortex;
retrieve the appropriate name when shown an object
PHG, parahippocampal gyrus; PPC, posterior parietal cortex;
but can point to the appropriate object when the name
PSC, peristriate cortex; SC, striate cortex; SMG, supramar-
ginal gyrus; SPL, superior parietal lobule; STG, superior tem-
is provided by the examiner.This is known as a one-way
poral gyrus; STS, superior temporal sulcus; TP, temporopolar
(or retrieval-based) naming decit. A two-way naming
cortex; W, Wernickes area. decit exists if the patient can neither provide nor rec-
ognize the correct name, indicating the presence of a
language comprehension impairment. Spontaneous speech
and includes a region known as Brocas area. An essential is described as uent if it maintains appropriate output
function of this area is to transform lexical representa- volume, phrase length, and melody or as nonuent if it
tions into their articulatory sequences so that the words is sparse, halting, and average utterance length is below
can be uttered in the form of spoken language. The four words.The examiner should also note if the speech
sequencing function of Brocas area also appears to is paraphasic or circumlocutious; if it shows a relative
involve the ordering of words into sentences that con- paucity of substantive nouns and action verbs versus
tain a meaning-appropriate syntax (grammar).Wernickes function words (prepositions, conjunctions); and if word
 142 TABLE 15-1
CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS

REPETITION OF
COMPREHENSION SPOKEN LANGUAGE NAMING FLUENCY

Wernickes Impaired Impaired Impaired Preserved or increased

Brocas Preserved (except Impaired Impaired Decreased
grammar)
Global Impaired Impaired Impaired Decreased
Conduction Preserved Impaired Impaired Preserved
SECTION II

Nonuent (motor) transcortical Preserved Preserved Impaired Impaired

Fluent (sensory) transcortical Impaired Preserved Impaired Preserved
Isolation Impaired Echolalia Impaired No purposeful speech
Anomic Preserved Preserved Impaired Preserved except for
word-nding pauses
Pure word deafness Impaired only for Impaired Preserved Preserved
spoken language
Clinical Manifestations of Neurologic Disease

Pure alexia Impaired only for reading Preserved Preserved Preserved

order, tenses, sufxes, prexes, plurals, and possessives are rigid one-to-one relationship and should be conceptual-
appropriate. Comprehension can be tested by assessing the ized within the context of the distributed network model.
patients ability to follow conversation, by asking yes-no Nonetheless, the classication of aphasias of acute onset
questions (Can a dog y?, Does it snow in sum- into specic clinical syndromes helps to determine the
mer?) or asking the patient to point to appropriate most likely anatomic distribution of the underlying
objects (Where is the source of illumination in this neurologic disease and has implications for etiology
room?). Statements with embedded clauses or passive and prognosis (Table 15-1). The syndromes listed in
voice construction (If a tiger is eaten by a lion, which Table 15-1 are most applicable to aphasias caused by
animal stays alive?) help to assess the ability to compre- cerebrovascular accidents (CVA). They can be divided
hend complex syntactic structure. Commands to close into central syndromes, which result from damage to
or open the eyes, stand up, sit down, or roll over should the two epicenters of the language network (Brocas and
not be used to assess overall comprehension since appro- Wernickes areas), and disconnection syndromes, which
priate responses aimed at such axial movements can be arise from lesions that interrupt the functional connec-
preserved in patients who otherwise have profound tivity of these centers with each other and with the other
comprehension decits. components of the language network. The syndromes
Repetition is assessed by asking the patient to repeat outlined below are idealizations; pure syndromes occur
single words, short sentences, or strings of words such as rarely.
No ifs, ands, or buts. The testing of repetition with
tongue-twisters such as hippopotamus or Irish con-
Wernickes Aphasia
stabulary provides a better assessment of dysarthria and
palilalia than aphasia. Aphasic patients may have little Comprehension is impaired for spoken and written lan-
difculty with tongue-twisters but have a particularly guage. Language output is uent but is highly paraphasic
hard time repeating a string of function words. It is and circumlocutious.The tendency for paraphasic errors
important to make sure that the number of words does may be so pronounced that it leads to strings of neolo-
not exceed the patients attention span. Otherwise, the gisms, which form the basis of what is known as jargon
failure of repetition becomes a reection of the nar- aphasia. Speech contains large numbers of function
rowed attention span rather than an indication of an words (e.g., prepositions, conjunctions) but few substan-
aphasic decit. Reading should be assessed for decits in tive nouns or verbs that refer to specic actions. The
reading aloud as well as comprehension. Writing is output is therefore voluminous but uninformative. For
assessed for spelling errors, word order, and grammar. example, a patient attempts to describe how his wife
Alexia describes an inability to either read aloud or accidentally threw away something important, perhaps
comprehend single words and simple sentences; agraphia his dentures: We dont need it anymore, she says. And
(or dysgraphia) is used to describe an acquired decit in with it when that was downstairs was my teeth-tick . . . a
the spelling or grammar of written language. . . . den . . . dentith . . . my dentist. And they happened to
The correspondence between individual decits of be in that bag . . . see? How could this have happened?
language function and lesion location does not display a How could a thing like this happen . . . So she says we
wont need it anymore . . . I didnt think wed use it. And lead to a characteristic agrammatism. Speech is tele- 143
now if I have any problems anybody coming a month graphic and pithy but quite informative. In the follow-
from now, 4 months from now, or 6 months from now, I ing passage, a patient with Brocas aphasia describes his
have a new dentist. Where my two . . . two little pieces medical history: I see . . . the dotor, dotor sent me . . .
of dentist that I use . . . that I . . . all gone. If she throws Bosson. Go to hospital. Dotor . . . kept me beside. Two,
the whole thing away . . . visit some friends of hers and tee days, doctor send me home.
she cant throw them away. Output may be reduced to a grunt or single word
Gestures and pantomime do not improve communi- (yes or no), which is emitted with different intona-
cation. The patient does not seem to realize that his or tions in an attempt to express approval or disapproval. In

CHAPTER 15
her language is incomprehensible and may appear angry addition to uency, naming and repetition are also
and impatient when the examiner fails to decipher the impaired. Comprehension of spoken language is intact,
meaning of a severely paraphasic statement. In some except for syntactically difcult sentences with passive
patients this type of aphasia can be associated with voice structure or embedded clauses. Reading compre-
severe agitation and paranoid behaviors. One area of hension is also preserved, with the occasional exception of
comprehension that may be preserved is the ability to a specic inability to read small grammatical words such as
follow commands aimed at axial musculature.The disso- conjunctions and pronouns. The last two features indicate

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

ciation between the failure to understand simple ques- that Brocas aphasia is not just an expressive or motor
tions (What is your name?) in a patient who rapidly disorder and that it may also involve a comprehension
closes his or her eyes, sits up, or rolls over when asked to decit for function words and syntax. Patients with Brocas
do so is characteristic of Wernickes aphasia and helps to aphasia can be tearful, easily frustrated, and profoundly
differentiate it from deafness, psychiatric disease, or depressed. Insight into their condition is preserved, in con-
malingering. Patients with Wernickes aphasia cannot trast to Wernickes aphasia. Even when spontaneous speech
express their thoughts in meaning-appropriate words is severely dysarthric, the patient may be able to display a
and cannot decode the meaning of words in any modal- relatively normal articulation of words when singing.This
ity of input.This aphasia therefore has expressive as well dissociation has been used to develop specic therapeutic
as receptive components. Repetition, naming, reading, approaches (melodic intonation therapy) for Brocas apha-
and writing are also impaired. sia. Additional neurologic decits usually include right
The lesion site most commonly associated with Wer- facial weakness, hemiparesis or hemiplegia, and a buccofa-
nickes aphasia is the posterior portion of the language net- cial apraxia characterized by an inability to carry out
work and tends to involve at least parts of Wernickes area. motor commands involving oropharyngeal and facial mus-
An embolus to the inferior division of the middle cerebral culature (e.g., patients are unable to demonstrate how to
artery, and to the posterior temporal or angular branches in blow out a match or suck through a straw).Visual elds are
particular, is the most common etiology (Chap. 21). Intrac- intact. The cause is most often infarction of Brocas area
erebral hemorrhage, severe head trauma, or neoplasm are (the inferior frontal convolution;B in Fig. 15-1) and sur-
other causes.A coexisting right hemi- or superior quadran- rounding anterior perisylvian and insular cortex, due to
tanopia is common, and mild right nasolabial attening occlusion of the superior division of the middle cerebral
may be found, but otherwise the examination is often artery (Chap. 21). Mass lesions including tumor, intracere-
unrevealing. The paraphasic, neologistic speech in an agi- bral hemorrhage, or abscess may also be responsible. Small
tated patient with an otherwise unremarkable neurologic lesions conned to the posterior part of Brocas area may
examination may lead to the suspicion of a primary psychi- lead to a nonaphasic and often reversible decit of speech
atric disorder such as schizophrenia or mania, but the other articulation, usually accompanied by mild right facial
components characteristic of acquired aphasia and the weakness. When the cause of Brocas aphasia is stroke,
absence of prior psychiatric disease usually settle the issue. recovery of language function generally peaks within 26
Some patients with Wernickes aphasia due to intracerebral months, after which time further progress is limited.
hemorrhage or head trauma may improve as the hemor-
rhage or the injury heals. In most other patients, prognosis Global Aphasia
for recovery is guarded.
Speech output is nonuent, and comprehension of spo-
ken language is severely impaired. Naming, repetition,
Brocas Aphasia
reading, and writing are also impaired. This syndrome
Speech is nonuent, labored, interrupted by many represents the combined dysfunction of Brocas and
word-nding pauses, and usually dysarthric. It is impov- Wernickes areas and usually results from strokes that
erished in function words but enriched in meaning- involve the entire middle cerebral artery distribution in
appropriate nouns and verbs. Abnormal word order and the left hemisphere. Most patients are initially mute or say
the inappropriate deployment of bound morphemes (word a few words, such as hi or yes. Related signs include
endings used to denote tenses, possessives, or plurals) right hemiplegia, hemisensory loss, and homonymous
 144 hemianopia. Occasionally, a patient with a lesion in Wer- pathologic function of the language network when it is
nickes area will present with a global aphasia that soon isolated from other regions of the brain. Brocas and
resolves into Wernickes aphasia. Wernickes areas tend to be spared, but there is damage
to the surrounding frontal, parietal, and temporal cortex.
Conduction Aphasia Lesions are patchy and can be associated with anoxia,
carbon monoxide poisoning, or complete watershed
Speech output is uent but paraphasic, comprehension zone infarctions.
of spoken language is intact, and repetition is severely
impaired. Naming and writing are also impaired. Read-
ing aloud is impaired, but reading comprehension is pre- Anomic Aphasia
SECTION II

served.The lesion sites spare Brocas and Wernickes areas This form of aphasia may be considered the minimal
but may induce a functional disconnection between the dysfunction syndrome of the language network. Articu-
two so that lexical representations formed in Wernickes lation, comprehension, and repetition are intact, but
area and adjacent regions cannot be conveyed to Brocas confrontation naming, word nding, and spelling are
area for assembly into corresponding articulatory pat- impaired. Speech is enriched in function words but
terns. Occasionally, a Wernickes area lesion gives rise to impoverished in substantive nouns and verbs denoting
Clinical Manifestations of Neurologic Disease

a transient Wernickes aphasia that rapidly resolves into a specic actions. Language output is uent but parapha-
conduction aphasia. The paraphasic output in conduc- sic, circumlocutious, and uninformative. The lesion sites
tion aphasia interferes with the ability to express mean- can be anywhere within the left hemisphere language
ing, but this decit is not nearly as severe as the one dis- network, including the middle and inferior temporal
played by patients with Wernickes aphasia. Associated gyri. Anomic aphasia is the single most common language dis-
neurologic signs in conduction aphasia vary according turbance seen in head trauma, metabolic encephalopathy, and
to the primary lesion site. Alzheimers disease.

Nonuent Transcortical Aphasia Pure Word Deafness

(Transcortical Motor Aphasia)
The most common causes are either bilateral or left-
The features are similar to Brocas aphasia, but repetition sided middle cerebral artery strokes affecting the supe-
is intact and agrammatism may be less pronounced. The rior temporal gyrus. The net effect of the underlying
neurologic examination may be otherwise intact, but a lesion is to interrupt the ow of information from the
right hemiparesis can also exist.The lesion site disconnects unimodal auditory association cortex to Wernickes area.
the intact language network from prefrontal areas of the Patients have no difculty understanding written lan-
brain and usually involves the anterior watershed zone guage and can express themselves well in spoken or
between anterior and middle cerebral artery territories written language. They have no difculty interpreting
or the supplementary motor cortex in the territory of the and reacting to environmental sounds since primary
anterior cerebral artery. auditory cortex and subcortical auditory relays are
intact. Since auditory information cannot be conveyed
Fluent Transcortical Aphasia to the language network, however, it cannot be decoded
(Transcortical Sensory Aphasia) into lexical representations and the patient reacts to
Clinical features are similar to those of Wernickes apha- speech as if it were in an alien tongue that cannot be
sia, but repetition is intact.The lesion site disconnects the deciphered. Patients cannot repeat spoken language but
intact core of the language network from other tem- have no difculty naming objects. In time, patients with
poroparietal association areas. Associated neurologic nd- pure word deafness teach themselves lip reading and
ings may include hemianopia. Cerebrovascular lesions may appear to have improved. There may be no addi-
(e.g., infarctions in the posterior watershed zone) or neo- tional neurologic ndings, but agitated paranoid reac-
plasms that involve the temporoparietal cortex posterior tions are frequent in the acute stages. Cerebrovascular
to Wernickes area are the most common causes. lesions are the most frequent cause.

Isolation Aphasia Pure Alexia without Agraphia

This rare syndrome represents a combination of the two This is the visual equivalent of pure word deafness. The
transcortical aphasias. Comprehension is severely impaired, lesions (usually a combination of damage to the left
and there is no purposeful speech output. The patient occipital cortex and to a posterior sector of the corpus
may parrot fragments of heard conversations (echolalia), callosumthe splenium) interrupt the ow of visual
indicating that the neural mechanisms for repetition are input into the language network.There is usually a right
at least partially intact. This condition represents the hemianopia, but the core language network remains
unaffected. The patient can understand and produce necessary for the movement are intact. Some forms of 145
spoken language, name objects in the left visual hemi- ideomotor apraxia represent a disconnection of the lan-
eld, repeat, and write. However, the patient acts as if guage network from pyramidal motor systems: commands
illiterate when asked to read even the simplest sentence to execute complex movements are understood but can-
because the visual information from the written words not be conveyed to the appropriate motor areas, even
(presented to the intact left visual hemield) cannot though the relevant motor mechanisms are intact. Bucco-
reach the language network. Objects in the left hemi- facial apraxia involves apraxic decits in movements of
eld may be named accurately because they activate the face and mouth. Limb apraxia encompasses apraxic
nonvisual associations in the right hemisphere, which, in decits in movements of the arms and legs. Ideomotor

CHAPTER 15
turn, can access the language network through transcal- apraxia is almost always caused by lesions in the left
losal pathways anterior to the splenium. Patients with hemisphere and is commonly associated with aphasic
this syndrome may also lose the ability to name colors, syndromes, especially Brocas aphasia and conduction
although they can match colors. This is known as a color aphasia. Its presence cannot be ascertained in patients
anomia. The most common etiology of pure alexia is a with language comprehension decits. The ability to
vascular lesion in the territory of the posterior cerebral follow commands aimed at axial musculature (close
artery or an inltrating neoplasm in the left occipital the eyes, stand up) is subserved by different pathways

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

cortex that involves the optic radiations as well as the and may be intact in otherwise severely aphasic and
crossing bers of the splenium. Since the posterior cere- apraxic patients. Patients with lesions of the anterior
bral artery also supplies medial temporal components of corpus callosum can display a special type of ideomotor
the limbic system, the patient with pure alexia may also apraxia conned to the left side of the body. Since the
experience an amnesia, but this is usually transient handling of real objects is not impaired, ideomotor
because the limbic lesion is unilateral. apraxia, by itself, causes no major limitation of daily liv-
ing activities.
Aphemia Ideational apraxia refers to a decit in the execution of
a goal-directed sequence of movements in patients who
There is an acute onset of severely impaired uency have no difculty executing the individual components
(often mutism), which cannot be accounted for by cor- of the sequence. For example, when asked to pick up a
ticobulbar, cerebellar, or extrapyramidal dysfunction. pen and write, the sequence of uncapping the pen, plac-
Recovery is the rule and involves an intermediate stage ing the cap at the opposite end, turning the point toward
of hoarse whispering.Writing, reading, and comprehen- the writing surface, and writing may be disrupted, and
sion are intact, so this is not a true aphasic syndrome. the patient may be seen trying to write with the wrong
Partial lesions of Brocas area or subcortical lesions that end of the pen or even with the removed cap. These
undercut its connections with other parts of the brain motor sequencing problems are usually seen in the con-
may be present. Occasionally, the lesion site is on the text of confusional states and dementias rather than focal
medial aspects of the frontal lobes and may involve the lesions associated with aphasic conditions. Limb-kinetic
supplementary motor cortex of the left hemisphere. apraxia involves a clumsiness in the actual use of tools that
cannot be attributed to sensory, pyramidal, extrapyramidal,
Apraxia or cerebellar dysfunction. This condition can emerge in
the context of focal premotor cortex lesions or corticobasal
This generic term designates a complex motor decit ganglionic degeneration.
that cannot be attributed to pyramidal, extrapyramidal,
cerebellar, or sensory dysfunction and that does not
arise from the patients failure to understand the nature Gerstmanns Syndrome
of the task. The form that is most frequently encoun- The combination of acalculia (impairment of simple arith-
tered in clinical practice is known as ideomotor apraxia. metic), dysgraphia (impaired writing), nger anomia (an
Commands to perform a specic motor act (cough, inability to name individual ngers such as the index or
blow out a match) or to pantomime the use of a com- thumb), and right-left confusion (an inability to tell whether
mon tool (a comb, hammer, straw, or toothbrush) in the a hand, foot, or arm of the patient or examiner is on the
absence of the real object cannot be followed. The right or left side of the body) is known as Gerstmanns
patients ability to comprehend the command is ascer- syndrome. In making this diagnosis it is important to
tained by demonstrating multiple movements and estab- establish that the nger and left-right naming decits
lishing that the correct one can be recognized. Some are not part of a more generalized anomia and that the
patients with this type of apraxia can imitate the appro- patient is not otherwise aphasic.When Gerstmanns syn-
priate movement (when it is demonstrated by the drome is seen in isolation, it is commonly associated
examiner) and show no impairment when handed the with damage to the inferior parietal lobule (especially
real object, indicating that the sensorimotor mechanisms the angular gyrus) in the left hemisphere.
 146 Aprosodia to the point where customary daily living activities
become compromised (Chap. 23). Alzheimers disease is
Variations of melodic stress and intonation inuence the
the single most common cause of dementia. The neu-
meaning and impact of spoken language. For example,
ropathology of Alzheimers disease causes the earliest and
the two statements He is clever. and He is clever? con-
most profound neuronal loss in memory-related parts of
tain an identical word choice and syntax but convey
the brain such as the entorhinal cortex and the hip-
vastly different messages because of differences in the
pocampus. This is why progressive forgetfulness for
intonation and stress with which the statements are
recent events and experiences is the cardinal feature of
uttered. This aspect of language is known as prosody.
Alzheimers disease. In time, the neuronal pathology in
Damage to perisylvian areas in the right hemisphere can
Alzheimers disease spreads to the language network and a
SECTION II

interfere with speech prosody and can lead to syndromes

progressive aphasia, usually of the anomic type, becomes
of aprosodia. Damage to right hemisphere regions corre-
added to the progressive amnesia. There are other pat-
sponding to Wernickes area can selectively impair decoding
terns of dementia, however, where neurodegeneration
of speech prosody, whereas damage to right hemisphere
initially targets the language rather than memory net-
regions corresponding to Brocas area yields a greater impair-
work of the brain, leading to the emergence of a pro-
ment in the ability to introduce meaning-appropriate
gressive aphasia that becomes the most prominent aspect
Clinical Manifestations of Neurologic Disease

prosody into spoken language. The latter decit is the

of the clinical picture during the initial phases of the
most common type of aprosodia identied in clinical
disease. Primary progressive aphasia (PPA) is the most
practicethe patient produces grammatically correct lan-
widely recognized syndrome with this pattern of selec-
guage with accurate word choice but the statements are
tive language impairment.
uttered in a monotone that interferes with the ability to
convey the intended stress and affect. Patients with this
type of aprosodia give the mistaken impression of being Clinical Presentation and Diagnosis of PPA
depressed or indifferent. The patient with PPA comes to medical attention
because of word-nding difculties, abnormal speech
Subcortical Aphasia patterns, and spelling errors of recent onset. PPA is diag-
nosed when other mental faculties such as memory for
Damage to subcortical components of the language net- daily events, visuospatial skills (assessed by tests of draw-
work (e.g., the striatum and thalamus of the left hemi- ing and face recognition), and comportment (assessed by
sphere) can also lead to aphasia.The resulting syndromes history obtained from a third party) remain relatively
contain combinations of decits in the various aspects of intact; when language is the major area of dysfunction
language but rarely t the specic patterns described in for the rst few years of the disease; and when structural
Table 15-1. In a patient with a CVA, an anomic aphasia brain imaging does not reveal a specic lesion, other than
accompanied by dysarthria or a uent aphasia with atrophy, to account for the language decit. Impairments
hemiparesis should raise the suspicion of a subcortical in other cognitive functions may also emerge, but the
lesion site. language dysfunction remains the most salient feature
and deteriorates most rapidly throughout the illness.
Progressive Aphasias
In clinical practice, acquired aphasias are most com- Language in PPA
monly encountered in one of two contexts: CVAs and The language impairment in PPA varies from patient to
degenerative diseases. Aphasias caused by CVAs start patient. Some patients cannot nd the right words to
suddenly and display maximal decits at the onset. The express thoughts; others cannot understand the meaning
underlying lesion is relatively circumscribed and associ- of heard or seen words; still others cannot name objects
ated with a total loss of neural function at the lesion site. in the environment. The language impairment can be
These are the classic aphasias described earlier where rel- uent (that is, with normal articulation, ow, and num-
atively reproducible relationships between lesion site and ber of words per utterance) or nonuent. The single
aphasia pattern can be discerned. Aphasias caused by most common sign of primary progressive aphasia is
neurodegenerative diseases have an insidious onset and anomia, manifested by an inability to come up with the
relentless progression so that the symptomatology changes right word during conversation and/or an inability to
over time. Since the neuronal loss within the areas name objects shown by the examiner. Many patients
encompassed by the neurodegeneration is partial and remain in an anomic phase through most of the disease
since it tends to include multiple components of the and experience a gradual intensication of word-nding
language network, distinctive clinical patterns and clinico- decits to the point of near-mutism. Others, however,
anatomic correlations are less obvious. proceed to develop distinct forms of agrammatism
Dementia is a generic term used to designate a neu- and/or word comprehension decits. The agrammatism
rodegenerative disease that impairs intellect and behavior consists of inappropriate word order and misuse of small
grammatical words. One patient, for example, sent the associated with neuronal loss in the lateral and anterior 147
following e-mail to her daughter: I will come my temporal cortex.
house in your car and drive my car into chicago. . . .You
will back get your car and my car park in my driveway. Neuropathology
Love, Mom. Comprehension decits, if present, start Approximately 30% of patients have shown the micro-
with an occasional inability to understand single low- scopic pathology of Alzheimers disease, presumably with
frequency words and gradually progress to encompass an atypical distribution of lesions. In the majority of
the comprehension of conversational speech. cases, the neuropathology falls within the family of fron-
The impairments of syntax, comprehension, naming, totemporal lobar degenerations (FTLD) and displays

CHAPTER 15
or writing in PPA are no different from those seen in various combinations of focal neuronal loss, gliosis, tau-
aphasias of cerebrovascular causes. However, they form positive inclusions, Pick bodies, and tau-negative ubiqui-
slightly different patterns. According to a classication tin inclusions (Chap. 23). Familial forms of PPA with
proposed by Gorno-Tempini and colleagues, three vari- tau-negative ubiquinated inclusions have recently been
ants of PPA can be recognized: an agrammatical variant linked to mutations of the progranulin gene on chromo-
characterized by poor uency and impaired syntax, a some 17. Apolipoprotein E and prion protein genotyp-
semantic variant characterized by preserved uency and ing has shown differences between patients with typical

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

syntax but poor single word comprehension, and a clinical patterns of Alzheimers disease and those with a
logopenic variant characterized by preserved syntax and diagnosis of PPA. The intriguing possibility has been
comprehension but frequent word-nding pauses dur- raised that a personal or family history of dyslexia may
ing spontaneous speech.The agrammatical variant is also be a risk factor for primary progressive aphasia, at least
known as progressive nonuent aphasia and displays simi- in some patients, suggesting that this disease may arise
larities to Brocas aphasia. However, dysarthria is usually on a background of genetic or developmental vulnera-
absent. The semantic variant of PPA is also known as bility affecting language-related areas of the brain.
semantic dementia and displays similarities to Wernickes
aphasia, but the comprehension difculty tends to be
milder. The most obvious difference between aphasias
caused by CVA and those caused by neurodegenerative
THE PARIETOFRONTAL NETWORK FOR
disease is the post-stroke improvement in CVA-related SPATIAL ORIENTATION: NEGLECT AND
aphasias, leading to a progressive crystallization of the RELATED CONDITIONS
subtypes listed in Table 15-1, versus the gradual deterio- HEMISPATIAL NEGLECT
ration that leads to a loss of syndromic specicity as the
disease progresses. Adaptive orientation to signicant events within the
extrapersonal space is subserved by a large-scale network
Pathophysiology containing three major cortical components.The cingulate
Patients with PPA display progressive atrophy (indica- cortex provides access to a limbic-motivational mapping
tive of neuronal loss), electroencephalographic slowing, of the extrapersonal space, the posterior parietal cortex to a
decreased blood ow (measured by single photon emis- sensorimotor representation of salient extrapersonal
sion CT) and decreased glucose utilization (measured events, and the frontal eye elds to motor strategies for
by positron emission tomography) that are most pro- attentional behaviors (Fig. 15-2). Subcortical compo-
nounced within the language network of the brain.The nents of this network include the striatum and the thala-
abnormalities may remain conned to left hemisphere mus. Contralesional hemispatial neglect represents one
perisylvian and anterior temporal cortices for many outcome of damage to any of the cortical or subcortical
years. The clinical focality of primary progressive aphasia components of this network. The traditional view that
is thus matched by the anatomic selectivity of the under- hemispatial neglect always denotes a parietal lobe lesion is inac-
lying pathologic process. curate. In keeping with this anatomic organization, the
The three variants display overlapping distributions of clinical manifestations of neglect display three behavioral
neuronal loss but the agrammatical variant is most components: sensory events (or their mental representa-
closely associated with atrophy in the anterior parts of tions) within the neglected hemispace have a lesser impact
the language network (where Brocas area is located), the on overall awareness; there is a paucity of exploratory and
semantic variant with atrophy in the temporal compo- orienting acts directed toward the neglected hemispace;
nents of the language network, and the logopenic vari- and the patient behaves as if the neglected hemispace
ant with atrophy in the temporoparietal component of was motivationally devalued.
the language network. The relationship between poor According to one model of spatial cognition, the
language comprehension and damage to Wernickes area, right hemisphere directs attention within the entire
which is a feature of CVA-related aphasias, is not present extrapersonal space, whereas the left hemisphere directs
in PPA. Instead, poor comprehension is most closely attention mostly within the contralateral right hemispace.
 148 placed on the left side of the tray; and may fail to read
the left half of sentences. When the examiner draws a
large circle [1215 cm (56 in.) in diameter] and asks
the patient to place the numbers 112 as if the circle
represented the face of a clock, there is a tendency to
crowd the numbers on the right side and leave the left
side empty. When asked to copy a simple line drawing,
the patient fails to copy detail on the left; and when
A asked to write, there is a tendency to leave an unusually
wide margin on the left.
SECTION II

Two bedside tests that are useful in assessing neglect

are simultaneous bilateral stimulation and visual target cancel-
lation. In the former, the examiner provides either uni-
lateral or simultaneous bilateral stimulation in the visual,
auditory, and tactile modalities. Following right hemi-
sphere injury, patients who have no difculty detecting
Clinical Manifestations of Neurologic Disease

unilateral stimuli on either side experience the bilater-

ally presented stimulus as coming only from the right.
This phenomenon is known as extinction and is a mani-
B festation of the sensory-representational aspect of
hemispatial neglect. In the target detection task, targets
FIGURE 15-2 (e.g., As) are interspersed with foils (e.g., other letters
Functional magnetic resonance imaging of language
of the alphabet) on a 21.5 28.0 cm (8.5 11 in.)
and spatial attention in neurologically intact subjects.
sheet of paper and the patient is asked to circle all the
The dark areas show regions of task-related signicant
targets. A failure to detect targets on the left is a manifes-
activation. ( A) The subjects were asked to determine if two
tation of the exploratory decit in hemispatial neglect
words were synonymous. This language task led to the
simultaneous activation of the two epicenters of the lan-
(Fig. 15-3A). Hemianopia, by itself, does not interfere
guage network, Brocas area (B) and Wernickes area (W).
with performance in this task since the patient is free to
The activations are exclusively in the left hemisphere. ( B ) turn the head and eyes to the left.The normal tendency
The subjects were asked to shift spatial attention to a in target detection tasks is to start from the left upper
peripheral target. This task led to the simultaneous activa- quadrant and move systematically in horizontal or ver-
tion of the three epicenters of the attentional network, the tical sweeps. Some patients show a tendency to start the
posterior parietal cortex (P), the frontal eye elds (F), and process from the right and proceed in a haphazard fashion.
the cingulate gyrus (CG). The activations are predominantly This represents a subtle manifestation of left neglect,
in the right hemisphere. (Courtesy of Darren Gitelman, MD; even if the patient eventually manages to detect all the
with permission.) appropriate targets. Some patients with neglect may also
deny the existence of hemiparesis and may even deny
ownership of the paralyzed limb, a condition known as
anosognosia.
Cerebrovascular lesions and neoplasms in the right
Consequently, unilateral left hemisphere lesions do not hemisphere are the most common causes of hemispatial
give rise to much contralesional neglect since the global neglect. Depending on the site of the lesion, the patient
attentional mechanisms of the right hemisphere can with neglect may also have hemiparesis, hemihypesthesia,
compensate for the loss of the contralaterally directed and hemianopia on the left, but these are not invariant
attentional functions of the left hemisphere. Unilateral ndings. The majority of patients display considerable
right hemisphere lesions, however, give rise to severe improvement of hemispatial neglect, usually within the
contralesional left hemispatial neglect because the unaf- rst several weeks.
fected left hemisphere does not contain ipsilateral atten-
tional mechanisms.This model is consistent with clinical
experience, which shows that contralesional neglect is
BLINTS SYNDROME, SIMULTANAGNOSIA,
more common, severe, and lasting after damage to the
DRESSING APRAXIA, AND CONSTRUCTION
right hemisphere than after damage to the left hemi-
APRAXIA
sphere. Severe neglect for the right hemispace is rare, Bilateral involvement of the network for spatial attention,
even in left handers with left hemisphere lesions. especially its parietal components, leads to a state of severe
Patients with severe neglect may fail to dress, shave, or spatial disorientation known as Blints syndrome. Blints
groom the left side of the body; may fail to eat food syndrome involves decits in the orderly visuomotor
 149

CHAPTER 15
Aphasia, Memory Loss, and Other Focal Cerebral Disorders
A

FIGURE 15-3
Evidence of left hemispatial
neglect and simultanagnosia.
A. A 47-year-old man with a
large frontoparietal lesion in the
right hemisphere was asked to
circle all the As. Only targets on
the right are circled. This is a
manifestation of left hemispatial
neglect. B. A 70-year-old woman
with a 2-year history of degener-
ative dementia was able to circle
most of the small targets but
ignored the larger ones. This is a
B manifestation of simultanagnosia.

scanning of the environment (oculomotor apraxia) and in simultanagnosia report that objects they look at may
accurate manual reaching toward visual targets (optic ataxia). suddenly vanish, probably indicating an inability to look
The third and most dramatic component of Blints syn- back at the original point of gaze after brief saccadic
drome is known as simultanagnosia and reects an inabil- displacements. Movement and distracting stimuli greatly
ity to integrate visual information in the center of gaze exacerbate the difculties of visual perception. Simul-
with more peripheral information. The patient gets tanagnosia can sometimes occur without the other two
stuck on the detail that falls in the center of gaze with- components of Blints syndrome.
out attempting to scan the visual environment for addi- A modication of the letter cancellation task described
tional information. The patient with simultanagnosia above can be used for the bedside diagnosis of simul-
misses the forest for the trees. Complex visual scenes tanagnosia. In this modication, some of the targets
cannot be grasped in their entirety, leading to severe (e.g., As) are made to be much larger than the others
limitations in the visual identication of objects and [7.510 cm vs 2.5 cm (34 in. vs 1 in.) in height], and all
scenes. For example, a patient who is shown a table targets are embedded among foils. Patients with simul-
lamp and asked to name the object may look at its tanagnosia display a counterintuitive but characteristic
circular base and call it an ash tray. Some patients with tendency to miss the larger targets (Fig. 15-3B). This
 150 occurs because the information needed for the identi- her own face in the mirror. This is not a perceptual
cation of the larger targets cannot be conned to the decit since prosopagnosic patients can easily tell if two
immediate line of gaze and requires the integration of faces are identical or not. Furthermore, a prosopagnosic
visual information across a more extensive eld of view. patient who cannot recognize a familiar face by visual
The greater difculty in the detection of the larger tar- inspection alone can use auditory cues to reach appro-
gets also indicates that poor acuity is not responsible for priate recognition if allowed to listen to the persons
the impairment of visual function and that the problem voice.The decit in prosopagnosia is therefore modality-
is central rather than peripheral. Blints syndrome specic and reects the existence of a lesion that prevents
results from bilateral dorsal parietal lesions; common set- the activation of otherwise intact multimodal templates
tings include watershed infarction between the middle by relevant visual input. Damasio has pointed out that
SECTION II

and posterior cerebral artery territories, hypoglycemia, the decit in prosopagnosia is not limited to the recog-
sagittal sinus thrombosis, or atypical forms of Alzheimers nition of faces but that it can also extend to the recogni-
disease. In patients with Blints syndrome due to stroke, tion of individual members of larger generic object
bilateral visual eld defects (usually inferior quadran- groups. For example, prosopagnosic patients characteris-
tanopias) are common. tically have no difculty with the generic identication
Another manifestation of bilateral (or right-sided) of a face as a face or of a car as a car, but they cannot
Clinical Manifestations of Neurologic Disease

dorsal parietal lobe lesions is dressing apraxia.The patient recognize the identity of an individual face or the make
with this condition is unable to align the body axis with of an individual car. This reects a visual recognition
the axis of the garment and can be seen struggling as he decit for proprietary features that characterize individ-
or she holds a coat from its bottom or extends his or her ual members of an object class. When recognition prob-
arm into a fold of the garment rather than into its lems become more generalized and extend to the generic
sleeve. Lesions that involve the posterior parietal cortex identication of common objects, the condition is known
also lead to severe difculties in copying simple line as visual object agnosia. In contrast to prosopagnosic
drawings. This is known as a construction apraxia and is patients, those with object agnosia cannot recognize a face
much more severe if the lesion is in the right hemi- as a face or a car as a car.
sphere. In some patients with right hemisphere lesions, It is important to distinguish visual object agnosia
the drawing difculties are conned to the left side of from anomia.The patient with anomia cannot name the
the gure and represent a manifestation of hemispatial object but can describe its use. In contrast, the patient
neglect; in others, there is a more universal decit in with visual agnosia is unable either to name a visually
reproducing contours and three-dimensional perspec- presented object or to describe its use.The characteristic
tive. Dressing apraxia and construction apraxia represent lesions in prosopagnosia and visual object agnosia consist
special instances of a more general disturbance in spatial of bilateral infarctions in the territory of the posterior
orientation. cerebral arteries. Associated decits can include visual
eld defects (especially superior quadrantanopias) or a
centrally based color blindness known as achromatopsia.
THE OCCIPITOTEMPORAL NETWORK Rarely, the responsible lesion is unilateral. In such cases,
FOR FACE AND OBJECT RECOGNITION: prosopagnosia is associated with lesions in the right
PROSOPAGNOSIA AND OBJECT hemisphere and object agnosia with lesions in the left.
AGNOSIA
Perceptual information about faces and objects is ini- THE LIMBIC NETWORK FOR MEMORY:
tially encoded in primary (striate) visual cortex and AMNESIAS
adjacent (upstream) peristriate visual association areas.
This information is subsequently relayed rst to the Limbic and paralimbic areas (such as the hippocampus,
downstream visual association areas of occipitotemporal amygdala, and entorhinal cortex), the anterior and
cortex and then to other heteromodal and paralimbic medial nuclei of the thalamus, the medial and basal parts
areas of the cerebral cortex. Bilateral lesions in the of the striatum, and the hypothalamus collectively con-
fusiform and lingual gyri of the occipitotemporal cortex stitute a distributed network known as the limbic system.
disrupt this process and interfere with the ability of other- The behavioral afliations of this network include the
wise intact perceptual information to activate the distrib- coordination of emotion, motivation, autonomic tone,
uted multimodal associations that lead to the recognition and endocrine function. An additional area of specializa-
of faces and objects.The resultant face and object recog- tion for the limbic network, and the one which is of
nition decits are known as prosopagnosia and visual object most relevance to clinical practice, is that of declarative
agnosia. (conscious) memory for recent episodes and experi-
The patient with prosopagnosia cannot recognize famil- ences. A disturbance in this function is known as an
iar faces, including, sometimes, the reection of his or amnestic state. In the absence of decits in motivation,
attention, language, or visuospatial function, the clinical hold the words online for at least 1 min.The nal phase 151
diagnosis of a persistent global amnestic state is always of the testing involves a retention period of 510 min,
associated with bilateral damage to the limbic network, during which the patient is engaged in other tasks. Ade-
usually within the hippocampo-entorhinal complex or quate recall at the end of this interval requires ofine
the thalamus. storage, retention, and retrieval. Amnestic patients fail
Although the limbic network is the site of damage this phase of the task and may even forget that they
for amnestic states, it is almost certainly not the storage were given a list of words to remember. Accurate recog-
site for memories. Memories are stored in widely dis- nition of the words by multiple choice in a patient who
tributed form throughout the cerebral cortex. The role cannot recall them indicates a less severe memory dis-

CHAPTER 15
attributed to the limbic network is to bind these distrib- turbance that affects mostly the retrieval stage of memory.
uted fragments into coherent events and experiences that The retrograde component of an amnesia can be assessed
can sustain conscious recall. Damage to the limbic net- with questions related to autobiographical or historic
work does not necessarily destroy memories but inter- events. The anterograde component of amnestic states is
feres with their conscious (declarative) recall in coherent usually much more prominent than the retrograde com-
form. The individual fragments of information remain ponent. In rare instances, usually associated with tempo-
preserved despite the limbic lesions and can sustain what ral lobe epilepsy or benzodiazepine intake, the retro-

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

is known as implicit memory. For example, patients with grade component may dominate.
amnestic states can acquire new motor or perceptual The assessment of memory can be quite challenging.
skills, even though they may have no conscious knowl- Bedside evaluations may only detect the most severe
edge of the experiences that led to the acquisition of these impairments. Less severe memory impairments, as in the
skills. case of patients with temporal lobe epilepsy, mild head
The memory disturbance in the amnestic state is injury, or early dementia, require quantitative evaluations
multimodal and includes retrograde and anterograde by neuropsychologists. Confusional states caused by toxic-
components. The retrograde amnesia involves an inability metabolic encephalopathies and some types of frontal
to recall experiences that occurred before the onset of lobe damage interfere with attentional capacity and lead
the amnestic state. Relatively recent events are more to secondary memory impairments, even in the absence
vulnerable to retrograde amnesia than more remote and of any limbic lesions. This sort of memory impairment
more extensively consolidated events. A patient who can be differentiated from the amnestic state by the
comes to the emergency department complaining that presence of additional impairments in the attention-
he cannot remember his identity but who can remem- related tasks described later in the section on the frontal
ber the events of the previous day is almost certainly not lobes.
suffering from a neurologic cause of memory distur- Many neurologic diseases can give rise to an amnestic
bance. The second and most important component of state. These include tumors (of the sphenoid wing, pos-
the amnestic state is the anterograde amnesia, which indi- terior corpus callosum, thalamus, or medial temporal
cates an inability to store, retain, and recall new knowl- lobe), infarctions (in the territories of the anterior or
edge. Patients with amnestic states cannot remember posterior cerebral arteries), head trauma, herpes simplex
what they ate a few minutes ago or the details of an encephalitis, Wernicke-Korsakoff encephalopathy, para-
important event they may have experienced a few hours neoplastic limbic encephalitis, and degenerative
ago. In the acute stages, there may also be a tendency to dementias such as Alzheimers or Picks disease.The one
ll in memory gaps with inaccurate, fabricated, and common denominator of all these diseases is that they
often implausible information. This is known as confabu- lead to the bilateral lesions within one or more compo-
lation. Patients with the amnestic syndrome forget that nents in the limbic network, most commonly the hip-
they forget and tend to deny the existence of a memory pocampus, entorhinal cortex, the mammillary bodies of
problem when questioned. the hypothalamus, and the limbic thalamus. Occasion-
The patient with an amnestic state is almost always ally, unilateral left-sided lesions can give rise to an
disoriented, especially to time. Accurate temporal orien- amnestic state, but the memory disorder tends to be
tation and accurate knowledge of current news rule out transient. Depending on the nature and distribution of
a major amnestic state. The anterograde component of the underlying neurologic disease, the patient may also
an amnestic state can be tested with a list of four to ve have visual eld decits, eye movement limitations, or
words read aloud by the examiner up to ve times or cerebellar ndings.
until the patient can immediately repeat the entire list Transient global amnesia is a distinctive syndrome usu-
without intervening delay. In the next phase of testing, ally seen in late middle age. Patients become acutely dis-
the patient is allowed to concentrate on the words and oriented and repeatedly ask who they are, where they
to rehearse them internally for 1 min before being asked to are, what they are doing. The spell is characterized by
recall them. Accurate performance in this phase indicates anterograde amnesia (inability to retain new information)
that the patient is motivated and sufciently attentive to and a retrograde amnesia for relatively recent events that
 152 occurred before the onset. The syndrome usually the patient becomes socially disinhibited and shows
resolves within 2448 h and is followed by the lling-in severe impairments of judgment, insight, and foresight.
of the period affected by the retrograde amnesia, The dissociation between intact cognitive function and
although there is persistent loss of memory for the events a total lack of even rudimentary common sense is strik-
that occurred during the ictus. Recurrences are noted in ing. Despite the preservation of all essential memory
~20% of patients. Migraine, temporal lobe seizures, and functions, the patient cannot learn from experience and
transient ischemic events in the posterior cerebral terri- continues to display inappropriate behaviors without
tory have been postulated as causes of transient global appearing to feel emotional pain, guilt, or regret when
amnesia. The absence of associated neurologic ndings such behaviors repeatedly lead to disastrous consequences.
may occasionally lead to the incorrect diagnosis of a The impairments may emerge only in real-life situations
SECTION II

psychiatric disorder. when behavior is under minimal external control and

may not be apparent within the structured environment
of the medical ofce. Testing judgment by asking
THE PREFRONTAL NETWORK FOR patients what they would do if they detected a re in a
ATTENTION AND BEHAVIOR theater or found a stamped and addressed envelope on
the road is not very informative since patients who answer
Clinical Manifestations of Neurologic Disease

Approximately one-third of all the cerebral cortex in these questions wisely in the ofce may still act very
the human brain is located in the frontal lobes. The foolishly in the more complex real-life setting. The
frontal lobes can be subdivided into motor-premotor, physician must therefore be prepared to make a diagno-
dorsolateral prefrontal, medial prefrontal, and orbitofrontal sis of frontal lobe disease on the basis of historic infor-
components.The terms frontal lobe syndrome and prefrontal mation alone even when the ofce examination of mental
cortex refer only to the last three of these four compo- state may be quite intact.
nents. These are the parts of the cerebral cortex that The abulic syndrome tends to be associated with dam-
show the greatest phylogenetic expansion in primates and age to the dorsolateral prefrontal cortex, and the disinhibi-
especially in humans. The dorsolateral prefrontal, medial tion syndrome with the medial prefrontal or orbitofrontal
prefrontal, and orbitofrontal areas, and the subcortical cortex. These syndromes tend to arise almost exclusively
structures with which they are interconnected (i.e., the after bilateral lesions, most frequently in the setting of head
head of the caudate and the dorsomedial nucleus of the trauma, stroke, ruptured aneurysms, hydrocephalus, tumors
thalamus), collectively make up a large-scale network (including metastases, glioblastoma, and falx or olfactory
that coordinates exceedingly complex aspects of human groove meningiomas), or focal degenerative diseases. Uni-
cognition and behavior. lateral lesions conned to the prefrontal cortex may remain
The prefrontal network plays an important role in silent until the pathology spreads to the other side. The
behaviors that require an integration of thought with emergence of developmentally primitive reexes, also
emotion and motivation. There is no simple formula known as frontal release signs, such as grasping (elicited
for summarizing the diverse functional affiliations of by stroking the palm) and sucking (elicited by stroking
the prefrontal network. Its integrity appears important the lips) are seen primarily in patients with large struc-
for the simultaneous awareness of context, options, tural lesions that extend into the premotor components
consequences, relevance, and emotional impact so as of the frontal lobes or in the context of metabolic
to allow the formulation of adaptive inferences, deci- encephalopathies.The vast majority of patients with pre-
sions, and actions. Damage to this part of the brain frontal lesions and frontal lobe behavioral syndromes do
impairs mental exibility, reasoning, hypothesis forma- not display these reexes.
tion, abstract thinking, foresight, judgment, the online Damage to the frontal lobe disrupts a variety of
(attentive) holding of information, and the ability to attention-related functions including working memory
inhibit inappropriate responses. Behaviors impaired by (the transient online holding of information), concentra-
prefrontal cortex lesions, especially those related to the tion span, the scanning and retrieval of stored informa-
manipulation of mental content, are often referred to tion, the inhibition of immediate but inappropriate
as executive functions. responses, and mental exibility. The capacity for focus-
Even very large bilateral prefrontal lesions may leave ing on a trend of thought and the ability to voluntarily
all sensory, motor, and basic cognitive functions intact shift the focus of attention from one thought or stimulus
while leading to isolated but dramatic alterations of per- to another can become impaired. Digit span (which
sonality and behavior. The most common clinical mani- should be seven forward and ve reverse) is decreased;
festations of damage to the prefrontal network take the the recitation of the months of the year in reverse order
form of two relatively distinct syndromes. In the frontal (which should take less than 15 s) is slowed; and the u-
abulic syndrome, the patient shows a loss of initiative, cre- ency in producing words starting with a, f, or s that can
ativity, and curiosity and displays a pervasive emotional be generated in 1 min (normally 12 per letter) is
blandness and apathy. In the frontal disinhibition syndrome, diminished even in nonaphasic patients. Characteristically,
there is a progressive slowing of performance as the task it is advisable to use the diagnostic term frontal net- 153
proceeds; e.g., the patient asked to count backwards by work syndrome, with the understanding that the respon-
3s may say 100, 97, 94, . . . 91, . . . 88, etc., and may not sible lesions can lie anywhere within this distributed
complete the task. In gono-go tasks (where the instruc- network.
tion is to raise the nger upon hearing one tap but to The patient with frontal lobe disease raises potential
keep it still upon hearing two taps), the patient shows a dilemmas in differential diagnosis: the abulia and bland-
characteristic inability to keep still in response to the ness may be misinterpreted as depression, and the disin-
no-go stimulus; mental exibility (tested by the ability hibition as idiopathic mania or acting-out. Appropriate
to shift from one criterion to another in sorting or match- intervention may be delayed while a treatable tumor

CHAPTER 15
ing tasks) is impoverished; distractibility by irrelevant stim- keeps expanding. An informed approach to frontal lobe
uli is increased; and there is a pronounced tendency for disease and its behavioral manifestations may help to
impersistence and perseveration. avoid such errors.
These attentional decits disrupt the orderly registra-
tion and retrieval of new information and lead to sec-
ondary memory decits. Such memory decits can be CARING FOR THE PATIENT WITH
differentiated from the primary memory impairments of DEFICITS OF HIGHER CEREBRAL

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

the amnestic state by showing that they improve when FUNCTION
the attentional load of the task is decreased. Working
memory (also known as immediate memory) is an atten- Some of the decits described in this chapter are so
tional function based on the temporary online holding of complex that they may bewilder not only the patient
information. It is closely associated with the integrity of and family but also the physician. It is imperative to
the prefrontal network and the ascending reticular activat- carry out a systematic clinical evaluation in order to
ing system. Retentive memory, on the other hand, depends characterize the nature of the decits and explain them
on the stable (ofine) storage of information and is associ- in lay terms to the patient and family. Such an explana-
ated with the integrity of the limbic network. The dis- tion can allay at least some of the anxieties, address the
tinction of the underlying neural mechanisms is illustrated mistaken impression that the decit (e.g., social disinhi-
by the observation that severely amnestic patients who bition or inability to recognize family members) is psy-
cannot remember events that occurred a few minutes ago chologically motivated, and lead to practical suggestions
may have intact if not superior working memory capacity for daily living activities. The consultation of a skilled
as shown in tests of digit span. neuropsychologist may aid in the formulation of diag-
Lesions in the caudate nucleus or in the dorsomedial nosis and management. Patients with simultanagnosia, for
nucleus of the thalamus (subcortical components of the example, may benet from the counterintuitive instruc-
prefrontal network) can also produce a frontal lobe syn- tion to stand back when they cannot nd an item so
drome. This is one reason why the mental state changes that a greater search area falls within the immediate eld
associated with degenerative basal ganglia diseases, such of gaze. Some patients with frontal lobe disease can be
as Parkinsons or Huntingtons disease, may take the extremely irritable and abusive to spouses and yet dis-
form of a frontal lobe syndrome. Because of its wide- play all the appropriate social graces during the visit to
spread connections with other regions of association the medical ofce. In such cases, the history may be
cortex, one essential computational role of the prefrontal more important than the bedside examination in chart-
network is to function as an integrator, or orchestrator, ing a course of treatment.
for other networks. Bilateral multifocal lesions of the cere- Reactive depression is common in patients with
bral hemispheres, none of which are individually large higher cerebral dysfunction and should be treated.These
enough to cause specic cognitive decits such as aphasia patients may be sensitive to the usual doses of antide-
or neglect, can collectively interfere with the connectivity pressants or anxiolytics and deserve a careful titration of
and integrating function of the prefrontal cortex. A dosage. Brain damage may cause a dissociation between
frontal lobe syndrome is the single most common feeling states and their expression, so that a patient who
behavioral prole associated with a variety of bilateral mul- may supercially appear jocular could still be suffering
tifocal brain diseases including metabolic encephalopathy, from an underlying depression that deserves to be treated.
multiple sclerosis, vitamin B12 deciency, and others. In In many cases, agitation may be controlled with reassur-
fact, the vast majority of patients with the clinical diag- ance. In other cases, treatment with sedating antidepres-
nosis of a frontal lobe syndrome tend to have lesions sants may become necessary. The use of neuroleptics for
that do not involve prefrontal cortex but involve either the control of agitation should be reserved for refractory
the subcortical components of the prefrontal network or cases since extrapyramidal side effects are frequent in
its connections with other parts of the brain. In order to patients with coexisting brain damage.
avoid making a diagnosis of frontal lobe syndrome Spontaneous improvement of cognitive decits due
in a patient with no evidence of frontal cortex disease, to acute neurologic lesions is common. It is most rapid
 154 in the rst few weeks but may continue for up to 2 years, Alzheimers disease, for example, causes the greatest destruc-
especially in young individuals with single brain lesions. tion in medial temporal areas belonging to the memory
The mechanisms for this recovery are incompletely network and is clinically characterized by a correspond-
understood. Some of the initial decits appear to arise ingly severe amnesia. There are other dementias where
from remote dysfunction (diaschisis) in parts of the brain memory is intact. Frontal lobe dementia results from a
that are interconnected with the site of initial injury. selective degeneration of the frontal lobe and leads to a
Improvement in these patients may reect, at least in gradual dissolution of behavior and complex attention.
part, a normalization of the remote dysfunction. Other Primary progressive aphasia is characterized by a gradual
mechanisms may involve functional reorganization in atrophy of the left perisylvian language network and
surviving neurons adjacent to the injury or the compen- leads to a progressive dissolution of language that can
SECTION II

satory use of homologous structures, e.g., the right supe- remain isolated for up to 10 years. An enlightened
rior temporal gyrus with recovery from Wernickes approach to the differential diagnosis and treatment of
aphasia. In some patients with large lesions involving these patients requires an understanding of the principles
Brocas and Wernickes areas, only Wernickes area may that link neural networks to higher cerebral functions.
show contralateral compensatory reorganization (or
bilateral functionality), giving rise to a situation where a FURTHER READINGS
Clinical Manifestations of Neurologic Disease

lesion that should have caused a global aphasia becomes

CATANI M, FFYCHTE H: The rises and falls of disconnection syn-
associated with a residual Brocas aphasia. Prognosis for dromes. Brain 128:2224, 2005
recovery from aphasia is best when Wernickes area is CRUTS M et al: Null mutations in progranulin cause ubiquitin-
spared. Cognitive rehabilitation procedures have been positive frontotemporal dementia linked to chromosome 17q21.
used in the treatment of higher cortical decits. There Nature 442:916, 2006
are few controlled studies, but some do show a benet HILLIS AE: Aphasia: Progress in the last quarter of a century. Neurol-
of rehabilitation in the recovery from hemispatial ogy 69:200, 2007
neglect and aphasia. Some types of decits may be more KNIBB JA et al: Clinical and pathological characterization of progres-
sive aphasia.Ann Neurol 59:156, 2006
prone to recovery than others. For example, patients LE BER I et al: Phenotype variability in progranulin mutation carri-
with nonuent aphasias are more likely to benet from ers: a clinical, neuropsychological, imaging and genetic study.
speech therapy than patients with uent aphasias and Brain 131:732, 2008
comprehension decits. In general, lesions that lead to a MESULAM M-M: Behavioral neuroanatomy: Large-scale networks,
denial of illness (e.g., anosognosia) are associated with association cortex, frontal syndromes, the limbic system and
cognitive decits that are more resistant to rehabilita- hemispheric specializations, in Principles of Behavioral and Cogni-
tion. The recovery from higher cortical dysfunction is tive Neurology, 2d ed, M-M Mesulam (ed). New York, Oxford
University Press, 2000, pp 1120
rarely complete. Periodic neuropsychological assessment ______: Representation, inference, and transcendent encoding in
is necessary for quantifying the pace of the improvement neurocognitive networks of the human brain. Ann Neurol
and for generating specic recommendations for cogni- 64:367, 2008
tive rehabilitation, modications in the home environ- : Current concepts: Primary progressive aphasiaa language-
ment, and the timetable for returning to school or work. based dementia. New Engl J Med 348:1535, 2003
In general medical practice, most patients with decits : The human frontal lobes: Transcending the default mode
in higher cognitive functions will be suffering from through contingent encoding, in Principles of Frontal Lobe Func-
tion, DT Stuss, RT Knight (eds). New York, Oxford University
dementia. There is a mistaken belief that dementias are
Press, 2002, pp 830
anatomically diffuse and that they cause global cognitive ROGALSKI E, MESULAM M: An update on primary progressive apha-
impairments. This is only true at the terminal stages. sia. Curr Neurol Neurosci Rep 7:388, 2007
During most of the clinical course, dementias are exquisitely SUMMERFIELD JJ et al: Orienting attention based on long-term
selective with respect to anatomy and cognitive pattern. memory experience. Neuron 49:905, 2006
 CHAPTER 16

SLEEP DISORDERS

Charles A. Czeisler I John W. Winkelman I Gary S. Richardson

I Physiology of Sleep and Wakefulness . . . . . . . . . . . . . . . . . . 155 Comorbid Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

States and Stages of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Restless Legs Syndrome (RLS) . . . . . . . . . . . . . . . . . . . . . . . 162
Organization of Human Sleep . . . . . . . . . . . . . . . . . . . . . . . . 156 Periodic Limb Movement Disorder (PLMD) . . . . . . . . . . . . . . 163
Neuroanatomy of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Evaluation of Daytime Sleepiness . . . . . . . . . . . . . . . . . . . . . 163
Neurochemistry of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Physiology of Circadian Rhythmicity . . . . . . . . . . . . . . . . . . . 157 Sleep Apnea Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Behavioral Correlates of Sleep States and Stages . . . . . . . . . 158 Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Physiologic Correlates of Sleep States and Stages . . . . . . . . 158 I Circadian Rhythm Sleep Disorders . . . . . . . . . . . . . . . . . . . . 167
I Disorders of Sleep and Wakefulness . . . . . . . . . . . . . . . . . . . 159 Medical Implications of Circadian Rhythmicity . . . . . . . . . . . . 169
Evaluation of Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Primary Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Disturbed sleep is among the most frequent health com- a mid-afternoon nap and a shortened night sleep. Two
plaints physicians encounter. More than one-half of principal systems govern the sleep-wake cycle: one
adults in the United States experience at least intermit- actively generates sleep and sleep-related processes and
tent sleep disturbances. For most, it is an occasional another times sleep within the 24-h day. Either intrinsic
night of poor sleep or daytime sleepiness. However, the abnormalities in these systems or extrinsic disturbances
Institute of Medicine estimates that 5070 million (environmental, drug- or illness-related) can lead to
Americans suffer from a chronic disorder of sleep and sleep or circadian rhythm disorders.
wakefulness, which can lead to serious impairment of
daytime functioning. In addition, such problems may STATES AND STAGES OF SLEEP
contribute to or exacerbate medical or psychiatric con-
ditions. Thirty years ago, many such complaints were States and stages of human sleep are dened on the basis
treated with hypnotic medications without further diag- of characteristic patterns in the electroencephalogram
nostic evaluation. Since then, a distinct class of sleep and (EEG), the electrooculogram (EOGa measure of eye-
arousal disorders has been identied. movement activity), and the surface electromyogram
(EMG) measured on the chin and neck. The continuous
recording of this array of electrophysiologic parameters to
PHYSIOLOGY OF SLEEP AND dene sleep and wakefulness is termed polysomnography.
WAKEFULNESS Polysomnographic proles dene two states of sleep:
(1) rapid-eye-movement (REM) sleep, and (2) non-
Most adults sleep 78 h per night, although the timing, rapid-eye-movement (NREM) sleep. NREM sleep is
duration, and internal structure of sleep vary among further subdivided into four stages, characterized by
healthy individuals and as a function of age. At the increasing arousal threshold and slowing of the cortical
extremes, infants and the elderly have frequent interrup- EEG. REM sleep is characterized by a low-amplitude,
tions of sleep. In the United States, adults of intermedi- mixed-frequency EEG similar to that of NREM stage 1
ate age tend to have one consolidated sleep episode per sleep. The EOG shows bursts of REM similar to those
day, although in some cultures sleep may be divided into seen during eyes-open wakefulness. Chin EMG activity
155
 156 is absent, reecting the brainstem-mediated muscle atonia A different age prole exists for REM sleep than for
that is characteristic of that state. slow-wave sleep. In infancy, REM sleep may comprise
50% of total sleep time, and the percentage is inversely
proportional to developmental age. The amount of
ORGANIZATION OF HUMAN SLEEP
REM sleep falls off sharply over the rst postnatal year
Normal nocturnal sleep in adults displays a consistent as a mature REM-NREM cycle develops; thereafter,
organization from night to night (Fig. 16-1). After sleep REM sleep occupies a relatively constant percentage of
onset, sleep usually progresses through NREM stages total sleep time.
14 within 4560 min. Slow-wave sleep (NREM stages
3 and 4) predominates in the rst third of the night and
SECTION II

NEUROANATOMY OF SLEEP
comprises 1525% of total nocturnal sleep time in
young adults. The percentage of slow-wave sleep is Experimental studies in animals have variously impli-
inuenced by several factors, most notably age (see cated the medullary reticular formation, the thalamus,
below). Prior sleep deprivation increases the rapidity of and the basal forebrain in the generation of sleep, while
sleep onset and both the intensity and amount of slow- the brainstem reticular formation, the midbrain, the sub-
wave sleep. thalamus, the thalamus, and the basal forebrain have all
Clinical Manifestations of Neurologic Disease

The rst REM sleep episode usually occurs in the been suggested to play a role in the generation of wake-
second hour of sleep. More rapid onset of REM sleep in fulness or EEG arousal.
a young adult (particularly if <30 min) may suggest Current models suggest that the capacity for sleep
pathology such as endogenous depression, narcolepsy, and wakefulness generation is distributed along an axial
circadian rhythm disorders, or drug withdrawal. NREM core of neurons extending from the brainstem ros-
and REM alternate through the night with an average trally to the basal forebrain. A cluster of -aminobutyric
period of 90110 min (the ultradian sleep cycle). acid (GABA) and galaninergic neurons in the ventrolat-
Overall, REM sleep constitutes 2025% of total sleep, eral preoptic (VLPO) hypothalamus is selectively acti-
and NREM stages 1 and 2 are 5060%. vated coincident with sleep onset.These neurons project
Age has a profound impact on sleep state organization to and inhibit multiple distinct wakefulness centers
(Fig. 16-1). Slow-wave sleep is most intense and promi- including the tuberomammilary (histaminergic) nucleus
nent during childhood, decreasing sharply at puberty and that are important to the ascending arousal system, indi-
across the second and third decades of life. After age 30, cating that the hypothalamic VLPO neurons play a key
there is a progressive decline in the amount of slow-wave executive role in sleep regulation.
sleep, and the amplitude of delta EEG activity comprising Specic regions in the pons are associated with the
slow-wave sleep is profoundly reduced. The depth of neurophysiologic correlates of REM sleep. Small lesions in
slow-wave sleep, as measured by the arousal threshold to the dorsal pons result in the loss of the descending muscle
auditory stimulation, also decreases with age. In the other- inhibition normally associated with REM sleep; microin-
wise healthy older person, slow-wave sleep may be com- jections of the cholinergic agonist carbachol into the pon-
pletely absent, particularly in males. tine reticular formation appear to produce a state with all

Awake
REM
1 Age
2 23
3
Sleep stage

Awake
REM
1 Age
2 68
3
4

00:00 02:00 04:00 06:00 08:00

Clock time
FIGURE 16-1
Stages of REM sleep (solid bars), the four stages of NREM sleep, frequent spontaneous awakenings, early sleep onset,
sleep, and wakefulness over the course of the entire night for and early morning awakening. (From the Division of Sleep
representative young and older adult men. Characteristic fea- Medicine, Brigham and Womens Hospital.)
tures of sleep in older people include reduction of slow-wave
of the features of REM sleep.These experimental manip- 157
? TIM ? PER3
ulations are mimicked by pathologic conditions in humans
and animals. In narcolepsy, for example, abrupt, complete, CRY1 PER2
or partial paralysis (cataplexy) occurs in response to a vari- CRY2
PER1
ety of stimuli. In dogs with this condition, physostigmine, a CK1E
central cholinesterase inhibitor, increases the frequency of

cataplectic attacks, while atropine decreases their fre-

CLOCK
BMAL1
quency. Conversely, in REM sleep behavior disorder (see
later), patients suffer from incomplete motor inhibition

CHAPTER 16
during REM sleep, resulting in involuntary, occasionally +
violent movement during REM sleep. E-Box Per1 gene
FIGURE 16-2
Model of the molecular feedback loop at the core of the
NEUROCHEMISTRY OF SLEEP mammalian circadian clock. The positive element of the
feedback loop (+) is the transcriptional activation of the Per1
Early experimental studies that focused on the raphe gene (and probably other clock genes) by a heterodimer of

Sleep Disorders
nuclei of the brainstem appeared to implicate serotonin as the transcription factors CLOCK and BMAL1 (also called
the primary sleep-promoting neurotransmitter, while cat- MOP3) bound to an E-box DNA regulatory element. The Per1
echolamines were considered to be responsible for wake- transcript and its product, the clock component PER1 pro-
fulness. Simple neurochemical models have given way to tein, accumulate in the cell cytoplasm. As it accumulates, the
more complex formulations involving multiple parallel PER1 protein is recruited into a multiprotein complex thought
waking systems. Pharmacologic studies suggest that hista- to contain other circadian clock component proteins such as
mine, acetylcholine, dopamine, serotonin, and noradrena- cryptochromes (CRYs), Period proteins (PERs), and others.
line are all involved in wake promotion. In addition, pontine This complex is then transported into the cell nucleus (across
cholinergic neurotransmission is known to play a role in the dotted line), where it functions as the negative element in
REM sleep generation.The alerting inuence of caffeine the feedback loop () by inhibiting the activity of the CLOCK-
implicates adenosine, whereas the hypnotic effect of ben- BMAL1 transcription factor heterodimer. As a consequence
zodiazepines and barbiturates suggests a role for endogenous of this action, the concentration of PER1 and other clock
ligands of the GABAA receptor complex. A newly charac- proteins in the inhibitory complex falls, allowing CLOCK-
terized neuropeptide, hypocretin (orexin), has recently been BMAL1 to activate transcription of Per1 and other genes and
implicated in the pathophysiology of narcolepsy (see begin another cycle. The dynamics of the 24-h molecular
later), but its role in normal sleep regulation remains to be cycle are controlled at several levels, including regulation of
dened. the rate of PER protein degradation by casein kinase-1
A variety of sleep-promoting substances have been epsilon (CK1E). Additional limbs of this genetic regulatory
identied, although it is not known whether they are network, omitted for the sake of clarity, are thought to con-
tribute stability. Question marks denote putative clock pro-
involved in the endogenous sleep-wake regulatory process.
teins, such as Timeless (TIM), as yet lacking genetic proof of
These include prostaglandin D2, delta sleepinducing pep-
a role in the mammalian clock mechanism. (Copyright Charles
tide, muramyl dipeptide, interleukin 1, fatty acid primary
J. Weitz, Ph.D., Department of Neurobiology, Harvard Med-
amides, and melatonin. The hypnotic effect of these sub-
ical School.)
stances is commonly limited to NREM or slow-wave
sleep, although peptides that increase REM sleep have also
been reported. Many putative sleep factors, including
interleukin 1 and prostaglandin D2, are immunologically between those rhythmic components passively evoked
active as well, suggesting a link between immune function by periodic environmental or behavioral changes (e.g.,
and sleep-wake states. the increase in blood pressure and heart rate upon
assumption of the upright posture) and those actively
driven by an endogenous oscillatory process (e.g., the
PHYSIOLOGY OF CIRCADIAN RHYTHMICITY circadian variation in plasma cortisol that persists under
The sleep-wake cycle is the most evident of the many a variety of environmental and behavioral conditions).
24-h rhythms in humans. Prominent daily variations also While it is now recognized that many peripheral
occur in endocrine, thermoregulatory, cardiac, pul- tissues in mammals have circadian clocks that regulate
monary, renal, gastrointestinal, and neurobehavioral diverse physiologic processes, these independent tissue-
functions. At the molecular level, endogenous circadian specic oscillations are coordinated by a central neural
rhythmicity is driven by self-sustaining transcriptional/ pacemaker located in the suprachiasmatic nuclei (SCN)
translational feedback loops (Fig. 16-2). In evaluating a of the hypothalamus. Bilateral destruction of these nuclei
daily variation in humans, it is important to distinguish results in a loss of the endogenous circadian rhythm of
 158 locomotor activity, which can be restored only by trans- PHYSIOLOGIC CORRELATES OF SLEEP
plantation of the same structure from a donor animal. STATES AND STAGES
The genetically determined period of this endogenous
All major physiologic systems are inuenced by sleep.
neural oscillator, which averages ~24.2 h in humans, is
Changes in cardiovascular function include a decrease in
normally synchronized to the 24-h period of the envi-
blood pressure and heart rate during NREM and partic-
ronmental light-dark cycle. Small differences in circadian
ularly during slow-wave sleep. During REM sleep, pha-
period underlie variations in diurnal preference, with
sic activity (bursts of eye movements) is associated with
the circadian period shorter in individuals who typically
variability in both blood pressure and heart rate medi-
rise early compared to those who typically go to bed late.
ated principally by the vagus. Cardiac dysrhythmias may
Entrainment of mammalian circadian rhythms by the
SECTION II

occur selectively during REM sleep. Respiratory func-

light-dark cycle is mediated via the retinohypothalamic
tion also changes. In comparison to relaxed wakefulness,
tract, a monosynaptic pathway that links specialized, pho-
respiratory rate becomes more regular during NREM
toreceptive retinal ganglion cells directly to the SCN.
sleep (especially slow-wave sleep) and tonic REM sleep
Humans are exquisitely sensitive to the resetting effects
and becomes very irregular during phasic REM sleep.
of light, particularly at the blue end (~460480 nm) of
Minute ventilation decreases in NREM sleep out of
the visible spectrum.
Clinical Manifestations of Neurologic Disease

proportion to the decrease in metabolic rate at sleep onset,

The timing and internal architecture of sleep are
resulting in a higher PCO2.
directly coupled to the output of the endogenous circa-
Endocrine function also varies with sleep. Slow-wave
dian pacemaker. Paradoxically, the endogenous circadian
sleep is associated with secretion of growth hormone,
rhythms of sleep tendency, sleepiness, and REM sleep
while sleep in general is associated with augmented
propensity all peak near the habitual wake time, just
secretion of prolactin. Sleep has a complex effect on the
after the nadir of the endogenous circadian temperature
secretion of luteinizing hormone (LH): during puberty,
cycle, whereas the circadian wake propensity rhythm
sleep is associated with increased LH secretion, whereas
peaks 13 h before the habitual bedtime.These rhythms
sleep in the postpubertal female inhibits LH secretion in
are thus timed to oppose the homeostatic decline of
the early follicular phase of the menstrual cycle. Sleep
sleep tendency during the habitual sleep episode and the
onset (and probably slow-wave sleep) is associated with
rise of sleep tendency throughout the usual waking day,
inhibition of thyroid-stimulating hormone and of the
respectively. Misalignment of the output of the endoge-
adrenocorticotropic hormonecortisol axis, an effect that
nous circadian pacemaker with the desired sleep-wake
is superimposed on the prominent circadian rhythms in
cycle can, therefore, induce insomnia, decreased alert-
the two systems.
ness, and impaired performance evident in night-shift
The pineal hormone melatonin is secreted predomi-
workers and airline travelers.
nantly at night in both day- and night-active species,
reecting the direct modulation of pineal activity by the
BEHAVIORAL CORRELATES OF SLEEP circadian pacemaker through a circuitous neural pathway
STATES AND STAGES from the SCN to the pineal gland. Melatonin secretion
Polysomnographic staging of sleep correlates with behav- is not dependent upon the occurrence of sleep, persist-
ioral changes during specic states and stages. During the ing in individuals kept awake at night. In addition, exoge-
transitional state between wakefulness and sleep (stage nous melatonin increases sleepiness and increases sleep
1 sleep), subjects may respond to faint auditory or visual duration when administered to healthy adults attempting
signals without awakening. Memory incorporation is to sleep during daylight hours, at a time when endoge-
inhibited at the onset of NREM stage 1 sleep, which may nous melatonin levels are low. The efcacy of melatonin
explain why individuals aroused from that transitional sleep as a sleep-promoting therapy for patients with insomnia
stage frequently deny having been asleep. Such transitions is currently not known.
may intrude upon behavioral wakefulness after sleep depri- Sleep is also accompanied by alterations of ther-
vation, notwithstanding attempts to remain continuously moregulatory function. NREM sleep is associated with
awake (see Shift-Work Disorder, later in the chapter). an attenuation of thermoregulatory responses to either
Awakenings from REM sleep are associated with recall heat or cold stress, and animal studies of thermosensitive
of vivid dream imagery >80% of the time.The reliability neurons in the hypothalamus document an NREM-
of dream recall increases with REM sleep episodes occur- sleep-dependent reduction of the thermoregulatory set-
ring later in the night. Imagery may also be reported after point. REM sleep is associated with complete absence
NREM sleep interruptions, though these typically lack of thermoregulatory responsiveness, effectively resulting
the detail and vividness of REM sleep dreams. The inci- in functional poikilothermy. However, the potential
dence of NREM sleep dream recall can be increased by adverse impact of this failure of thermoregulation is
selective REM sleep deprivation, suggesting that REM blunted by inhibition of REM sleep by extreme ambient
sleep and dreaming per se are not inexorably linked. temperatures.
DISORDERS OF SLEEP AND can be invaluable; some patients may be unaware of, 159
WAKEFULNESS or will underreport, such potentially embarrassing
symptoms as heavy snoring or falling asleep while
driving.
Patients with excessive sleepiness should be advised
Approach to the Patient:
to avoid all driving until effective therapy has been
SLEEP DISORDERS achieved.
Completion by the patient of a day-by-day sleep-
Patients may seek help from a physician because of work-drug log for at least 2 weeks can help the physi-

CHAPTER 16
one of several symptoms: (1) an acute or chronic cian understand the nature of the complaint better.
inability to initiate or maintain sleep adequately at Work times and sleep times (including daytime naps
night (insomnia); (2) chronic fatigue, sleepiness, or and nocturnal awakenings) as well as drug and alco-
tiredness during the day; or (3) a behavioral manifes- hol use, including caffeine and hypnotics, should be
tation associated with sleep itself. Complaints of noted each day.
insomnia or excessive daytime sleepiness should be Polysomnography is necessary for the diagnosis of
approached as symptoms (much like fever or pain) of

Sleep Disorders
specic disorders such as narcolepsy and sleep apnea
underlying disorders. Knowledge of the differential and may be of utility in other settings as well. In
diagnosis of these presenting complaints is essential to addition to the three electrophysiologic variables used
identify any underlying medical disorder. Only then to dene sleep states and stages, the standard clinical
can appropriate treatment, rather than nonspecic polysomnogram includes measures of respiration (res-
approaches (e.g., over-the-counter sleeping aids), be piratory effort, air ow, and oxygen saturation), ante-
applied. Diagnoses of exclusion, such as primary rior tibialis EMG, and electrocardiogram.
insomnia, should be made only after other diagnoses
have been ruled out. Table 16-1 outlines the diag-
nostic and therapeutic approach to the patient with a
complaint of excessive daytime sleepiness. EVALUATION OF INSOMNIA
A careful history is essential. In particular, the dura-
tion, severity, and consistency of the symptoms are Insomnia is the complaint of inadequate sleep; it can be
important, along with the patients estimate of the classied according to the nature of sleep disruption and
consequences of the sleep disorder on waking func- the duration of the complaint. Insomnia is subdivided
tion. Information from a friend or family member into difculty falling asleep (sleep onset insomnia), frequent
or sustained awakenings (sleep maintenance insomnia), early

TABLE 16-1
EVALUATION OF THE PATIENT WITH THE COMPLAINT OF EXCESSIVE DAYTIME SOMNOLENCE

FINDINGS ON HISTORY AND

PHYSICAL EXAMINATION DIAGNOSTIC EVALUATION DIAGNOSIS THERAPY

Obesity, snoring, hypertension Polysomnography with Obstructive Continuous positive airway pressure;
respiratory monitoring sleep apnea ENT surgery (e.g., uvulopalatopharyngoplasty);
dental appliance; pharmacologic therapy (e.g.,
protriptyline); weight loss
Cataplexy, hypnogogic Polysomnography with Narcolepsy- Stimulants (e.g., modanil, methylphenidate);
hallucinations, sleep multiple sleep latency cataplexy REM-suppressant antidepressants (e.g.,
paralysis, family history testing syndrome protriptyline); genetic counseling
Restless legs, disturbed Assesment for Restless legs Treatment of predisposing condition, if possible;
sleep, predisposing predisposing medical syndrome dopamine agonists (e.g., pramipexole,
medical condition (e.g., iron conditions ropinirole)
deciency or renal failure)
Disturbed sleep, predisposing Sleep-wake diary Insomnias Treatment of predisposing condition and/or
medical conditions (e.g., recording (see text) change in therapy, if possible; behavioral
asthma) and/or predisposing therapy; short-acting benzodiazepine receptor
medical therapies (e.g., agonist (e.g., zolpidem)
theophylline)

Note: ENT, ears, nose, throat; REM, rapid eye movement; EMG, electromyogram.
 160 morning awakenings (sleep offset insomnia), or persistent occurring at other times. Subsyndromal psychiatric
sleepiness/fatigue despite sleep of adequate duration disorders (e.g., anxiety and mood complaints), negative
(nonrestorative sleep). Similarly, the duration of the symp- conditioning to the sleep environment (psychophysio-
tom inuences diagnostic and therapeutic considera- logic insomnia, see later in the chapter), amplication of
tions. An insomnia complaint lasting one to several the time spent awake (paradoxical insomnia), physiologic
nights (within a single episode) is termed transient insom- hyperarousal, and poor sleep hygiene (see earlier) may all
nia and is typically the result of situational stress or a be present. As these processes may be both causes and
change in sleep schedule or environment (e.g., jet lag consequences of chronic insomnia, many individuals
disorder). Short-term insomnia lasts from a few days to will have a progressive course to their symptoms in
3 weeks. Disruption of this duration is usually associated which the severity is proportional to the chronicity, and
SECTION II

with more protracted stress, such as recovery from much of the complaint may persist even after effective
surgery or short-term illness. Long-term insomnia, or treatment of the initial inciting etiology. Treatment of
chronic insomnia, lasts for months or years and, in contrast insomnia is often directed to each of the putative con-
with short-term insomnia, requires a thorough evalua- tributing factors: behavior therapies for anxiety and neg-
tion of underlying causes (see below). Chronic insomnia ative conditioning (see later), pharmacotherapy and/or
is often a waxing and waning disorder, with spontaneous psychotherapy for mood/anxiety disorders, and an
Clinical Manifestations of Neurologic Disease

or stressor-induced exacerbations. emphasis on maintenance of good sleep hygiene.

An occasional night of poor sleep, typically in the set- If insomnia persists after treatment of these contribut-
ting of stress or excitement about external events, is both ing factors, empirical pharmacotherapy is often used on
common and without lasting consequences. However, a nightly or intermittent basis. A variety of sedative
persistent insomnia can lead to impaired daytime func- compounds are used for this purpose. Alcohol and anti-
tion, injury due to accidents, and the development of histamines are the most commonly used nonprescrip-
major depression. In addition, there is emerging evidence tion sleep aids. The former may help with sleep onset
that individuals with chronic insomnia have increased uti- but is associated with sleep disruption during the night
lization of health care resources, even after controlling for and can escalate into abuse, dependence, and withdrawal
co-morbid medical and psychiatric disorders. in the predisposed individual. Antihistamines may be of
All insomnias can be exacerbated and perpetuated by benet when used intermittently but often produce
behaviors that are not conducive to initiating or main- rapid tolerance and may have multiple side effects (espe-
taining sleep. Inadequate sleep hygiene is characterized by a cially anticholinergic), which limit their use, particularly
behavior pattern prior to sleep or a bedroom environ- in the elderly. Benzodiazepine-receptor agonists are the
ment that is not conducive to sleep. Noise or light in the most effective and well-tolerated class of medications for
bedroom can interfere with sleep, as can a bed partner insomnia. The broad range of half-lives allows exibility
with periodic limb movements during sleep or one who in the duration of sedative action. The most commonly
snores loudly. Clocks can heighten the anxiety about the prescribed agents in this family are zaleplon (520 mg),
time it has taken to fall asleep. Drugs that act on the with a half-life of 12 h; zolpidem (510 mg) and tria-
central nervous system, large meals, vigorous exercise, or zolam (0.1250.25 mg), with half-lives of 23 h; eszopi-
hot showers just before sleep may all interfere with sleep clone (13 mg), with a half-life of 5.58 h; and
onset. Many individuals participate in stressful work- temazepam (1530 mg) and lorazepam (0.52 mg), with
related activities in the evening, producing a state half-lives of 612 h. Generally, side effects are minimal
incompatible with sleep onset. In preference to hypnotic when the dose is kept low and the serum concentration
medications, patients should be counseled to avoid is minimized during the waking hours (by using the
stressful activities before bed, develop a soporic bed- shortest-acting, effective agent). Recent data suggest that
time ritual, and to prepare and reserve the bedroom at least one benzodiazepine receptor agonist (eszopi-
environment for sleeping. Consistent, regular rising clone) continues to be effective for 6 months of nightly
times should be maintained daily, including weekends. use. However, longer durations of use have not been
evaluated, and it is unclear whether this is true of other
agents in this class. Moreover, with even brief continu-
PRIMARY INSOMNIA ous use of benzodiazepine-receptor agonists, rebound
Many patients with chronic insomnia have no clear, insomnia can occur upon discontinuation. The likeli-
single identiable underlying cause for their difculties hood of rebound insomnia and tolerance can be mini-
with sleep. Rather, such patients often have multiple eti- mized by short durations of treatment, intermittent use,
ologies for their insomnia, which may evolve over the or gradual tapering of the dose. For acute insomnia,
years. In addition, the chief sleep complaint may change nightly use of a benzodiazepine receptor agonist for a max-
over time, with initial insomnia predominating at one imum of 24 weeks is advisable. For chronic insomnia,
point, and multiple awakenings or nonrestorative sleep intermittent use is recommended, unless the consequences
of untreated insomnia outweigh concerns regarding latency, frequent awakenings from sleep, and early morn- 161
chronic use. Benzodiazepine receptor agonists should be ing awakening can all occur. Recovery is generally
avoided, or used very judiciously, in patients with a his- rapid, usually within a few weeks. Treatment is sympto-
tory of substance or alcohol abuse. The heterocyclic matic, with intermittent use of hypnotics and resolution
antidepressants (trazodone, amitriptyline, and doxepin) of the underlying stress. Altitude insomnia describes a
are the most commonly prescribed alternatives to ben- sleep disturbance that is a common consequence of
zodiazepine receptor agonists due to their lack of abuse exposure to high altitude. Periodic breathing of the
potential and lower cost.Trazodone (25100 mg) is used Cheyne-Stokes type occurs during NREM sleep about
more commonly than the tricyclic antidepressants as it half the time at high altitude, with restoration of a regu-

CHAPTER 16
has a much shorter half-life (59 h), has much less anti- lar breathing pattern during REM sleep. Both hypoxia
cholinergic activity (sparing patients, particularly the and hypocapnia are thought to be involved in the devel-
elderly, constipation, urinary retention, and tachycardia), opment of periodic breathing. Frequent awakenings and
is associated with less weight gain, and is much safer in poor quality sleep characterize altitude insomnia, which is
overdose.The risk of priapism is small (~1 in 10,000). generally worse on the rst few nights at high altitude but
may persist. Treatment with acetazolamide can decrease
time spent in periodic breathing and substantially reduce

Sleep Disorders
Psychophysiologic Insomnia
hypoxia during sleep.
Persistent psychophysiologic insomnia is a behavioral disorder
in which patients are preoccupied with a perceived inabil-
ity to sleep adequately at night.This sleep disorder begins COMORBID INSOMNIA
like any other acute insomnia; however, the poor sleep
Insomnia Associated with Mental Disorders
habits and sleep-related anxiety (insomnia phobia) per-
sist long after the initial incident. Such patients become Approximately 80% of patients with psychiatric disorders
hyperaroused by their own efforts to sleep or by the sleep describe sleep complaints. There is considerable hetero-
environment, and the insomnia becomes a conditioned or geneity, however, in the nature of the sleep disturbance
learned response. Patients may be able to fall asleep more both between conditions and among patients with the
easily at unscheduled times (when not trying) or outside same condition. Depression can be associated with sleep
the home environment. Polysomnographic recording in onset insomnia, sleep maintenance insomnia, or early
patients with psychophysiologic insomnia reveals an morning wakefulness. However, hypersomnia occurs in
objective sleep disturbance, often with an abnormally long some depressed patients, especially adolescents and those
sleep latency; frequent nocturnal awakenings; and an with either bipolar or seasonal (fall/winter) depression
increased amount of stage 1 transitional sleep. Rigorous (Chap. 49). Indeed, sleep disturbance is an important
attention should be paid to improving sleep hygiene, cor- vegetative sign of depression and may commence before
rection of counterproductive, arousing behaviors before any mood changes are perceived by the patient. Consis-
bedtime, and minimizing exaggerated beliefs regarding the tent polysomnographic ndings in depression include
negative consequences of insomnia. Behavioral therapies decreased REM sleep latency, lengthened rst REM
are the treatment modality of choice, with intermittent use sleep episode, and shortened rst NREM sleep episode;
of medications. When patients are awake for >20 min, however, these ndings are not specic for depression,
they should read or perform other relaxing activities to and the extent of these changes varies with age and
distract themselves from insomnia-related anxiety. In addi- symptomatology. Depressed patients also show decreased
tion, bedtime and wake time should be scheduled to slow-wave sleep and reduced sleep continuity.
restrict time in bed to be equal to their perceived total In mania and hypomania, sleep latency is increased and
sleep time. This will generally produce sleep deprivation, total sleep time can be reduced. Patients with anxiety disor-
greater sleep drive, and, eventually, better sleep. Time in ders tend not to show the changes in REM sleep and slow-
bed can then be gradually expanded. In addition, methods wave sleep seen in endogenously depressed patients. Chronic
directed toward producing relaxation in the sleep setting alcoholics lack slow-wave sleep, have decreased amounts of
(e.g., meditation, muscle relaxation) are encouraged. REM sleep (as an acute response to alcohol), and have fre-
quent arousals throughout the night.This is associated with
impaired daytime alertness.The sleep of chronic alcoholics
Adjustment Insomnia (Acute Insomnia) may remain disturbed for years after discontinuance of
This typically develops after a change in the sleeping alcohol usage. Sleep architecture and physiology are dis-
environment (e.g., in an unfamiliar hotel or hospital turbed in schizophrenia (with a decreased amount of stage 4
bed) or before or after a signicant life event, such as a sleep and a lack of augmentation of REM sleep following
change of occupation, loss of a loved one, illness, or anx- REM sleep deprivation); chronic schizophrenics often
iety over a deadline or examination. Increased sleep show day-night reversal, sleep fragmentation, and insomnia.
 162 Insomnia Associated with Neurologic Cardiac ischemia may also be associated with sleep dis-
Disorders ruption. The ischemia itself may result from increases in
A variety of neurologic diseases result in sleep disruption sympathetic tone as a result of sleep apnea. Patients may
through both indirect, nonspecic mechanisms (e.g., pain present with complaints of nightmares or vivid, disturbing
in cervical spondylosis or low back pain) or by impair- dreams, with or without awareness of the more classic
ment of central neural structures involved in the genera- symptoms of angina or of the sleep disordered breathing.
tion and control of sleep itself. For example, dementia Treatment of the sleep apnea may substantially improve
from any cause has long been associated with distur- the angina and the nocturnal sleep quality. Paroxysmal
bances in the timing of the sleep-wake cycle, often char- nocturnal dyspnea can also occur as a consequence of sleep-
associated cardiac ischemia that causes pulmonary conges-
SECTION II

acterized by nocturnal wandering and an exacerbation of

symptomatology at night (so-called sundowning). tion exacerbated by the recumbent posture.
Epilepsy may rarely present as a sleep complaint Chronic obstructive pulmonary disease is also associated
(Chap. 20). Often the history is of abnormal behavior, at with sleep disruption, as is cystic brosis, menopause, hyper-
times with convulsive movements during sleep. The dif- thyroidism, gastroesophageal reux, chronic renal failure, and
ferential diagnosis includes REM sleep behavior disor- liver failure.
Clinical Manifestations of Neurologic Disease

der, sleep apnea syndrome, and periodic movements of

sleep (see earlier). Diagnosis requires nocturnal polysomno- Medication-, Drug-, or Alcohol-Dependent
graphy with a full EEG montage. Other neurologic dis- Insomnia
eases associated with abnormal movements, such as Disturbed sleep can result from ingestion of a wide vari-
Parkinsons disease, hemiballismus, Huntingtons chorea, and ety of agents. Caffeine is perhaps the most common phar-
Tourette syndrome (Chaps. 24 and 25), are also associated macologic cause of insomnia. It produces increased
with disrupted sleep, presumably through secondary mech- latency to sleep onset, more frequent arousals during
anisms. However, the abnormal movements themselves are sleep, and a reduction in total sleep time for up to 814 h
greatly reduced during sleep. Headache syndromes (migraine after ingestion. Even small amounts of coffee can signi-
or cluster headache) may show sleep-associated exacerba- cantly disturb sleep in some patients; therefore, a 1- to
tions (Chap. 6) by unknown mechanisms. 2-month trial without caffeine should be attempted in
Fatal familial insomnia is a rare hereditary disorder caused patients with these symptoms. Similarly, alcohol and nico-
by degeneration of anterior and dorsomedial nuclei of the tine can interfere with sleep, despite the fact that many
thalamus. Insomnia is a prominent early symptom. Patients patients use them to relax and promote sleep. Although
develop progressive autonomic dysfunction, followed by alcohol can increase drowsiness and shorten sleep latency,
dysarthria, myoclonus, coma, and death. The pathogenesis even moderate amounts of alcohol increase awakenings in
is a mutation in the prion gene (Chap. 38). the second half of the night. In addition, alcohol ingestion
prior to sleep is contraindicated in patients with sleep
apnea because of the inhibitory effects of alcohol on
Insomnia Associated with Other upper airway muscle tone. Acutely, amphetamines and
Medical Disorders cocaine suppress both REM sleep and total sleep time,
A number of medical conditions are associated with dis- which return to normal with chronic use. Withdrawal
ruptions of sleep. The association is frequently nonspe- leads to a REM sleep rebound. A number of prescribed
cic, e.g., sleep disruption due to chronic pain from medications can produce insomnia. Antidepressants, sym-
rheumatologic disorders. Attention to this association is pathomimetics, and glucocorticoids are common causes.
important in that sleep-associated symptoms are often In addition, severe rebound insomnia can result from the
the presenting or most bothersome complaint.Treatment acute withdrawal of hypnotics, especially following the
of the underlying medical problem is the most useful use of high doses of benzodiazepines with a short half-
approach. Sleep disruption can also result from the use of life. For this reason, hypnotic doses should be low to
medications such as glucocorticoids (see later). moderate and prolonged drug tapering is encouraged.
One prominent association is between sleep disrup-
tion and asthma. In many asthmatics there is a prominent
RESTLESS LEGS SYNDROME (RLS)
daily variation in airway resistance that results in marked
increases in asthmatic symptoms at night, especially during Patients with this sensory-motor disorder report an irre-
sleep. In addition, treatment of asthma with theophylline- sistible urge to move the legs, or sometimes the upper
based compounds, adrenergic agonists, or glucocorticoids extremities that is often associated with a creepy-crawling
can independently disrupt sleep. When sleep disruption or aching dysesthesias deep within the affected limbs. For
is a side effect of asthma treatment, inhaled glucocorti- most patients with RLS, the dysesthesias and restlessness
coids (e.g., beclomethasone) that do not disrupt sleep are much worse in the evening or night compared to the
may provide a useful alternative. daytime and frequently interferes with the ability to fall
asleep.The symptoms appear with inactivity and are tem- 5.0-s extensions of the great toe and dorsiexion of the 163
porarily relieved by movement. In contrast, paresthesias foot, which recur every 2040 s during NREM sleep, in
secondary to peripheral neuropathy persist with activity. episodes lasting from minutes to hours, as documented
The severity of this chronic disorder may wax and wane by bilateral surface EMG recordings of the anterior tib-
over time and can be exacerbated by sleep deprivation, ialis on polysomnography. PLMS is the principal objec-
caffeine, alcohol, serotonergic antidepressants, and preg- tive polysomnographic nding in 17% of patients with
nancy. The prevalence is 15% of young to middle-aged insomnia and 11% of those with excessive daytime som-
adults and 1020% of those >60 years.There appear to be nolence (Fig. 16-3). It is often unclear whether it is an
important differences in RLS prevalence among racial incidental nding or the cause of disturbed sleep. When

CHAPTER 16
groups, with higher prevalence in those of Northern deemed to be the latter, PLMS is called PLMD. PLMS
European ancestry. Roughly one-third of patients (partic- occurs in a wide variety of sleep disorders (including
ularly those with an early age of onset) will have multiple narcolepsy, sleep apnea, REM sleep behavior disorder,
affected family members.At least three separate chromoso- and various forms of insomnia) and may be associated
mal loci have been identied in familial RLS, though no with frequent arousals and an increased number of
gene has been identied to date. Iron deciency and renal sleep-stage transitions. The pathophysiology is not well
failure may cause RLS, which is then considered sec- understood, though individuals with high spinal transec-

Sleep Disorders
ondary RLS.The symptoms of RLS are exquisitely sensi- tions can exhibit periodic leg movements during sleep,
tive to dopaminergic drugs (e.g., pramipexole 0.250.5 suggesting the existence of a spinal generator.Treatment
mg q8PM or ropinirole 0.54.0 mg q8PM), which are the options include dopaminergic medications or benzodi-
treatments of choice. Opiods, benzodiazepines, and azepines.
gabapentin may also be of therapeutic value. Most patients
with restless legs also experience periodic limb movements
EVALUATION OF DAYTIME SLEEPINESS
of sleep, although the reverse is not the case.
Daytime impairment due to sleep loss may be difcult
to quantify for several reasons. First, sleepiness is not
PERIODIC LIMB MOVEMENT DISORDER
necessarily proportional to subjectively assessed sleep
(PLMD)
deprivation. In obstructive sleep apnea, for example, the
Periodic limb movements of sleep (PLMS), previously known repeated brief interruptions of sleep associated with
as nocturnal myoclonus, consists of stereotyped, 0.5- to resumption of respiration at the end of apneic episodes

Snoring sounds

Nasal/oral airflow

Respiratory effort

98 97 97 98 97 97 98 98 98
Arterial O2 saturation 94 93 95 96 95 95 94 95 93
93
90 89 91 92 92
90 92 90 88 90
86

A 30 s

EEG

Chin EMG

Heart Rate

R.A.T. EMG

L.A.T. EMG

B 30 s

FIGURE 16-3
Polysomnographic recordings of (A) obstructive sleep with a relatively constant intermovement interval and are
apnea and (B) periodic limb movement of sleep. Note the associated with changes in the EEG and heart rate accelera-
snoring and reduction in air ow in the presence of continued tion (lower panel). R.A.T., right anterior tibialis; L.A.T., left
respiratory effort, associated with the subsequent oxygen anterior tibialis. (From the Division of Sleep Medicine,
desaturation (upper panel). Periodic limb movements occur Brigham and Womens Hospital.)
 164 result in daytime sleepiness, despite the fact that the driving be suspended until successful treatment or a
patient may be unaware of the sleep fragmentation. schedule modication can be instituted.
Second, subjective descriptions of waking impairment The distinction between fatigue and sleepiness can be
vary from patient to patient. Patients may describe them- useful in the differentiation of patients with complaints
selves as sleepy, fatigued, or tired and may have a of fatigue or tiredness in the setting of disorders such as
clear sense of the meaning of those terms, while others bromyalgia, chronic fatigue syndrome (Chap. 47), or
may use the same terms to describe a completely differ- endocrine deciencies such as hypothyroidism or Addi-
ent condition. Third, sleepiness, particularly when pro- sons disease. Although patients with these disorders can
found, may affect judgment in a manner analogous to typically distinguish their daytime symptoms from the
ethanol, such that subjective awareness of the condition sleepiness that occurs with sleep deprivation, substantial
SECTION II

and the consequent cognitive and motor impairment is overlap can occur.This is particularly true when the pri-
reduced. Finally, patients may be reluctant to admit that mary disorder also results in chronic sleep disruption
sleepiness is a problem, both because they are generally (e.g., sleep apnea in hypothyroidism) or in abnormal
unaware of what constitutes normal alertness and sleep (e.g., bromyalgia).
because sleepiness is generally viewed pejoratively, Although clinical evaluation of the complaint of
ascribed more often to a decit in motivation than to an excessive sleepiness is usually adequate, objective quan-
Clinical Manifestations of Neurologic Disease

inadequately addressed physiologic sleep need. tication is sometimes necessary. Assessment of daytime
Specic questioning about the occurrence of sleep functioning as an index of the adequacy of sleep can be
episodes during normal waking hours, both intentional made with the multiple sleep latency test (MSLT), which
and unintentional, is necessary to determine the extent involves repeated measurement of sleep latency (time to
of the adverse effects of sleepiness on a patients daytime onset of sleep) under standardized conditions during a
function. Specic areas to be addressed include the day following quantied nocturnal sleep. The average
occurrence of inadvertent sleep episodes while driving latency across four to six tests (administered every 2 h
or in other safety-related settings, sleepiness while at across the waking day) provides an objective measure of
work or school (and the relationship of sleepiness to daytime sleep tendency. Disorders of sleep that result in
work and school performance), and the effect of sleepi- pathologic daytime somnolence can be reliably distin-
ness on social and family life. Driving is particularly haz- guished with the MSLT. In addition, the multiple mea-
ardous for patients with increased sleepiness. Reaction surements of sleep onset may identify direct transitions
time is equally impaired by 24 h of sleep loss as by a from wakefulness to REM sleep that are suggestive of
blood alcohol level of 0.10 g/dL. More than half of specic pathologic conditions (e.g., narcolepsy).
Americans admit to driving when drowsy. An estimated
250,000 motor vehicle crashes per year are due to
NARCOLEPSY
drowsy drivers, thus causing 20% of all serious crash
injuries. Drowsy driving legislation, aimed at improving Narcolepsy is both a disorder of the ability to sustain
education of all drivers about the hazards of driving wakefulness voluntarily and a disorder of REM sleep
drowsy and establishing sanctions comparable to those regulation (Table 16-2). The classic narcolepsy tetrad
for drunk driving, is pending in several states. Screening consists of excessive daytime somnolence plus three spe-
for sleep disorders, provision of an adequate number of cic symptoms related to an intrusion of REM sleep
safe highway rest areas, maintenance of unobstructed characteristics (e.g., muscle atonia, vivid dream imagery)
shoulder rumble strips, and strict enforcement and com- into the transition between wakefulness and sleep:
pliance monitoring of hours-of-service policies are
needed to reduce the risk of sleep-related transportation
crashes. Evidence for signicant daytime impairment [in
association either with the diagnosis of a primary sleep TABLE 16-2
disorder, such as narcolepsy or sleep apnea, or with PREVALENCE OF SYMPTOMS IN NARCOLEPSY
imposed or self-selected sleep-wake schedules (see Shift-
SYMPTOM PREVALENCE, %
Work Disorder, later)] raises the issue of the physicians
responsibility to notify motor vehicle licensing authori- Excessive daytime somnolence 100
ties of the increased risk of sleepiness-related vehicle Disturbed sleep 87
Cataplexy 76
accidents. As with epilepsy, legal requirements vary from
Hypnagogic hallucinations 68
state to state, and existing legal precedents do not pro- Sleep paralysis 64
vide a consistent interpretation of the balance between Memory problems 50
the physicians responsibility and the patients right to
privacy. At a minimum, physicians should document dis- Source: Modied from TA Roth, L Merlotti in SA Burton et al (eds),
cussions with the patient regarding the increased risk of Narcolepsy 3rd International Symposium: Selected Symposium Pro-
operating a vehicle, as well as a recommendation that ceedings, Chicago, Matrix Communications, 1989.
(1) sudden weakness or loss of muscle tone without loss reliably. Hypnogogic and hypnopompic hallucinations 165
of consciousness, often elicited by emotion (cataplexy); and sleep paralysis are often found in nonnarcoleptic
(2) hallucinations at sleep onset (hypnogogic hallucina- individuals and may be present in only one-half of nar-
tions) or upon awakening (hypnopompic hallucinations); coleptics. Nocturnal sleep disruption is commonly
and (3) muscle paralysis upon awakening (sleep paralysis). observed in narcolepsy but is also a nonspecic symp-
The severity of cataplexy varies, as patients may have two tom. Similarly, a history of automatic behavior during
to three attacks per day or per decade. Some patients wakefulness (a trancelike state during which simple
with objectively conrmed narcolepsy (see later) may motor behaviors persist) is not specic for narcolepsy
show no evidence of cataplexy. In those with cataplexy, and serves principally to corroborate the presence of

CHAPTER 16
the extent and duration of an attack may also vary, from daytime somnolence.
a transient sagging of the jaw lasting a few seconds to
rare cases of accid paralysis of the entire voluntary
musculature for up to 2030 min. Symptoms of nar-
colepsy typically begin in the second decade, although Treatment:
the onset ranges from ages 550. Once established, the NARCOLEPSY
disease is chronic without remissions. Secondary forms The treatment of narcolepsy is symptomatic. Somno-

Sleep Disorders
of narcolepsy have been described (e.g., after head lence is treated with wake-promoting therapeutics.
trauma). Modanil is now the drug of choice, principally because
Narcolepsy affects about 1 in 4000 people in the it is associated with fewer side effects than older stimu-
United States and appears to have a genetic basis. lants and has a long half-life; 200400 mg is given as a
Recently, several convergent lines of evidence suggest single daily dose. Older drugs such as methylphenidate
that the hypothalamic neuropeptide hypocretin (orexin) (10 mg bid to 20 mg qid) or dextroamphetamine (10 mg
is involved in the pathogenesis of narcolepsy: (1) a muta- bid) are still used as alternatives, particularly in refrac-
tion in the hypocretin receptor 2 gene has been associ- tory patients. These latter medications are now available
ated with canine narcolepsy; (2) hypocretin knockout in slow-release formulations, extending their duration of
mice that are genetically unable to produce this neu- action and allowing once daily dosing.
ropeptide exhibit behavioral and electrophysiologic fea- Treatment of the REM-related phenomena cataplexy,
tures resembling human narcolepsy; and (3) cerebrospinal hypnogogic hallucinations, and sleep paralysis requires
uid levels of hypocretin are reduced in most patients the potent REM sleep suppression produced by antide-
who have narcolepsy with cataplexy. The inheritance pressant medications. The tricyclic antidepressants
pattern of narcolepsy in humans is more complex than in [e.g., protriptyline (1040 mg/d) and clomipramine
the canine model. However, almost all narcoleptics with (2550 mg/d)] and the selective serotonin reuptake
cataplexy are positive for HLA DQB10602, suggesting inhibitors (SSRIs) [e.g., uoxetine (1020 mg/d)] are
that an autoimmune process may be responsible. commonly used for this purpose. Efcacy of the antide-
pressants is limited largely by anticholinergic side effects
Diagnosis (tricyclics) and by sleep disturbance and sexual dysfunc-
tion (SSRIs). Alternately, gamma hydroxybutyrate (GHB),
The diagnostic criteria continue to be a matter of given at bed time, and 4 h later, is effective in reducing
debate. Certainly, objective verication of excessive day- daytime cataplectic episodes. Adequate nocturnal sleep
time somnolence, typically with MSLT mean sleep time and planned daytime naps (when possible) are
latencies <8 min, is an essential if nonspecic diagnostic important preventative measures.
feature. Other conditions that cause excessive sleepiness,
such as sleep apnea or chronic sleep deprivation, must
be rigorously excluded. The other objective diagnostic
feature of narcolepsy is the presence of REM sleep in at
SLEEP APNEA SYNDROMES
least two of the naps during the MSLT. Abnormal regu-
lation of REM sleep is also manifested by the appear- Respiratory dysfunction during sleep is a common, seri-
ance of REM sleep immediately or within minutes after ous cause of excessive daytime somnolence as well as of
sleep onset in 50% of narcoleptic patients, a rarity in disturbed nocturnal sleep. An estimated 25 million
unaffected individuals maintaining a conventional sleep- individuals in the United States have a reduction or ces-
wake schedule.The REM-related symptoms of the classic sation of breathing for 10150 s, from thirty to several
narcolepsy tetrad are variably present. There is increasing hundred times every night during sleep. These episodes
evidence that narcoleptics with cataplexy (one-half to may be due to either an occlusion of the airway (obstructive
two-thirds of patients) may represent a more homoge- sleep apnea), absence of respiratory effort (central sleep
neous group than those without this symptom. How- apnea), or a combination of these factors (mixed sleep apnea)
ever, a history of cataplexy can be difcult to establish (Fig. 16-3). Failure to recognize and treat these conditions
 166 appropriately may lead to impairment of daytime alert- patient is usually unaware of the problem. The typical
ness, increased risk of sleep-related motor vehicle acci- age of onset is 1720 years, and spontaneous remission
dents, hypertension and other serious cardiovascular usually occurs by 40 years. Sex distribution appears to
complications, and increased mortality. Sleep apnea is be equal. In many cases, the diagnosis is made during
particularly prevalent in overweight men and in the dental examination, damage is minor, and no treatment
elderly, yet it is estimated to remain undiagnosed in is indicated. In more severe cases, treatment with a rub-
8090% of affected individuals.This is unfortunate since ber tooth guard is necessary to prevent disguring tooth
effective treatments are available. injury. Stress management or, in some cases, biofeedback
can be useful when bruxism is a manifestation of psy-
chological stress. There are anecdotal reports of benet
SECTION II

PARASOMNIAS
using benzodiazepines.
The term parasomnia refers to abnormal behaviors or
experiences that arise from or occur during sleep. A
Sleep Enuresis
continuum of parasomnias arises from NREM sleep,
from brief confusional arousals to sleepwalking and Bedwetting, like sleepwalking and night terrors, is
night terrors.The presenting complaint is usually related another parasomnia that occurs during sleep in the
Clinical Manifestations of Neurologic Disease

to the behavior itself, but the parasomnias can disturb young. Before age 5 or 6, nocturnal enuresis should
sleep continuity or lead to mild impairments in daytime probably be considered a normal feature of develop-
alertness. Two main parasomnias occur in REM sleep: ment. The condition usually improves spontaneously by
REM sleep behavior disorder (RBD), which will be puberty, has a prevalence in late adolescence of 13%,
described later, and nightmare disorder. and is rare in adulthood. In older patients with enuresis a
distinction must be made between primary and sec-
Sleepwalking (Somnambulism) ondary enuresis, the latter being dened as bedwetting
in patients who have previously been fully continent for
Patients affected by this disorder carry out automatic 612 months. Treatment of primary enuresis is reserved
motor activities that range from simple to complex. for patients of appropriate age (>5 or 6 years) and con-
Individuals may walk, urinate inappropriately, eat, or exit sists of bladder training exercises and behavioral therapy.
from the house while remaining only partially aware. Urologic abnormalities are more common in primary
Full arousal may be difcult, and individuals may rarely enuresis and must be assessed by urologic examination.
respond to attempted awakening with agitation or even Important causes of secondary enuresis include emo-
violence. Sleepwalking arises from stage 3 or 4 NREM tional disturbances, urinary tract infections or malforma-
sleep, usually in the rst 2 hours of the night, and is tions, cauda equina lesions, epilepsy, sleep apnea, and
most common in children and adolescents, when these certain medications. Symptomatic pharmacotherapy is
sleep stages are most robust. Episodes are usually isolated usually accomplished with desmopressin (0.2 mg qhs),
but may be recurrent in 16% of patients. The cause is oxybutynin chloride (510 mg qhs) or imipramine
unknown, though it has a familial basis in roughly one- (1050 mg qhs).
third of cases.

Sleep Terrors Miscellaneous Parasomnias

This disorder, also called pavor nocturnus, occurs primarily Other clinical entities may be characterized as a para-
in young children during the rst several hours after sleep somnia or a sleep-related movement disorder in that
onset, in stages 3 and 4 of NREM sleep. The child sud- they occur selectively during sleep and are associated
denly screams, exhibiting autonomic arousal with sweat- with some degree of sleep disruption. Examples include
ing, tachycardia, and hyperventilation. The individual may jactatio capitis nocturna (nocturnal headbanging, rhythmic
be difcult to arouse and rarely recalls the episode on movement disorder), confusional arousals, sleep-related
awakening in the morning. Parents are usually reassured to eating disorder, and nocturnal leg cramps.
learn that the condition is self-limited and benign and that
no specic therapy is indicated. Both sleep terrors and REM Sleep Behavior Disorder (RBD)
sleepwalking represent abnormalities of arousal. In con-
trast, nightmares occur during REM sleep and cause full RBD is a rare condition that is distinct from other para-
arousal, with intact memory for the unpleasant episode. somnias in that it occurs during REM sleep. It primarily
aficts men of middle age or older, many of whom have
an existing, or developing, neurologic disease. Approxi-
Sleep Bruxism
mately one-half of patients with RBD will develop
Bruxism is an involuntary, forceful grinding of teeth Parkinsons disease (Chap. 24) within 1020 years. Pre-
during sleep that affects 1020% of the population. The senting symptoms consist of agitated or violent behavior
during sleep, as reported by a bed partner. In contrast to rhythms. A large-scale clinical trial evaluating the safety 167
typical somnambulism, injury to the patient or bed part- and efcacy of melatonin as a treatment for jet lag disor-
ner is not uncommon, and, upon awakening, the patient der and other circadian sleep disorders is needed.
reports vivid, often unpleasant, dream imagery. The
principal differential diagnosis is nocturnal seizures, Shift-Work Disorder
which can be excluded with polysomnography. In RBD,
seizure activity is absent on the EEG, and disinhibition More than 7 million workers in the United States regu-
of the usual motor atonia is observed in the EMG dur- larly work at night, either on a permanent or rotating
ing REM sleep, at times associated with complex motor schedule. In addition, each week millions more elect to

CHAPTER 16
behaviors. The pathogenesis is unclear, but damage to remain awake at night to meet deadlines, drive long dis-
brainstem areas mediating descending motor inhibition tances, or participate in recreational activities. This
during REM sleep may be responsible. In support of this results in both sleep loss and misalignment of the circa-
hypothesis are the remarkable similarities between RBD dian rhythm with respect to the sleep-wake cycle.
and the sleep of animals with bilateral lesions of the pon- Studies of regular night-shift workers indicate that
tine tegmentum in areas controlling REM sleep motor the circadian timing system usually fails to adapt success-
inhibition.Treatment with clonazepam (0.51.0 mg qhs) fully to such inverted schedules.This leads to a misalign-

Sleep Disorders
provides sustained improvement in almost all reported ment between the desired work-rest schedule and the
cases. output of the pacemaker and in disturbed daytime sleep
in most individuals. Sleep deprivation, increased length
of time awake prior to work, and misalignment of circa-
dian phase produce decreased alertness and perfor-
CIRCADIAN RHYTHM SLEEP
mance, increased reaction time, and increased risk of
DISORDERS
performance lapses, thereby resulting in greater safety
A subset of patients presenting with either insomnia or hazards among night workers and other sleep-deprived
hypersomnia may have a disorder of sleep timing rather individuals. Sleep disturbance nearly doubles the risk of
than sleep generation. Disorders of sleep timing can be a fatal work accident. Additional problems include
either organic (i.e., due to an intrinsic defect in the cir- higher rates of cancer and of cardiac, gastrointestinal, and
cadian pacemaker or its input from entraining stimuli) reproductive disorders in chronic night-shift workers.
or environmental (i.e., due to a disruption of exposure to Sleep onset is associated with marked attenuation in
entraining stimuli from the environment). Regardless of perception of both auditory and visual stimuli and lapses
etiology, the symptoms reect the inuence of the of consciousness.The sleepy individual may thus attempt to
underlying circadian pacemaker on sleep-wake function. perform routine and familiar motor tasks during the transi-
Thus, effective therapeutic approaches should aim to tion state between wakefulness and sleep (stage 1 sleep)
entrain the oscillator at an appropriate phase. in the absence of adequate processing of sensory input
from the environment. Motor vehicle operators are espe-
cially vulnerable to sleep-related accidents since the sleep-
Jet Lag Disorder deprived driver or operator often fails to heed the warning
More than 60 million persons experience transmeridian signs of fatigue. Such attempts to override the powerful
air travel annually, which is often associated with exces- biologic drive for sleep by the sheer force of will can yield
sive daytime sleepiness, sleep onset insomnia, and fre- a catastrophic outcome when sleep processes intrude
quent arousals from sleep, particularly in the latter half of involuntarily upon the waking brain. Such sleep-related
the night. Gastrointestinal discomfort is common. The attentional failures typically last only seconds but are
syndrome is transient, typically lasting 214 d depending known on occasion to persist for longer durations. These
on the number of time zones crossed, the direction of frequent brief intrusions of stage 1 sleep into behavioral
travel, and the travelers age and phase-shifting capacity. wakefulness are a major component of the impaired psy-
Travelers who spend more time outdoors reportedly chomotor performance seen with sleepiness. There is a
adapt more quickly than those who remain in hotel signicant increase in the risk of sleep-related, fatal-to-
rooms, presumably due to bright (outdoor) light expo- the-driver highway crashes in the early morning and late
sure. Avoidance of antecedent sleep loss and obtaining afternoon hours, coincident with bimodal peaks in the
nap sleep on the afternoon prior to overnight travel daily rhythm of sleep tendency.
greatly reduces the difculty of extended wakefulness. Medical housestaff constitute another group of work-
Laboratory studies suggest that sub-milligram doses of ers at risk for accidents and other adverse consequences
the pineal hormone melatonin can enhance sleep ef- of lack of sleep and misalignment of the circadian
ciency, but only if taken when endogenous melatonin rhythm. Recent research has demonstrated that the
concentrations are low (i.e., during biologic daytime), practice of scheduling interns and residents to work
and that melatonin may induce phase shifts in human shifts of 30 consecutive hours both doubles the risk of
 168 attentional failures among intensive care unit interns night work, (2) the frequency of shift rotation so that
working at night and signicantly increases the risk of shifts do not rotate more than once every 23 weeks, (3)
serious medical errors in intensive care units. Moreover, the number of consecutive night shifts, and (4) the
working for >24 h consecutively increases the risk of duration of night shifts. Shift durations of >16 h should
needlestick injuries and more than doubles the risk of be universally recognized as increasing the risk of sleep-
motor vehicle crashes on the commute home. Some related errors and performance lapses to a level that is
20% of hospital interns report making a fatigue-related unacceptable in nonemergency circumstances.
mistake that injured a patient, and 5% admit making a
mistake that results in the death of a patient.
From 510% of individuals scheduled to work at
SECTION II

night or in the early morning hours have much greater

Delayed Sleep Phase Disorder
than average difculties remaining awake during night
work and sleeping during the day; these individuals are Delayed sleep phase disorder is characterized by: (1)
diagnosed with chronic and severe shift-work disorder reported sleep onset and wake times intractably later
(SWD). Patients with this disorder have a level of exces- than desired, (2) actual sleep times at nearly the same
sive sleepiness during night work and insomnia during clock hours daily, and (3) essentially normal all-night
Clinical Manifestations of Neurologic Disease

day sleep that the physician judges to be clinically signif- polysomnography except for delayed sleep onset.
icant; the condition is associated with an increased risk Patients exhibit an abnormally delayed endogenous cir-
of sleep-related accidents and with some of the illnesses cadian phase, with the temperature minimum during
associated with night-shift work. Patients with chronic the constant routine occurring later than normal. This
and severe SWD are profoundly sleepy at night. In fact, delayed phase could be due to: (1) an abnormally long,
their sleep latencies during night work average just 2 min, genetically determined intrinsic period of the endoge-
comparable to mean sleep latency durations of patients nous circadian pacemaker; (2) an abnormally reduced
with narcolepsy or severe daytime sleep apnea. phase-advancing capacity of the pacemaker; or (3) an
irregular prior sleep-wake schedule, characterized by
frequent nights when the patient chooses to remain
awake well past midnight (for social, school, or work
Treatment: reasons). In most cases, it is difcult to distinguish
SHIFT-WORK DISORDER among these factors, since patients with an abnormally
Caffeine is frequently used to promote wakefulness.
long intrinsic period are more likely to choose such
However, it cannot forestall sleep indenitely, and it
late-night activities because they are unable to sleep at
does not shield users from sleep-related performance
that time. Patients tend to be young adults. This self-
lapses. Postural changes, exercise, and strategic place-
perpetuating condition can persist for years and does
ment of nap opportunities can sometimes temporarily
not usually respond to attempts to reestablish normal
reduce the risk of fatigue-related performance lapses.
bedtime hours. Treatment methods involving bright-
Properly timed exposure to bright light can facilitate
light phototherapy during the morning hours or mela-
rapid adaptation to night-shift work.
tonin administration in the evening hours show promise
While many techniques (e.g., light treatment) used to
in these patients, although the relapse rate is high.
facilitate adaptation to night shift work may help
patients with this disorder, modanil is the only thera- Advanced Sleep Phase Disorder
peutic intervention that has ever been evaluated as a
Advanced sleep phase disorder (ASPD) is the converse
treatment for this specic patient population. Modanil
of the delayed sleep phase syndrome. Most commonly,
(200 mg, taken 3060 min before the start of each night
this syndrome occurs in older people, 15% of whom
shift) is approved by the U.S. Food and Drug Administra-
report that they cannot sleep past 5 A.M., with twice that
tion as a treatment for the excessive sleepiness during
number complaining that they wake up too early at least
night work in patients with SWD. Although treatment
several times per week. Patients with ASPD experience
with modanil signicantly increases sleep latency and
excessive daytime sleepiness during the evening hours,
reduces the risk of lapses of attention during night
when they have great difculty remaining awake, even
work, SWD patients remain excessively sleepy at night,
in social settings.Typically, patients awaken from 35 A.M.
even while being treated with modanil.
each day, often several hours before their desired wake
Safety programs should promote education about
times. In addition to age-related ASPD, an early-onset
sleep and increase awareness of the hazards associated
familial variant of this condition has also been reported.
with night work. The goal should be to minimize both
In one such family, autosomal dominant ASPD was due
sleep deprivation and circadian disruption. Work sched-
to a missense mutation in a circadian clock component
ules should be designed to minimize: (1) exposure to
(PER2, as shown in Fig. 16-2) that altered the circadian
period. Patients with ASPD may benet from bright- understanding of the possible role of circadian rhythmic- 169
light phototherapy during the evening hours, designed ity in the acute destabilization of a chronic condition
to reset the circadian pacemaker to a later hour. such as atherosclerotic disease could improve the under-
standing of the pathophysiology.
Non-24-Hour Sleep-Wake Disorder Diagnostic and therapeutic procedures may also be
affected by the time of day at which data are collected.
This condition can occur when the maximal phase- Examples include blood pressure, body temperature, the
advancing capacity of the circadian pacemaker is not ade- dexamethasone suppression test, and plasma cortisol levels.
quate to accommodate the difference between the 24-h The timing of chemotherapy administration has been

CHAPTER 16
geophysical day and the intrinsic period of the pacemaker reported to have an effect on the outcome of treatment.
in the patient.Alternatively, patients self-selected exposure Few physicians realize the extent to which routine mea-
to articial light may drive the circadian pacemaker to a sures are affected by the time (or sleep/wake state) when
>24-h schedule.Affected patients are not able to maintain the measurement is made.
a stable phase relationship between the output of the In addition, both the toxicity and effectiveness of
pacemaker and the 24-h day. Such patients typically pre- drugs can vary during the day. For example, more than a
sent with an incremental pattern of successive delays in vefold difference has been observed in mortality rates

Sleep Disorders
sleep onsets and wake times, progressing in and out of following administration of toxic agents to experimental
phase with local time. When the patients endogenous animals at different times of day. Anesthetic agents are
rhythms are out of phase with the local environment, particularly sensitive to time-of-day effects. Finally, the
insomnia coexists with excessive daytime sleepiness. Con- physician must be increasingly aware of the public
versely, when the endogenous rhythms are in phase with health risks associated with the ever-increasing demands
the local environment, symptoms remit. The intervals made by the duty-rest-recreation schedules in our
between symptomatic periods may last several weeks to round-the-clock society.
several months. Blind individuals unable to perceive light
are particularly susceptible to this disorder. Nightly low-
dose (0.5 mg) melatonin administration has been reported FURTHER READINGS
to improve sleep and, in some cases, to induce synchro- BLOOM HG et al: Evidence-based recommendations for the assess-
nization of the circadian pacemaker. ment and management of sleep disorders in older persons. J Am
Geriatr Soc 57:761, 2009
BRADLEY TD, FLORAS JS: Obstructive sleep apnoea and its cardiovas-
MEDICAL IMPLICATIONS OF CIRCADIAN cular consequences. Lancet 373:82, 2009
RHYTHMICITY FLEMONS WW: Clinical practice. Obstructive sleep apnea. N Engl J
Prominent circadian variations have been reported in Med 347:498, 2002
SCAMMELL TE: The neurobiology, diagnosis, and treatment of nar-
the incidence of acute myocardial infarction, sudden
colepsy.Ann Neurol 53:154, 2003
cardiac death, and stroke, the leading causes of death in SILBER MH: Clinical practice. Chronic insomnia. N Engl J Med
the United States. Platelet aggregability is increased after 353:803, 2005
arising in the early morning hours, coincident with the WISE MS et al: Treatment of narcolepsy and other hypersomnias of
peak incidence of these cardiovascular events. A better central origin. Sleep 30: 1712, 2009
 CHAPTER 17

DISORDERS OF VISION

Jonathan C. Horton

I The Human Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . 170 I Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

I Clinical Assessment of Visual Function . . . . . . . . . . . . . . . . . 171 Red or Painful Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
Refractive State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Transient or Sudden Visual Loss . . . . . . . . . . . . . . . . . . . . . . 178
Visual Acuity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 Chronic Visual Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Pupils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 Proptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Eye Movements and Alignment . . . . . . . . . . . . . . . . . . . . . . . 173 Ptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Stereopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Double Vision (Diplopia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Color Vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Visual Fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

impinging upon the retina into a continuously varying bar-

THE HUMAN VISUAL SYSTEM
rage of action potentials that propagates along the primary
The visual system provides a supremely efcient means optic pathway to visual centers within the brain.There are
for the rapid assimilation of information from the envi- a million ganglion cells in each retina, and hence a million
ronment to aid in the guidance of behavior. The act of bers in each optic nerve.
seeing begins with the capture of images focused by the Ganglion cell axons sweep along the inner surface of
cornea and lens upon a light-sensitive membrane in the the retina in the nerve ber layer, exit the eye at the optic
back of the eye, called the retina. The retina is actually disc, and travel through the optic nerve, optic chiasm, and
part of the brain, banished to the periphery to serve as a optic tract to reach targets in the brain. The majority of
transducer for the conversion of patterns of light energy bers synapse upon cells in the lateral geniculate body, a
into neuronal signals. Light is absorbed by photopigment thalamic relay station. Cells in the lateral geniculate body
in two types of receptors: rods and cones. In the human project in turn to the primary visual cortex.This massive
retina there are 100 million rods and 5 million cones. afferent retinogeniculocortical sensory pathway provides
The rods operate in dim (scotopic) illumination. The the neural substrate for visual perception. Although the
cones function under daylight (photopic) conditions. lateral geniculate body is the main target of the retina,
The cone system is specialized for color perception and separate classes of ganglion cells project to other subcorti-
high spatial resolution.The majority of cones are located cal visual nuclei involved in different functions. Ganglion
within the macula, the portion of the retina serving the cells that mediate pupillary constriction and circadian
central 10 of vision. In the middle of the macula a small rhythms are light sensitive, owing to a novel visual pig-
pit termed the fovea, packed exclusively with cones, pro- ment, melanopsin. Pupil responses are mediated by input
vides best visual acuity. to the pretectal olivary nuclei in the midbrain. The pre-
Photoreceptors hyperpolarize in response to light, acti- tectal nuclei send their output to the Edinger-Westphal
vating bipolar, amacrine, and horizontal cells in the inner nuclei, which in turn provide parasympathetic innerva-
nuclear layer. After processing of photoreceptor responses tion to the iris sphincter via an interneuron in the ciliary
by this complex retinal circuit, the ow of sensory infor- ganglion. Circadian rhythms are timed by a retinal projec-
mation ultimately converges upon a nal common path- tion to the suprachiasmatic nucleus.Visual orientation and
way: the ganglion cells.These cells translate the visual image eye movements are served by retinal input to the superior
170
colliculus. Gaze stabilization and optokinetic reexes are VISUAL ACUITY 171
governed by a group of small retinal targets known col-
The Snellen chart is used to test acuity at a distance of
lectively as the brainstem accessory optic system.
6 m (20 ft). For convenience, a scale version of the Snellen
The eyes must be rotated constantly within their
chart, called the Rosenbaum card, is held at 36 cm (14 in)
orbits to place and maintain targets of visual interest
from the patient (Fig. 17-1). All subjects should be able
upon the fovea. This activity, called foveation, or looking,
to read the 6/6 m (20/20 ft) line with each eye using
is governed by an elaborate efferent motor system. Each
their refractive correction, if any. Patients who need read-
eye is moved by six extraocular muscles, supplied by cra-
ing glasses because of presbyopia must wear them for
nial nerves from the oculomotor (III), trochlear (IV),
accurate testing with the Rosenbaum card. If 6/6 (20/20)

CHAPTER 17
and abducens (VI) nuclei. Activity in these ocular motor
nuclei is coordinated by pontine and midbrain mecha-
nisms for smooth pursuit, saccades, and gaze stabilization
during head and body movements. Large regions of the
frontal and parietooccipital cortex control these brain-
stem eye movement centers by providing descending
supranuclear input.

Disorders of Vision
CLINICAL ASSESSMENT OF VISUAL
FUNCTION
REFRACTIVE STATE
In approaching the patient with reduced vision, the rst
step is to decide whether refractive error is responsible. In
emmetropia, parallel rays from innity are focused perfectly
upon the retina. Sadly, this condition is enjoyed by only a
minority of the population. In myopia, the globe is too
long, and light rays come to a focal point in front of the
retina. Near objects can be seen clearly, but distant objects
require a diverging lens in front of the eye. In hyperopia,
the globe is too short, and hence a converging lens is used
to supplement the refractive power of the eye. In astigma-
tism, the corneal surface is not perfectly spherical, necessi-
tating a cylindrical corrective lens. In recent years it has
become possible to correct refractive error with the
excimer laser by performing LASIK (laser in situ ker-
atomileusis) to alter the curvature of the cornea.
With the onset of middle age, presbyopia develops as
the lens within the eye becomes unable to increase its
refractive power to accommodate upon near objects. To
compensate for presbyopia, the emmetropic patient must
use reading glasses. The patient already wearing glasses
for distance correction usually switches to bifocals. The
only exception is the myopic patient, who may achieve
clear vision at near simply by removing glasses containing
the distance prescription.
Refractive errors usually develop slowly and remain
stable after adolescence, except in unusual circum-
stances. For example, the acute onset of diabetes mellitus FIGURE 17-1
can produce sudden myopia because of lens edema The Rosenbaum card is a miniature, scale version of the
induced by hyperglycemia.Testing vision through a pin- Snellen chart for testing visual acuity at near. When the
hole aperture is a useful way to screen quickly for visual acuity is recorded, the Snellen distance equivalent
refractive error. If the visual acuity is better through a should bear a notation indicating that vision was tested at
pinhole than with the unaided eye, the patient needs a near, not at 6 m (20 ft), or else the Jaeger number system
refraction to obtain best corrected visual acuity. should be used to report the acuity.
 172 acuity is not present in each eye, the deciency in vision
must be explained. If worse than 6/240 (20/800), acuity
should be recorded in terms of counting ngers, hand
motions, light perception, or no light perception. Legal
blindness is dened by the Internal Revenue Service as a
best corrected acuity of 6/60 (20/200) or less in the bet-
ter eye, or a binocular visual eld subtending 20 or less.
For driving the laws vary by state, but most require a
corrected acuity of 6/12 (20/40) in at least one eye for
A
unrestricted privileges. Patients with a homonymous
SECTION II

hemianopia should not drive.

PUPILS
The pupils should be tested individually in dim light
with the patient xating on a distant target. If they
Clinical Manifestations of Neurologic Disease

respond briskly to light, there is no need to check the

near response, because isolated loss of constriction (mio-
sis) to accommodation does not occur. For this reason,
the ubiquitous abbreviation PERRLA (pupils equal, B
round, and reactive to light and accommodation) implies
a wasted effort with the last step. However, it is impor-
tant to test the near response if the light response is poor or
absent. Light-near dissociation occurs with neurosyphilis
(Argyll Robertson pupil), lesions of the dorsal midbrain
(obstructive hydrocephalus, pineal region tumors), and
after aberrant regeneration (oculomotor nerve palsy,Adies
tonic pupil).
An eye with no light perception has no pupillary C
response to direct light stimulation. If the retina or optic
nerve is only partially injured, the direct pupillary response FIGURE 17-2
Demonstration of a relative afferent pupil defect (Marcus
will be weaker than the consensual pupillary response
Gunn pupil) in the left eye, done with the patient xating
evoked by shining a light into the other eye.This relative
upon a distant target. A. With dim background lighting, the
afferent pupillary defect (Marcus Gunn pupil) can be
pupils are equal and relatively large. B. Shining a ashlight
elicited with the swinging ashlight test (Fig. 17-2). It
into the right eye evokes equal, strong constriction of both
is an extremely useful sign in retrobulbar optic neuritis pupils. C. Swinging the ashlight over to the damaged left
and other optic nerve diseases, where it may be the sole eye causes dilation of both pupils, although they remain
objective evidence for disease. smaller than in A. Swinging the ashlight back over to the
Subtle inequality in pupil size, up to 0.5 mm, is a healthy right eye would result in symmetric constriction back
fairly common nding in normal persons.The diagnosis to the appearance shown in B. Note that the pupils always
of essential or physiologic anisocoria is secure as long as remain equal; the damage to the left retina/optic nerve is
the relative pupil asymmetry remains constant as ambi- revealed by weaker bilateral pupil constriction to a ashlight
ent lighting varies. Anisocoria that increases in dim light in the left eye compared with the right eye. (From P Levatin,
indicates a sympathetic paresis of the iris dilator muscle. Arch Ophthalmol 62:768, 1959.)
The triad of miosis with ipsilateral ptosis and anhidrosis
constitutes Horners syndrome, although anhidrosis is an
inconstant feature. Brainstem stroke, carotid dissection,
or neoplasm impinging upon the sympathetic chain are are infection (herpes zoster, inuenza), trauma (blunt, pen-
occasionally identied as the cause of Horners syn- etrating, surgical), or ischemia (diabetes, temporal arteritis).
drome, but most cases are idiopathic. After denervation of the iris sphincter the pupil does not
Anisocoria that increases in bright light suggests a respond well to light, but the response to near is often
parasympathetic palsy. The rst concern is an oculomotor relatively intact. When the near stimulus is removed, the
nerve paresis.This possibility is excluded if the eye move- pupil redilates very slowly compared with the normal pupil,
ments are full and the patient has no ptosis or diplopia. hence the term tonic pupil. In Adies syndrome, a tonic pupil
Acute pupillary dilation (mydriasis) can occur from damage occurs in conjunction with weak or absent tendon reexes
to the ciliary ganglion in the orbit. Common mechanisms in the lower extremities.This benign disorder, which occurs
predominantly in healthy young women, is assumed to STEREOPSIS 173
represent a mild dysautonomia. Tonic pupils are also asso-
Stereoacuity is determined by presenting targets with reti-
ciated with Shy-Drager syndrome, segmental hypohidrosis,
nal disparity separately to each eye using polarized images.
diabetes, and amyloidosis. Occasionally, a tonic pupil is dis-
The most popular ofce tests measure a range of thresh-
covered incidentally in an otherwise completely normal,
olds from 80040 seconds of arc. Normal stereoacuity is
asymptomatic individual. The diagnosis is conrmed by
40 seconds of arc. If a patient achieves this level of
placing a drop of dilute (0.125%) pilocarpine into each
stereoacuity, one is assured that the eyes are aligned
eye. Denervation hypersensitivity produces pupillary con-
orthotropically and that vision is intact in each eye. Ran-
striction in a tonic pupil, whereas the normal pupil shows
dom dot stereograms have no monocular depth cues and

CHAPTER 17
no response. Pharmacologic dilation from accidental or
provide an excellent screening test for strabismus and
deliberate instillation of anticholinergic agents (atropine,
amblyopia in children.
scopolamine drops) into the eye can also produce pupillary
mydriasis. In this situation, normal strength (1%) pilo-
carpine causes no constriction. COLOR VISION
Both pupils are affected equally by systemic medica-
tions. They are small with narcotic use (morphine, The retina contains three classes of cones, with visual

Disorders of Vision
heroin) and large with anticholinergics (scopolamine). pigments of differing peak spectral sensitivity: red (560 nm),
Parasympathetic agents (pilocarpine, demecarium bro- green (530 nm), and blue (430 nm). The red and green
mide) used to treat glaucoma produce miosis. In any cone pigments are encoded on the X chromosome; the
patient with an unexplained pupillary abnormality, a blue cone pigment on chromosome 7. Mutations of the
slit-lamp examination is helpful to exclude surgical blue cone pigment are exceedingly rare. Mutations of
trauma to the iris, an occult foreign body, perforating the red and green pigments cause congenital X-linked
injury, intraocular inammation, adhesions (synechia), color blindness in 8% of men. Affected individuals are
angle-closure glaucoma, and iris sphincter rupture from not truly color blind; rather, they differ from normal
blunt trauma. subjects in how they perceive color and how they com-
bine primary monochromatic lights to match a given
color. Anomalous trichromats have three cone types,
EYE MOVEMENTS AND ALIGNMENT but a mutation in one cone pigment (usually red or
Eye movements are tested by asking the patient with green) causes a shift in peak spectral sensitivity, alter-
both eyes open to pursue a small target such as a penlight ing the proportion of primary colors required to
into the cardinal elds of gaze. Normal ocular versions achieve a color match. Dichromats have only two
are smooth, symmetric, full, and maintained in all direc- cone types and will therefore accept a color match
tions without nystagmus. Saccades, or quick rexation based upon only two primary colors. Anomalous
eye movements, are assessed by having the patient look trichromats and dichromats have 6/6 (20/20) visual
back and forth between two stationary targets. The eyes acuity, but their hue discrimination is impaired. Ishi-
should move rapidly and accurately in a single jump to hara color plates can be used to detect red-green color
their target. Ocular alignment can be judged by holding blindness. The test plates contain a hidden number,
a penlight directly in front of the patient at about 1 m. If visible only to subjects with color confusion from red-
the eyes are straight, the corneal light reex will be cen- green color blindness. Because color blindness is almost
tered in the middle of each pupil. To test eye alignment exclusively X-linked, it is worth screening only male
more precisely, the cover test is useful. The patient is children.
instructed to gaze upon a small xation target in the dis- The Ishihara plates are often used to detect acquired
tance. One eye is covered suddenly while observing the defects in color vision, although they are intended as a
second eye. If the second eye shifts to xate upon the screening test for congenital color blindness. Acquired
target, it was misaligned. If it does not move, the rst eye defects in color vision frequently result from disease of
is uncovered and the test is repeated on the second eye. If the macula or optic nerve. For example, patients with a
neither eye moves, the eyes are aligned orthotropically. If history of optic neuritis often complain of color desat-
the eyes are orthotropic in primary gaze but the patient uration long after their visual acuity has returned to
complains of diplopia, the cover test should be per- normal. Color blindness can also occur from bilateral
formed with the head tilted or turned in whatever direc- strokes involving the ventral portion of the occipital
tion elicits diplopia. With practice the examiner can lobe (cerebral achromatopsia). Such patients can per-
detect an ocular deviation (heterotropia) as small as 12 ceive only shades of gray and may also have difculty
with the cover test. Deviations can be measured by plac- recognizing faces (prosopagnosia). Infarcts of the domi-
ing prisms in front of the misaligned eye to determine nant occipital lobe sometimes give rise to color
the power required to neutralize the xation shift evoked anomia. Affected patients can discriminate colors, but
by covering the other eye. they cannot name them.
 174 VISUAL FIELDS (Fig. 17-3A). By generating an automated printout of
light thresholds, these static perimeters provide a sensi-
Vision can be impaired by damage to the visual system
tive means of detecting scotomas in the visual eld.
anywhere from the eyes to the occipital lobes. One can
They are exceedingly useful for serial assessment of
localize the site of the lesion with considerable accuracy
visual function in chronic diseases such as glaucoma or
by mapping the visual eld decit by nger confronta-
pseudotumor cerebri.
tion and then correlating it with the topographic
The crux of visual eld analysis is to decide whether
anatomy of the visual pathway (Fig. 17-3). Quantitative
a lesion is before, at, or behind the optic chiasm. If a
visual eld mapping is performed by computer-driven
scotoma is conned to one eye, it must be due to a
perimeters (Humphrey, Octopus) that present a target of
lesion anterior to the chiasm, involving either the optic
SECTION II

variable intensity at xed positions in the visual eld

Clinical Manifestations of Neurologic Disease

FIGURE 17-3
Ventral view of the brain, correlating patterns of visual using a gray scale format. Areas of visual eld loss are
eld loss with the sites of lesions in the visual pathway. shown in black. The examples of common monocular,
The visual elds overlap partially, creating 120 of central prechiasmal eld defects are all shown for the right eye. By
binocular eld anked by a 40 monocular crescent on either convention, the visual elds are always recorded with the left
side. The visual eld maps in this gure were done with a eyes eld on the left, and the right eyes eld on the right,
computer-driven perimeter (Humphrey Instruments, Carl Zeiss, just as the patient sees the world.
Inc.). It plots the retinal sensitivity to light in the central 30
nerve or retina. Retinal lesions produce scotomas that homonymous hemianopia, i.e., a temporal hemield defect 175
correspond optically to their location in the fundus. For in the contralateral eye and a matching nasal hemield
example, a superior-nasal retinal detachment results in defect in the ipsilateral eye (Fig. 17-3I). A unilateral
an inferior-temporal eld cut. Damage to the macula postchiasmal lesion leaves the visual acuity in each eye
causes a central scotoma (Fig. 17-3B). unaffected, although the patient may read the letters on
Optic nerve disease produces characteristic patterns only the left or right half of the eye chart. Lesions of the
of visual eld loss. Glaucoma selectively destroys axons optic radiations tend to cause poorly matched or
that enter the superotemporal or inferotemporal poles of incongruous eld defects in each eye. Damage to the optic
the optic disc, resulting in arcuate scotomas shaped like a radiations in the temporal lobe (Meyers loop) produces a

CHAPTER 17
Turkish scimitar, which emanate from the blind spot and superior quadrantic homonymous hemianopia (Fig. 17-3J),
curve around xation to end at against the horizontal whereas injury to the optic radiations in the parietal lobe
meridian (Fig. 17-3C). This type of eld defect mirrors results in an inferior quadrantic homonymous hemianopia
the arrangement of the nerve ber layer in the temporal (Fig. 17-3K ). Lesions of the primary visual cortex give rise
retina. Arcuate or nerve ber layer scotomas also occur to dense, congruous hemianopic eld defects. Occlusion
from optic neuritis, ischemic optic neuropathy, optic of the posterior cerebral artery supplying the occipital lobe
disc drusen, and branch retinal artery or vein occlusion. is a frequent cause of total homonymous hemianopia.

Disorders of Vision
Damage to the entire upper or lower pole of the Some patients with hemianopia after occipital stroke have
optic disc causes an altitudinal eld cut that follows the macular sparing, because the macular representation at the
horizontal meridian (Fig. 17-3D). This pattern of visual tip of the occipital lobe is supplied by collaterals from
eld loss is typical of ischemic optic neuropathy but also the middle cerebral artery (Fig. 17-3L). Destruction of
occurs from retinal vascular occlusion, advanced glau- both occipital lobes produces cortical blindness.This con-
coma, and optic neuritis. dition can be distinguished from bilateral prechiasmal
About half the bers in the optic nerve originate visual loss by noting that the pupil responses and optic
from ganglion cells serving the macula. Damage to fundi remain normal.
papillomacular bers causes a cecocentral scotoma
encompassing the blind spot and macula (Fig. 17-3E). If
the damage is irreversible, pallor eventually appears in DISORDERS
the temporal portion of the optic disc. Temporal pallor
from a cecocentral scotoma may develop in optic neuri- RED OR PAINFUL EYE
tis, nutritional optic neuropathy, toxic optic neuropathy, Corneal Abrasions
Lebers hereditary optic neuropathy, and compressive
optic neuropathy. It is worth mentioning that the tem- These are seen best by placing a drop of uorescein in
poral side of the optic disc is slightly more pale than the the eye and looking with the slit lamp using a cobalt-
nasal side in most normal individuals. Therefore, it can blue light. A penlight with a blue lter will sufce if no
sometimes be difcult to decide whether the temporal slit lamp is available. Damage to the corneal epithelium is
pallor visible on fundus examination represents a patho- revealed by yellow uorescence of the exposed basement
logic change. Pallor of the nasal rim of the optic disc is a membrane underlying the epithelium. It is important to
less equivocal sign of optic atrophy. check for foreign bodies.To search the conjunctival for-
At the optic chiasm, bers from nasal ganglion cells nices, the lower lid should be pulled down and the
decussate into the contralateral optic tract. Crossed bers upper lid everted. A foreign body can be removed with
are damaged more by compression than uncrossed bers. a moistened cotton-tipped applicator after placing a
As a result, mass lesions of the sellar region cause a tempo- drop of topical anesthetic, such as proparacaine, in the
ral hemianopia in each eye. Tumors anterior to the optic eye. Alternatively, it may be possible to ush the foreign
chiasm, such as meningiomas of the tuberculum sella, pro- body from the eye by irrigating copiously with saline or
duce a junctional scotoma characterized by an optic neu- articial tears. If the corneal epithelium has been
ropathy in one eye and a superior-temporal eld cut in abraded, antibiotic ointment and a patch should be applied
the other eye (Fig. 17-3G). More symmetric compression to the eye. A drop of an intermediate-acting cycloplegic,
of the optic chiasm by a pituitary adenoma, meningioma, such as cyclopentolate hydrochloride 1%, helps to reduce
craniopharyngioma, glioma, or aneurysm results in a pain by relaxing the ciliary body.The eye should be reex-
bitemporal hemianopia (Fig. 17-3H).The insidious devel- amined the next day. Minor abrasions may not require
opment of a bitemporal hemianopia often goes unnoticed patching and cycloplegia.
by the patient and will escape detection by the physician
unless each eye is tested separately.
Subconjunctival Hemorrhage
It is difcult to localize a postchiasmal lesion accurately,
because injury anywhere in the optic tract, lateral genicu- This results from rupture of small vessels bridging the
late body, optic radiations, or visual cortex can produce a potential space between the episclera and conjunctiva.
 176 Blood dissecting into this space can produce a spectacu- slightly. The most common viral etiology is adenovirus
lar red eye, but vision is not affected and the hemorrhage infection. It causes a watery discharge, mild foreign-
resolves without treatment. Subconjunctival hemorrhage body sensation, and photophobia. Bacterial infection
is usually spontaneous but can occur from blunt trauma, tends to produce a more mucopurulent exudate. Mild
eye rubbing, or vigorous coughing. Occasionally it is a cases of infectious conjunctivitis are usually treated empir-
clue to an underlying bleeding disorder. ically with broad-spectrum topical ocular antibiotics, such
as sulfacetamide 10%, polymixin-bacitracin-neomycin,
Pinguecula or trimethoprim-polymixin combination. Smears and
cultures are usually reserved for severe, resistant, or recur-
This is a small, raised conjunctival nodule at the temporal rent cases of conjunctivitis.To prevent contagion, patients
SECTION II

or nasal limbus. In adults such lesions are extremely com- should be admonished to wash their hands frequently,
mon and have little signicance, unless they become not to touch their eyes, and to avoid direct contact with
inamed (pingueculitis).A pterygium resembles a pinguecula others.
but has crossed the limbus to encroach upon the corneal
surface. Removal is justied when symptoms of irritation
or blurring develop, but recurrence is a common problem. Allergic Conjunctivitis
Clinical Manifestations of Neurologic Disease

This condition is extremely common and often mistaken

Blepharitis
for infectious conjunctivitis. Itching, redness, and epiphora
This refers to inammation of the eyelids. The most are typical. The palpebral conjunctiva may become
common form occurs in association with acne rosacea or hypertropic with giant excrescences called cobblestone
seborrheic dermatitis.The eyelid margins are usually col- papillae. Irritation from contact lenses or any chronic for-
onized heavily by staphylococci. Upon close inspection, eign body can also induce formation of cobblestone
they appear greasy, ulcerated, and crusted with scaling papillae. Atopic conjunctivitis occurs in subjects with atopic
debris that clings to the lashes.Treatment consists of warm dermatitis or asthma. Symptoms caused by allergic con-
compresses, strict eyelid hygiene, and topical antibiotics junctivitis can be alleviated with cold compresses, topical
such as erythromycin. An external hordeolum (sty) is caused vasoconstrictors, antihistamines, and mast cell stabilizers
by staphylococcal infection of the supercial accessory such as cromolyn sodium. Topical glucocorticoid solu-
glands of Zeis or Moll located in the eyelid margins. An tions provide dramatic relief of immune-mediated forms
internal hordeolum occurs after suppurative infection of of conjunctivitis, but their long-term use is ill-advised
the oil-secreting meibomian glands within the tarsal plate because of the complications of glaucoma, cataract, and
of the eyelid. Systemic antibiotics, usually tetracyclines, are secondary infection. Topical nonsteroidal anti-inamma-
sometimes necessary for treatment of meibomian gland tory agents (NSAIDs) such as ketorolac tromethamine
inammation (meibomitis) or chronic, severe blepharitis. are a better alternative.
A chalazion is a painless, granulomatous inammation of a
meibomian gland that produces a pealike nodule within
the eyelid. It can be incised and drained, or injected with Keratoconjunctivitis Sicca
glucocorticoids. Basal cell, squamous cell, or meibomian
Also known as dry eye, it produces a burning, foreign-
gland carcinoma should be suspected for any nonhealing,
body sensation, injection, and photophobia. In mild
ulcerative lesion of the eyelids.
cases the eye appears surprisingly normal, but tear pro-
duction measured by wetting of a lter paper (Schirmer
Dacrocystitis strip) is decient. A variety of systemic drugs, including
An inammation of the lacrimal drainage system, this can antihistaminic, anticholinergic, and psychotropic med-
produce epiphora (tearing) and ocular injection. Gentle ications, result in dry eye by reducing lacrimal secretion.
pressure over the lacrimal sac evokes pain and reux of Disorders that involve the lacrimal gland directly, such as
mucus or pus from the tear puncta. Dacrocystitis usually sarcoidosis or Sjgrens syndrome, also cause dry eye.
occurs after obstruction of the lacrimal system. It is treated Patients may develop dry eye after radiation therapy if
with topical and systemic antibiotics, followed by probing the treatment eld includes the orbits. Problems with
or surgery to reestablish patency. Entropion (inversion of ocular drying are also common after lesions affecting
the eyelid) or ectropion (sagging or eversion of the eyelid) cranial nerves V or VII. Corneal anesthesia is particularly
can also lead to epiphora and ocular irritation. dangerous, because the absence of a normal blink reex
exposes the cornea to injury without pain to warn the
patient. Dry eye is managed by frequent and liberal
Conjunctivitis
application of articial tears and ocular lubricants. In
This is the most common cause of a red, irritated eye. severe cases the tear puncta can be plugged or cauterized
Pain is minimal, and the visual acuity is reduced only to reduce lacrimal outow.
Keratitis zoster eruption in any branch of the trigeminal nerve 177
but are particularly common when vesicles form on the
This is a threat to vision because of the risk of corneal
nose, reecting nasociliary (V1) nerve involvement
clouding, scarring, and perforation. Worldwide, the two
(Hutchinsons sign). Herpes zoster ophthalmicus pro-
leading causes of blindness from keratitis are trachoma
duces corneal dendrites, which can be difcult to distin-
from chlamydial infection and vitamin A deciency
guish from those seen in herpes simplex. Stromal keratitis,
related to malnutrition. In the United States, contact lenses
anterior uveitis, raised intraocular pressure, ocular motor
play a major role in corneal infection and ulceration.They
nerve palsies, acute retinal necrosis, and postherpetic
should not be worn by anyone with an active eye infec-
scarring and neuralgia are other common sequelae.
tion. In evaluating the cornea, it is important to differenti-

CHAPTER 17
Herpes zoster ophthalmicus is treated with antiviral
ate between a supercial infection (keratoconjunctivitis) and
agents and cycloplegics. In severe cases, glucocorticoids
a deeper, more serious ulcerative process. The latter is
may be added to prevent permanent visual loss from
accompanied by greater visual loss, pain, photophobia,
corneal scarring.
redness, and discharge. Slit-lamp examination shows dis-
ruption of the corneal epithelium, a cloudy inltrate or
abscess in the stroma, and an inammatory cellular reac- Episcleritis

Disorders of Vision
tion in the anterior chamber. In severe cases, pus settles at This is an inammation of the episclera, a thin layer of
the bottom of the anterior chamber, giving rise to a connective tissue between the conjunctiva and sclera.
hypopyon. Immediate empirical antibiotic therapy should Episcleritis resembles conjunctivitis but is a more local-
be initiated after corneal scrapings are obtained for Grams ized process and discharge is absent. Most cases of epis-
stain, Giemsa stain, and cultures. Fortied topical antibi- cleritis are idiopathic, but some occur in the setting of
otics are most effective, supplemented with subconjuncti- an autoimmune disease. Scleritis refers to a deeper, more
val antibiotics as required. A fungal etiology should always severe inammatory process, frequently associated with a
be considered in the patient with keratitis. Fungal infec- connective tissue disease such as rheumatoid arthritis,
tion is common in warm humid climates, especially after lupus erythematosus, polyarteritis nodosa, Wegeners
penetration of the cornea by plant or vegetable material. granulomatosis, or relapsing polychondritis. The inam-
mation and thickening of the sclera can be diffuse or
Herpes Simplex nodular. In anterior forms of scleritis, the globe assumes
The herpes viruses are a major cause of blindness from a violet hue and the patient complains of severe ocular
keratitis. Most adults in the United States have serum tenderness and pain.With posterior scleritis the pain and
antibodies to herpes simplex, indicating prior viral infec- redness may be less marked, but there is often proptosis,
tion. Primary ocular infection is generally caused by her- choroidal effusion, reduced motility, and visual loss.
pes simplex type 1, rather than type 2. It manifests as a Episcleritis and scleritis should be treated with NSAIDs.
unilateral follicular blepharoconjunctivitis, easily con- If these agents fail, topical or even systemic glucocorti-
fused with adenoviral conjunctivitis unless telltale vesicles coid therapy may be necessary, especially if an underly-
appear on the periocular skin or conjunctiva. A dendritic ing autoimmune process is active.
pattern of corneal epithelial ulceration revealed by uo-
rescein staining is pathognomonic for herpes infection Uveitis
but is seen in only a minority of primary infections.
Recurrent ocular infection arises from reactivation of the Involving the anterior structures of the eye, this is also
latent herpes virus.Viral eruption in the corneal epithe- called iritis or iridocyclitis. The diagnosis requires slit-lamp
lium may result in the characteristic herpes dendrite. examination to identify inammatory cells oating in the
Involvement of the corneal stroma produces edema, vas- aqueous humor or deposited upon the corneal endothe-
cularization, and iridocyclitis. Herpes keratitis is treated lium (keratic precipitates). Anterior uveitis develops in
with topical antiviral agents, cycloplegics, and oral acy- sarcoidosis, ankylosing spondylitis, juvenile rheumatoid
clovir. Topical glucocorticoids are effective in mitigating arthritis, inammatory bowel disease, psoriasis, Reiters
corneal scarring but must be used with extreme caution syndrome, and Behets disease. It is also associated with
because of the danger of corneal melting and perfora- herpes infections, syphilis, Lyme disease, onchocerciasis,
tion. Topical glucocorticoids also carry the risk of pro- tuberculosis, and leprosy. Although anterior uveitis can
longing infection and inducing glaucoma. occur in conjunction with many diseases, no cause is
found to explain the majority of cases. For this reason,
laboratory evaluation is usually reserved for patients with
Herpes Zoster recurrent or severe anterior uveitis.Treatment is aimed at
Herpes zoster from reactivation of latent varicella (chick- reducing inammation and scarring by judicious use of
enpox) virus causes a dermatomal pattern of painful topical glucocorticoids. Dilation of the pupil reduces
vesicular dermatitis. Ocular symptoms can occur after pain and prevents the formation of synechiae.
 178 Posterior Uveitis headache, prompting a fruitless workup for abdominal
or neurologic disease. The diagnosis is made by measur-
This is diagnosed by observing inflammation of the
ing the intraocular pressure during an acute attack or by
vitreous, retina, or choroid on fundus examination. It is
observing a narrow chamber angle by means of a spe-
more likely than anterior uveitis to be associated with
cially mirrored contact lens. Acute angle closure is
an identiable systemic disease. Some patients have
treated with acetazolamide (PO or IV), topical beta
panuveitis, or inammation of both the anterior and
blockers, prostaglandin analogues, 2-adrenergic ago-
posterior segments of the eye. Posterior uveitis is a
nists, and pilocarpine to induce miosis. If these measures
manifestation of autoimmune diseases such as sarcoido-
fail, a laser can be used to create a hole in the peripheral
sis, Behets disease, Vogt-Koyanagi-Harada syndrome,
iris to relieve pupillary block. Many physicians are reluc-
SECTION II

and inammatory bowel disease (Fig. 17-4). It also

tant to dilate patients routinely for fundus examination
accompanies diseases such as toxoplasmosis, onchocer-
because they fear precipitating an angle-closure glaucoma.
ciasis, cysticercosis, coccidioidomycosis, toxocariasis, and
The risk is actually remote and more than outweighed
histoplasmosis; infections caused by organisms such as
by the potential benet to patients of discovering a
Candida, Pneumocystis carinii, Cryptococcus, Aspergillus, her-
hidden fundus lesion visible only through a fully dilated
pes, and cytomegalovirus; and other diseases such as
pupil. Moreover, a single attack of angle closure after
Clinical Manifestations of Neurologic Disease

syphilis, Lyme disease, tuberculosis, cat-scratch disease,

pharmacologic dilation rarely causes any permanent dam-
Whipples disease, and brucellosis. In multiple sclerosis,
age to the eye and serves as an inadvertent provocative
chronic inammatory changes can develop in the extreme
test to identify patients with narrow angles who would
periphery of the retina (pars planitis or intermediate
benet from prophylactic laser iridectomy.
uveitis).

Acute Angle-Closure Glaucoma Endophthalmitis

This is a rare and frequently misdiagnosed cause of a This occurs from bacterial, viral, fungal, or parasitic
red, painful eye. Susceptible eyes have a shallow anterior infection of the internal structures of the eye. It is usu-
chamber, either because the eye has a short axial length ally acquired by hematogenous seeding from a remote
(hyperopia) or a lens enlarged by the gradual develop- site. Chronically ill, diabetic, or immunosuppressed
ment of cataract. When the pupil becomes mid-dilated, patients, especially those with a history of indwelling IV
the peripheral iris blocks aqueous outow via the ante- catheters or positive blood cultures, are at greatest risk
rior chamber angle and the intraocular pressure rises for endogenous endophthalmitis. Although most patients
abruptly, producing pain, injection, corneal edema, have ocular pain and injection, visual loss is sometimes
obscurations, and blurred vision. In some patients, ocular the only symptom. Septic emboli, from a diseased heart
symptoms are overshadowed by nausea, vomiting, or valve or a dental abscess, that lodge in the retinal circula-
tion can give rise to endophthalmitis. White-centered
retinal hemorrhages (Roths spots) are considered pathog-
nomonic for subacute bacterial endocarditis, but they
also appear in leukemia, diabetes, and many other condi-
tions. Endophthalmitis also occurs as a complication of
ocular surgery, occasionally months or even years after
the operation. An occult penetrating foreign body or
unrecognized trauma to the globe should be considered
in any patient with unexplained intraocular infection or
inammation.

TRANSIENT OR SUDDEN VISUAL LOSS

Amaurosis Fugax
This term refers to a transient ischemic attack of the
FIGURE 17-4
retina (Chap. 21). Because neural tissue has a high rate of
Retinal vasculitis, uveitis, and hemorrhage in a 32-year- metabolism, interruption of blood ow to the retina for
old woman with Crohns disease. Note that the veins are more than a few seconds results in transient monocular
frosted with a white exudate. Visual acuity improved from blindness, a term used interchangeably with amaurosis
20/400 to 20/20 following treatment with intravenous methyl- fugax. Patients describe a rapid fading of vision like a
prednisolone. curtain descending, sometimes affecting only a portion
 in patients with diseased valves, atrial brillation, or wall 179
motion abnormalities.
In rare instances, amaurosis fugax occurs from low
central retinal artery perfusion pressure in a patient with
a critical stenosis of the ipsilateral carotid artery and
poor collateral ow via the circle of Willis. In this situa-
tion, amaurosis fugax develops when there is a dip in
systemic blood pressure or a slight worsening of the
carotid stenosis. Sometimes there is contralateral motor

CHAPTER 17
or sensory loss, indicating concomitant hemispheric
cerebral ischemia.
Retinal arterial occlusion also occurs rarely in associa-
tion with retinal migraine, lupus erythematosus, anticar-
FIGURE 17-5 diolipin antibodies (Fig. 17-6), anticoagulant deciency
Hollenhorst plaque lodged at the bifurcation of a retinal states (protein S, protein C, and antithrombin III de-
arteriole proves that a patient is shedding emboli from either ciency), pregnancy, IV drug abuse, blood dyscrasias, dys-

Disorders of Vision
the carotid artery, great vessels, or heart. proteinemias, and temporal arteritis.
Marked systemic hypertension causes sclerosis of retinal
arterioles, splinter hemorrhages, focal infarcts of the nerve
of the visual eld. Amaurosis fugax usually occurs from ber layer (cotton-wool spots), and leakage of lipid and
an embolus that becomes stuck within a retinal arteriole uid (hard exudate) into the macula (Fig. 17-7). In
(Fig. 17-5). If the embolus breaks up or passes, ow is hypertensive crisis, sudden visual loss can result from
restored and vision returns quickly to normal without vasospasm of retinal arterioles and retinal ischemia. In
permanent damage. With prolonged interruption of addition, acute hypertension may produce visual loss from
blood ow, the inner retina suffers infarction. Ophthal- ischemic swelling of the optic disc. Patients with acute
moscopy reveals zones of whitened, edematous retina hypertensive retinopathy should be treated by lowering
following the distribution of branch retinal arterioles. the blood pressure. However, the blood pressure should
Complete occlusion of the central retinal artery pro- not be reduced precipitously, because there is a danger of
duces arrest of blood ow and a milky retina with a optic disc infarction from sudden hypoperfusion.
cherry-red fovea (Fig. 17-6). Emboli are composed of Impending branch or central retinal vein occlusion can
either cholesterol (Hollenhorst plaque), calcium, or produce prolonged visual obscurations that resemble those
platelet-brin debris. The most common source is an described by patients with amaurosis fugax. The veins
atherosclerotic plaque in the carotid artery or aorta, appear engorged and phlebitic, with numerous retinal
although emboli can also arise from the heart, especially hemorrhages (Fig. 17-8). In some patients, venous blood

FIGURE 17-6
Central retinal artery occlusion combined with ischemic FIGURE 17-7
optic neuropathy in a 19-year-old woman with an elevated Hypertensive retinopathy with scattered ame (splinter)
titer of anticardiolipin antibodies. Note the orange dot (rather hemorrhages and cotton-wool spots (nerve ber layer
than cherry red) corresponding to the fovea and the spared infarcts) in a patient with headache and a blood pressure of
patch of retina just temporal to the optic disc. 234/120.
 180 into two forms: arteritic and nonarteritic. The nonar-
teritic form of AION is most common. No specic cause
can be identied, although diabetes and hypertension are
frequent risk factors. No treatment is available. About 5%
of patients, especially those older than 60 years, develop
the arteritic form of AION in conjunction with giant cell
(temporal) arteritis. It is urgent to recognize arteritic
AION so that high doses of glucocorticoids can be insti-
tuted immediately to prevent blindness in the second eye.
Symptoms of polymyalgia rheumatica may be present; the
SECTION II

sedimentation rate and C-reactive protein level are usually

elevated. In a patient with visual loss from suspected
arteritic AION, temporal artery biopsy is mandatory to
FIGURE 17-8 conrm the diagnosis. Glucocorticoids should be started
Central retinal vein occlusion can produce massive retinal immediately, without waiting for the biopsy to be com-
hemorrhage (blood and thunder), ischemia, and vision loss. pleted. The diagnosis of arteritic AION is difcult to
Clinical Manifestations of Neurologic Disease

sustain in the face of a negative temporal artery biopsy,

but such cases do occur rarely.
ow recovers spontaneously, while others evolve a frank
obstruction with extensive retinal bleeding (blood and Posterior Ischemic Optic Neuropathy
thunder appearance), infarction, and visual loss. Venous This is an infrequent cause of acute visual loss, induced
occlusion of the retina is often idiopathic, but hyperten- by the combination of severe anemia and hypotension.
sion, diabetes, and glaucoma are prominent risk factors. Cases have been reported after major blood loss during
Polycythemia, thrombocythemia, or other factors leading surgery, exsanguinating trauma, gastrointestinal bleeding,
to an underlying hypercoagulable state should be cor- and renal dialysis. The fundus usually appears normal,
rected; aspirin treatment may be benecial. although optic disc swelling develops if the process
extends far enough anteriorly.Vision can be salvaged in
Anterior Ischemic Optic Neuropathy (AION) some patients by prompt blood transfusion and reversal
This is caused by insufcient blood ow through the pos- of hypotension.
terior ciliary arteries supplying the optic disc. It produces
painless, monocular visual loss that is usually sudden, Optic Neuritis
although some patients have progressive worsening. The
optic disc appears swollen and surrounded by nerve ber This is a common inammatory disease of the optic
layer splinter hemorrhages (Fig. 17-9). AION is divided nerve. In the Optic Neuritis Treatment Trial (ONTT),
the mean age of patients was 32 years, 77% were women,
92% had ocular pain (especially with eye movements),
and 35% had optic disc swelling. In most patients, the
demyelinating event was retrobulbar and the ocular fun-
dus appeared normal on initial examination (Fig. 17-10),
although optic disc pallor slowly developed over subse-
quent months.
Virtually all patients experience a gradual recovery of
vision after a single episode of optic neuritis, even with-
out treatment.This rule is so reliable that failure of vision
to improve after a rst attack of optic neuritis casts doubt
upon the original diagnosis. Treatment with high-dose
IV methylprednisolone (250 mg every 6 h for 3 days)
followed by oral prednisone (1 mg/kg per day for 11 days)
makes no difference in nal acuity (measured 6 months
after the attack), but the recovery of visual function
FIGURE 17-9 occurs more rapidly.
Anterior ischemic optic neuropathy from temporal arteri- For some patients, optic neuritis remains an isolated
tis in a 78-year-old woman with pallid disc swelling, hemor- event. However, the ONTT showed that the 10-year
rhage, visual loss, myalgia, and an erythrocyte sedimentation cumulative probability of developing clinically denite
rate of 86 mm/h. multiple sclerosis following optic neuritis is 38%. In
 181

CHAPTER 17
FIGURE 17-10 FIGURE 17-11
Retrobulbar optic neuritis is characterized by a normal fun- Optic atrophy is not a specic diagnosis, but refers to the
dus examination initially, hence the rubric, the doctor sees combination of optic disc pallor, arteriolar narrowing, and

Disorders of Vision
nothing, and the patient sees nothing. Optic atrophy devel- nerve ber layer destruction produced by a host of eye dis-
ops after severe or repeated attacks. eases, especially optic neuropathies.

patients with two or more demyelinating plaques on visual loss can also develop gradually and produce optic
brain magnetic resonance (MR) imaging, treatment with atrophy (Fig. 17-11) without a phase of acute optic disc
interferon beta-1a can retard the development of more edema. Many agents have been implicated as a cause of
lesions. In summary, an MR scan is recommended in toxic optic neuropathy, but the evidence supporting the
every patient with a rst attack of optic neuritis. When association for many is weak. The following is a partial
visual loss is severe (worse than 20/100), treatment with list of potential offending drugs or toxins: disulram,
intravenous followed by oral glucocorticoids hastens ethchlorvynol, chloramphenicol, amiodarone, monoclonal
recovery. If multiple lesions are present on the MR scan, anti-CD3 antibody, ciprooxacin, digitalis, streptomycin,
treatment with interferon beta-1a should be considered. lead, arsenic, thallium, D-penicillamine, isoniazid, eme-
tine, and sulfonamides. Deciency states, induced either
Lebers Hereditary Optic Neuropathy by starvation, malabsorption, or alcoholism, can lead to
insidious visual loss. Thiamine, vitamin B12, and folate
This disease usually affects young men, causing gradual, levels should be checked in any patient with unex-
painless, severe, central visual loss in one eye, followed plained, bilateral central scotomas and optic pallor.
weeks or months later by the same process in the other
eye. Acutely, the optic disc appears mildly plethoric with
surface capillary telangiectases, but no vascular leakage on Papilledema
uorescein angiography. Eventually optic atrophy ensues.
Lebers optic neuropathy is caused by a point mutation at This connotes bilateral optic disc swelling from raised
codon 11778 in the mitochondrial gene encoding nicoti- intracranial pressure (Fig. 17-12). Headache is a frequent,
namide adenine dinucleotide dehydrogenase (NADH) but not invariable, accompaniment. All other forms of
subunit 4.Additional mutations responsible for the disease optic disc swelling, e.g., from optic neuritis or ischemic
have been identied, most in mitochondrial genes encod- optic neuropathy, should be called optic disc edema.
ing proteins involved in electron transport. Mitochondrial This convention is arbitrary but serves to avoid confusion.
mutations causing Lebers neuropathy are inherited from Often it is difcult to differentiate papilledema from other
the mother by all her children, but usually only sons forms of optic disc edema by fundus examination alone.
develop symptoms. There is no treatment. Transient visual obscurations are a classic symptom of
papilledema. They can occur in only one eye or simulta-
neously in both eyes. They usually last seconds but can
Toxic Optic Neuropathy
persist longer. Obscurations follow abrupt shifts in posture
This can result in acute visual loss with bilateral optic or happen spontaneously. When obscurations are pro-
disc swelling and central or cecocentral scotomas. Such longed or spontaneous, the papilledema is more threaten-
cases have been reported to result from exposure to ing. Visual acuity is not affected by papilledema unless
ethambutol, methyl alcohol (moonshine), ethylene glycol the papilledema is severe, long-standing, or accompanied
(antifreeze), or carbon monoxide. In toxic optic neuropathy, by macular edema and hemorrhage. Visual eld testing
 182
SECTION II

FIGURE 17-12 FIGURE 17-13

Papilledema means optic disc edema from raised intracra- Optic disc drusen are calcied deposits of unknown etiol-
nial pressure. This obese young woman with pseudotumor ogy within the optic disc. They are sometimes confused with
Clinical Manifestations of Neurologic Disease

cerebri was misdiagnosed as a migraineur until fundus papilledema.

examination was performed, showing optic disc elevation,
hemorrhages, and cotton-wool spots.

shows enlarged blind spots and peripheral constriction the surface of the optic disc. However, in many patients
(Fig. 17-3F). With unremitting papilledema, peripheral they are hidden beneath the surface, producing pseudo-
visual eld loss progresses in an insidious fashion while papilledema. It is important to recognize optic disc drusen
the optic nerve develops atrophy. In this setting, reduction to avoid an unnecessary evaluation for papilledema.
of optic disc swelling is an ominous sign of a dying nerve Ultrasound or CT scanning is sensitive for detection of
rather than an encouraging indication of resolving buried optic disc drusen because they contain calcium.
papilledema. In most patients, optic disc drusen are an incidental,
Evaluation of papilledema requires neuroimaging innocuous nding, but they can produce visual obscura-
to exclude an intracranial lesion. MR angiography is tions. On perimetry they give rise to enlarged blind spots
appropriate in selected cases to search for a dural venous and arcuate scotomas from damage to the optic disc.With
sinus occlusion or an arteriovenous shunt. If neuroradio- increasing age, drusen tend to become more exposed on
logic studies are negative, the subarachnoid opening the disc surface as optic atrophy develops. Hemorrhage,
pressure should be measured by lumbar puncture. An choroidal neovascular membrane, and AION are more
elevated pressure, with normal cerebrospinal uid, points likely to occur in patients with optic disc drusen. No treat-
by exclusion to the diagnosis of pseudotumor cerebri (idio- ment is available.
pathic intracranial hypertension).The majority of patients
are young, female, and obese. Treatment with a carbonic Vitreous Degeneration
anhydrase inhibitor such as acetazolamide lowers intracra-
nial pressure by reducing the production of cerebrospinal This occurs in all individuals with advancing age, lead-
uid. Weight reduction is vital but often unsuccessful. If ing to visual symptoms. Opacities develop in the vitre-
acetazolamide and weight loss fail, and visual eld loss is ous, casting annoying shadows upon the retina. As the
progressive, a shunt should be performed without delay eye moves, these distracting oaters move synchro-
to prevent blindness. Occasionally, emergency surgery nously, with a slight lag caused by inertia of the vitreous
is required for sudden blindness caused by fulminant gel.Vitreous traction upon the retina causes mechanical
papilledema. stimulation, resulting in perception of ashing lights.
This photopsia is brief and conned to one eye, in con-
trast to the bilateral, prolonged scintillations of cortical
Optic Disc Drusen
migraine. Contraction of the vitreous can result in sud-
These are refractile deposits within the substance of the den separation from the retina, heralded by an alarming
optic nerve head (Fig. 17-13). They are unrelated to shower of oaters and photopsia.This process, known as
drusen of the retina, which occur in age-related macular vitreous detachment, is a frequent involutional event in the
degeneration. Optic disc drusen are most common in elderly. It is not harmful unless it damages the retina. A
people of northern European descent. Their diagnosis is careful examination of the dilated fundus is important in
obvious when they are visible as glittering particles upon any patient complaining of oaters or photopsia to
search for peripheral tears or holes. If such a lesion is Classic Migraine 183
found, laser application can forestall a retinal detach-
(See also Chap. 6) This usually occurs with a visual aura
ment. Occasionally a tear ruptures a retinal blood vessel,
lasting about 20 min. In a typical attack, a small central
causing vitreous hemorrhage and sudden loss of vision.
disturbance in the eld of vision marches toward the
On attempted ophthalmoscopy the fundus is hidden by
periphery, leaving a transient scotoma in its wake. The
a dark red haze of blood. Ultrasound is required to
expanding border of migraine scotoma has a scintillating,
examine the interior of the eye for a retinal tear or
dancing, or zig-zag edge, resembling the bastions of a
detachment. If the hemorrhage does not resolve sponta-
fortied city, hence the term fortication spectra. Patients
neously, the vitreous can be removed surgically.Vitreous
descriptions of fortication spectra vary widely and can

CHAPTER 17
hemorrhage also occurs from the fragile neovascular
be confused with amaurosis fugax. Migraine patterns usu-
vessels that proliferate on the surface of the retina in
ally last longer and are perceived in both eyes, whereas
diabetes, sickle cell anemia, and other ischemic ocular
amaurosis fugax is briefer and occurs in only one eye.
diseases.
Migraine phenomena also remain visible in the dark or
with the eyes closed. Generally they are conned to either
Retinal Detachment the right or left visual hemield, but sometimes both

Disorders of Vision
elds are involved simultaneously. Patients often have a
This produces symptoms of oaters, ashing lights, and a long history of stereotypic attacks. After the visual symp-
scotoma in the peripheral visual eld corresponding to toms recede, headache develops in most patients.
the detachment (Fig. 17-14). If the detachment
includes the fovea, there is an afferent pupil defect and Transient Ischemic Attacks
the visual acuity is reduced. In most eyes, retinal detach-
ment starts with a hole, ap, or tear in the peripheral Vertebrobasilar insufciency may result in acute
retina (rhegmatogenous retinal detachment). Patients homonymous visual symptoms. Many patients mistak-
with peripheral retinal thinning (lattice degeneration) enly describe symptoms in their left or right eye, when
are particularly vulnerable to this process. Once a break in fact they are occurring in the left or right hemield
has developed in the retina, liquied vitreous is free to of both eyes. Interruption of blood supply to the visual
enter the subretinal space, separating the retina from the cortex causes a sudden fogging or graying of vision,
pigment epithelium. The combination of vitreous trac- occasionally with ashing lights or other positive phe-
tion upon the retinal surface and passage of uid behind nomena that mimic migraine. Cortical ischemic attacks
the retina leads inexorably to detachment. Patients with are briefer in duration than migraine, occur in older
a history of myopia, trauma, or prior cataract extraction patients, and are not followed by headache.There may be
are at greatest risk for retinal detachment. The diagnosis associated signs of brainstem ischemia, such as diplopia,
is conrmed by ophthalmoscopic examination of the vertigo, numbness, weakness, or dysarthria.
dilated eye.
Stroke
This occurs when interruption of blood supply from the
posterior cerebral artery to the visual cortex is pro-
longed. The only nding on examination is a homony-
mous visual eld defect that stops abruptly at the vertical
meridian. Occipital lobe stroke is usually due to throm-
botic occlusion of the vertebrobasilar system, embolus, or
dissection. Lobar hemorrhage, tumor, abscess, and arteri-
ovenous malformation are other common causes of hemi-
anopic cortical visual loss.

Factitious (Functional, Nonorganic) Visual Loss

This is claimed by hysterics or malingerers. The latter
comprise the vast majority, seeking sympathy, special treat-
ment, or nancial gain by feigning loss of sight.The diag-
FIGURE 17-14 nosis is suspected when the history is atypical, physical
Retinal detachment appears as an elevated sheet of retinal ndings are lacking or contradictory, inconsistencies
tissue with folds. In this patient the fovea was spared, so emerge on testing, and a secondary motive can be identi-
acuity was normal, but a superior detachment produced an ed. In our litigious society, the fraudulent pursuit of rec-
inferior scotoma. ompense has spawned an epidemic of factitious visual loss.
 184 CHRONIC VISUAL LOSS
Cataract
This is a clouding of the lens sufcient to reduce vision.
Most cataracts develop slowly as a result of aging, leading
to gradual impairment of vision.The formation of cataract
occurs more rapidly in patients with a history of ocular
trauma, uveitis, or diabetes mellitus. Cataracts are acquired
in a variety of genetic diseases, such as myotonic dystro-
phy, neurobromatosis type 2, and galactosemia. Radiation
SECTION II

therapy and glucocorticoid treatment can induce cataract

as a side effect. The cataracts associated with radiation or
glucocorticoids have a typical posterior subcapsular loca-
tion. Cataract can be detected by noting an impaired red FIGURE 17-15
reex when viewing light reected from the fundus with Glaucoma results in cupping as the neural rim is
an ophthalmoscope or by examining the dilated eye using destroyed and the central cup becomes enlarged and exca-
Clinical Manifestations of Neurologic Disease

the slit lamp. vated. The cup-to-disc ratio is about 0.7/1.0 in this patient.
The only treatment for cataract is surgical extraction
of the opacied lens. Over a million cataract operations
are performed each year in the United States.The oper-
ation is generally done under local anesthesia on an out- and visual eld loss have intraocular pressures that appar-
patient basis. A plastic or silicone intraocular lens is ently never exceed the normal limit of 20 mm Hg (so-
placed within the empty lens capsule in the posterior called low-tension glaucoma).
chamber, substituting for the natural lens and leading to In acute angle-closure glaucoma, the eye is red and
rapid recovery of sight. More than 95% of patients who painful due to abrupt, severe elevation of intraocular
undergo cataract extraction can expect an improvement pressure. Such cases account for only a minority of glau-
in vision. In some patients, the lens capsule remaining in coma cases: most patients have open, anterior chamber
the eye after cataract extraction eventually turns cloudy, angles. The cause of raised intraocular pressure in open
causing secondary loss of vision. A small opening is angle glaucoma is unknown, but it is associated with
made in the lens capsule with a laser to restore clarity. gene mutations in the heritable forms.
Glaucoma is usually painless (except in angle-closure
Glaucoma glaucoma). Foveal acuity is spared until end-stage dis-
ease is reached. For these reasons, severe and irreversible
This is a slowly progressive, insidious optic neuropathy, damage can occur before either the patient or physician
usually associated with chronic elevation of intraocular recognizes the diagnosis. Screening of patients for glau-
pressure. In Americans of African descent it is the leading coma by noting the cup-to-disc ratio on ophthal-
cause of blindness. The mechanism whereby raised moscopy and by measuring intraocular pressure is vital.
intraocular pressure injures the optic nerve is not under- Glaucoma is treated with topical adrenergic agonists,
stood. Axons entering the inferotemporal and superotem- cholinergic agonists, beta blockers, and prostaglandin ana-
poral aspects of the optic disc are damaged rst, producing logues. Occasionally, systemic absorption of beta blocker
typical nerve ber bundle or arcuate scotomas on peri- from eye drops can be sufcient to cause side effects of
metric testing. As bers are destroyed, the neural rim of bradycardia, hypotension, heart block, bronchospasm, or
the optic disc shrinks and the physiologic cup within the depression.Topical or oral carbonic anhydrase inhibitors
optic disc enlarges (Fig. 17-15).This process is referred to are used to lower intraocular pressure by reducing
as pathologic cupping. The cup-to-disc diameter is aqueous production. Laser treatment of the trabecular
expressed as a ratio (e.g., 0.2/1). The cup-to-disc ratio meshwork in the anterior chamber angle improves
ranges widely in normal individuals, making it difcult to aqueous outow from the eye. If medical or laser treat-
diagnose glaucoma reliably simply by observing an unusu- ments fail to halt optic nerve damage from glaucoma, a
ally large or deep optic cup. Careful documentation of ser- lter must be constructed surgically (trabeculectomy) or
ial examinations is helpful. In the patient with physiologic a valve placed to release aqueous from the eye in a con-
cupping, the large cup remains stable, whereas in the trolled fashion.
patient with glaucoma it expands relentlessly over the
years. Detection of visual eld loss by computerized
Macular Degeneration
perimetry also contributes to the diagnosis. Finally, most
patients with glaucoma have raised intraocular pressure. This is a major cause of gradual, painless, bilateral central
However, many patients with typical glaucomatous cupping visual loss in the elderly. The old term, senile macular
degeneration, misinterpreted by many patients as an in age-related macular degeneration have not improved 185
unattering reference, has been replaced with age-related vision in most patients. However, outcomes have been
macular degeneration. It occurs in a nonexudative (dry) more encouraging for patients with choroidal neovascu-
form and an exudative (wet) form. Inammation may be lar membranes from ocular histoplasmosis syndrome.
important in both forms of macular degeneration; Major or repeated hemorrhage under the retina from
recent genetic data indicates that susceptibility is associ- neovascular membranes results in brosis, development
ated with variants in the gene for complement factor H, of a round (disciform) macular scar, and permanent loss
an inhibitor of the alternative complement pathway.The of central vision.
nonexudative process begins with the accumulation of

CHAPTER 17
extracellular deposits, called drusen, underneath the reti- Central Serous Chorioretinopathy
nal pigment epithelium. On ophthalmoscopy, they are
pleomorphic but generally appear as small discrete This primarily affects men between 20 and 50 years of
yellow lesions clustered in the macula (Fig. 17-16). age. Leakage of serous uid from the choroid causes small,
With time they become larger, more numerous, and localized detachment of the retinal pigment epithelium
conuent.The retinal pigment epithelium becomes focally and the neurosensory retina. These detachments produce
detached and atrophic, causing visual loss by interfering acute or chronic symptoms of metamorphopsia and

Disorders of Vision
with photoreceptor function. Treatment with vitamins blurred vision when the macula is involved.They are dif-
C and E, beta carotene, and zinc may retard dry macular cult to visualize with a direct ophthalmoscope because
degeneration. the detached retina is transparent and only slightly ele-
Exudative macular degeneration, which develops in vated. Diagnosis of central serous chorioretinopathy is
only a minority of patients, occurs when neovascular made easily by uorescein angiography, which shows dye
vessels from the choroid grow through defects in streaming into the subretinal space. The cause of central
Bruchs membrane into the potential space beneath the serous chorioretinopathy is unknown. Symptoms may
retinal pigment epithelium. Leakage from these vessels resolve spontaneously if the retina reattaches, but recur-
produces elevation of the retina and pigment epithe- rent detachment is common. Laser photocoagulation has
lium, with distortion (metamorphopsia) and blurring of beneted some patients with this condition.
vision. Although onset of these symptoms is usually
gradual, bleeding from subretinal choroidal neovascular Diabetic Retinopathy
membranes sometimes causes acute visual loss.The neo-
vascular membranes can be difcult to see on fundus A rare disease until 1921, when the discovery of insulin
examination because they are beneath the retina. Fluo- resulted in a dramatic improvement in life expectancy
rescein or indocyanine green angiography is extremely for patients with diabetes mellitus, it is now a leading
useful for their detection. Neovascular membranes are cause of blindness in the United States. The retinopathy
treated with either photodynamic therapy or intraocular of diabetes takes years to develop but eventually appears
injection of vascular endothelial growth factor antago- in nearly all cases. Regular surveillance of the dilated
nists. Surgical attempts to remove subretinal membranes fundus is crucial for any patient with diabetes. In
advanced diabetic retinopathy, the proliferation of neovas-
cular vessels leads to blindness from vitreous hemorrhage,
retinal detachment, and glaucoma. These complications
can be avoided in most patients by administration of
panretinal laser photocoagulation at the appropriate point
in the evolution of the disease.

Retinitis Pigmentosa
This is a general term for a disparate group of rod and
cone dystrophies characterized by progressive night blind-
ness, visual eld constriction with a ring scotoma, loss of
acuity, and an abnormal electroretinogram (ERG). It
occurs sporadically or in an autosomal recessive, domi-
nant, or X-linked pattern. Irregular black deposits of
clumped pigment in the peripheral retina, called bone
FIGURE 17-16 spicules because of their vague resemblance to the spicules
Age-related macular degeneration begins with the accu- of cancellous bone, give the disease its name (Fig. 17-17).
mulation of drusen within the macula. They appear as scat- The name is actually a misnomer because retinitis pig-
tered yellow subretinal deposits. mentosa is not an inammatory process. Most cases are
 186
SECTION II

FIGURE 17-17 FIGURE 17-18

Retinitis pigmentosa with black clumps of pigment in the Melanoma of the choroid, appearing as an elevated dark
retinal periphery known as bone spicules. There is also mass in the inferior temporal fundus, just encroaching upon
Clinical Manifestations of Neurologic Disease

atrophy of the retinal pigment epithelium, making the vascu- the fovea.
lature of the choroid easily visible.

due to a mutation in the gene for rhodopsin, the rod and loss of vision. A small melanoma is often difcult to
photopigment, or in the gene for peripherin, a glycopro- differentiate from a benign choroidal nevus. Serial exam-
tein located in photoreceptor outer segments.Vitamin A inations are required to document a malignant pattern of
(15,000 IU/day) slightly retards the deterioration of the growth.Treatment of melanoma is controversial. Options
ERG in patients with retinitis pigmentosa but has no include enucleation, local resection, and irradiation.
benecial effect on visual acuity or elds. Some forms of Metastatic tumors to the eye outnumber primary tumors.
retinitis pigmentosa occur in association with rare, hered- Breast and lung carcinoma have a special propensity to
itary systemic diseases (olivopontocerebellar degenera- spread to the choroid or iris. Leukemia and lymphoma
tion, Bassen-Kornzweig disease, Kearns-Sayre syndrome, also commonly invade ocular tissues. Sometimes their
Refsums disease). Chronic treatment with chloroquine, only sign on eye examination is cellular debris in the vit-
hydroxychloroquine, and phenothiazines (especially thior- reous, which can masquerade as a chronic posterior
idazine) can produce visual loss from a toxic retinopathy uveitis. Retrobulbar tumor of the optic nerve (meningioma,
that resembles retinitis pigmentosa. glioma) or chiasmal tumor (pituitary adenoma, menin-
gioma) produces gradual visual loss with few objective
Epiretinal Membrane ndings, except for optic disc pallor. Rarely, sudden
expansion of a pituitary adenoma from infarction and
This is a brocellular tissue that grows across the inner bleeding (pituitary apoplexy) causes acute retrobulbar visual
surface of the retina, causing metamorphopsia and loss, with headache, nausea, and ocular motor nerve
reduced visual acuity from distortion of the macula. A palsies. In any patient with visual eld loss or optic atro-
crinkled, cellophane-like membrane is visible on the phy, CT or MR scanning should be considered if the
retinal examination. Epiretinal membrane is most com- cause remains unknown after careful review of the his-
mon in patients older than 50 years and is usually unilat- tory and thorough examination of the eye.
eral. Most cases are idiopathic, but some occur as a result
of hypertensive retinopathy, diabetes, retinal detachment,
or trauma. When visual acuity is reduced to the level of PROPTOSIS
about 6/24 (20/80), vitrectomy and surgical peeling of
the membrane to relieve macular puckering are recom- When the globes appear asymmetric, the clinician must
mended. Contraction of an epiretinal membrane some- rst decide which eye is abnormal. Is one eye recessed
times gives rise to a macular hole. Most macular holes, within the orbit (enophthalmos) or is the other eye protu-
however, are caused by local vitreous traction within the berant (exophthalmos, or proptosis)? A small globe or a
fovea.Vitrectomy can improve acuity in selected cases. Horners syndrome can give the appearance of enoph-
thalmos. True enophthalmos occurs commonly after
trauma, from atrophy of retrobulbar fat, or fracture of
Melanoma and Other Tumors
the orbital oor. The position of the eyes within the
Melanoma is the most common primary tumor of the eye orbits is measured using a Hertel exophthalmometer, a
(Fig. 17-18). It causes photopsia, an enlarging scotoma, hand-held instrument that records the position of the
anterior corneal surface relative to the lateral orbital rim. blindness, septic cavernous sinus thrombosis, and menin- 187
If this instrument is not available, relative eye position gitis. To avert this disaster, orbital cellulitis should be
can be judged by bending the patients head forward and managed aggressively in the early stages, with immediate
looking down upon the orbits. A proptosis of only 2 mm imaging of the orbits and antibiotic therapy that
in one eye is detectable from this perspective.The devel- includes coverage of methicillin-resistant Staphylococcus
opment of proptosis implies a space-occupying lesion in aureus. Prompt surgical drainage of an orbital abscess or
the orbit, and usually warrants CT or MR imaging. paranasal sinusitis is indicated if optic nerve function
deteriorates despite antibiotics.
Graves Ophthalmopathy

CHAPTER 17
This is the leading cause of proptosis in adults.The prop- Tumors
tosis is often asymmetric and can even appear to be uni- Tumors of the orbit cause painless, progressive proptosis.
lateral. Orbital inammation and engorgement of the The most common primary tumors are hemangioma,
extraocular muscles, particularly the medial rectus and the lymphangioma, neurobroma, dermoid cyst, adenoid
inferior rectus, account for the protrusion of the globe. cystic carcinoma, optic nerve glioma, optic nerve menin-
Corneal exposure, lid retraction, conjunctival injection, gioma, and benign mixed tumor of the lacrimal gland.

Disorders of Vision
restriction of gaze, diplopia, and visual loss from optic Metastatic tumor to the orbit occurs frequently in breast
nerve compression are cardinal symptoms. Graves oph- carcinoma, lung carcinoma, and lymphoma. Diagnosis
thalmopathy is treated with oral prednisone (60 mg/d) for by ne-needle aspiration followed by urgent radiation
1 month, followed by a taper over several months, topical therapy can sometimes preserve vision.
lubricants, eyelid surgery, eye muscle surgery, or orbital
decompression. Radiation therapy is not effective.
Carotid Cavernous Fistulas
Orbital Pseudotumor With anterior drainage through the orbit these produce
proptosis, diplopia, glaucoma, and corkscrew, arterialized
This is an idiopathic, inammatory orbital syndrome, fre- conjunctival vessels. Direct stulas usually result from
quently confused with Graves ophthalmopathy. Symptoms trauma. They are easily diagnosed because of the promi-
are pain, limited eye movements, proptosis, and congestion. nent signs produced by high-ow, high-pressure shunting.
Evaluation for sarcoidosis, Wegeners granulomatosis, and Indirect stulas, or dural arteriovenous malformations, are
other types of orbital vasculitis or collagen-vascular disease more likely to occur spontaneously, especially in older
is negative. Imaging often shows swollen eye muscles women. The signs are more subtle and the diagnosis is
(orbital myositis) with enlarged tendons. By contrast, in frequently missed. The combination of slight proptosis,
Graves ophthalmopathy the tendons of the eye muscles are diplopia, enlarged muscles, and an injected eye is often
usually spared.The Tolosa-Hunt syndrome may be regarded mistaken for thyroid ophthalmopathy. A bruit heard upon
as an extension of orbital pseudotumor through the supe- auscultation of the head, or reported by the patient, is a
rior orbital ssure into the cavernous sinus. The diagnosis valuable diagnostic clue. Imaging shows an enlarged supe-
of orbital pseudotumor is difcult. Biopsy of the orbit fre- rior ophthalmic vein in the orbits. Carotid cavernous
quently yields nonspecic evidence of fat inltration by shunts can be eliminated by intravascular embolization.
lymphocytes, plasma cells, and eosinophils. A dramatic
response to a therapeutic trial of systemic glucocorticoids
indirectly provides the best conrmation of the diagnosis. PTOSIS
Blepharoptosis
Orbital Cellulitis
This is an abnormal drooping of the eyelid. Unilateral or
This causes pain, lid erythema, proptosis, conjunctival bilateral ptosis can be congenital, from dysgenesis of the
chemosis, restricted motility, decreased acuity, afferent levator palpebrae superioris, or from abnormal insertion
pupillary defect, fever, and leukocytosis. It often arises of its aponeurosis into the eyelid. Acquired ptosis can
from the paranasal sinuses, especially by contiguous develop so gradually that the patient is unaware of the
spread of infection from the ethmoid sinus through the problem. Inspection of old photographs is helpful in
lamina papyracea of the medial orbit. A history of recent dating the onset. A history of prior trauma, eye surgery,
upper respiratory tract infection, chronic sinusitis, thick contact lens use, diplopia, systemic symptoms (e.g., dys-
mucous secretions, or dental disease is signicant in any phagia or peripheral muscle weakness), or a family his-
patient with suspected orbital cellulitis. Blood cultures tory of ptosis should be sought. Fluctuating ptosis that
should be obtained, but they are usually negative. Most worsens late in the day is typical of myasthenia gravis.
patients respond to empirical therapy with broad- Examination should focus upon evidence for proptosis,
spectrum IV antibiotics. Occasionally, orbital cellulitis eyelid masses or deformities, inammation, pupil
follows an overwhelming course, with massive proptosis, inequality, or limitation of motility. The width of the
 188 palpebral ssures is measured in primary gaze to quanti- limitation of adduction, elevation, and depression, a
tate the degree of ptosis. The ptosis will be underesti- pupil-sparing oculomotor nerve palsy is likely (see next
mated if the patient compensates by lifting the brow section). Rarely, a lesion affecting the small, central sub-
with the frontalis muscle. nucleus of the oculomotor complex will cause bilateral
ptosis with normal eye movements and pupils.
Mechanical Ptosis
DOUBLE VISION (DIPLOPIA)
This occurs in many elderly patients from stretching and
redundancy of eyelid skin and subcutaneous fat (derma- The rst point to clarify is whether diplopia persists in
tochalasis). The extra weight of these sagging tissues either eye after covering the opposite eye. If it does, the
SECTION II

causes the lid to droop. Enlargement or deformation of diagnosis is monocular diplopia. The cause is usually
the eyelid from infection, tumor, trauma, or inamma- intrinsic to the eye and therefore has no dire implica-
tion also results in ptosis on a purely mechanical basis. tions for the patient. Corneal aberrations (e.g., kerato-
conus, pterygium), uncorrected refractive error, cataract,
or foveal traction may give rise to monocular diplopia.
Aponeurotic Ptosis Occasionally it is a symptom of malingering or psychi-
Clinical Manifestations of Neurologic Disease

This is an acquired dehiscence or stretching of the atric disease. Diplopia alleviated by covering one eye is
aponeurotic tendon, which connects the levator muscle binocular diplopia and is caused by disruption of ocular
to the tarsal plate of the eyelid. It occurs commonly in alignment. Inquiry should be made into the nature of
older patients, presumably from loss of connective tissue the double vision (purely side-by-side versus partial ver-
elasticity. Aponeurotic ptosis is also a frequent sequela of tical displacement of images), mode of onset, duration,
eyelid swelling from infection or blunt trauma to the intermittency, diurnal variation, and associated neuro-
orbit, cataract surgery, or hard contact lens usage. logic or systemic symptoms. If the patient has diplopia
while being examined, motility testing should reveal a
deciency corresponding to the patients symptoms.
Myogenic Ptosis However, subtle limitation of ocular excursions is often
The causes of myogenic ptosis include myasthenia gravis difcult to detect. For example, a patient with a slight
(Chap. 42) and a number of rare myopathies that mani- left abducens nerve paresis may appear to have full eye
fest with ptosis. The term chronic progressive external oph- movements, despite a complaint of horizontal diplopia
thalmoplegia refers to a spectrum of systemic diseases upon looking to the left. In this situation, the cover test
caused by mutations of mitochondrial DNA. As the provides a more sensitive method for demonstrating the
name implies, the most prominent ndings are symmet- ocular misalignment. It should be conducted in primary
ric, slowly progressive ptosis and limitation of eye move- gaze, and then with the head turned and tilted in each
ments. In general, diplopia is a late symptom because all direction. In the above example, a cover test with the
eye movements are reduced equally. In the Kearns-Sayre head turned to the right will maximize the xation shift
variant, retinal pigmentary changes and abnormalities of evoked by the cover test.
cardiac conduction develop. Peripheral muscle biopsy Occasionally, a cover test performed in an asympto-
shows characteristic ragged-red bers. Oculopharyngeal matic patient during a routine examination will reveal
dystrophy is a distinct autosomal dominant disease with an ocular deviation. If the eye movements are full and
onset in middle age, characterized by ptosis, limited eye the ocular misalignment is equal in all directions of gaze
movements, and trouble swallowing. Myotonic dystrophy, (concomitant deviation), the diagnosis is strabismus. In
another autosomal dominant disorder, causes ptosis, this condition, which affects about 1% of the popula-
ophthalmoparesis, cataract, and pigmentary retinopathy. tion, fusion is disrupted in infancy or early childhood.
Patients have muscle wasting, myotonia, frontal balding, To avoid diplopia, vision is suppressed from the nonx-
and cardiac abnormalities. ating eye. In some children, this leads to impaired vision
(amblyopia, or lazy eye) in the deviated eye.
Binocular diplopia occurs from a wide range of
Neurogenic Ptosis
processes: infectious, neoplastic, metabolic, degenerative,
This results from a lesion affecting the innervation to inammatory, and vascular. One must decide if the diplopia
either of the two muscles that open the eyelid: Mllers is neurogenic in origin or due to restriction of globe rota-
muscle or the levator palpebrae superioris. Examination tion by local disease in the orbit. Orbital pseudotumor,
of the pupil helps to distinguish between these two pos- myositis, infection, tumor, thyroid disease, and muscle
sibilities. In Horners syndrome, the eye with ptosis has a entrapment (e.g., from a blowout fracture) cause restrictive
smaller pupil and the eye movements are full. In an ocu- diplopia.The diagnosis of restriction is usually made by rec-
lomotor nerve palsy, the eye with the ptosis has a larger, ognizing other associated signs and symptoms of local
or a normal, pupil. If the pupil is normal but there is orbital disease in conjunction with imaging.
Myasthenia Gravis to the red nucleus results in ipsilateral oculomotor palsy 189
and contralateral tremor, chorea, and athetosis. Claudes
(See Chap. 42) This is a major cause of diplopia. The
syndrome incorporates features of both the aforemen-
diplopia is often intermittent, variable, and not conned
tioned syndromes, by injury to both the red nucleus and
to any single ocular motor nerve distribution.The pupils
the superior cerebellar peduncle. Finally, in Webers syn-
are always normal. Fluctuating ptosis may be present.
drome, injury to the cerebral peduncle causes ipsilateral
Many patients have a purely ocular form of the disease,
oculomotor palsy with contralateral hemiparesis.
with no evidence of systemic muscular weakness. The
In the subarachnoid space the oculomotor nerve is
diagnosis can be conrmed by an IV edrophonium
vulnerable to aneurysm, meningitis, tumor, infarction,
injection or by an assay for antiacetylcholine receptor

CHAPTER 17
and compression. In cerebral herniation the nerve
antibodies. Negative results from these tests do not
becomes trapped between the edge of the tentorium
exclude the diagnosis. Botulism from food or wound
and the uncus of the temporal lobe. Oculomotor palsy
poisoning can mimic ocular myasthenia.
can also occur from midbrain torsion and hemorrhages
After restrictive orbital disease and myasthenia gravis
during herniation. In the cavernous sinus, oculomotor
are excluded, a lesion of a cranial nerve supplying inner-
palsy arises from carotid aneurysm, carotid cavernous s-
vation to the extraocular muscles is the most likely cause
tula, cavernous sinus thrombosis, tumor (pituitary ade-

Disorders of Vision
of binocular diplopia.
noma, meningioma, metastasis), herpes zoster infection,
and the Tolosa-Hunt syndrome.
Oculomotor Nerve The etiology of an isolated, pupil-sparing oculomotor
palsy often remains an enigma, even after neuroimaging
The third cranial nerve innervates the medial, inferior, and extensive laboratory testing. Most cases are thought
and superior recti; inferior oblique; levator palpebrae to result from microvascular infarction of the nerve,
superioris; and the iris sphincter. Total palsy of the ocu- somewhere along its course from the brainstem to the
lomotor nerve causes ptosis, a dilated pupil, and leaves orbit. Usually the patient complains of pain. Diabetes,
the eye down and out because of the unopposed hypertension, and vascular disease are major risk factors.
action of the lateral rectus and superior oblique. This Spontaneous recovery over a period of months is the
combination of ndings is obvious. More challenging is rule. If this fails to occur, or if new ndings develop, the
the diagnosis of early or partial oculomotor nerve palsy. diagnosis of microvascular oculomotor nerve palsy
In this setting, any combination of ptosis, pupil dilation, should be reconsidered. Aberrant regeneration is com-
and weakness of the eye muscles supplied by the oculo- mon when the oculomotor nerve is injured by trauma or
motor nerve may be encountered. Frequent serial exam- compression (tumor, aneurysm). Miswiring of sprouting
inations during the evolving phase of the palsy help bers to the levator muscle and the rectus muscles results
ensure that the diagnosis is not missed.The advent of an in elevation of the eyelid upon downgaze or adduction.
oculomotor nerve palsy with a pupil involvement, espe- The pupil also constricts upon attempted adduction, ele-
cially when accompanied by pain, suggests a compressive vation, or depression of the globe. Aberrant regeneration
lesion, such as a tumor or circle of Willis aneurysm. is not seen after oculomotor palsy from microvascular
Neuroimaging should be obtained, along with a CT or infarct and hence vitiates that diagnosis.
MR angiogram. Occasionally, a catheter arteriogram must
be done to exclude an aneurysm.
Trochlear Nerve
A lesion of the oculomotor nucleus in the rostral
midbrain produces signs that differ from those caused by The fourth cranial nerve originates in the midbrain, just
a lesion of the nerve itself. There is bilateral ptosis caudal to the oculomotor nerve complex. Fibers exit the
because the levator muscle is innervated by a single cen- brainstem dorsally and cross to innervate the contralat-
tral subnucleus.There is also weakness of the contralateral eral superior oblique.The principal actions of this muscle
superior rectus, because it is supplied by the oculomotor are to depress and to intort the globe. A palsy therefore
nucleus on the other side. Occasionally both superior results in hypertropia and excyclotorsion. The cyclotor-
recti are weak. Isolated nuclear oculomotor palsy is rare. sion is seldom noticed by patients. Instead, they complain
Usually neurologic examination reveals additional signs to of vertical diplopia, especially upon reading or looking
suggest brainstem damage from infarction, hemorrhage, down.The vertical diplopia is also exacerbated by tilting
tumor, or infection. the head toward the side with the muscle palsy, and alle-
Injury to structures surrounding fascicles of the ocu- viated by tilting it away.This head tilt test is a cardinal
lomotor nerve descending through the midbrain has diagnostic feature.
given rise to a number of classic eponymic designations. Isolated trochlear nerve palsy occurs from all the causes
In Nothnagels syndrome, injury to the superior cerebellar listed above for the oculomotor nerve, except aneurysm.
peduncle causes ipsilateral oculomotor palsy and con- The trochlear nerve is particularly apt to suffer injury
tralateral cerebellar ataxia. In Benedikts syndrome, injury after closed head trauma.The free edge of the tentorium
 190 is thought to impinge upon the nerve during a concussive As mentioned above for isolated trochlear or oculomo-
blow. Most isolated trochlear nerve palsies are idiopathic tor palsy, most cases are assumed to represent microvas-
and hence diagnosed by exclusion as microvascular. cular infarcts because they often occur in the setting of
Spontaneous improvement occurs over a period of diabetes or other vascular risk factors. Some cases may
months in most patients. A base-down prism (conve- develop as a postinfectious mononeuritis (e.g., following
niently applied to the patients glasses as a stick-on Fresnel a viral u). Patching one eye or applying a temporary
lens) may serve as a temporary measure to alleviate prism will provide relief of diplopia until the palsy
diplopia. If the palsy does not resolve, the eyes can be resolves. If recovery is incomplete, eye muscle surgery can
realigned by weakening the inferior oblique muscle. nearly always realign the eyes, at least in primary posi-
tion. A patient with an abducens palsy that fails to
SECTION II

Abducens Nerve improve should be reevaluated for an occult etiology

(e.g., chordoma, carcinomatous meningitis, carotid cav-
The sixth cranial nerve innervates the lateral rectus mus- ernous stula, myasthenia gravis).
cle. A palsy produces horizontal diplopia, worse on gaze
to the side of the lesion. A nuclear lesion has different
consequences, because the abducens nucleus contains Multiple Ocular Motor Nerve Palsies
Clinical Manifestations of Neurologic Disease

interneurons that project via the medial longitudinal fas-

These should not be attributed to spontaneous
ciculus to the medial rectus subnucleus of the contralat-
microvascular events affecting more than one cranial
eral oculomotor complex.Therefore, an abducens nuclear
nerve at a time.This remarkable coincidence does occur,
lesion produces a complete lateral gaze palsy, from weak-
especially in diabetic patients, but the diagnosis is made
ness of both the ipsilateral lateral rectus and the contralat-
only in retrospect after exhausting all other diagnostic
eral medial rectus. Fovilles syndrome following dorsal
alternatives. Neuroimaging should focus on the cav-
pontine injury includes lateral gaze palsy, ipsilateral facial
ernous sinus, superior orbital ssure, and orbital apex,
palsy, and contralateral hemiparesis incurred by damage to
where all three ocular motor nerves are in close proxim-
descending corticospinal bers. Millard-Gubler syndrome
ity. In the diabetic or compromised host, fungal infec-
from ventral pontine injury is similar, except for the eye
tion (Aspergillus, Mucorales, Cryptococcus) is a frequent
ndings. There is lateral rectus weakness only, instead of
cause of multiple nerve palsies. In the patient with sys-
gaze palsy, because the abducens fascicle is injured rather
temic malignancy, carcinomatous meningitis is a likely
than the nucleus. Infarct, tumor, hemorrhage, vascular
diagnosis. Cytologic examination may be negative
malformation, and multiple sclerosis are the most com-
despite repeated sampling of the cerebrospinal uid.The
mon etiologies of brainstem abducens palsy.
cancer-associated Lambert-Eaton myasthenic syndrome
After leaving the ventral pons, the abducens nerve
can also produce ophthalmoplegia. Giant cell (temporal)
runs forward along the clivus to pierce the dura at the
arteritis occasionally manifests as diplopia from ischemic
petrous apex, where it enters the cavernous sinus.Along its
palsies of extraocular muscles. Fisher syndrome, an ocu-
subarachnoid course it is susceptible to meningitis, tumor
lar variant of Guillain-Barr, produces ophthalmoplegia
(meningioma, chordoma, carcinomatous meningitis), sub-
with areexia and ataxia. Often the ataxia is mild, and
arachnoid hemorrhage, trauma, and compression by
the reexes are normal. Antiganglioside antibodies
aneurysm or dolichoectatic vessels. At the petrous apex,
(GQ1b) can be detected in about 50% of cases.
mastoiditis can produce deafness, pain, and ipsilateral
abducens palsy (Gradenigos syndrome). In the cavernous
sinus, the nerve can be affected by carotid aneurysm,
Supranuclear Disorders of Gaze
carotid cavernous stula, tumor (pituitary adenoma,
meningioma, nasopharyngeal carcinoma), herpes infec- These are often mistaken for multiple ocular motor
tion, and Tolosa-Hunt syndrome. nerve palsies. For example, Wernickes encephalopathy
Unilateral or bilateral abducens palsy is a classic sign can produce nystagmus and a partial decit of horizon-
of raised intracranial pressure.The diagnosis can be con- tal and vertical gaze that mimics a combined abducens
rmed if papilledema is observed on fundus examina- and oculomotor nerve palsy. The disorder occurs in mal-
tion. The mechanism is still debated but is probably nourished or alcoholic patients and can be reversed by
related to rostral-caudal displacement of the brainstem. thiamine. Infarct, hemorrhage, tumor, multiple sclerosis,
The same phenomenon accounts for abducens palsy from encephalitis, vasculitis, and Whipples disease are other
low intracranial pressure (e.g., after lumbar puncture, important causes of supranuclear gaze palsy. Disorders of
spinal anesthesia, or spontaneous dural cerebrospinal uid vertical gaze, especially downwards saccades, are an early
leak). feature of progressive supranuclear palsy. Smooth pursuit
Treatment of abducens palsy is aimed at prompt correc- is affected later in the course of the disease. Parkinsons
tion of the underlying cause. However, the cause remains disease, Huntingtons chorea, and olivopontocerebellar
obscure in many instances, despite diligent evaluation. degeneration can also affect vertical gaze.
 The frontal eye eld of the cerebral cortex is involved 191
in generation of saccades to the contralateral side. After
hemispheric stroke, the eyes usually deviate towards the
lesioned side because of the unopposed action of the
frontal eye eld in the normal hemisphere. With time,
this decit resolves. Seizures generally have the opposite
effect: the eyes deviate conjugately away from the irrita-
tive focus. Parietal lesions disrupt smooth pursuit of targets
moving toward the side of the lesion. Bilateral parietal

CHAPTER 17
lesions produce Balints syndrome, characterized by
impaired eye-hand coordination (optic ataxia), difculty
initiating voluntary eye movements (ocular apraxia), and
visuospatial disorientation (simultanagnosia).

Horizontal Gaze

Disorders of Vision
Descending cortical inputs mediating horizontal gaze
ultimately converge at the level of the pons. Neurons in
the paramedian pontine reticular formation are respon-
sible for controlling conjugate gaze toward the same
side. They project directly to the ipsilateral abducens
nucleus. A lesion of either the paramedian pontine retic-
ular formation or the abducens nucleus causes an ipsilat-
eral conjugate gaze palsy. Lesions at either locus produce
nearly identical clinical syndromes, with the following
exception: vestibular stimulation (oculocephalic maneu-
ver or caloric irrigation) will succeed in driving the eyes
conjugately to the side in a patient with a lesion of the
paramedian pontine reticular formation, but not in a
patient with a lesion of the abducens nucleus.

Internuclear Ophthalmoplegia
This results from damage to the medial longitudinal fas-
ciculus ascending from the abducens nucleus in the pons
to the oculomotor nucleus in the midbrain (hence,
internuclear). Damage to bers carrying the conju-
gate signal from abducens interneurons to the contralat-
eral medial rectus motoneurons results in a failure of
adduction on attempted lateral gaze. For example, a
patient with a left internuclear ophthalmoplegia will
have slowed or absent adducting movements of the left
eye (Fig. 17-19). A patient with bilateral injury to the
medial longitudinal fasciculus will have bilateral inter-
nuclear ophthalmoplegia. Multiple sclerosis is the most
common cause, although tumor, stroke, trauma, or any
brainstem process may be responsible. One-and-a-half
syndrome is due to a combined lesion of the medial lon-
gitudinal fasciculus and the abducens nucleus on the FIGURE 17-19
same side.The patients only horizontal eye movement is Left internuclear ophthalmoplegia (INO). A. In primary posi-
abduction of the eye on the other side. tion of gaze the eyes appear normal. B. Horizontal gaze to the
left is intact. C. On attempted horizontal gaze to the right, the
left eye fails to adduct. In mildly affected patients the eye may
Vertical Gaze
adduct partially, or more slowly than normal. Nystagmus is
This is controlled at the level of the midbrain.The neu- usually present in the abducted eye. D. T2-weighted axial MRI
ronal circuits affected in disorders of vertical gaze are image through the pons showing a demyelinating plaque in
not fully elucidated, but lesions of the rostral interstitial the left medial longitudinal fasciculus (arrow).
 192 nucleus of the medial longitudinal fasciculus and the Gaze-Evoked Nystagmus
interstitial nucleus of Cajal cause supranuclear paresis of This is the most common form of jerk nystagmus.
upgaze, downgaze, or all vertical eye movements. Distal When the eyes are held eccentrically in the orbits, they
basilar artery ischemia is the most common etiology. have a natural tendency to drift back to primary posi-
Skew deviation refers to a vertical misalignment of the tion. The subject compensates by making a corrective
eyes, usually constant in all positions of gaze.The nding saccade to maintain the deviated eye position. Many
has poor localizing value because skew deviation has normal patients have mild gaze-evoked nystagmus.
been reported after lesions in widespread regions of the Exaggerated gaze-evoked nystagmus can be induced by
brainstem and cerebellum. drugs (sedatives, anticonvulsants, alcohol); muscle paresis;
SECTION II

myasthenia gravis; demyelinating disease; and cerebello-

Parinauds Syndrome pontine angle, brainstem, and cerebellar lesions.
Also known as dorsal midbrain syndrome, this is a distinct
supranuclear vertical gaze disorder from damage to the Vestibular Nystagmus
posterior commissure. It is a classic sign of hydrocephalus Vestibular nystagmus results from dysfunction of the
from aqueductal stenosis. Pineal region tumors, cysticer- labyrinth (Mnires disease), vestibular nerve, or
cosis, and stroke also cause Parinauds syndrome. Features
Clinical Manifestations of Neurologic Disease

vestibular nucleus in the brainstem. Peripheral vestibular

include loss of upgaze (and sometimes downgaze), con- nystagmus often occurs in discrete attacks, with symptoms
vergence-retraction nystagmus on attempted upgaze, of nausea and vertigo. There may be associated tinnitus
downwards ocular deviation (setting sun sign), lid retrac- and hearing loss. Sudden shifts in head position may
tion (Colliers sign), skew deviation, pseudoabducens provoke or exacerbate symptoms.
palsy, and light-near dissociation of the pupils.
Downbeat Nystagmus
Nystagmus Downbeat nystagmus occurs from lesions near the cranio-
This is a rhythmical oscillation of the eyes, occurring cervical junction (Chiari malformation, basilar invagina-
physiologically from vestibular and optokinetic stimulation tion). It has also been reported in brainstem or cerebellar
or pathologically in a wide variety of diseases (Chap. 9). stroke, lithium or anticonvulsant intoxication, alcoholism,
Abnormalities of the eyes or optic nerves, present at birth and multiple sclerosis. Upbeat nystagmus is associated
or acquired in childhood, can produce a complex, with damage to the pontine tegmentum, from stroke,
searching nystagmus with irregular pendular (sinusoidal) demyelination, or tumor.
and jerk features. This nystagmus is commonly referred
to as congenital sensory nystagmus. It is a poor term, because Opsoclonus
even in children with congenital lesions, the nystagmus
does not appear until several months of age. Congenital This rare, dramatic disorder of eye movements consists
motor nystagmus, which looks similar to congenital sensory of bursts of consecutive saccades (saccadomania). When
nystagmus, develops in the absence of any abnormality of the saccades are conned to the horizontal plane, the
the sensory visual system.Visual acuity is also reduced in term ocular utter is preferred. It can occur from viral
congenital motor nystagmus, probably by the nystagmus encephalitis, trauma, or a paraneoplastic effect of neu-
itself, but seldom below a level of 20/200. roblastoma, breast carcinoma, and other malignancies. It
has also been reported as a benign, transient phenomenon
Jerk Nystagmus in otherwise healthy patients.
This is characterized by a slow drift off the target, fol-
lowed by a fast corrective saccade. By convention, the
nystagmus is named after the quick phase. Jerk nystag- FURTHER READINGS
mus can be downbeat, upbeat, horizontal (left or right), ALBERT DM et al (eds): Albert and Jakobiecs Principles and Practice of
and torsional. The pattern of nystagmus may vary with Ophthalmology, 3d ed. Philadelphia, Saunders, 2007
gaze position. Some patients will be oblivious to their DAMICO DJ: Clinical practice: Primary Retinal Detachment. N Engl
nystagmus. Others will complain of blurred vision, or a J Med 359:2346, 2008
subjective, to-and-fro movement of the environment ROSENFELD PJ et al: Ranibizumab for neovascular age-related macu-
lar degeneration. N Engl J Med 355:1419, 2006
(oscillopsia) corresponding to their nystagmus. Fine nys-
RUTAR T et al: Ophthalmic manifestations of infections caused by
tagmus may be difcult to see upon gross examination the USA300 clone of community-associated methicillin-resistant
of the eyes. Observation of nystagmoid movements of Staphylococcus aureus. Ophthalmology 113:1455, 2006
the optic disc on ophthalmoscopy is a sensitive way to TING AY et al: Genetics of age-related macular degeneration. Curr
detect subtle nystagmus. Opin Ophthalmol 20:369, 2009
 CHAPTER 18

DISORDERS OF SMELL, TASTE, AND HEARING

Anil K. Lalwani

Smell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Denitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Physiology of Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Physiology of Smell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 Genetic Causes of Hearing Loss . . . . . . . . . . . . . . . . . . . . . . 199
Disorders of the Sense of Smell . . . . . . . . . . . . . . . . . . . . . . 194 Disorders of the Sense of Hearing . . . . . . . . . . . . . . . . . . . . . 201
Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Laboratory Assessment of Hearing . . . . . . . . . . . . . . . . . . . . 204
Denitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Physiology of Taste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Disorders of the Sense of Taste . . . . . . . . . . . . . . . . . . . . . . 197

to as an odorant. Each category of smell dysfunction can

SMELL be further subclassied as total (applying to all odorants)
The sense of smell determines the avor and palatability or partial (dysfunction of only select odorants).
of food and drink and serves, along with the trigeminal
system, as a monitor of inhaled chemicals, including PHYSIOLOGY OF SMELL
dangerous substances such as natural gas, smoke, and air
pollutants. Olfactory dysfunction affects ~1% of individ- The olfactory epithelium is located in the superior part of
uals younger than 60 years and more than one-half of the nasal cavities and is highly variable in its distribution
the population beyond this age. between individuals. Over time the olfactory epithelium
loses its homogeneity, as small areas undergo metaplasia
producing islands of respiratory-like epithelium. This
DEFINITIONS process is thought to be secondary to insults from envi-
Smell is the perception of odor by the nose. Taste is the ronmental toxins, bacteria, and viruses.The primary sen-
perception of salty, sweet, sour, or bitter by the tongue. sory neuron in the olfactory epithelium is the bipolar
Related sensations during eating such as somatic sensa- cell.The dendritic process of the bipolar cell has a bulb-
tions of coolness, warmth, and irritation are mediated shaped vesicle that projects into the mucous layer and
through the trigeminal, glossopharyngeal, and vagal affer- bears six to eight cilia containing odorant receptors. On
ents in the nose, oral cavity, tongue, pharynx, and larynx. average, each bipolar cell elaborates 56 cm2 (9 in.2) of
Flavor is the complex interaction of taste, smell, and surface area to receive olfactory stimuli. These primary
somatic sensation. Terms relating to disorders of smell sensory neurons are unique among sensory systems in
include anosmia, an absence of the ability to smell; hypos- that they are short-lived, regularly replaced, and regener-
mia, a decreased ability to smell; hyperosmia, an increased ate and establish new central connections after injury.
sensitivity to an odorant; dysosmia, distortion in the per- Basal stem cells, located on the basal surface of the olfac-
ception of an odor; phantosmia, perception of an odorant tory epithelium, are the progenitors that differentiate
where none is present; and agnosia, inability to classify, into new bipolar cells (Fig. 18-1).
contrast, or identify odor sensations verbally, even though Between 50 and 200 unmyelinated axons of receptor
the ability to distinguish between odorants or to recog- cells form the la of the olfactory nerve; they pass through
nize them may be normal. An odor stimulus is referred the cribriform plate to terminate within spherical masses
193
 194
Olfactory
Olfactory
bulb
bulb

Axons
FIGURE 18-1
Cribriform Olfaction. Olfactory sensory neurons (bipolar cells)
plate are embedded in a small area of specialized
Olfactory
epithelium Olfactory epithelium in the dorsal posterior recess of the
SECTION II

sensory nasal cavity. These neurons project axons to the

neurons olfactory bulb of the brain, a small ovoid structure
that rests on the cribriform plate of the ethmoid
Dendrite
bone. Odorants bind to specic receptors on olfac-
tory cilia and initiate a cascade of action potential
Mucous layer Cilia Basal events that lead to the production of action poten-
cells tials in the sensory axons.
Clinical Manifestations of Neurologic Disease

of neuropil, termed glomeruli, in the olfactory bulb. acetylcholine receptors; and neurotransmitter receptors
Olfactory ensheathing cells, which have features resem- for dopamine, serotonin, and substance P. In humans,
bling glia of both the central and peripheral nervous sys- there are 3001000 olfactory receptor genes belonging
tems, surround the axons along their course. The to 20 different families located in clusters at >25 differ-
glomeruli are the focus of a high degree of convergence ent chromosomal locations. Each olfactory neuron
of information, since many more bers enter than leave expresses only one or, at most, a few receptor genes, thus
them. The main second-order neurons are mitral cells. providing the molecular basis of odor discrimination.
The primary dendrite of each mitral cell extends into a Bipolar cells that express similar receptors appear to be
single glomerulus. Axons of the mitral cells project along scattered across discrete spatial zones. These similar cells
with the axons of adjacent tufted cells to the limbic sys- converge on a select few glomeruli in the olfactory
tem, including the anterior olfactory nucleus and the bulb. The result is a potential spatial map of how we
amygdala. Cognitive awareness of smell requires stimula- receive odor stimuli, much like the tonotopic organiza-
tion of the prepiriform cortex or amygdaloid nuclei. tion of how we perceive sound.
A secondary site of olfactory chemosensation is
located in the epithelium of the vomeronasal organ, a
tubular structure that opens on the ventral aspect of the DISORDERS OF THE SENSE OF SMELL
nasal septum. In humans, this structure is rudimentary These are caused by conditions that interfere with the
and nonfunctional, without central projections. Sensory access of the odorant to the olfactory neuroepithelium
neurons located in the vomeronasal organ detect (transport loss), injure the receptor region (sensory loss),
pheromones, nonvolatile chemical signals that in lower or damage central olfactory pathways (neural loss). Cur-
mammals trigger innate and stereotyped reproductive rently no clinical tests exist to differentiate these differ-
and social behaviors, as well as neuroendocrine changes. ent types of olfactory losses. Fortunately, the history of
The sensation of smell begins with introduction of an the disease provides important clues to the cause. The
odorant to the cilia of the bipolar neuron. Most odor- leading causes of olfactory disorders are summarized in
ants are hydrophobic; as they move from the air phase of Table 18-1; the most common etiologies are head
the nasal cavity to the aqueous phase of the olfactory trauma in children and young adults, and viral infections
mucous, they are transported toward the cilia by small in older adults.
water-soluble proteins called odorant-binding proteins and Head trauma is followed by unilateral or bilateral
reversibly bind to receptors on the cilia surface. Binding impairment of smell in up to 15% of cases; anosmia is
leads to conformational changes in the receptor protein, more common than hyposmia. Olfactory dysfunction is
activation of G proteincoupled second messengers, and more common when trauma is associated with loss of
generation of action potentials in the primary neurons. consciousness, moderately severe head injury (grades
Intensity appears to be coded by the amount of ring in IIV), and skull fracture. Frontal injuries and fractures
the afferent neurons. disrupt the cribriform plate and olfactory axons that
Olfactory receptor proteins belong to the large family perforate it. Sometimes there is an associated cere-
of G proteincoupled receptors that also includes brospinal uid (CSF) rhinorrhea resulting from a tearing
rhodopsins; - and -adrenergic receptors; muscarinic of the dura overlying the cribriform plate and paranasal
TABLE 18-1 disease, amyotrophic lateral sclerosis, and multiple sclerosis. 195
CAUSES OF OLFACTORY DYSFUNCTION In Alzheimers and Parkinsons, olfactory loss may be the
rst clinical sign of the disease. In Parkinsons disease, bilat-
Transport Losses Neural Losses
Allergic rhinitis AIDS
eral olfactory decits occur more commonly than the car-
Bacterial rhinitis and sinusitis Alcoholism dinal signs of the disorder such as tremor. In multiple scle-
Congenital abnormalities Alzheimers disease rosis, olfactory loss is related to lesions visible by MRI, in
Nasal neoplasms Cigarette smoke olfactory processing areas in the temporal and frontal lobes.
Nasal polyps Depression Dysosmia, subjective distortions of olfactory percep-
Nasal septal deviation Diabetes mellitus tion, may occur with intranasal diseases that partially

CHAPTER 18
Nasal surgery Drugs/toxins impair smell or during recovery from a neurogenic
Viral infections Huntingtons chorea
Sensory Losses Hypothyroidism
anosmia. Most dysosmic disorders consist of disagreeable
Drugs Kallmann syndrome odors, sometimes accompanied by distortions of taste.
Neoplasms Malnutrition Dysosmia also can occur with depression.
Radiation therapy Neoplasms
Toxin exposure Neurosurgery
Viral infections Parkinsons disease

Disorders of Smell, Taste, and Hearing

Trauma
Vitamin B12 deciency
Zinc deciency Approach to the Patient:
DISORDERS OF THE SENSE OF SMELL
Unilateral anosmia is rarely a complaint and is only
recognized by testing of smell in each nasal cavity sepa-
rately. Bilateral anosmia, on the other hand, brings
sinuses. Anosmia may also follow blows to the occiput.
patients to medical attention. Anosmic patients usually
Once traumatic anosmia develops, it is usually perma-
complain of a loss of the sense of taste even though
nent; only 10% of patients ever improve or recover. Per-
their taste thresholds may be within normal limits. In
version of the sense of smell may occur as a transient
actuality, they are complaining of a loss of avor detec-
phase in the recovery process.
tion, which is mainly an olfactory function.The physi-
Viral infections can destroy the olfactory neuroep-
cal examination should include a thorough inspection
ithelium, which is then replaced by respiratory epithe-
of the ears, upper respiratory tract, and head and neck.
lium. Parainuenza virus type 3 appears to be especially
A neurologic examination emphasizing the cranial
detrimental to human olfaction. HIV infection is associ-
nerves and cerebellar and sensorimotor function is
ated with subjective distortion of taste and smell, which
essential.Any signs of depression should be noted.
may become more severe as the disease progresses. The
Sensory olfactory function can be assessed by sev-
loss of taste and smell may play an important role in the
eral methods.The Odor Stix test uses a commercially
development and progression of HIV-associated wasting.
available odor-producing magic markerlike pen held
Congenital anosmias are rare but important. Kallmann
~815 cm (36 in.) from the patients nose. The
syndrome is an X-linked disorder characterized by con-
30-cm alcohol test uses a freshly opened isopropyl
genital anosmia and hypogonadotropic hypogonadism
alcohol packet held ~30 cm (12 in.) from the patients
resulting from a failure of migration from the olfactory
nose. There is a commercially available scratch-and-
placode of olfactory receptor neurons and neurons syn-
sniff card containing three odors available for gross
thesizing gonadotropin-releasing hormone. Anosmia can
testing of olfaction. A superior test is the University
also occur in albinos. The receptor cells are present but
of Pennsylvania Smell Identication Test (UPSIT).
are hypoplastic, lack cilia, and do not project above the
This consists of a 40-item, forced choice, scratch-and-
surrounding supporting cells.
sniff paradigm. For example, one of the items reads,
Meningiomas of the inferior frontal region are the most
This odor smells most like (a) chocolate, (b) banana,
frequent neoplastic cause of anosmia; loss of smell may be
(c) onion, or (d) fruit punch.The test is highly reliable,
the only neurologic abnormality. Rarely, anosmia can occur
is sensitive to age and sex differences, and provides an
with gliomas of the frontal lobe. Occasionally, pituitary ade-
accurate quantitative determination of the olfactory
nomas, craniopharyngiomas, suprasellar meningiomas, and
decit.The UPSIT, which is a forced-choice test, can
aneurysms of the anterior part of the circle of Willis
also be used to identify malingerers who typically
extend forward and damage olfactory structures. These
report fewer correct responses than would be
tumors and hamartomas may also induce seizures with
expected by chance.The average score for total anos-
olfactory hallucinations, indicating involvement of the
mics is slightly higher than that expected on the basis
uncus of the temporal lobe.
of chance because of the inclusion of some odorants
Olfactory dysfunction is common in a variety of neuro-
that act by trigeminal stimulation.
logic diseases, including Alzheimers disease, Parkinsons
 196 Olfactory threshold testing is another method of In addition, early recognition and counseling can help
assessing olfactory function. Following assessment of patients to compensate for the loss of smell. The inci-
sensory olfactory function, the detection threshold dence of natural gasrelated accidents is disproportion-
for an odorant such as methyl ethyl carbinol is estab- ately high in the elderly, perhaps due in part to the
lished using graduated concentrations for each side of gradual loss of smell. Mercaptan, the pungent odor in
the nose. Nasal resistance can also be measured with natural gas, is an olfactory stimulant that does not acti-
anterior rhinomanometry for each side of the nose. vate taste receptors. Many elderly with olfactory dys-
CT or MRI of the head is required to rule out function experience a decrease in avor sensation and
paranasal sinusitis; neoplasms of the anterior cranial nd it necessary to hyperavor food, usually by increas-
SECTION II

fossa, nasal cavity, or paranasal sinuses; or unsuspected ing the amount of salt in their diet.
fractures of the anterior cranial fossa. Bone abnormal-
ities are best seen with CT. MRI is the most sensitive
method to visualize olfactory bulbs, ventricles, and
other soft tissue of the brain. Coronal CT is optimal
for assessing cribriform plate, anterior cranial fossa,
TASTE
Clinical Manifestations of Neurologic Disease

and sinus anatomy. Compared with disorders of smell, gustatory disorders

Biopsy of the olfactory epithelium is possible. are uncommon. Loss of olfactory sensitivity is often
However, given the widespread degeneration of the accompanied by complaints of loss of the sense of taste,
olfactory epithelium and intercalation of respiratory usually with normal detection thresholds for taste.
epithelium in the olfactory area of adults with no
apparent olfactory dysfunction, biopsy results must be
interpreted with caution. DEFINITIONS
Disturbances of the sense of taste may be categorized as
total ageusia, total absence of gustatory function or
inability to detect the qualities of sweet, salt, bitter, or
Treatment: sour; partial ageusia, ability to detect some but not all of
DISORDERS OF THE SENSE OF SMELL the qualitative gustatory sensations; specic ageusia, inabil-
Therapy for patients with transport olfactory losses due ity to detect the taste quality of certain substances; total
to allergic rhinitis, bacterial rhinitis and sinusitis, polyps, hypogeusia, decreased sensitivity to all tastants; partial
neoplasms, and structural abnormalities of the nasal hypogeusia, decreased sensitivity to some tastants; and dys-
cavities can be undertaken with a high likelihood for geusia or phantogeusia, distortion in the perception of a
improvement. Allergy management; antibiotic therapy; tastant, i.e., the perception of the wrong quality when a
topical and systemic glucocorticoid therapy; and tastant is presented or the perception of a taste when
surgery for nasal polyps, deviation of the nasal septum, there has been no tastant ingested. Confusion between
and chronic hyperplastic sinusitis are frequently effec- sour and bitter, and less commonly between salty and
tive in restoring the sense of smell. bitter, may represent a semantic misunderstanding or
There is no proven treatment for sensorineural olfac- have a true pathophysiologic basis. It may be possible to
tory losses. Fortunately, spontaneous recovery often differentiate between the loss of avor recognition in
occurs. Zinc and vitamin therapy (especially with vita- patients with olfactory losses who complain of a loss of
min A) are advocated by some. Profound zinc deciency taste as well as smell by asking if they are able to taste
can produce loss and distortion of the sense of smell sweetness in sodas, saltiness in potato chips, etc.
but is not a clinically important problem except in very
limited geographic areas. The epithelial degeneration PHYSIOLOGY OF TASTE
associated with vitamin A deciency can cause anos-
mia, but in western societies the prevalence of vitamin
The taste receptor cells are located in the taste buds,
spherical groups of cells arranged in a pattern resem-
A deciency is low. Exposure to cigarette smoke and
bling the segments of a citrus fruit (Fig. 18-2). At the
other airborne toxic chemicals can cause metaplasia of
surface, the taste bud has a pore into which microvilli of
the olfactory epithelium, and spontaneous recovery can
the receptor cells project. Unlike the olfactory system,
occur if the insult is removed. Counseling of patients is
the receptor cell is not the primary neuron. Instead, gus-
therefore helpful in such cases.
tatory afferent nerve bers contact individual taste
More than one-half of people older than 60 years suf-
receptor cells. The papillae lie along the lateral margin
fer from olfactory dysfunction. No effective treatment
and dorsum of the tongue; at the junction of the dor-
exists for presbyosmia, but patients are often reassured
sum and the base of the tongue; and in the palate,
to learn that this problem is common in their age group.
epiglottis, larynx, and esophagus.
 Chorda tympani Tastants gain access to the receptor cells through the 197
nerve (VII)
taste pore. Four classes of taste have been traditionally
Glossopharyngeal
nerve (IX)
recognized: sweet, salt, sour, and bitter, and more
recently umami (monosodium glutamate, disodium
gluanylate, disodium inosinate). Tastants enter the taste
pore in a solution and initiate transduction by either
Circumvallate activating receptors coupled to G-proteins or by directly
activating ion channels on the microvillae within the
taste bud. Individual gustatory afferent bers almost

CHAPTER 18
Serous always respond to a number of different chemicals. As
gland with olfaction and other sensory systems, intensity
Foliate appears to be encoded by the quantity of neural activity.
The sense of taste is mediated through the facial,
Taste glossopharyngeal, and vagal nerves. The chorda tympani
bud branch of the facial nerve subserves taste from the ante-
rior two-thirds of the tongue.The posterior third of the

Disorders of Smell, Taste, and Hearing

A B Fungiform
tongue is supplied by the lingual branch of the glos-
sopharyngeal nerve. Afferents from the palate travel with
Taste pore the greater supercial petrosal nerve to the geniculate
ganglion and then via the facial nerve to the brainstem.
The internal branch of the superior laryngeal nerve of
the vagus nerve contains the taste afferents from the lar-
Epithelial cell
ynx, including the epiglottis and esophagus.
Taste cell The central connections of the nerves terminate in
the brainstem in the nucleus of the tractus solitarius.The
central pathway from the nucleus of the tractus solitarius
Basal cell projects to the ipsilateral parabrachial nuclei of the pons.
Gustatory afferent Two divergent pathways project from the parabrachial
To sensory nerve
ganglion nuclei. One ascends to the gustatory relay in the dorsal
C
thalamus, synapses, and continues to the cortex of the
insula. There is also evidence for a direct pathway from
FIGURE 18-2
the parabrachial nuclei to the cortex. (Olfaction and
Taste. A. The taste buds of the anterior two-thirds of the
tongue are innervated by the gustatory bers that travel in a
gustation appear to be unique among sensory systems in
branch of the facial nerve (VII) called the chorda tympani. The
that at least some bers bypass the thalamus.) The other
taste buds of the posterior third of the tongue are innervated pathway from the parabrachial nuclei goes to the ventral
by gustatory bers that travel in the lingual branch of the forebrain, including the lateral hypothalamus, substantia
glossopharyngeal nerve (IX). [Adapted from ER Kandel et al innominata, central nucleus of the amygdala, and the
(eds): Principles of Neural Science, 4th ed., New York, stria terminalis.
McGraw-Hill, 2000; with permission.] B. The main types of
taste papillae are shown in schematic cross sections. Each DISORDERS OF THE SENSE OF TASTE
type predominates in specic areas of the tongue, as indi-
Disorders of the sense of taste are caused by conditions
cated by the arrows from A. C. Each taste bud contains
that interfere with the access of the tastant to the recep-
50150 taste cells that extend from the base of the taste bud
tor cells in the taste bud (transport loss), injure receptor
to the taste pore, where the apical microvilli of taste cells
have contact with tastants dissolved in saliva and taste pore
cells (sensory loss), or damage gustatory afferent nerves
mucus. Access of tastants to the basolateral regions of these
and central gustatory pathways (neural loss) (Table 18-2).
cells is generally prevented by tight junctions between taste Transport gustatory losses result from xerostomia due to
cells. Taste cells are short-lived cells that are replaced from many causes, including Sjgrens syndrome, radiation
stem cells at the base of the taste bud. Three types of taste therapy, heavy-metal intoxication, and bacterial coloniza-
cells in each taste bud (light cells, dark cells, and intermedi- tion of the taste pore. Sensory gustatory losses are caused by
ate cells) may represent different stages of differentiation or inammatory and degenerative diseases in the oral cavity;
different cell lineages. Taste stimuli, detected at the apical a vast number of drugs, particularly those that interfere
end of the taste cell, induce action potentials that cause the with cell turnover such as antithyroid and antineoplastic
release of neurotransmitter at synapses formed at the base agents; radiation therapy to the oral cavity and pharynx;
of the taste cell with gustatory bers that transmit signals to viral infections; endocrine disorders; neoplasms; and aging.
the brain. Neural gustatory losses occur with neoplasms, trauma, and
 198 TABLE 18-2
CAUSES OF GUSTATORY DYSFUNCTION Approach to the Patient:
DISORDERS OF THE SENSE OF TASTE
Transport Gustatory Losses Neural Gustatory Losses
Drugs Diabetes mellitus
Patients who complain of loss of taste should be eval-
Heavy-metal intoxication Hypothyroidism uated for both gustatory and olfactory function. Clin-
Radiation therapy Oral neoplasms ical assessment of taste is not as well developed or
Sjgrens syndrome Oral surgery standardized as that of smell. The rst step is to per-
Xerostomia Radiation therapy form suprathreshold whole-mouth taste testing for
Sensory Gustatory Losses Renal disease quality, intensity, and pleasantness perception of four
Aging Stroke and other CNS taste qualities: sweet, salty, sour, and bitter. Most com-
SECTION II

Candidiasis disorders
Drugs (antithyroid and Trauma
monly used reagents for taste testing are sucrose, citric
antineoplastic) Upper respiratory tract acid or hydrochloric acid, caffeine or quinine (sulfate
Endocrine disorders infections or hydrochloride), and sodium chloride. The taste
Oral neoplasms stimuli should be freshly prepared and have similar
Pemphigus viscosity. For quantication, detection thresholds are
Radiation therapy obtained by applying graduated dilutions to the
Clinical Manifestations of Neurologic Disease

Viral infections (especially tongue quadrants or by whole-mouth sips. Electric

with herpes viruses)
taste testing (electrogustometry) is used clinically to
identify taste decits in specic quadrants of the
tongue. Regional gustatory testing may also be per-
formed to assess for the possibility of loss localized to
one or several receptor elds as a result of a periph-
eral or central lesion. The history of the disease and
surgical procedures in which the gustatory afferents are localization studies provide important clues to the
injured.Taste buds degenerate when their gustatory affer- causes of the taste disturbance. For example, absence
ents are transected but remain when their somatosensory of taste on the anterior two-thirds of the tongue asso-
afferents are severed. Patients with renal disease have ciated with a facial paralysis indicates that the lesion is
increased thresholds for sweet and sour tastes, which proximal to the juncture of the chorda tympani
resolves with dialysis. branch with the facial nerve in the mastoid.
A side effect of medication is the single most com-
mon cause of taste dysfunction in clinical practice.
Xerostomia, regardless of the etiology, can be associated
with taste dysfunction. It is associated with poor oral
clearance and poor dental hygiene and can adversely Treatment:
affect the oral mucosa, all leading to dysgeusia. However, DISORDERS OF THE SENSE OF TASTE
severe salivary gland failure does not necessarily lead to Treatment of gustatory disorders is limited. No effective
taste complaints. Xerostomia, the use of antibiotics or therapies exist for the sensorineural disorders of taste.
glucocorticoids, or immunodeciency can lead to over- Altered taste due to surgical stretch injury of the chorda
growth of Candida; overgrowth alone, without thrush or tympani nerve usually improves within 34 months,
overt signs of infection, can be associated with bad taste while dysfunction is usually permanent with transection
or hypogeusia. When taste dysfunction occurs in a of the nerve. Taste dysfunction following trauma may
patient at risk for fungal overgrowth, a trial of nystatin resolve spontaneously without intervention and is more
or other antifungal medication is warranted. likely to do so than posttraumatic smell dysfunction.
Upper respiratory infections and head trauma can Idiopathic alterations of taste sensitivity usually remain
lead to both smell and taste dysfunction; taste is more stable or worsen; zinc and vitamin therapy are of
likely to improve than smell. The mechanism of taste unproven value. Directed therapy to address factors that
disturbance in these situations is not well understood. affect taste perception can be of value. Xerostomia can
Trauma to the chorda tympani branch of the facial be treated with articial saliva, providing some benet
nerve during middle ear surgery or third molar extrac- to patients with a disturbed salivary milieu. Oral pilo-
tions is relatively common and can cause dysgeusia. carpine may be benecial for a variety of forms of xeros-
Bilateral chorda tympani injuries are usually associated tomia. Appropriate treatment of bacterial and fungal
with hypogeusia, whereas unilateral lesions produce only infections of the oral cavity can be of great help in
limited symptoms. improving taste function. Taste disturbance related to
As noted above, aging itself may be associated with drugs can often be resolved by changing the prescribed
reduced taste sensitivity. The taste dysfunction may be medication.
limited to a single compound and may be mild.
 mechanoreceptors.The afferent innervation relates prin- 199
HEARING cipally to the inner hair cells, and the efferent innerva-
Hearing loss is one of the most common sensory disor- tion relates principally to outer hair cells. The motility
ders in humans and can present at any age. Nearly 10% of the outer hair cells alters the micromechanics of the
of the adult population has some hearing loss, and one- inner hair cells, creating a cochlear amplier, which
third of individuals >65 years have a hearing loss of suf- explains the exquisite sensitivity and frequency selectiv-
cient magnitude to require a hearing aid. ity of the cochlea.
Beginning in the cochlea, the frequency specicity is
maintained at each point of the central auditory pathway:
PHYSIOLOGY OF HEARING

CHAPTER 18
dorsal and ventral cochlear nuclei, trapezoid body, superior
(Fig. 18-3) The function of the external and middle ear olivary complex, lateral lemniscus, inferior colliculus,
is to amplify sound to facilitate mechanotransduction by medial geniculate body, and auditory cortex. At low fre-
hair cells in the inner ear. Sound waves enter the exter- quencies, individual auditory nerve bers can respond
nal auditory canal and set the tympanic membrane in more or less synchronously with the stimulating tone. At
motion, which in turn moves the malleus, incus, and higher frequencies, phase-locking occurs so that neurons
stapes of the middle ear. Movement of the footplate of alternate in response to particular phases of the cycle of the

Disorders of Smell, Taste, and Hearing

the stapes causes pressure changes in the uid-lled sound wave. Intensity is encoded by the amount of neural
inner ear eliciting a traveling wave in the basilar mem- activity in individual neurons, the number of neurons that
brane of the cochlea. The tympanic membrane and the are active, and the specic neurons that are activated.
ossicular chain in the middle ear serve as an impedance-
matching mechanism, improving the efciency of
GENETIC CAUSES OF HEARING LOSS
energy transfer from air to the uid-lled inner ear.
Stereocilia of the hair cells of the organ of Corti, More than half of childhood hearing impairment is
which rests on the basilar membrane, are in contact with thought to be hereditary; hereditary hearing impair-
the tectorial membrane and are deformed by the travel- ment (HHI) can also manifest later in life. HHI may
ing wave. A point of maximal displacement of the basilar be classied as either nonsyndromic, when hearing loss is
membrane is determined by the frequency of the stimu- the only clinical abnormality, or syndromic, when hearing
lating tone. High-frequency tones cause maximal dis- loss is associated with anomalies in other organ systems.
placement of the basilar membrane near the base of the Nearly two-thirds of HHIs are nonsyndromic, and the
cochlea. As the frequency of the stimulating tone remaining one-third are syndromic. Between 70 and 80%
decreases, the point of maximal displacement moves of nonsyndromic HHI is inherited in an autosomal reces-
toward the apex of the cochlea. sive manner and designated DFNB; another 1520% is
The inner and outer hair cells of the organ of autosomal dominant (DFNA). Less than 5% is X-linked or
Corti have different innervation patterns, but both are maternally inherited via the mitochondria.

External acoustic Bony labyrinth

Semicircular
meatus Middle ear (contains perilymph)
canals Anterior
Membranous labyrinth
Stapes Semicircular canals (contains endolymph)
Posterior
Incus
Cochlea Inner Ampulla of
Malleus semicircular canal
ear Lateral
Vestibulocochlear
nerve Utricle
Auricle or Saccule
pinna Cochlea

External Tympanic
acoustic membrane Vestibule Oval
canal window
Eustachian tube
Round
Lobe window Cochlear
duct
A External ear B
FIGURE 18-3
Ear anatomy. A. Drawing of modied coronal section through and inner ear demonstrated. B. High-resolution view of
external ear and temporal bone, with structures of the middle inner ear.
 200 Nearly 100 loci harboring genes for nonsyndromic factors (POU3F4, POU4F3), ion channels (KCNQ4,
HHI have been mapped, with equal numbers of domi- SLC26A4), and gap junction proteins (GJB2, GJB3,
nant and recessive modes of inheritance; numerous genes GJB6). Several of these genes, including connexin 26
have now been cloned (Table 18-3). The hearing genes (GJB2),TECTA, and TMC1, cause both autosomal dom-
fall into the categories of structural proteins (MYH9, inant and recessive forms of nonsyndromic HHI. In gen-
MYO7A, MYO15, TECTA, DIAPH1), transcription eral, the hearing loss associated with dominant genes has

TABLE 18-3
SECTION II

HEREDITARY HEARING IMPAIRMENT GENES

DESIGNATION GENE FUNCTION

Autosomal Dominant
CRYM Thyroid hormone binding protein
Clinical Manifestations of Neurologic Disease

DFNA1 DIAPH1 Cytoskeletal protein

DFNA2 GJB3 (Cx31) Gap junctions
DFNA2 KCNQ4 Potassium channel
DFNA3 GJB2 (Cx26) Gap junctions
DFNA3 GJB6 (Cx30) Gap junctions
DFNA4 MYH14 Class II nonmuscle myosin
DFNA5 DFNA5 Unknown
DFNA6/14/38 WFS Transmembrane protein
DFNA8/12 TECTA Tectorial membrane protein
DFNA9 COCH Unknown
DFNA10 EYA4 Developmental gene
DFNA11 MYO7A Cytoskeletal protein
DFNA13 COL11A2 Cytoskeletal protein
DFNA15 POU4F3 Transcription factor
DFNA17 MYH9 Cytoskeletal protein
DFNA20/26 ACTG1 Cytoskeletal protein
DFNA22 MYO6 Unconventional myosin
DFNA28 TFCP2L3 Transcription factor
DFNA36 TMC1 Transmembrane protein
DFNA48 MYO1A Unconventional myosin
Autosomal Recessive
SLC26A5 (Prestin) Motor protein
DFNB1 GJB2 (CX26) Gap junction
GJB6(CX30) Gap junction
DFNB2 MYO7A Cytoskeletal protein
DFNB3 MYO15 Cytoskeletal protein
DFNB4 PDS(SLC26A4) Chloride/iodide transporter
DFNB6 TMIE Transmembrane protein
DFNB7/B11 TMC1 Transmembrane protein
DFNB9 OTOF Trafcking of membrane vesicles
DFNB8/10 TMPRSS3 Transmembrane serine protease
DFNB12 CDH23 Intercellular adherence protein
DFNB16 STRC Stereocilia protein
DFNB18 USH1C Unknown
DFNB21 TECTA Tectorial membrane protein
DFNB22 OTOA Gel attachement to nonsensory cell
DFNB23 PCDH15 Morphogenesis and cohesion
DFNB28 TRIOBP Cytoskeletal-organizing protein
DFNB29 CLDN14 Tight junctions
DFNB30 MYO3A Hybrid motor-signaling myosin
DFNB31 WHRN PDZ domaincontaining protein
DFNB36 ESPN Ca-insensitive actin-bundling protein
DFNB37 MYO6 Unconventional myosin
DFNB67 TMHS Unknown function; tetraspan protein
its onset in adolescence or adulthood and varies in sever- syndrome (prolonged QT interval and hearing loss), 201
ity, whereas the hearing loss associated with recessive neurobromatosis type 2 (bilateral acoustic schwan-
inheritance is congenital and profound. Connexin 26 is noma), and mitochondrial disorders [mitochondrial
particularly important because it is associated with nearly encephalopathy, lactic acidosis, and stroke-like episodes
20% of cases of childhood deafness. Two frame-shift (MELAS); myoclonic epilepsy and ragged red bers
mutations, 35delG and 167delT, account for >50% of the (MERRF); progressive external ophthalmoplegia (PEO)]
cases; however, screening for these two mutations alone is (Table 18-4).
insufcient to diagnose GJB2-related recessive deafness.
The 167delT mutation is highly prevalent in Ashkenazi

CHAPTER 18
Jews; ~1 in 1765 individuals in this population are DISORDERS OF THE SENSE OF HEARING
homozygous and affected.The hearing loss can also vary
among the members of the same family, suggesting that Hearing loss can result from disorders of the auricle,
other genes or factors inuence the auditory phenotype. external auditory canal, middle ear, inner ear, or central
The contribution of genetics to presbycusis (see auditory pathways (Fig. 18-4). In general, lesions in the
later) is also becoming better understood. In addition to auricle, external auditory canal, or middle ear cause conductive
GJB2, several other nonsyndromic genes are associated hearing losses, whereas lesions in the inner ear or eighth nerve

Disorders of Smell, Taste, and Hearing

with hearing loss that progresses with age. Sensitivity to cause sensorineural hearing losses.
aminoglycoside ototoxicity can be maternally transmit-
ted through a mitochondrial mutation. Susceptibility to
noise-induced hearing loss may also be genetically Conductive Hearing Loss
determined. This results from obstruction of the external auditory
There are >400 syndromic forms of hearing loss. canal by cerumen, debris, and foreign bodies; swelling of
These include Usher syndrome (retinitis pigmentosa and the lining of the canal; atresia or neoplasms of the canal;
hearing loss),Waardenburg syndrome (pigmentary abnor- perforations of the tympanic membrane; disruption of
mality and hearing loss), Pendred syndrome (thyroid the ossicular chain, as occurs with necrosis of the long
organication defect and hearing loss), Alport syndrome process of the incus in trauma or infection; otosclerosis;
(renal disease and hearing loss), Jervell and Lange-Nielsen or uid, scarring, or neoplasms in the middle ear. Rarely,

TABLE 18-4
SYNDROMIC HEREDITARY HEARING IMPAIRMENT GENES

SYNDROME GENE FUNCTION

Alport syndrome COL4A3-5 Cytoskeletal protein

BOR syndrome EYA1 Developmental gene
SIX1 Developmental gene
Jervell and Lange-Nielsen KVLQT1 Delayed rectier K+ channel
syndrome KCNE1 Delayed rectier K+ channel
Norrie disease Norrin Cell-cell interactions
Pendred syndrome SLC26A4 Chloride/iodide transporter
Treacher Collins TCOF1 Nucleolar-cytoplasmic transport
Usher syndrome MYO7A Cytoskeletal protein
USH1C Unknown
CDH23 Intercellular adherence protein
PCDH15 Cell adhesion molecule
SANS Harmonin associated protein
USH2A Cell adhesion molecule
VLGR1 G proteincoupled receptor
USH3 Unknown
WS type I, III PAX3 Transcription factor
WS type II MITF Transcription factor
SLUG Transcription factor
WS type IV EDNRB Endothelin-B receptor
EDN3 Endothelin-B receptor ligand
SOX10 Transcription factor

Note: BOR, branchio-oto-renal syndrome; WS, Waardenburg syndrome.

 202
Hearing Loss
Cerumen impaction
TM perforation
Cholesteatoma History
SOM abnormal normal
AOM
External auditory Otologic examination Pure tone and
canal atresia/ speech audiometry
stenosis
Eustachian tube
dysfunction
Tympanosclerosis
SECTION II

Conductive HL Mixed HL SNHL

Impedence audiometry Impedence audiometry Acute Chronic

Asymmetric/symmetric

normal abnormal normal abnormal

CNS infection Asymmetric Symmetric
Clinical Manifestations of Neurologic Disease

Tumors
Otosclerosis AOM Stapes gusher AOM Cerebellopontine
Cerumen SOM syndrome* TM perforation* angle
impaction TM perforation* Inner ear Cholesteatoma* CNS Inner ear
Ossicular Eustachian tube malformation* Temporal bone Stroke malformation*
fixation dysfunction Otosclerosis trauma* Trauma* Presbycusis
Cholesteatoma* Cerumen Temporal bone Middle ear tumors* Noise exposure
Temporal bone impaction trauma* glomus MRI/BAER Radiation therapy
trauma* Cholesteatoma* tympanicum
Temporal bone glomus jugulare
trauma* normal abnormal
Ossicular
discontinuity*
Middle ear tumor*
Endolymphatic hydrops Labyrinthitis*
Labyrinthitis* Inner ear malformations*
Perilymphatic fistula* Cerebellopontine angle tumors
Radiation therapy Arachnoid cyst; facial nerve tumor;
lipoma; meningioma; vestibular
schwannoma
Multiple sclerosis

FIGURE 18-4
An algorithm for the approach to hearing loss. HL, hear- membrane; SOM, serous otitis media; AOM, acute otitis
ing loss; SNHL, sensorineural hearing loss; TM, tympanic media; *, CT scan of temporal bone; , MRI scan.

inner-ear malformations may present as conductive impairment usually presents between the late teens to
hearing loss beginning in adulthood. the forties. In women, the otosclerotic process is acceler-
Cholesteatoma, stratied squamous epithelium in the ated during pregnancy, and the hearing loss is often rst
middle ear or mastoid, occurs frequently in adults.This is noticeable at this time. A hearing aid or a simple outpa-
a benign, slowly growing lesion that destroys bone and tient surgical procedure (stapedectomy) can provide ade-
normal ear tissue. Theories of pathogenesis include trau- quate auditory rehabilitation. Extension of otosclerosis
matic implantation and invasion, immigration and inva- beyond the stapes footplate to involve the cochlea
sion through a perforation, and metaplasia following (cochlear otosclerosis) can lead to mixed or sensorineural
chronic infection and irritation. On examination, there is hearing loss. Fluoride therapy to prevent hearing loss
often a perforation of the tympanic membrane lled with from cochlear otosclerosis is of uncertain value.
cheesy white squamous debris. A chronically draining ear Eustachian tube dysfunction is extremely common in
that fails to respond to appropriate antibiotic therapy adults and may predispose to acute otitis media (AOM)
should raise suspicion of a cholesteatoma. Conductive or serous otitis media (SOM). Trauma, AOM, or chronic
hearing loss secondary to ossicular erosion is common. otitis media are the usual factors responsible for tympanic
Surgery is required to remove this destructive process. membrane perforation. While small perforations often
Conductive hearing loss with a normal ear canal and heal spontaneously, larger defects usually require surgical
intact tympanic membrane suggests ossicular pathology. intervention.Tympanoplasty is highly effective (>90%) in
Fixation of the stapes from otosclerosis is a common cause the repair of tympanic membrane perforations. Otoscopy
of low-frequency conductive hearing loss. It occurs equally is usually sufcient to diagnose AOM, SOM, chronic
in men and women and is inherited as an autosomal otitis media, cerumen impaction, tympanic membrane
dominant trait with incomplete penetrance. Hearing perforation, and eustachian tube dysfunction.
Sensorineural Hearing Loss Unfortunately, there is no effective therapy for hearing 203
loss, tinnitus, or aural fullness from Mnires disease.
Damage to the hair cells of the organ of Corti may be Sensorineural hearing loss may also result from any
caused by intense noise, viral infections, ototoxic drugs neoplastic, vascular, demyelinating, infectious, or degen-
(e.g., salicylates, quinine and its synthetic analogues, erative disease or trauma affecting the central auditory
aminoglycoside antibiotics, loop diuretics such as pathways. HIV leads to both peripheral and central
furosemide and ethacrynic acid, and cancer chemothera- auditory system pathology and is associated with sen-
peutic agents such as cisplatin), fractures of the temporal sorineural hearing impairment.
bone, meningitis, cochlear otosclerosis (see earlier), A nding of conductive and sensory hearing loss in
Mnires disease, and aging. Congenital malformations

CHAPTER 18
combination is termed mixed hearing loss. Mixed hearing
of the inner ear may be the cause of hearing loss in losses are due to pathology of both the middle and inner
some adults. Genetic predisposition alone or in concert ear, as can occur in otosclerosis involving the ossicles and the
with environmental exposures may also be responsible. cochlea, head trauma, chronic otitis media, cholesteatoma,
Presbycusis (age-associated hearing loss) is the most middle ear tumors, and some inner ear malformations.
common cause of sensorineural hearing loss in adults. In Trauma resulting in temporal bone fractures may be
the early stages, it is characterized by symmetric, gentle associated with conductive, sensorineural, or mixed

Disorders of Smell, Taste, and Hearing

to sharply sloping high-frequency hearing loss. With hearing loss. If the fracture spares the inner ear, there
progression, the hearing loss involves all frequencies. may simply be conductive hearing loss due to rupture of
More importantly, the hearing impairment is associated the tympanic membrane or disruption of the ossicular
with signicant loss in clarity.There is a loss of discrimi- chain. These abnormalities can be surgically corrected.
nation for phonemes, recruitment (abnormal growth of Profound hearing loss and severe vertigo are associated
loudness), and particular difculty in understanding with temporal bone fractures involving the inner ear. A
speech in noisy environments. Hearing aids may provide perilymphatic stula associated with leakage of inner-
limited rehabilitation once the word recognition score ear uid into the middle ear can occur and may require
deteriorates below 50%. Cochlear implants are the treat- surgical repair. An associated facial nerve injury is not
ment of choice when hearing aids prove inadequate, uncommon. CT is best suited to assess fracture of the
even when hearing loss is incomplete. traumatized temporal bone, evaluate the ear canal, and
Mnires disease is characterized by episodic vertigo, determine the integrity of the ossicular chain and the
uctuating sensorineural hearing loss, tinnitus, and aural involvement of the inner ear. CSF leaks that accompany
fullness. Tinnitus and/or deafness may be absent during temporal bone fractures are usually self-limited; the
the initial attacks of vertigo, but invariably appear as the value of prophylactic antibiotics is uncertain.
disease progresses and increase in severity during acute Tinnitus is dened as the perception of a sound when
attacks. The annual incidence of Mnires disease is there is no sound in the environment. It may have a
0.57.5 per 1000; onset is most frequently in the fth buzzing, roaring, or ringing quality and may be pulsatile
decade of life but may also occur in young adults or the (synchronous with the heartbeat).Tinnitus is often associ-
elderly. Histologically, there is distention of the endolym- ated with either a conductive or sensorineural hearing
phatic system (endolymphatic hydrops) leading to degen- loss. The pathophysiology of tinnitus is not well under-
eration of vestibular and cochlear hair cells. This may stood.The cause of the tinnitus can usually be determined
result from endolymphatic sac dysfunction secondary to by nding the cause of the associated hearing loss.Tinnitus
infection, trauma, autoimmune disease, inammatory may be the rst symptom of a serious condition such as a
causes, or tumor; an idiopathic etiology constitutes the vestibular schwannoma. Pulsatile tinnitus requires evalua-
largest category and is most accurately referred to as tion of the vascular system of the head to exclude vascular
Mnires disease. Although any pattern of hearing loss tumors such as glomus jugulare tumors, aneurysms, and
can be observed, typically, low-frequency, unilateral sen- stenotic arterial lesions; it may also occur with SOM.
sorineural hearing impairment is present. MRI should be
obtained to exclude retrocochlear pathology such as a
cerebellopontine angle tumor or demyelinating disorder.
Therapy is directed toward the control of vertigo. A Approach to the Patient:
low-salt diet is the mainstay of treatment for control of DISORDERS OF THE SENSE OF HEARING
rotatory vertigo. Diuretics, a short course of glucocorti- The goal in the evaluation of a patient with auditory
coids, and intratympanic gentamicin may also be useful complaints is to determine (1) the nature of the hearing
adjuncts in recalcitrant cases. Surgical therapy of vertigo impairment (conductive vs. sensorineural vs. mixed), (2)
is reserved for unresponsive cases and includes endolym- the severity of the impairment (mild, moderate, severe,
phatic sac decompression, labyrinthectomy, and vestibular profound), (3) the anatomy of the impairment (external
nerve section. Both labyrinthectomy and vestibular nerve ear, middle ear, inner ear, or central auditory pathway),
section abolish rotatory vertigo in >90% of patients.
 204 and (4) the etiology.The history should elicit character- then the stem is placed on the mastoid process; for
istics of the hearing loss, including the duration of deaf- direct contact, it may be placed on teeth or dentures.
ness, unilateral vs. bilateral involvement, nature of onset The patient is asked to indicate whether the tone is
(sudden vs. insidious), and rate of progression (rapid vs. louder by air conduction or bone conduction. Nor-
slow). Symptoms of tinnitus, vertigo, imbalance, aural mally, and in the presence of sensorineural hearing
fullness, otorrhea, headache, facial nerve dysfunction, loss, a tone is heard louder by air conduction than by
and head and neck paresthesias should be noted. Infor- bone conduction; however, with conductive hearing
mation regarding head trauma, exposure to ototoxins, loss of 30 dB (see Audiologic Assessment, below), the
occupational or recreational noise exposure, and family bone-conduction stimulus is perceived as louder than
SECTION II

history of hearing impairment may also be important.A the air-conduction stimulus. For the Weber test, the
sudden onset of unilateral hearing loss, with or without stem of a vibrating tuning fork is placed on the head
tinnitus, may represent a viral infection of the inner ear in the midline and the patient asked whether the tone
or a stroke. Patients with unilateral hearing loss (sensory is heard in both ears or better in one ear than in the
or conductive) usually complain of reduced hearing, other. With a unilateral conductive hearing loss, the
poor sound localization, and difculty hearing clearly tone is perceived in the affected ear. With a unilateral
Clinical Manifestations of Neurologic Disease

with background noise. Gradual progression of a hear- sensorineural hearing loss, the tone is perceived in the
ing decit is common with otosclerosis, noise-induced unaffected ear. A 5-dB difference in hearing between
hearing loss, vestibular schwannoma, or Mnires dis- the two ears is required for lateralization.
ease. Small vestibular schwannomas typically present
with asymmetric hearing impairment, tinnitus, and
imbalance (rarely vertigo); cranial neuropathy, in partic-
ular of the trigeminal or facial nerve, may accompany
larger tumors. In addition to hearing loss, Mnires dis- LABORATORY ASSESSMENT OF HEARING
ease may be associated with episodic vertigo, tinnitus, Audiologic Assessment
and aural fullness. Hearing loss with otorrhea is most
The minimum audiologic assessment for hearing loss
likely due to chronic otitis media or cholesteatoma.
should include the measurement of pure tone air-
Examination should include the auricle, external ear
conduction and bone-conduction thresholds, speech
canal, and tympanic membrane.The external ear canal
reception threshold, discrimination score, tympanome-
of the elderly is often dry and fragile; it is preferable to
try, acoustic reexes, and acoustic-reex decay. This test
clean cerumen with wall-mounted suction and ceru-
battery provides a screening evaluation of the entire
men loops and to avoid irrigation. In examining the
auditory system and allows one to determine whether
eardrum, the topography of the tympanic membrane
further differentiation of a sensory (cochlear) from a
is more important than the presence or absence of the
neural (retrocochlear) hearing loss is indicated.
light reex. In addition to the pars tensa (the lower
Pure tone audiometry assesses hearing acuity for pure
two-thirds of the eardrum), the pars accida above the
tones. The test is administered by an audiologist and is
short process of the malleus should also be examined
performed in a sound-attenuated chamber. The pure
for retraction pockets that may be evidence of chronic
tone stimulus is delivered with an audiometer, an elec-
eustachian tube dysfunction or cholesteatoma. Insuf-
tronic device that allows the presentation of specic fre-
ation of the ear canal is necessary to assess tympanic
quencies (generally between 250 and 8000 Hz) at specic
membrane mobility and compliance. Careful inspec-
intensities. Air and bone conduction thresholds are estab-
tion of the nose, nasopharynx, and upper respiratory
lished for each ear. Air conduction thresholds are deter-
tract is indicated. Unilateral serous effusion should
mined by presenting the stimulus in air with the use of
prompt a beroptic examination of the nasopharynx
headphones. Bone conduction thresholds are determined
to exclude neoplasms. Cranial nerves should be evalu-
by placing the stem of a vibrating tuning fork or an
ated with special attention to facial and trigeminal
oscillator of an audiometer in contact with the head.
nerves, which are commonly affected with tumors
In the presence of a hearing loss, broad-spectrum noise
involving the cerebellopontine angle.
is presented to the nontest ear for masking purposes so
The Rinne and Weber tuning fork tests, with a
that responses are based on perception from the ear
512-Hz tuning fork, are used to screen for hearing
under test.
loss, differentiate conductive from sensorineural hear-
The responses are measured in decibels.An audiogram is
ing losses, and to conrm the ndings of audiologic
a plot of intensity in decibels of hearing threshold versus
evaluation. Rinnes test compares the ability to hear by
frequency. A decibel (dB) is equal to 20 times the loga-
air conduction with the ability to hear by bone con-
rithm of the ratio of the sound pressure required to
duction. The tines of a vibrating tuning fork are held
achieve threshold in the patient to the sound pressure
near the opening of the external auditory canal, and
required to achieve threshold in a normal hearing person.
Therefore, a change of 6 dB represents doubling of sound SRT also suggests a lesion in the eighth nerve or central 205
pressure, and a change of 20 dB represents a tenfold auditory pathways.
change in sound pressure. Loudness, which depends on Tympanometry measures the impedance of the middle
the frequency, intensity, and duration of a sound, doubles ear to sound and is useful in diagnosis of middle-ear
with approximately each 10-dB increase in sound pres- effusions. A tympanogram is the graphic representation of
sure level. Pitch, on the other hand, does not directly cor- change in impedance or compliance as the pressure in
relate with frequency. The perception of pitch changes the ear canal is changed. Normally, the middle ear is
slowly in the low and high frequencies. In the middle most compliant at atmospheric pressure, and the com-
tones, which are important for human speech, pitch varies pliance decreases as the pressure is increased or

CHAPTER 18
more rapidly with changes in frequency. decreased; this pattern is seen with normal hearing or in
Pure tone audiometry establishes the presence and the presence of sensorineural hearing loss. Compliance
severity of hearing impairment, unilateral vs. bilateral that does not change with change in pressure suggests
involvement, and the type of hearing loss. Conductive middle-ear effusion. With a negative pressure in the
hearing losses with a large mass component, as is often middle ear, as with eustachian tube obstruction, the
seen in middle-ear effusions, produce elevation of point of maximal compliance occurs with negative pres-
thresholds that predominate in the higher frequencies. sure in the ear canal. A tympanogram in which no point

Disorders of Smell, Taste, and Hearing

Conductive hearing losses with a large stiffness compo- of maximal compliance can be obtained is most com-
nent, as in xation of the footplate of the stapes in early monly seen with discontinuity of the ossicular chain. A
otosclerosis, produce threshold elevations in the lower reduction in the maximal compliance peak can be seen
frequencies. Often, the conductive hearing loss involves in otosclerosis.
all frequencies, suggesting involvement of both stiffness During tympanometry, an intense tone elicits con-
and mass. In general, sensorineural hearing losses such as traction of the stapedius muscle. The change in compli-
presbycusis affect higher frequencies more than lower ance of the middle ear with contraction of the stapedius
frequencies. An exception is Mnires disease, which is muscle can be detected. The presence or absence of this
characteristically associated with low-frequency sen- acoustic reex is important in the anatomic localization of
sorineural hearing loss. Noise-induced hearing loss has facial nerve paralysis as well as hearing loss. Normal or
an unusual pattern of hearing impairment in which the elevated acoustic reex threshold in an individual with
loss at 4000 Hz is greater than at higher frequencies. sensorineural hearing impairment suggests a cochlear
Vestibular schwannomas characteristically affect the hearing loss. Assessment of acoustic reex decay helps dif-
higher frequencies, but any pattern of hearing loss can ferentiate sensory from neural hearing losses. In neural
be observed. hearing loss, the reex adapts or decays with time.
Speech recognition requires greater synchronous Otoacoustic emissions (OAE) can be measured with
neural ring than is necessary for appreciation of pure microphones inserted into the external auditory canal.
tones. Speech audiometry tests the clarity with which one The emissions may be spontaneous or evoked with
hears. The speech reception threshold (SRT) is dened as sound stimulation. The presence of OAEs indicates that
the intensity at which speech is recognized as a mean- the outer hair cells of the organ of Corti are intact and
ingful symbol and is obtained by presenting two-syllable can be used to assess auditory thresholds and to distin-
words with an equal accent on each syllable. The inten- guish sensory from neural hearing losses.
sity at which the patient can repeat 50% of the words
correctly is the SRT. Once the SRT is determined, dis-
Evoked Responses
crimination or word recognition ability is tested by pre-
senting one-syllable words at 2540 dB above the SRT. Electrocochleography measures the earliest evoked poten-
The words are phonetically balanced in that the tials generated in the cochlea and the auditory nerve.
phonemes (speech sounds) occur in the list of words at Receptor potentials recorded include the cochlear
the same frequency that they occur in ordinary conver- microphonic, generated by the outer hair cells of the
sational English. An individual with normal hearing organ of Corti, and the summating potential, generated
or conductive hearing loss can repeat 88100% of the by the inner hair cells in response to sound. The whole
phonetically balanced words correctly. Patients with a nerve action potential representing the composite ring
sensorineural hearing loss have variable loss of discrimi- of the rst-order neurons can also be recorded during
nation. As a general rule, neural lesions produce greater electrocochleography. Clinically, the test is useful in the
decits in discrimination than do lesions in the inner diagnosis of Mnires disease, where an elevation of the
ear. For example, in a patient with mild asymmetric sen- ratio of summating potential to action potential is seen.
sorineural hearing loss, a clue to the diagnosis of Brainstem auditory evoked responses (BAERs) are useful
vestibular schwannoma is the presence of a substantial in differentiating the site of sensorineural hearing loss.
deterioration in discrimination ability. Deterioration in In response to sound, ve distinct electrical potentials
discrimination ability at higher intensities above the arising from different stations along the peripheral and
 206 central auditory pathway can be identied using com- Tympanostomy tubes allow the prompt return of nor-
puter averaging from scalp surface electrodes. BAERs are mal hearing in individuals with middle-ear effusions.
valuable in situations in which patients cannot or will Hearing aids are effective and well-tolerated in patients
not give reliable voluntary thresholds. They are also used with conductive hearing losses.
to assess the integrity of the auditory nerve and brain- Patients with mild, moderate, and severe sen-
stem in various clinical situations, including intraopera- sorineural hearing losses are regularly rehabilitated with
tive monitoring and in determination of brain death. hearing aids of varying conguration and strength.
The vestibular-evoked myogenic potential (VEMP) test Hearing aids have been improved to provide greater
elicits a vestibulocollic reex whose afferent limb arises delity and have been miniaturized. The current genera-
from acoustically sensitive cells in the saccule, with sig-
SECTION II

tion of hearing aids can be placed entirely within the

nals conducted via the inferior vestibular nerve.VEMP is ear canal, thus reducing any stigma associated with
a biphasic, short-latency response recorded from the ton- their use. In general, the more severe the hearing
ically contracted sternocleidomastoid muscle in response impairment, the larger the hearing aid required for audi-
to loud auditory clicks or tones.VEMPs may be dimin- tory rehabilitation. Digital hearing aids lend themselves
ished or absent in patients with early and late Mnires to individual programming, and multiple and direc-
disease, vestibular neuritis, benign paroxysmal positional
Clinical Manifestations of Neurologic Disease

tional microphones at the ear level may be helpful in

vertigo, and vestibular schwannoma. On the other hand, noisy surroundings. Since all hearing aids amplify noise
the threshold for VEMPs may be lower in cases of supe- as well as speech, the only absolute solution to the
rior canal dehiscence and perilymphatic stula. problem of noise is to place the microphone closer to
the speaker than the noise source. This arrangement is
not possible with a self-contained, cosmetically accept-
Imaging Studies
able device.
The choice of radiologic tests is largely determined by In many situations, including lectures and the the-
whether the goal is to evaluate the bony anatomy of the ater, hearing-impaired persons benet from assistive
external, middle, and inner ear or to image the auditory devices that are based on the principle of having the
nerve and brain. Axial and coronal CT of the temporal speaker closer to the microphone than any source of
bone with ne 1-mm cuts is ideal for determining the noise. Assistive devices include infrared and frequency-
caliber of the external auditory canal, integrity of the modulated (FM) transmission as well as an electromag-
ossicular chain, and presence of middle-ear or mastoid netic loop around the room for transmission to the indi-
disease; it can also detect inner-ear malformations. CT is viduals hearing aid. Hearing aids with telecoils can also
also ideal for the detection of bone erosion with chronic be used with properly equipped telephones in the
otitis media and cholesteatoma. MRI is superior to CT same way.
for imaging of retrocochlear pathology such as vestibular In the event that the hearing aid provides inade-
schwannoma, meningioma, other lesions of the cerebel- quate rehabilitation, cochlear implants may be appro-
lopontine angle, demyelinating lesions of the brainstem, priate. Criteria for implantation include severe to pro-
and brain tumors. Both CT and MRI are equally capa- found hearing loss with word recognition score 30%
ble of identifying inner-ear malformations and assessing under best aided conditions. Worldwide, >20,000 deaf
cochlear patency for preoperative evaluation of patients individuals (including 4000 children) have received
for cochlear implantation. cochlear implants. Cochlear implants are neural pros-
theses that convert sound energy to electrical energy
and can be used to stimulate the auditory division of
the eighth nerve directly. In most cases of profound
hearing impairment, the auditory hair cells are lost but
Treatment: the ganglionic cells of the auditory division of the
DISORDERS OF THE SENSE eighth nerve are preserved. Cochlear implants consist of
OF HEARING
electrodes that are inserted into the cochlea through
In general, conductive hearing losses are amenable to the round window, speech processors that extract
surgical correction, while sensorineural hearing losses acoustical elements of speech for conversion to electri-
are more difcult to manage. Atresia of the ear canal can cal currents, and a means of transmitting the electrical
be surgically repaired, often with signicant improve- energy through the skin. Patients with implants experi-
ment in hearing. Tympanic membrane perforations due ence sound that helps with speech reading, allows open-
to chronic otitis media or trauma can be repaired with set word recognition, and helps in modulating the persons
an outpatient tympanoplasty. Likewise, conductive hear- own voice. Usually, within 3 months after implanta-
ing loss associated with otosclerosis can be treated by tion, adult patients can understand speech without
stapedectomy, which is successful in 9095% of cases. visual cues. With the current generation of multichannel
 cochlear implants, nearly 75% of patients are able to antibiotics can largely be prevented by careful monitor- 207
converse on the telephone. For individuals who have ing of serum peak and trough levels.
had both eighth nerves destroyed by trauma or bilateral Some 10 million Americans have noise-induced hear-
vestibular schwannomas (e.g., neurobromatosis type 2), ing loss, and 20 million are exposed to hazardous noise in
brainstem auditory implants placed near the cochlear their employment. Noise-induced hearing loss can be
nucleus may provide auditory rehabilitation. prevented by avoidance of exposure to loud noise or by
Tinnitus often accompanies hearing loss. As for back- regular use of ear plugs or uid-lled ear muffs to atten-
ground noise, tinnitus can degrade speech comprehen- uate intense sound. High-risk activities for noise-induced
sion in individuals with hearing impairment. Therapy for hearing loss include wood and metal working with elec-

CHAPTER 18
tinnitus is usually directed toward minimizing the trical equipment and target practice and hunting with
appreciation of tinnitus. Relief of the tinnitus may be small rearms. All internal-combustion and electric
obtained by masking it with background music. Hearing engines, including snow and leaf blowers, snowmobiles,
aids are also helpful in tinnitus suppression, as are tinni- outboard motors, and chain saws, require protection of
tus maskers, devices that present a sound to the the user with hearing protectors. Virtually all noise-
affected ear that is more pleasant to listen to than the induced hearing loss is preventable through education,
which should begin before the teenage years. Programs

Disorders of Smell, Taste, and Hearing

tinnitus. The use of a tinnitus masker is often followed
by several hours of inhibition of the tinnitus. Antide- of industrial conservation of hearing are required when
pressants have been shown to be benecial in helping the exposure over an 8-h period averages 85 dB.Workers
patients cope with tinnitus. in such noisy environments can be protected with pre-
Hard-of-hearing individuals often benet from a employment audiologic assessment, the mandatory use of
reduction in unnecessary noise (e.g., radio or television) hearing protectors, and annual audiologic assessments.
to enhance the signal-to-noise ratio. Speech compre-
hension is aided by lip reading; therefore the impaired ACKNOWLEDGMENT
listener should be seated so that the face of the speaker
The author acknowledges the contributions of Dr. James B. Snow, Jr.,
is well-illuminated and easily seen. Although speech
to this chapter.
should be in a loud, clear voice, one should be aware
that in sensorineural hearing losses in general and in
hard-of-hearing elderly in particular, recruitment FURTHER READINGS
(abnormal perception of loud sounds) may be trouble-
BRESLIN PA, HUANG L: Human taste: Peripheral anatomy, taste trans-
some. Above all, optimal communication cannot take duction, and coding.Adv Otorhinolaryngol 63:152, 2006
place without both parties giving it their full and undi- DOTY RL: The olfactory system and its disorders. Semin neurol
vided attention. 29:74, 2009
DULAC C: Sparse encoding of natural scents. Neuron 50:816, 2006
GATES GA, MILLS JH: Presbycusis. Lancet 366:1111, 2005
HASIN-BRUMSHTEIN Y et al: Human olfaction: from genomic varia-
PREVENTION tion to phenotypic diversity. Trends Genet. 25:178, 2009
HECKMANN JG, LANG CJ: Neurological causes of taste disorders. Adv
Conductive hearing losses may be prevented by prompt Otorhinolaryngol 63:255, 2006
antibiotic therapy of adequate duration for AOM and by KATZ DB et al: Receptors, circuits, and behaviors: new directions in
ventilation of the middle ear with tympanostomy tubes chemical senses. J Neurosci 28:11802, 2008
in middle-ear effusions lasting 12 weeks. Loss of LALWANI AK (ed): Current Diagnosis and Treatment in Otolaryngology
vestibular function and deafness due to aminoglycoside Head & Neck Surgery, 2d ed. New York, McGraw-Hill, 2007
This page intentionally left blank
 SECTION III

DISEASES OF
THE CENTRAL
NERVOUS SYSTEM
 CHAPTER 19

MECHANISMS OF NEUROLOGIC DISEASES

Stephen L. Hauser I M. Flint Beal

I Neurogenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
I Ion Channels and Channelopathies . . . . . . . . . . . . . . . . . . . . 211
I Neurotransmitters and Neurotransmitter Receptors . . . . . . . 212
I Signaling Pathways and Gene Transcription . . . . . . . . . . . . . 213
I Myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
I Neurotrophic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
I Stem Cells and Transplantation . . . . . . . . . . . . . . . . . . . . . . . 216
I Cell DeathExcitotoxicity and Apoptosis . . . . . . . . . . . . . . . 217
I Protein Aggregation and Neurodegeneration . . . . . . . . . . . . . 219
I Systems Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

The human nervous system is the organ of conscious- monogenic causes of common phenotypes. Examples of
ness, cognition, ethics, and behavior; as such, it is the the latter include mutations of the amyloid precursor
most intricate structure known to exist. More than one- protein in familial Alzheimers disease, the microtubule-
third of the 23,000 genes encoded in the human genome associated protein tau (MAPT) in frontotemporal dementia,
are expressed in the nervous system. Each mature brain is and -synuclein in Parkinsons disease. These discoveries
composed of 100 billion neurons, several million miles of have been profoundly important because the mutated
axons and dendrites, and >1015 synapses. Neurons exist gene in the familial disorder often encodes a protein that
within a dense parenchyma of multifunctional glial cells is also pathogenetically involved (although not mutated)
that synthesize myelin, preserve homeostasis, and regulate in the typical, sporadic form. The common mechanism
immune responses. Measured against this background of involves disordered processing and, ultimately, aggregation
complexity, the achievements of molecular neuroscience of the protein, leading to cell death (see Protein Aggrega-
have been extraordinary. This chapter reviews selected tion and Neurodegeneration, later in the chapter).
themes in neuroscience that provide a context for under- There is great optimism that complex genetic disor-
standing fundamental mechanisms underlying neurologic ders, caused by combinations of both genetic and envi-
disorders. ronmental factors, have now become tractable problems.
The development of new genetic approaches, such as
NEUROGENETICS haplotype mapping for the efcient screening of variants
genome-wide along with advances in high-throughput
The landscape of neurology has been transformed by sequencing, are beginning to delineate incompletely
modern molecular genetics. More than 350 different penetrant genetic variants that inuence susceptibility
disease-causing genes have now been identied, and to, or modify the expression of, complex diseases includ-
>1000 neurologic disorders have been genetically mapped ing age-related macular degeneration, type 2 diabetes
to various chromosomal locations. The vast majority of mellitus, and Alzheimers disease.
these represent highly penetrant mutations that cause rare Not all genetic diseases of the nervous system are caused
neurologic disorders; alternatively, they represent rare by simple changes in the linear nucleotide sequence of

210
genes. As the complex architecture of the human genome Imprinting refers to an epigenetic feature, present for a 211
becomes better defined, many disorders that result subset of genes, in which the predominant expression of
from alterations in copy numbers of genes (gene-dosage one allele is determined by its parent-of-origin.The distinc-
effects) resulting from unequal crossing-over are likely to be tive neurodevelopmental disorders Prader-Willi syndrome
identied.The rst copy-number disorders to be recognized (mild mental retardation and endocrine abnormalities)
were Charcot-Marie-Tooth disease type 1A (CMT1A), and Angelman syndrome (cortical atrophy, cerebellar
caused by a duplication in the gene encoding the myelin dysmyelination, Purkinje cell loss) are classic examples of
protein PMP22, and the reciprocal deletion of the gene imprinting disorders whose distinctive features are
causing hereditary liability to pressure palsies (HNPP) determined by whether the paternal or maternal copy
(Chap. 40). Gene-dosage effects are causative in some cases of chromosome of the critical genetic region 15q11-13
of Parkinsons disease (-synuclein), Alzheimers disease was responsible. Preferential allelic expression, whether
(amyloid precursor protein), spinal muscular atrophy (sur- due to imprinting, resistance to X-inactivation, or other
vival motor neuron 2), the dysmyelinating disorder mechanisms, is likely to play a major role in determining
Pelizaeus-Merzbacher syndrome (proteolipid protein 1), complex behaviors and susceptibility to many neuro-
late-onset leukodystrophy (lamin B1), and a variety of logic and psychiatric disorders.
developmental neurologic disorders. It is now evident that
copy-number variations contribute substantially to normal

CHAPTER 19
human genomic variation for numerous genes involved in ION CHANNELS AND CHANNELOPATHIES
neurologic function, regulation of cell growth, and regula-
tion of metabolism. It is also likely that gene-dosage effects The resting potential of neurons and the action poten-
will inuence many behavioral phenotypes, learning disor- tials responsible for impulse conduction are generated by
ders, and autism spectrum disorders. ion currents and ion channels. Most ion channels are
The role of splicing variation as a contributor to neuro- gated, meaning that they can transition between confor-

Mechanisms of Neurologic Diseases

logic disease is another area of active investigation. Alterna- mations that are open or closed to ion conductance.
tive splicing refers to the inclusion of different combinations Individual ion channels are distinguished by the specic
of exons in mature mRNA, resulting in the potential for ions they conduct; by their kinetics; and by whether
many different protein products encoded by a single gene. they directly sense voltage, are linked to receptors for
Alternative splicing represents a powerful mechanism for neurotransmitters or other ligands such as neurotrophins,
generation of complexity and variation, and this mecha- or are activated by second messengers.The diverse char-
nism appears to be highly prevalent in the nervous system, acteristics of different ion channels provide a means by
affecting key processes such as neurotransmitter receptors which neuronal excitability can be exquisitely modu-
and ion channels. Numerous diseases are already known to lated at both the cellular and the subcellular levels. Dis-
result from abnormalities in alternative splicing. Increased orders of ion channelschannelopathiesare responsi-
inclusion of exon 10-containing transcripts of MAPT can ble for a growing list of human neurologic diseases
cause frontotemporal dementia. Aberrant splicing also (Table 19-1). Most are caused by mutations in ion
contributes to the pathogenesis of Duchenne, myotonic, channel genes or by autoantibodies against ion channel
and fascioscapulohumeral muscular dystrophies; ataxia proteins. One example is epilepsy, a syndrome of diverse
telangiectasia; neurobromatosis; some inherited ataxias; causes characterized by repetitive, synchronous ring of
and fragile X syndrome; among other disorders. It is also neuronal action potentials. Action potentials are nor-
likely that subtle variations of splicing will inuence many mally generated by the opening of sodium channels and
genetically complex disorders. Recently a splicing variant the inward movement of sodium ions down the intra-
of the interleukin 7 receptor chain, resulting in produc- cellular concentration gradient. Depolarization of
tion of more soluble and less membrane-bound receptor, the neuronal membrane opens potassium channels,
was found to be associated with susceptibility to multiple resulting in outward movement of potassium ions,
sclerosis (MS) in multiple different populations. repolarization, closure of the sodium channel, and
Epigenetics refers to the mechanisms by which levels hyperpolarization. Sodium or potassium channel sub-
of gene expression can be exquisitely modulated, not by unit genes have long been considered candidate dis-
variations in the primary genetic sequence of DNA but ease genes in inherited epilepsy syndromes, and recently
rather by postgenomic alterations in DNA and chro- such mutations have been identified. These mutations
matin structure, which inuence how, when, and where appear to alter the normal gating function of these
genes are expressed. DNA methylation, as well as channels, increasing the inherent excitability of neuronal
methylation and acetylation of histone proteins that membranes in regions where the abnormal channels
interact with nuclear DNA to form chromatin, are key are expressed.
mediators of these events. Epigenetic processes appear to Whereas the specic clinical manifestations of chan-
be dynamically active even in postmitotic neurons. nelopathies are quite variable, one common feature is
 212 TABLE 19-1
EXAMPLES OF NEUROLOGIC CHANNELOPATHIES

CATEGORY DISORDER CHANNEL TYPE MUTATED GENE CHAP. REF.

Genetic
Ataxias Episodic ataxia-1 K KCNA1 26
Episodic ataxia-2 Ca CACNL1A
Spinocerebellar ataxia-6 Ca CACNL1A
Migraine Familial hemiplegic migraine 1 Ca CACNL1A 6
Familial hemiplegic migraine 2 Na SCN1A
Epilepsy Benign neonatal familial convulsions
Generalized epilepsy with febrile K KCNQ2, KCNQ3 20
convulsions plus Na SCN1B
Periodic paralysis Hyperkalemic periodic paralysis Na SCN4A 43
Hypokalemic periodic paralysis Ca CACNL1A3
Myotonia Myotonia congenita Cl CLCN1 43
Paramyotonia congenita Na SCN4A
Deafness Jorvell and Lange-Nielsen syndrome K KCNQ1, KCNE1 18
SECTION III

(deafness, prolonged QT interval,

and arrythmia)
Autosomal dominant progressive deafness K KCNQ4
Autoimmune
Paraneoplastic Limbic encephalitis Kv1 39
Acquired neuromyotonia Kv1 39
Diseases of the Central Nervous System

Cerebellar ataxia Ca (P/Q type) 39

Lambert-Eaton syndrome Ca (P/Q type) 39

that manifestations tend to be intermittent or paroxys- the synaptic cleft, where they bind to receptors on the
mal, such as occurs in epilepsy, migraine, ataxia, myoto- postsynaptic cell. Secreted neurotransmitters are elimi-
nia, or periodic paralysis. Exceptions are clinically nated by reuptake into the presynaptic neuron (or glia),
progressive channel disorders such as autosomal domi- by diffusion away from the synaptic cleft, and/or by spe-
nant hearing impairment. The genetic channelopathies cic inactivation. In addition to the classic neurotransmit-
identied to date are all uncommon disorders caused by ters, many neuropeptides have been identied as denite
obvious mutations in channel genes. As the full reper- or probable neurotransmitters; these include substance P,
toire of human ion channels and related proteins is neurotensin, enkephalins, -endorphin, histamine, vasoac-
identied, it is likely that additional channelopathies will tive intestinal polypeptide, cholecystokinin, neuropeptide
be discovered. In addition to rare disorders that result Y, and somatostatin. Peptide neurotransmitters are synthe-
from obvious mutations, it is also likely that less pene- sized in the cell body rather than the nerve terminal and
trant allelic variations in channel genes or in their pat- may colocalize with classic neurotransmitters in single
tern of expression might underlie susceptibility to some neurons. Nitric oxide and carbon monoxide are gases that
common forms of epilepsy, migraine, or other disorders. appear also to function as neurotransmitters, in part by
For example, mutations in the T-type Ca channel gene signaling in a retrograde fashion from the postsynaptic to
CACNA1H, as well as a K channel (KCND2) and vari- the presynaptic cell.
ous GABA receptor genes, have been associated with an Neurotransmitters modulate the function of postsy-
increased risk for epilepsy. naptic cells by binding to specic neurotransmitter recep-
tors, of which there are two major types. Ionotropic receptors
are direct ion channels that open after engagement by the
NEUROTRANSMITTERS AND neurotransmitter. Metabotropic receptors interact with G
NEUROTRANSMITTER RECEPTORS proteins, stimulating production of second messengers
and activating protein kinases, which modulate a variety
Synaptic neurotransmission is the predominant means by of cellular events. Ionotropic receptors are multiple sub-
which neurons communicate with each other. Classic unit structures, whereas metabotropic receptors are com-
neurotransmitters are synthesized in the presynaptic region posed of single subunits only. One important difference
of the nerve terminal; stored in vesicles; and released into between ionotropic and metabotropic receptors is that
the kinetics of ionotropic receptor effects are fast (gener- the X-linked form of CMT disease (Chap. 40). Muta- 213
ally <1 ms) because neurotransmitter binding directly tions in either of two gap junction proteins expressed in
alters the electrical properties of the postsynaptic cell, the inner earconnexin 26 and connexin 31result in
whereas metabotropic receptors function over longer autosomal dominant progressive hearing loss (Chap. 18).
time periods. These different properties contribute to the Glial calcium waves mediated through gap junctions also
potential for selective and nely modulated signaling by appear to explain the phenomenon of spreading depres-
neurotransmitters. sion associated with migraine auras and the march of
Neurotransmitter systems are perturbed in a large epileptic discharges. Spreading depression is a neural
number of clinical disorders, examples of which are high- response that follows a variety of different stimuli and is
lighted in Table19-2. One example is the involvement characterized by a circumferentially expanding negative
of dopaminergic neurons originating in the substantia potential that propagates at a characteristic speed of
nigra of the midbrain and projecting to the striatum 20 m/s and is associated with an increase in extracellular
(nigrostriatal pathway) in Parkinsons disease and in heroin potassium.
addicts after the ingestion of the toxin MPTP (1-
methyl-4-phenyl-1,2,5,6-tetrahydropyridine).
A second important dopaminergic system arising in SIGNALING PATHWAYS AND GENE
the midbrain is the mediocorticolimbic pathway, which TRANSCRIPTION

CHAPTER 19
is implicated in the pathogenesis of addictive behaviors
including drug reward. Its key components include the The fundamental issue of how memory, learning, and
midbrain ventral tegmental area (VTA), median fore- thinking are encoded in the nervous system is likely to be
brain bundle, and nucleus accumbens (Fig. 48-2). The claried by identifying the signaling pathways involved in
cholinergic pathway originating in the nucleus basalis of neuronal differentiation, axon guidance, and synapse for-
Meynert plays a role in memory function in Alzheimers mation, and by understanding how these pathways are

Mechanisms of Neurologic Diseases

disease. modulated by experience. Many families of transcription
Addictive drugs share the property of increasing dopamine factors, each comprising multiple individual components,
release in the nucleus accumbens. Amphetamine increases are expressed in the nervous system. Elucidation of these
intracellular release of dopamine from vesicles and signaling pathways has already begun to provide insights
reverses transport of dopamine through the dopamine into the cause of a variety of neurologic disorders, includ-
transporters. Patients prone to addiction show increased ing inherited disorders of cognition such as X-linked
activation of the nucleus accumbens following adminis- mental retardation. This problem affects ~1 in 500 males,
tration of amphetamine. Cocaine binds to dopamine trans- and linkage studies in different families suggest that as
porters and inhibits dopamine reuptake. Ethanol inhibits many as 60 different X-chromosome encoded genes may
inhibitory neurons in the VTA, leading to increased be responsible. Rett syndrome, a common cause of (domi-
dopamine release in the nucleus accumbens. Opioids nant) X-linked progressive mental retardation in females, is
also disinhibit these dopaminergic neurons by binding due to a mutation in a gene (MECP2) encoding a DNA-
to receptors expressed by GABA-containing interneu- binding protein involved in transcriptional repression. As
rons in the VTA. Nicotine increases dopamine release by the X chromosome comprises only ~3% of germline
activating nicotinic acetylcholine receptors on cell bod- DNA, then by extrapolation the number of genes that
ies and nerve terminals of dopaminergic VTA neurons. potentially contribute to clinical disorders affecting intelli-
Tetrahydrocannabinol, the active ingredient of cannabis, gence in humans must be potentially very large. As dis-
also increases dopamine levels in the nucleus accum- cussed below, there is increasing evidence that abnormal
bens. Blockade of dopamine in the nucleus accumbens gene transcription may play a role in neurodegenerative
can terminate the rewarding effects of addictive drugs. diseases, such as Huntingtons disease, in which proteins
Not all cell-to-cell communication in the nervous with polyglutamine expansions bind to and sequester tran-
system occurs via neurotransmission. Gap junctions pro- scription factors.A critical transcription factor for neuronal
vide for direct neuron-neuron electrical conduction and survival is CREB (cyclic adenosine monophosphate
also create openings for the diffusion of ions and responsive element-binding) protein, which also plays an
metabolites between cells. In addition to neurons, gap important role in memory in the hippocampus.
junctions are also widespread in glia, creating a syn-
cytium that protects neurons by removing glutamate and
potassium from the extracellular environment. Gap junc- MYELIN
tions consist of membrane-spanning proteins, termed
connexins, that pair across adjacent cells. Mechanisms that Myelin is the multilayered insulating substance that sur-
involve gap junctions have been related to a variety of neu- rounds axons and speeds impulse conduction by permit-
rologic disorders. Mutations in connexin 32, a gap junction ting action potentials to jump between naked regions of
protein expressed by Schwann cells, are responsible for axons (nodes of Ranvier) and across myelinated segments.
 214 TABLE 19-2
PRINCIPAL CLASSIC NEUROTRANSMITTERS

NEUROTRANSMITTER ANATOMY CLINICAL ASPECTS

Acetylcholine (ACh) Motor neurons in spinal cord Acetylcholinesterases (nerve gases)

O neuromuscular junction Myasthenia gravis (antibodies to ACh
receptor)
CH3COCH2N(CH3)3 Congenital myasthenic syndromes
(mutations in ACh receptor subunits)
Lambert-Eaton syndrome (antibodies to
Ca channels impair ACh release)
Botulism (toxin disrupts ACh release by
exocytosis)
Basal forebrain widespread cortex Alzheimers disease (selective cell death)
Autosomal dominant frontal lobe epilepsy
(mutations in CNS ACh receptor)
Interneurons in striatum Parkinsons disease (tremor)
Autonomic nervous system
(preganglionic and postganglionic
SECTION III

parasympathetic; preganglionic
sympathetic)

Dopamine Substantia nigra striatum Parkinsons disease (selective cell death)

HO
(nigrostriatal pathway) MPTP parkinsonism (toxin transported into
Substantia nigra limbic system neurons)
Diseases of the Central Nervous System

and widespread cortex Addiction, behavioral disorders

HO CH2CH2NH3
Arcuate nucleus of hypothalamus Inhibits prolactin secretion
anterior pituitary (via portal veins)

Norepinephrine (NE) Locus coeruleus (pons) limbic Mood disorders (MAOA inhibitors and
HO system, hypothalamus, cortex tricyclics increase NE and improve
Medulla locus coeruleus, depression)
HO CHCH2NH2 spinal cord Anxiety
Postganglionic neurons of Orthostatic tachycardia syndrome
OH sympathetic nervous system (mutations in NE transporter)

Serotonin Pontine raphe nuclei Mood disorders (SSRIs improve

HO
CH2CH2NH2
widespread projections depression)
Medulla/pons dorsal horn of Migraine pain pathway
N spinal cord Pain pathway
H

-Aminobutyric acid (GABA) Major inhibitory neurotransmitter in Stiff person syndrome (antibodies to
H2NCH2CH2CH2 COOH brain; widespread cortical interneurons glutamic acid decarboxylase, the
and long projection pathways biosynthetic enzyme for GABA)
Epilepsy (gabapentin and valproic acid
increase GABA)

Glycine Major inhibitory neurotransmitter Spasticity

H2NCH2 COOH in spinal cord Hyperekplexia (myoclonic startle syndrome)
due to mutations in glycine receptor

Glutamate Major excitatory neurotransmitter; Seizures due to ingestion of domoic acid

H2NCHCH2CH2COOH located throughout CNS, including (a glutamate analogue)
cortical pyramidal cells Rasmussens encephalitis (antibody against
COOH glutamate receptor 3)
Excitotoxic cell death

Note: CNS, central nervous system; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MAOA, monoamine oxidase A; SSRI, selective sero-
tonin reuptake inhibitor.
 MOG PMP22 215

PLP P0

Myelin basic protein

Myelin basic protein

P0 PLP

MAG GQ1b
GM1 Cx32

FIGURE 19-1
The molecular architecture of the myelin sheath illustrating PMP22 are responsible for another inherited neuropathy
the most important disease-related proteins. The illustration termed hereditary liability to pressure palsies (Chap. 40).
represents a composite of CNS and PNS myelin. Proteins In multiple sclerosis (MS), myelin basic protein (MBP) and

CHAPTER 19
restricted to CNS myelin are shown in green, proteins of PNS the quantitatively minor CNS protein, myelin oligodendrocyte
myelin are lavender, and proteins present in both CNS and glycoprotein (MOG), are likely T cell and B cell antigens,
PNS are red. In the CNS, the X-linked allelic disorders, respectively. The location of MOG at the outermost lamella of
Pelizaeus-Merzbacher disease and one variant of familial the CNS myelin membrane may facilitate its targeting by
spastic paraplegia, are caused by mutations in the gene for autoantibodies. In the PNS, autoantibodies against myelin
proteolipid protein (PLP) that normally promotes extracellular gangliosides are implicated in a variety of disorders, includ-
compaction between adjacent myelin lamellae. The homo- ing GQ1b in the Fisher variant of Guillain-Barr syndrome,

Mechanisms of Neurologic Diseases

logue of PLP in the PNS is the P0 protein, mutations in which GM1 in multifocal motor neuropathy, and sulfatide con-
cause the neuropathy Charcot-Marie-Tooth disease (CMT) stituents of myelin-associated glycoprotein (MAG) in periph-
type 1B. The most common form of CMT is the 1A subtype eral neuropathies associated with monoclonal gammopathies
caused by a duplication of the PMP22 gene; deletions in (Chap. 41).

Molecular interactions between the myelin membrane and survival; some have additional functions, including
and axon are required to maintain the stability, function, roles in neurotransmission and in the synaptic reorgani-
and normal lifespan of both structures. A single oligo- zation involved in learning and memory. The neu-
dendrocyte usually ensheaths multiple axons in the cen- rotrophin (NT) family contains nerve growth factor
tral nervous system (CNS), whereas in the peripheral (NGF), brain-derived neurotrophic factor (BDNF),
nervous system (PNS) each Schwann cell typically NT3, and NT4/5. The neurotrophins act at TrK and
myelinates a single axon. Myelin is a lipid-rich material p75 receptors to promote survival of neurons. Because
formed by a spiraling process of the membrane of the of their survival-promoting and antiapoptotic effects,
myelinating cell around the axon, creating multiple mem- neurotrophic factors are in theory outstanding candi-
brane bilayers that are tightly apposed (compact myelin) by dates for therapy of disorders characterized by prema-
charged protein interactions. Several inhibitors of axon ture death of neurons such as occurs in amyotrophic
growth are expressed on the innermost (periaxonal) lateral sclerosis (ALS) and other degenerative motor
lamellae of the myelin membrane (see Stem Cells and neuron disorders. Knockout mice lacking receptors for
Transplantation, below). A number of clinically impor- ciliary neurotrophic factor (CNTF) or BDNF show loss
tant neurologic disorders are caused by inherited muta- of motor neurons, and experimental motor neuron
tions in myelin proteins of the CNS or PNS (Fig. 19-1). death can be rescued by treatment with various neu-
Constituents of myelin also have a propensity to be tar- rotrophic factors including CNTF, BDNF, and vascular
geted as autoantigens in autoimmune demyelinating dis- endothelial growth factor (VEGF). However, in phase 3
orders (Fig. 19-2). clinical trials, growth factors were ineffective in human
ALS. The growth factor glial-derived neurotrophic fac-
tor (GDNF) is important for survival of dopaminergic
NEUROTROPHIC FACTORS neurons. It has shown promising neurorestorative effects
in experimental models of Parkinsons disease and is
Neurotrophic factors (Table 19-3) are secreted proteins being tested using gene therapy in early-stage human
that modulate neuronal growth, differentiation, repair, clinical trials.
 216 Mg2+ Mg2+

Glutamate NMDA receptor Glutamate NMDA receptor

Glycine-(D-series) Glycine-(D-series)

Preserved
Impaired ATP generation
ATP generation
[Ca2+]
[Ca2+]
Mitochondrial swelling,
NOS rupture of outer membrane
NOS NO + O2 ONOO
PTP activation
NO + O2 Oxidative
stress
[Ca2+]
O2 O2
[Ca2+]
Caspase 9
AIF Cytc
SOD Catalase
O2 H2O2 H2O
SECTION III

ONOO Hydrogen peroxide

Peroxynitrite
OH AIF Apaf1 + dATP
Hydrogen ion

Protein oxidation N le
Nuc eus Nu
Nucle
uc
ucle
eus
Lipid peroxidation Activation of
DNA/RNA oxidation PARS caspase cascade
activation
Diseases of the Central Nervous System

ATP depletion
NAD depletion Cell death by apoptosis
Cell death by necrosis

A B
FIGURE 19-2
Involvement of mitochondria in cell death. A severe excito- insult can occur due either to an abnormality in an excitotoxi-
toxic insult (A) results in cell death by necrosis, whereas a city amino acid receptor, allowing more Ca2+ ux, or to
mild excitotoxic insult (B) results in apoptosis. After a severe impaired functioning of other ionic channels or of energy pro-
insult (such as ischemia), there is a large increase in gluta- duction, which may allow the voltage-dependent NMDA
mate activation of NMDA receptors, an increase in intracellu- receptor to be activated by ambient concentrations of gluta-
lar Ca2+ concentrations, activation of nitric oxide synthase mate. This event can then lead to increased mitochondrial
(NOS), and increased mitochondrial Ca2+ and superoxide Ca2+ and free radical production, yet relatively preserved ATP
generation followed by the formation of ONOO. This sequence generation. The mitochondria may then release cytochrome c
results in damage to cellular macromolecules including DNA, (Cytc), caspase 9, apoptosis-inducing factor (AIF), and per-
leading to activation of poly-ADP-ribose polymerase (PARS). haps other mediators that lead to apoptosis. The precise role
Both mitochondrial accumulation of Ca2+ and oxidative dam- of the PTP in this mode of cell death is still being claried,
age lead to activation of the permeability transition pore (PTP) but there does appear to be involvement of the adenine
that is linked to excitotoxic cell death. A mild excitotoxic nucleotide transporter that is a key component of the PTP.

growth, survival, differentiation, and migration of these

STEM CELLS AND TRANSPLANTATION
cells exists in the mature nervous system. In rodents,
The nervous system is traditionally considered to be a neural stem cells, dened as progenitor cells capable of
nonmitotic organ, in particular with respect to neurons. differentiating into mature cells of neural or glial lineage,
These concepts have been challenged by the nding that have been experimentally propagated from fetal CNS
neural progenitor or stem cells exist in the adult CNS and neuroectodermal tissues and also from adult germi-
that are capable of differentiation, migration over long nal matrix and ependyma regions. Human fetal CNS
distances, and extensive axonal arborization and synapse tissue is also capable of differentiation into cells with neu-
formation with appropriate targets.These capabilities also ronal, astrocyte, and oligodendrocyte morphology when
indicate that the repertoire of factors required for cultured in the presence of growth factors. Impressively,
TABLE 19-3 development. Human ES cells can be differentiated into 217
NEUROTROPHIC FACTORS dopaminergic neurons, which reverse symptoms of
Parkinsons disease in experimental animal models. Studies
Neurotrophin family Transforming growth factor
Nerve growth factor family
of transplantation for patients with Huntingtons disease
Brain-derived Glial-derived neurotrophic have also reported encouraging, although very prelimi-
neurotrophic factor family nary, results. Oligodendrocyte precursor cells transplanted
Neurotrophin-3 Neurturin into mice with a dysmyelinating disorder effectively
Neurotrophin-4 Persephin migrated in the new environment, interacted with axons,
Neurotrophin-6 Fibroblast growth factor and mediated myelination; such experiments raise hope
Cytokine family family that similar transplantation strategies may be feasible in
Ciliary neurotrophic factor Hepatocyte growth factor
Leukemia inhibitory factor Insulin-like growth factor
human disorders of myelin such as MS. The promise of
Interleukin-6 (IGF) family stem cells for treatment of both neurodegenerative dis-
Cardiotrophin-1 IGF-1 eases and neural injury is great, but development has
IGF-2 been slowed by unresolved concerns over safety (includ-
ing the theoretical risk of malignant transformation of
transplanted cells), ethics (particularly with respect to use
of fetal tissue), and efcacy.

CHAPTER 19
In developing brain, the extracellular matrix provides
such cells could be stably engrafted into mouse CNS tis- stimulatory and inhibitory signals that promote neuronal
sue, creating neural chimeras. Another approach is to use migration, neurite outgrowth, and axonal extension.
somatic cell nuclear transfer, in which cell nuclei are placed After neuronal damage, reexpression of inhibitory mole-
inside an enucleated oocyte and then differentiated into cules such as chondroitin sulfate proteoglycans may pre-
stem cells with an identical genetic background to the vent tissue regeneration. Chondroitinase degraded these

Mechanisms of Neurologic Diseases

donor. This technique has been utilized successfully in inhibitory molecules and enhanced axonal regeneration
animal models of Parkinsons disease. Once the repertoire and motor recovery in a rat model of spinal cord injury.
of signals required for cell type specication is better Several myelin proteins, specically Nogo, oligodendro-
understood, differentiation into specic neural or glial cyte myelin glycoprotein (OMGP), and myelin-associated
subpopulations can be directed in vitro; such cells could glycoprotein (MAG), may also interfere with axon
also be engineered to express therapeutic molecules. regeneration. Sialidase, which cleaves one class of recep-
Another promising approach is to utilize growth factors, tors for MAG, enhances axonal outgrowth. Antibodies
such as BDNF, to stimulate endogenous stem cells to against Nogo promote regeneration after experimental
proliferate and migrate to areas of neuronal damage. focal ischemia or spinal cord injury. Nogo, OMGP, and
Administration of epidermal growth factor with brob- MAG all bind to the same neural receptor, the Nogo
last growth factor replenished up to 50% of hippocampal receptor, which mediates its inhibitory function via the
CA1 neurons a month after global ischemia in rats. The p75 neurotrophin receptor signaling.
new neurons made connections and improved perfor-
mance in a memory task.
Although stem cells hold tremendous promise for the CELL DEATHEXCITOTOXICITY
treatment of debilitating neurologic diseases, such as AND APOPTOSIS
Parkinsons disease and spinal cord injury, it should be
emphasized that medical application is in its infancy. Excitotoxicity refers to neuronal cell death caused by acti-
Major obstacles are the generation of position- and vation of excitatory amino acid receptors (Fig. 19-3).
neurotransmitter-dened subtypes of neurons and their Compelling evidence for a role of excitotoxicity, espe-
isolation as pure populations of the desired cells. This is cially in ischemic neuronal injury, is derived from exper-
crucial to avoid persistence of undifferentiated embry- iments in animal models. Experimental models of stroke
onic stem (ES) cells, which can generate tumors. The are associated with increased extracellular concentrations
establishment of appropriate neural connections and of the excitatory amino acid neurotransmitter glutamate,
afferent control is also critical. For instance, human ES and neuronal damage is attenuated by denervation of
motor neurons will need to be introduced at multiple glutamate-containing neurons or the administration of
segments in the neuraxis, and then their axons will need glutamate receptor antagonists. The distribution of cells
to regenerate from the spinal cord to distal musculature. sensitive to ischemia corresponds closely with that of
Experimental transplantation of human fetal dopamin- N-methyl-D-aspartate (NMDA) receptors (except for cere-
ergic neurons in patients with Parkinsons disease has bellar Purkinje cells, which are vulnerable to hypoxia-
shown that these transplanted cells can survive within the ischemia but lack NMDA receptors); and competitive
host striatum; however, some patients developed disabling and noncompetitive NMDA antagonists are effective in
dyskinesias and this approach is no longer in clinical preventing focal ischemia. In global cerebral ischemia,
 218 Rolling Triggering Strong adhesion Extravasation

Flow B cell

Activated
lymphocyte
Gelatinases
CD 31 LFA-1
4 Integrin
ICAM
VCAM

Basal lamina
Blood-brain Chemokines
barrier Microglia/macrophages
and cytokines
endothelium
Astrocytes
Activated Heat shock T cell
proteins activation
SECTION III

Microglia/
macrophages IFN-
IL-2

Fc receptor
Chemokines
IL-1, IL-12 Antibody
Brain tissue complement
TNF, IFN, free radicals, vasoactive amines,
Diseases of the Central Nervous System

complement, proteases, cytokines, eicosanoids

Myelin damage

FIGURE 19-3
A model for experimental allergic encephalomyelitis (EAE). recruitment of a secondary inammatory wave; and immune-
Crucial steps for disease initiation and progression include mediated myelin destruction. ICAM, intercellular adhesion
peripheral activation of preexisting autoreactive T cells; hom- molecule; LFA-1, leukocyte function-associated antigen-1;
ing to the CNS and extravasation across the blood-brain bar- VCAM, vascular cell adhesion molecule; IFN, interferon; IL,
rier; reactivation of T cells by exposed autoantigens; secre- interleukin; TNF, tumor necrosis factor.
tion of cytokines; activation of microglia and astrocytes and

non-NMDA receptors (kainic acid and AMPA) are acti- polymerase, or those that overexpress superoxide dismu-
vated, and antagonists to these receptors are protective. tase, are resistant to focal ischemia.
Experimental brain damage induced by hypoglycemia is Although excitotoxicity is clearly implicated in the
also attenuated by NMDA antagonists. pathogenesis of cell death in stroke, to date treatment
Excitotoxicity is not a single event but rather a cascade with NMDA antagonists has not proven to be clinically
of cell injury. Excitotoxicity causes inux of calcium into useful. Transient receptor potentials (TRP) are calcium
cells, and much of the calcium is sequestered in mito- channels that are activated by oxidative stress in parallel
chondria rather than in the cytoplasm. Increased cytoplas- with excitotoxic signal pathways. In addition, glutamate-
mic calcium causes metabolic dysfunction and free radical independent pathways of calcium inux via acid-sensing
generation; activates protein kinases, phospholipases, nitric ion channels have been identied.These channels trans-
oxide synthase, proteases, and endonucleases; and inhibits port calcium in the setting of acidosis and substrate
protein synthesis. Activation of nitric oxide synthase gen- depletion, and pharmacologic blockade of these chan-
erates nitric oxide (NO), which can react with superox- nels markedly attenuates stroke injury. These channels
ide (O2) to generate peroxynitrite (ONOO), which offer a potential new therapeutic target for stroke.
may play a direct role in neuronal injury. Another critical Apoptosis, or programmed cell death, plays an impor-
pathway is activation of poly-ADP-ribose polymerase, tant role in both physiologic and pathologic conditions.
which occurs in response to free radicalmediated DNA During embryogenesis, apoptotic pathways operate to
damage. Experimentally, mice with knockout mutations destroy neurons that fail to differentiate appropriately or
of neuronal nitric oxide synthase or poly-ADP-ribose reach their intended targets. There is mounting evidence
for an increased rate of apoptotic cell death in a variety of ubiquitin carboxy-terminal hydrolase. Parkin, which causes 219
acute and chronic neurologic diseases. Apoptosis is char- autosomal recessive early-onset Parkinsons disease, is a
acterized by neuronal shrinkage, chromatin condensation, ubiquitin ligase. The characteristic histopathologic feature
and DNA fragmentation, whereas necrotic cell death is of Parkinsons disease is the Lewy body, an eosinophilic
associated with cytoplasmic and mitochondrial swelling cytoplasmic inclusion that contains both neurolaments
followed by dissolution of the cell membrane. Apoptotic and -synuclein. Huntingtons disease and cerebellar
and necrotic cell death can coexist or be sequential degenerations are associated with expansions of polyglut-
events, depending on the severity of the initiating insult. amine repeats in proteins, which aggregate to produce
Cellular energy reserves appear to have an important role neuronal intranuclear inclusions. Familial ALS is associ-
in these two forms of cell death, with apoptosis favored ated with superoxide dismutase mutations and cytoplas-
under conditions in which ATP levels are preserved. Evi- mic inclusions containing superoxide dismutase. In
dence of DNA fragmentation has been found in a num- autosomal dominant neurohypophyseal diabetes insipidus,
ber of degenerative neurologic disorders, including mutations in vasopressin result in abnormal protein pro-
Alzheimers disease, Huntingtons disease, and ALS. The cessing, accumulation in the endoplasmic reticulum, and
best characterized genetic neurologic disorder related to cell death.
apoptosis is infantile spinal muscular atrophy (Werdnig- The current major scientic question is whether pro-
Hoffmann disease), in which two genes thought to be tein aggregates contribute to neuronal death or whether

CHAPTER 19
involved in the apoptosis pathways are causative. they are merely secondary bystanders. A major focus in all
Mitochondria are essential in controlling specic the neurodegenerative diseases is now on small protein
apoptosis pathways. The redistribution of cytochrome c, aggregates termed oligomers.These may be the toxic species
as well as apoptosis-inducing factor (AIF), from mito- of -amyloid, -synuclein, and proteins with expanded
chondria during apoptosis leads to the activation of a polyglutamines such as are associated with Huntingtons
cascade of intracellular proteases known as caspases. disease. Protein aggregates are usually ubiquinated, which

Mechanisms of Neurologic Diseases

Caspase-independent apoptosis occurs after DNA dam- targets them for degradation by the 26S component of the
age, activation of poly-ADP-ribose polymerase, and proteosome. An inability to degrade protein aggregates
translocation of AIF into the nucleus. Redistribution of could lead to cellular dysfunction, impaired axonal trans-
cytochrome c is prevented by overproduction of the apop- port, and cell death by apoptotic mechanisms.
totic protein BCL2 and is promoted by the proapoptotic In experimental models of Huntingtons disease and
protein BAX. These pathways may be triggered by acti- cerebellar degeneration, protein aggregates are not well
vation of a large pore in the mitochondrial inner mem- correlated with neuronal death and may be protective.
brane known as the permeability transition pore, although A substantial body of evidence suggests that the mutant
in other circumstances they occur independently. proteins with polyglutamine expansions in these diseases
Recent studies suggest that blocking the mitochondrial bind to transcription factors and that this contributes to
pore reduces both hypoglycemic and ischemic cell disease pathogenesis. In Huntingtons disease there is
death. Mice decient in cyclophilin D, a key protein dysfunction of the transcriptional co-regulator, PGC-
involved in opening the permeability transition pore, are 1, a key regulator of mitochondrial biogenesis. Agents
resistant to necrosis produced by focal cerebral ischemia. that upregulate gene transcription are neuroprotective in
animal models of these diseases. A number of com-
pounds have been developed to block -amyloid pro-
PROTEIN AGGREGATION AND duction and/or aggregation, and these agents are being
NEURODEGENERATION studied in early clinical trials in humans.

The possibility that protein aggregation plays a role in

the pathogenesis of neurodegenerative diseases is a major SYSTEMS NEUROSCIENCE
focus of current research. Protein aggregation is a major
histopathologic hallmark of neurodegenerative diseases. Systems neuroscience refers to study of the functions of
Deposition of -amyloid is strongly implicated in the neurocircuits and how they relate to brain function,
pathogenesis of Alzheimers disease. Genetic mutations in behavior, motor activity, and cognition. Brain imaging
familial Alzheimers disease cause increased production of techniques, primarily functional MRI (fMRI) and posi-
-amyloid with 42 amino acids, which has an increased tion emission tomography (PET), have made it possible
propensity to aggregate, as compared to -amyloid with to investigate cognitive processes such as perception,
40 amino acids. Mutations in genes encoding the MAPT making judgments, paying attention, and thinking. This
lead to altered splicing of tau and the production of neu- has allowed insights into how networks of neurons
robrillary tangles in frontotemporal dementia and pro- operate to produce behavior. Many of these studies at
gressive supranuclear palsy. Familial Parkinsons disease is present are based on determining the connectivity of
associated with mutations in -synuclein, parkin, and the neural circuits and how they operate, and how this can
 220 be then modeled to produce improved understanding of with declarative memory consolidation, but it also
physiologic processes. fMRI uses contrast mechanisms involves activation in the ventral medial prefrontal cor-
related to physiologic changes in tissue, and brain perfu- tex. Consolidation of memory over time results in
sion can be studied by observing the time-course of decreased activity of the hippocampus and progressively
changes in brain water signal as a bolus of injected stronger activation in the ventral medial prefrontal
paramagnetic gadolinium contrast moves through the region associated with retrieval of consolidated memo-
brain. More recently, to study intrinsic contrast-related ries. An elegant study used MRI to identify the brain
local changes in blood oxygenation with brain activity, protein KIBRA as being signicantly associated with
blood-oxygen-level-dependent (BOLD) contrast has human memory performance. This locus was initially
been used to provide a rapid noninvasive approach for identied in a genome-wide screen of three indepen-
functional assessment. These techniques have been reli- dent populations, which were studied in relation to the
ably utilized in the eld of both behavior and cognitive inability to perform verbal memory tasks. Several
sciences. One example is the use of fMRI to demon- KIBRA alleles were associated with improved free recall
strate mirror neuron systems, imitative pathways acti- performance. The authors then utilized fMRI to detect
vated when observing actions of others (Fig. 19-4). KIBRA alleledependent differences in hippocampal
Mirror neurons are thought to be important for social activation during memory retrieval. These experiments
conditioning and for many forms of learning, and provided strong evidence that KIBRA plays a direct role
SECTION III

abnormalities in mirror neurons may underlie some in human memory function. fMRI has also been uti-
autism disorders. Data also suggest that enhancement of lized to identify sequences of brain activation involved
mirror neuron pathways might have potential for reha- in normal movements and alterations in their activation
bilitation after stroke. Other examples of the use of associated with both injury and recovery, and to plan
fMRI include the study of memory. Recent studies have neurosurgical operations. Diffusion tensor imaging is a
shown that not only is hippocampal activity correlated recently developed MRI technique that can measure
Diseases of the Central Nervous System

B C

FIGURE 19-4
Mirror neuron systems are bilaterally activated during presented to the right visual eld (in red, left visual cortex)
imitation. A. Bilateral activations (circled in yellow) in inferior and to the left visual eld (in blue, right visual cortex). C. Lat-
frontal mirror neuron areas during imitation, as measured by eralized primary motor activation for hand actions imitated
BOLD fMRI signal changes. In red, activation during right with the right hand (in red, left motor cortex) and with the left
hand imitation. In blue, activation during left hand imitation. hand (in blue, right motor cortex). (From L. Aziz-Zadeh et al:
B. In contrast, there is lateralized (contralateral) primary visual J Neurosci 26:2964, 2006.)
activation of the primary visual cortex for imitated actions
macroscopic axonal organization in nervous system tis- disease onset delay and survival extension in transgenic ALS 221
sues; it appears to be useful in assessing myelin and mice. Gene Ther. 12:2134, 2009
axonal injuries as well as brain development. KRIEGSTEIN A, ALVAREZ-BUYLLA A: The glial nature of embryonic
and adult neural stem cells.Annu Rev Neurosci. 32:149, 2009
LIN MT, BEAL MF: Mitochondrial dysfunction and oxidative stress in
neurodegenerative diseases. Nature 443:787, 2006
LUKONG KE et al: RNA-binding proteins in human genetic disease.
FURTHER READINGS
Trends Genet. 24:416, 2008
BATES TC et al: Association of KIBRA and memory. Neurosci Lett MEHLER MF: Epigenetics and the nervous system. Ann Neurol
458:140, 2009 64:602, 2008
BURATTI E, BARALLE FE:The molecular links between TDP-43 dys- ROY NS et al: Functional engraftment of human ES cellderived
function and neurodegenration.Adv Genet 66:1, 2009 dopaminergic neurons enriched by coculture with telomerase-
CATTENEO L, RIZZOLATTI G:The mirror neuron system.Arch Neurol. immortalized midbrain astrocytes. Nat Med 12:1259, 2006
66:557, 2009 TAKASHIMA A et al: Declarative memory consolidation in humans: A
DOYLE KP et al: Mechanisms of ischemic brain damage. Neurophar- prospective functional magnetic resonance imaging study. Proc
macology 55:310, 2008 Natl Acad Sci USA 103:756, 2006
HWANG DH et al: Intrathecal transplantation of human neural stem YANG LJS et al: Sialidase enhances spinal axon outgrowth in vivo.
cells overexpressing VEGF provide behavioral improvement, Proc Natl Acad Sci USA 103:11057, 2006

CHAPTER 19
Mechanisms of Neurologic Diseases
 CHAPTER 20

SEIZURES AND EPILEPSY

Daniel H. Lowenstein

I Classication of Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 Electrophysiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Partial Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Brain Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Generalized Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 I Differential Diagnosis of Seizures . . . . . . . . . . . . . . . . . . . . . . 234
Unclassied Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
I Epilepsy Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 Psychogenic Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Juvenile Myoclonic Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . 226 Status Epilepticus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Lennox-Gastaut Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 226 I Beyond Seizures: Other Management Issues . . . . . . . . . . . . 243
Mesial Temporal Lobe Epilepsy Syndrome . . . . . . . . . . . . . . 226 Interictal Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
I The Causes of Seizures and Epilepsy . . . . . . . . . . . . . . . . . . 226 Mortality of Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Causes According to Age . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 Psychosocial Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
I Basic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Employment, Driving, and Other Activities . . . . . . . . . . . . . . . 244
Mechanisms of Seizure Initiation and Propagation . . . . . . . . . 230 I Special Issues Related to Women and Epilepsy . . . . . . . . . . 244
Mechanisms of Epileptogenesis . . . . . . . . . . . . . . . . . . . . . . 231 Catamenial Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Genetic Causes of Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . 231 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Mechanisms of Action of Antiepileptic Drugs . . . . . . . . . . . . 232 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
History and Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Breast-Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

A seizure (from the Latin sacire, to take possession of ) among the many causes of epilepsy there are various
is a paroxysmal event due to abnormal, excessive, hyper- epilepsy syndromes in which the clinical and pathologic
synchronous discharges from an aggregate of central characteristics are distinctive and suggest a specic under-
nervous system (CNS) neurons. Depending on the dis- lying etiology.
tribution of discharges, this abnormal CNS activity can Using the denition of epilepsy as two or more unpro-
have various manifestations, ranging from dramatic con- voked seizures, the incidence of epilepsy is ~0.30.5% in
vulsive activity to experiential phenomena not readily different populations throughout the world, and the
discernible by an observer. Although a variety of factors prevalence of epilepsy has been estimated at 510 persons
inuence the incidence and prevalence of seizures, per 1000.
~510% of the population will have at least one seizure,
with the highest incidence occurring in early childhood
and late adulthood. CLASSIFICATION OF SEIZURES
The meaning of the term seizure needs to be carefully
distinguished from that of epilepsy. Epilepsy describes a Determining the type of seizure that has occurred is
condition in which a person has recurrent seizures due to essential for focusing the diagnostic approach on partic-
a chronic, underlying process. This denition implies ular etiologies, selecting the appropriate therapy, and
that a person with a single seizure, or recurrent seizures providing potentially vital information regarding prog-
due to correctable or avoidable circumstances, does not nosis. In 1981, the International League against Epilepsy
necessarily have epilepsy. Epilepsy refers to a clinical (ILAE) published a modied version of the Interna-
phenomenon rather than a single disease entity, since tional Classication of Epileptic Seizures that has con-
there are many forms and causes of epilepsy. However, tinued to be a useful classication system (Table 20-1).
222
TABLE 20-1 involuntary movements of the contralateral, left hand. 223
CLASSIFICATION OF SEIZURES These movements are typically clonic (i.e., repetitive, exion/
extension movements) at a frequency of ~23 Hz; pure
1. Partial seizures
a. Simple partial seizures (with motor, sensory,
tonic posturing may be seen as well. Since the cortical
autonomic, or psychic signs) region controlling hand movement is immediately adja-
b. Complex partial seizures cent to the region for facial expression, the seizure may
c. Partial seizures with secondary generalization also cause abnormal movements of the face synchronous
2. Primarily generalized seizures with the movements of the hand. The electroencephalo-
a. Absence (petit mal) gram (EEG) recorded with scalp electrodes during the
b. Tonic-clonic (grand mal) seizure (i.e., an ictal EEG) may show abnormal discharges
c. Tonic
d. Atonic
in a very limited region over the appropriate area of cere-
e. Myoclonic bral cortex if the seizure focus involves the cerebral con-
3. Unclassied seizures vexity. Seizure activity occurring within deeper brain
a. Neonatal seizures structures is often not recorded by the standard EEG,
b. Infantile spasms however, and may require intracranial electrodes for its
detection.
Three additional features of partial motor seizures are

CHAPTER 20
worth noting. First, in some patients the abnormal
motor movements may begin in a very restricted region
This system is based on the clinical features of seizures such as the ngers and gradually progress (over seconds
and associated electroencephalographic ndings. Other to minutes) to include a larger portion of the extremity.
potentially distinctive features such as etiology or cellular This phenomenon, described by Hughlings Jackson and
substrate are not considered in this classication system, known as a Jacksonian march, represents the spread of

Seizures and Epilepsy

although this will undoubtedly change in the future as seizure activity over a progressively larger region of
more is learned about the pathophysiologic mechanisms motor cortex. Second, patients may experience a local-
that underlie specic seizure types. ized paresis (Todds paralysis) for minutes to many hours
A fundamental principle is that seizures may be either in the involved region following the seizure. Third, in
partial (synonymous with focal) or generalized. Partial rare instances the seizure may continue for hours or
seizures are those in which the seizure activity is restricted days. This condition, termed epilepsia partialis continua, is
to discrete areas of the cerebral cortex. Generalized seizures often refractory to medical therapy.
involve diffuse regions of the brain simultaneously. Partial Simple partial seizures may also manifest as changes in
seizures are usually associated with structural abnormali- somatic sensation (e.g., paresthesias), vision (ashing lights
ties of the brain. In contrast, generalized seizures may or formed hallucinations), equilibrium (sensation of falling
result from cellular, biochemical, or structural abnormali- or vertigo), or autonomic function (ushing, sweating,
ties that have a more widespread distribution. piloerection). Simple partial seizures arising from the tem-
poral or frontal cortex may also cause alterations in hearing,
PARTIAL SEIZURES olfaction, or higher cortical function (psychic symptoms).
This includes the sensation of unusual, intense odors (e.g.,
Partial seizures occur within discrete regions of the burning rubber or kerosene) or sounds (crude or highly
brain. If consciousness is fully preserved during the complex sounds), or an epigastric sensation that rises from
seizure, the clinical manifestations are considered rela- the stomach or chest to the head. Some patients describe
tively simple and the seizure is termed a simple partial odd, internal feelings such as fear, a sense of impending
seizure. If consciousness is impaired, the symptomatology change, detachment, depersonalization, dj vu, or illusions
is more complex and the seizure is termed a complex par- that objects are growing smaller (micropsia) or larger
tial seizure. An important additional subgroup comprises (macropsia). When such symptoms precede a complex
those seizures that begin as partial seizures and then spread partial or secondarily generalized seizure, these simple par-
diffusely throughout the cortex, i.e., partial seizures with tial seizures serve as a warning, or aura.
secondary generalization.
Complex Partial Seizures
Simple Partial Seizures
Complex partial seizures are characterized by focal
Simple partial seizures cause motor, sensory, autonomic, or seizure activity accompanied by a transient impairment
psychic symptoms without an obvious alteration in con- of the patients ability to maintain normal contact with
sciousness. For example, a patient having a partial motor the environment. The patient is unable to respond
seizure arising from the right primary motor cortex in the appropriately to visual or verbal commands during the
vicinity controlling hand movement will note the onset of seizure and has impaired recollection or awareness of the
 224 ictal phase. The seizures frequently begin with an aura GENERALIZED SEIZURES
(i.e., a simple partial seizure) that is stereotypic for the
By denition, generalized seizures arise from both cere-
patient. The start of the ictal phase is often a sudden
bral hemispheres simultaneously. However, it is currently
behavioral arrest or motionless stare, which marks the
impossible to exclude entirely the existence of a focal
onset of the period of amnesia. The behavioral arrest is
region of abnormal activity that initiates the seizure
usually accompanied by automatisms, which are involun-
prior to rapid secondary generalization. For this reason,
tary, automatic behaviors that have a wide range of man-
generalized seizures may be practically dened as bilat-
ifestations.Automatisms may consist of very basic behav-
eral clinical and electrographic events without any
iors such as chewing, lip smacking, swallowing, or
detectable focal onset. Fortunately, several types of gen-
picking movements of the hands, or more elaborate
eralized seizures have distinctive features that facilitate
behaviors such as a display of emotion or running. The
clinical diagnosis.
patient is typically confused following the seizure, and
the transition to full recovery of consciousness may
range from seconds up to an hour. Examination imme- Absence Seizures (Petit Mal)
diately following the seizure may show an anterograde
amnesia or, in cases involving the dominant hemisphere, Absence seizures are characterized by sudden, brief
a postictal aphasia. lapses of consciousness without loss of postural control.
SECTION III

The routine interictal (i.e., between seizures) EEG in The seizure typically lasts for only seconds, conscious-
patients with complex partial seizures is often normal or ness returns as suddenly as it was lost, and there is no
may show brief discharges termed epileptiform spikes, or postictal confusion. Although the brief loss of conscious-
sharp waves. Since complex partial seizures can arise from ness may be clinically inapparent or the sole manifesta-
the medial temporal lobe or inferior frontal lobe, i.e., tion of the seizure discharge, absence seizures are usually
regions distant from the scalp, the EEG recorded during accompanied by subtle, bilateral motor signs such as
rapid blinking of the eyelids, chewing movements, or
Diseases of the Central Nervous System

the seizure may be nonlocalizing. However, the seizure

focus is often detected using sphenoidal or surgically small-amplitude, clonic movements of the hands.
placed intracranial electrodes. Absence seizures usually begin in childhood (48
The range of potential clinical behaviors linked to years) or early adolescence and are the main seizure type
complex partial seizures is so broad that extreme caution in 1520% of children with epilepsy. The seizures can
is advised before concluding that stereotypic episodes of occur hundreds of times per day, but the child may be
bizarre or atypical behavior are not due to seizure activ- unaware of or unable to convey their existence. Since
ity. In such cases additional, detailed EEG studies may be the clinical signs of the seizures are subtle, especially to
helpful. new parents, it is not surprising that the rst clue to
absence epilepsy is often unexplained daydreaming
and a decline in school performance recognized by a
Partial Seizures with Secondary Generalization teacher.
Partial seizures can spread to involve both cerebral The electrophysiologic hallmark of typical absence
hemispheres and produce a generalized seizure, usually seizures is a generalized, symmetric, 3-Hz spike-and-wave
of the tonic-clonic variety (discussed later). Secondary discharge that begins and ends suddenly, superimposed on a
generalization is observed frequently following simple normal EEG background. Periods of spike-and-wave dis-
partial seizures, especially those with a focus in the charges lasting more than a few seconds usually correlate
frontal lobe, but may also be associated with partial with clinical signs, but the EEG often shows many more
seizures occurring elsewhere in the brain. A partial brief bursts of abnormal cortical activity than were sus-
seizure with secondary generalization is often difcult to pected clinically. Hyperventilation tends to provoke these
distinguish from a primary generalized tonic-clonic electrographic discharges and even the seizures themselves
seizure, since bystanders tend to emphasize the more and is routinely used when recording the EEG.
dramatic, generalized convulsive phase of the seizure and Typical absence seizures are often associated with
overlook the more subtle, focal symptoms present at generalized, tonic-clonic seizures, but patients usually
onset. In some cases, the focal onset of the seizure have no other neurologic problems and respond well to
becomes apparent only when a careful history identies treatment with specic anticonvulsants. Although esti-
a preceding aura (i.e., simple partial seizure). Often, mates vary, ~6070% of such patients will have a sponta-
however, the focal onset is not clinically evident and neous remission during adolescence.
may be established only through careful EEG analysis.
Nonetheless, distinguishing between these two entities is
Atypical Absence Seizures
extremely important, as there may be substantial differ-
ences in the evaluation and treatment of partial versus Atypical absence seizures have features that deviate both
generalized seizure disorders. clinically and electrophysiologically from typical absence
seizures. For example, the lapse of consciousness is usu- polyspike discharges. In the clonic phase, the high- 225
ally of longer duration and less abrupt in onset and ces- amplitude activity is typically interrupted by slow waves
sation, and the seizure is accompanied by more obvious to create a spike-and-wave pattern. The postictal EEG
motor signs that may include focal or lateralizing fea- shows diffuse slowing that gradually recovers as the patient
tures. The EEG shows a generalized, slow spike-and- awakens.
wave pattern with a frequency of 2.5/s, as well as other There are many variants of the generalized tonic-clonic
abnormal activity. Atypical absence seizures are usually seizure, including pure tonic and pure clonic seizures.
associated with diffuse or multifocal structural abnor- Brief tonic seizures lasting only a few seconds are espe-
malities of the brain and therefore may accompany cially noteworthy since they are usually associated with
other signs of neurologic dysfunction such as mental specic epileptic syndromes having mixed seizure phe-
retardation. Furthermore, the seizures are less responsive notypes, such as the Lennox-Gastaut syndrome (discussed
to anticonvulsants compared to typical absence seizures. later).

Generalized, Tonic-Clonic Seizures Atonic Seizures

(Grand Mal)
Atonic seizures are characterized by sudden loss of pos-
Primary generalized, tonic-clonic seizures are the main tural muscle tone lasting 12 s. Consciousness is briey

CHAPTER 20
seizure type in ~10% of all persons with epilepsy. They impaired, but there is usually no postictal confusion. A
are also the most common seizure type resulting from very brief seizure may cause only a quick head drop or
metabolic derangements and are therefore frequently nodding movement, while a longer seizure will cause
encountered in many different clinical settings. The the patient to collapse.This can be extremely dangerous,
seizure usually begins abruptly without warning, since there is a substantial risk of direct head injury with
although some patients describe vague premonitory the fall. The EEG shows brief, generalized spike-and-

Seizures and Epilepsy

symptoms in the hours leading up to the seizure. This wave discharges followed immediately by diffuse slow
prodrome is distinct from the stereotypic auras associated waves that correlate with the loss of muscle tone. Similar
with focal seizures that secondarily generalize.The initial to pure tonic seizures, atonic seizures are usually seen in
phase of the seizure is usually tonic contraction of mus- association with known epileptic syndromes.
cles throughout the body, accounting for a number of
the classic features of the event. Tonic contraction of the Myoclonic Seizures
muscles of expiration and the larynx at the onset will
produce a loud moan or ictal cry. Respirations are Myoclonus is a sudden and brief muscle contraction that
impaired, secretions pool in the oropharynx, and cyanosis may involve one part of the body or the entire body. A
develops. Contraction of the jaw muscles may cause bit- normal, common physiologic form of myoclonus is the
ing of the tongue. A marked enhancement of sympa- sudden jerking movement observed while falling asleep.
thetic tone leads to increases in heart rate, blood pressure, Pathologic myoclonus is most commonly seen in associ-
and pupillary size. After 1020 s, the tonic phase of the ation with metabolic disorders, degenerative CNS dis-
seizure typically evolves into the clonic phase, produced eases, or anoxic brain injury (Chap. 22). Although the
by the superimposition of periods of muscle relaxation distinction from other forms of myoclonus is imprecise,
on the tonic muscle contraction. The periods of relax- myoclonic seizures are considered to be true epileptic
ation progressively increase until the end of the ictal phase, events since they are caused by cortical (versus subcorti-
which usually lasts no more than 1 min. The postictal cal or spinal) dysfunction.The EEG may show bilaterally
phase is characterized by unresponsiveness, muscular ac- synchronous spike-and-wave discharges synchronized
cidity, and excessive salivation that can cause stridorous with the myoclonus, although these can be obscured by
breathing and partial airway obstruction. Bladder or bowel movement artifact. Myoclonic seizures usually coexist
incontinence may occur at this point. Patients gradually with other forms of generalized seizure disorders but are
regain consciousness over minutes to hours, and during the predominant feature of juvenile myoclonic epilepsy
this transition there is typically a period of postictal con- (discussed below).
fusion. Patients subsequently complain of headache,
fatigue, and muscle ache that can last for many hours.
UNCLASSIFIED SEIZURES
The duration of impaired consciousness in the postictal
phase can be extremely long, i.e., many hours, in patients Not all seizure types can be classied as partial or gener-
with prolonged seizures or underlying CNS diseases such alized. This appears to be especially true of seizures that
as alcoholic cerebral atrophy. occur in neonates and infants. The distinctive pheno-
The EEG during the tonic phase of the seizure types of seizures at these early ages likely result, in part,
shows a progressive increase in generalized low-voltage from differences in neuronal function and connectivity
fast activity, followed by generalized high-amplitude, in the immature versus mature CNS.
 226 EPILEPSY SYNDROMES appears to be essential in the pathophysiology of MTLE
for many patients (Fig. 20-1). Recognition of this syn-
Epilepsy syndromes are disorders in which epilepsy is a drome is especially important because it tends to be
predominant feature, and there is sufcient evidence refractory to treatment with anticonvulsants but responds
(e.g., through clinical, EEG, radiologic, or genetic obser- extremely well to surgical intervention. Advances in the
vations) to suggest a common underlying mechanism. understanding of basic mechanisms of epilepsy have
Three important epilepsy syndromes are listed below; come through studies of experimental models of
additional examples with a known genetic basis are MTLE, discussed later.
given in Table 20-2.

THE CAUSES OF SEIZURES

JUVENILE MYOCLONIC EPILEPSY AND EPILEPSY
Juvenile myoclonic epilepsy (JME) is a generalized seizure
disorder of unknown cause that appears in early adoles- Seizures are a result of a shift in the normal balance of
cence and is usually characterized by bilateral myoclonic excitation and inhibition within the CNS. Given the
jerks that may be single or repetitive. The myoclonic numerous properties that control neuronal excitability, it
seizures are most frequent in the morning after awaken- is not surprising that there are many different ways to
SECTION III

ing and can be provoked by sleep deprivation. Con- perturb this normal balance, and therefore many differ-
sciousness is preserved unless the myoclonus is especially ent causes of both seizures and epilepsy. Three clinical
severe. Many patients also experience generalized tonic- observations emphasize how a variety of factors deter-
clonic seizures, and up to one-third have absence seizures. mine why certain conditions may cause seizures or
The condition is otherwise benign, and although com- epilepsy in a given patient.
plete remission is uncommon, the seizures respond well
Diseases of the Central Nervous System

1. The normal brain is capable of having a seizure under the

to appropriate anticonvulsant medication. There is often appropriate circumstances, and there are differences between
a family history of epilepsy, and genetic linkage studies individuals in the susceptibility or threshold for seizures.
suggest a polygenic cause. For example, seizures may be induced by high fevers
in children who are otherwise normal and who
LENNOX-GASTAUT SYNDROME never develop other neurologic problems, including
epilepsy. However, febrile seizures occur only in a
Lennox-Gastaut syndrome occurs in children and is relatively small proportion of children. This implies
dened by the following triad: (1) multiple seizure types there are various underlying endogenous factors that
(usually including generalized tonic-clonic, atonic, and inuence the threshold for having a seizure. Some
atypical absence seizures); (2) an EEG showing slow (<3 of these factors are clearly genetic, as it has been
Hz) spike-and-wave discharges and a variety of other shown that a family history of epilepsy will inu-
abnormalities; and (3) impaired cognitive function in ence the likelihood of seizures occurring in other-
most but not all cases. Lennox-Gastaut syndrome is asso- wise normal individuals. Normal development also
ciated with CNS disease or dysfunction from a variety plays an important role, since the brain appears to
of causes, including developmental abnormalities, peri- have different seizure thresholds at different matura-
natal hypoxia/ischemia, trauma, infection, and other tional stages.
acquired lesions. The multifactorial nature of this syn- 2. There are a variety of conditions that have an extremely
drome suggests that it is a nonspecic response of the high likelihood of resulting in a chronic seizure disorder.
brain to diffuse neural injury. Unfortunately, many One of the best examples of this is severe, penetrat-
patients have a poor prognosis due to the underlying ing head trauma, which is associated with up to a
CNS disease and the physical and psychosocial conse- 50% risk of subsequent epilepsy. The high propen-
quences of severe, poorly controlled epilepsy. sity for severe traumatic brain injury to lead to
epilepsy suggests that the injury results in a long-
lasting pathologic change in the CNS that trans-
MESIAL TEMPORAL LOBE EPILEPSY
forms a presumably normal neural network into
SYNDROME
one that is abnormally hyperexcitable. This process
Mesial temporal lobe epilepsy (MTLE) is the most com- is known as epileptogenesis, and the specic changes
mon syndrome associated with complex partial seizures that result in a lowered seizure threshold can be
and is an example of a symptomatic, partial epilepsy considered epileptogenic factors. Other processes asso-
with distinctive clinical, electroencephalographic, and ciated with epileptogenesis include stroke, infections,
pathologic features (Table 20-3). High-resolution MRI and abnormalities of CNS development. Likewise, the
can detect the characteristic hippocampal sclerosis that genetic abnormalities associated with epilepsy likely
TABLE 20-2 227
EXAMPLES OF GENES ASSOCIATED WITH EPILEPSY SYNDROMESa

GENE (LOCUS) FUNCTION OF GENE CLINICAL SYNDROME COMMENTS

CHRNA4 Nicotinic acetylcholine Autosomal dominant nocturnal Rare; rst identied in a large
(20q13.2) receptor subunit; mutations frontal lobe epilepsy (ADNFLE); Australian family; other families
cause alterations in Ca2+ childhood onset; brief, nighttime found to have mutations in
ux through the receptor; seizures with prominent motor CHRNA2 or CHRNB2, and some
this may reduce amount movements; often misdiagnosed families appear to have mutations
of GABA release in as primary sleep disorder at other loci
presynaptic terminals
KCNQ2 Voltage-gated potassium Benign familial neonatal Rare; other families found to have
(20q13.3) channel subunits; mutation convulsions (BFNC); autosomal mutations in KCNQ3; sequence and
in pore regions may cause dominant inheritance; onset in functional homology to KCNQ1,
a 2040% reduction of 1st week of life in infants who mutations of which cause long QT
potassium currents, which are otherwise normal; remission syndrome and a cardiac-auditory
will lead to impaired usually within weeks to months; syndrome
repolarization long-term epilepsy in 1015%
subunit of a voltage-gated

CHAPTER 20
SCN1B Generalized epilepsy with febrile Incidence uncertain; GEFS+ identied
(19q12.1) sodium channel; mutation seizures plus (GEFS+); autosomal in other families with mutations in
disrupts disulde bridge that dominant inheritance; presents other sodium channel subunits
is crucial for structure of with febrile seizures at median (SCN1A and SCN2A) and GABAA
extracellular domain; mutated 1 year, which may persist receptor subunit (GABRG2 and
subunit leads to slower >6 years, then variable seizure GABRA1); signicant phenotypic
sodium channel inactivation types not associated with fever heterogeneity within same family,
including members with febrile

Seizures and Epilepsy

seizures only
LGI1 (10q24) Leucine-rich glioma-inactivated Autosomal dominant partial Mutations found in approximately
1 gene; previous evidence for epilepsy with auditory features 50% of families containing two or
role in glial tumor progression; (ADPEAF); a form of idiopathic more subjects with idiopathic
protein homology suggests lateral temporal lobe epilepsy localization-related epilepsy with
a possible role in nervous with auditory symptoms or ictal auditory symptoms, suggesting
system development aphasia as a major simple partial that at least one other gene may
seizure manifestation; age of underlie this syndrome. LGI1 is the
onset usually between 10 and only gene identied so far in
25 years temporal lobe epilepsy
CSTB Cystatin B, a noncaspase Progressive myoclonus epilepsy Overall rare, but relatively common in
cysteine protease inhibitor; (PME) (Unverricht-Lundborg Finland and Western Mediterranean
normal protein may block disease); autosomal recessive (>1 in 20,000); precise role of
neuronal apoptosis by inheritance; age of onset between cystatin B in human disease
inhibiting caspases directly 6 and 15 years, myoclonic unknown, although mice with null
or indirectly (via cathepsins), seizures, ataxia, and progressive mutations of cystatin B have similar
or controlling proteolysis cognitive decline; brain shows syndrome
neuronal degeneration
EPM2A (6q24) Laforin, a protein tyrosine Progressive myoclonus epilepsy Most common PME in Southern
phosphatase (PTP); may (Laforas disease); autosomal Europe, Middle East, Northern
inuence glycogen recessive inheritance; onset age Africa, and Indian subcontinent;
metabolism, which is known 619 years, death within 10 years; genetic heterogeneity; unknown
to be regulated by brain degeneration associated whether seizure phenotype due to
phosphatases with polyglucosan intracellular degeneration or direct effects of
inclusion bodies in numerous abnormal laforin expression.
organs
Doublecortin Doublecortin, expressed Classic lissencephaly associated Relatively rare but of uncertain
(Xq21-24) primarily in frontal lobes; with severe mental retardation incidence, recent increased
function unknown; potentially and seizures in men; subcortical ascertainment due to improved
an intracellular signaling band heterotopia with more subtle imaging techniques; relationship
molecule ndings in women (presumably between migration defect and
due to random X-inactivation); seizure phenotype unknown
X-linked dominant

a
The rst four syndromes listed in the table (ADNFLE, BFNC, GEFS+, and ADPEAF) are examples of idiopathic epilepsies associated with identied
gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype.
Note: GABA, -aminobutyric acid; PME, progressive myoclonus epilepsy.
 228 TABLE 20-3
CHARACTERISTICS OF THE MESIAL TEMPORAL LOBE EPILEPSY SYNDROME
History
History of febrile seizures Rare secondarily generalized seizures
Family history of epilepsy Seizures may remit and reappear
Early onset Seizures often intractable
Clinical observations
Aura common Postictal disorientation, memory loss,
Behavioral arrest/stare dysphasia (with focus in dominant
Complex automatisms hemisphere)
Unilateral posturing
Laboratory studies
Unilateral or bilateral anterior temporal spikes on EEG
Hypometabolism on interictal PET
Hypoperfusion on interictal SPECT
Material-specic memory decits on intracranial amobarbital (Wada) test
MRI ndings
Small hippocampus with increased signal on T2-weighted sequences
SECTION III

Small temporal lobe

Enlarged temporal horn
Pathologic ndings
Highly selective loss of specic cell populations within hippocampus in most cases

Note: EEG, electroencephalogram; PET, positron emission tomography; SPECT, single photon emission
computed tomography.
Diseases of the Central Nervous System

involve processes that trigger the appearance of spe- even years between seizures. This implies there are
cic sets of epileptogenic factors. important provocative or precipitating factors that induce
3. Seizures are episodic. Patients with epilepsy have seizures seizures in patients with epilepsy. Similarly, precipitating
intermittently and, depending on the underlying cause, factors are responsible for causing the single seizure in
many patients are completely normal for months or someone without epilepsy. Precipitants include those
due to intrinsic physiologic processes, such as psycho-
logical or physical stress, sleep deprivation, or hormonal
changes associated with the menstrual cycle.They also
include exogenous factors such as exposure to toxic
substances and certain medications.
These observations emphasize the concept that the
many causes of seizures and epilepsy result from a
dynamic interplay between endogenous factors, epilepto-
genic factors, and precipitating factors. The potential role
of each needs to be carefully considered when determin-
ing the appropriate management of a patient with seizures.
For example, the identication of predisposing factors
(e.g., family history of epilepsy) in a patient with febrile
seizures may increase the necessity for closer follow-up
and a more aggressive diagnostic evaluation. Finding an
epileptogenic lesion may help in the estimation of seizure
recurrence and duration of therapy. Finally, removal or
FIGURE 20-1
modication of a precipitating factor may be an effective
Mesial temporal lobe epilepsy. The EEG suggested a right and safer method for preventing further seizures than the
temporal lobe focus. Coronal high-resolution T2-weighted prophylactic use of anticonvulsant drugs.
fast spin echo magnetic resonance image obtained through
the body of the hippocampus demonstrates abnormal high-
CAUSES ACCORDING TO AGE
signal intensity in the right hippocampus (white arrows; com-
pare with the normal hippocampus on the left, black arrows) In practice, it is useful to consider the etiologies of seizures
consistent with mesial temporal sclerosis. based on the age of the patient, as age is one of the most
important factors determining both the incidence and replacement.The idiopathic or inherited forms of benign 229
the likely causes of seizures or epilepsy (Table 20-4). neonatal convulsions are also seen during this time period.
During the neonatal period and early infancy, potential The most common seizures arising in late infancy and
causes include hypoxic-ischemic encephalopathy, trauma, early childhood are febrile seizures, which are seizures
CNS infection, congenital CNS abnormalities, and meta- associated with fevers but without evidence of CNS
bolic disorders. Babies born to mothers using neurotoxic infection or other dened causes.The overall prevalence
drugs such as cocaine, heroin, or ethanol are susceptible to is 35% and even higher in some parts of the world,
drug-withdrawal seizures in the rst few days after such as Asia. Patients often have a family history of
delivery. Hypoglycemia and hypocalcemia, which can febrile seizures or epilepsy. Febrile seizures usually occur
occur as secondary complications of perinatal injury, are between 3 months and 5 years of age and have a peak
also causes of seizures early after delivery. Seizures due to incidence between 18 and 24 months. The typical sce-
inborn errors of metabolism usually present once regular nario is a child who has a generalized, tonic-clonic
feeding begins, typically 23 days after birth. Pyridoxine seizure during a febrile illness in the setting of a com-
(vitamin B6) deciency, an important cause of neonatal mon childhood infection such as otitis media, respira-
seizures, can be effectively treated with pyridoxine tory infection, or gastroenteritis. The seizure is likely to
occur during the rising phase of the temperature curve
(i.e., during the rst day) rather than well into the course

CHAPTER 20
of the illness. A simple febrile seizure is a single, isolated
TABLE 20-4 event, brief, and symmetric in appearance. Complex
CAUSES OF SEIZURES febrile seizures are characterized by repeated seizure
Neonates Perinatal hypoxia and ischemia activity, duration >15 min, or by focal features. Approxi-
(<1 month) Intracranial hemorrhage and trauma mately one-third of patients with febrile seizures will
Acute CNS infection have a recurrence, but <10% have three or more episodes.

Seizures and Epilepsy

Metabolic disturbances Recurrences are much more likely when the febrile
(hypoglycemia, hypocalcemia, seizure occurs in the rst year of life. Simple febrile
hypomagnesemia, pyridoxine seizures are not associated with an increase in the risk of
deciency)
developing epilepsy, while complex febrile seizures have
Drug withdrawal
Developmental disorders a risk of 25%; other risk factors include the presence of
Genetic disorders preexisting neurologic decits and a family history of
Infants and Febrile seizures nonfebrile seizures.
children Genetic disorders (metabolic, Childhood marks the age at which many of the well-
(>1 mo and degenerative, primary epilepsy dened epilepsy syndromes present. Some children who
<12 years) syndromes) are otherwise normal develop idiopathic, generalized
CNS infection tonic-clonic seizures without other features that t into
Developmental disorders
Trauma
specic syndromes. Temporal lobe epilepsy usually pre-
Idiopathic sents in childhood and may be related to mesial tempo-
Adolescents Trauma ral lobe sclerosis (as part of the MTLE syndrome) or
(1218 years) Genetic disorders other focal abnormalities such as cortical dysgenesis.
Infection Other types of partial seizures, including those with sec-
Brain tumor ondary generalization, may be the relatively late mani-
Illicit drug use festation of a developmental disorder, an acquired lesion
Idiopathic such as head trauma, CNS infection (especially viral
Young adults Trauma
(1835 years) Alcohol withdrawal
encephalitis), or very rarely a CNS tumor.
Illicit drug use The period of adolescence and early adulthood is one of
Brain tumor transition during which the idiopathic or genetically
Idiopathic based epilepsy syndromes, including JME and juvenile
Older adults Cerebrovascular disease absence epilepsy, become less common, while epilepsies
(>35 years) Brain tumor secondary to acquired CNS lesions begin to predomi-
Alcohol withdrawal nate. Seizures that begin in patients in this age range
Metabolic disorders (uremia, hepatic
may be associated with head trauma, CNS infections
failure, electrolyte abnormalities,
hypoglycemia)
(including parasitic infections such as cysticercosis), brain
Alzheimers disease and other tumors, congenital CNS abnormalities, illicit drug use,
degenerative CNS diseases or alcohol withdrawal.
Idiopathic Head trauma is a common cause of epilepsy in ado-
lescents and adults. The head injury can be caused by a
Note: CNS, central nervous system. variety of mechanisms, and the likelihood of developing
 230 epilepsy is strongly correlated with the severity of the TABLE 20-5
injury.A patient with a penetrating head wound, depressed DRUGS AND OTHER SUBSTANCES THAT CAN CAUSE
skull fracture, intracranial hemorrhage, or prolonged SEIZURES
posttraumatic coma or amnesia has a 4050% risk of Alkylating agents (e.g., busulfan, chlorambucil)
developing epilepsy, while a patient with a closed head Antimalarials (chloroquine, meoquine)
injury and cerebral contusion has a 525% risk. Recur- Antimicrobials/antivirals
rent seizures usually develop within 1 year after head -lactam and related compounds
trauma, although intervals of 10 years are well known. Quinolones
In controlled studies, mild head injury, dened as a con- Acyclovir
cussion with amnesia or loss of consciousness of <30 min, Isoniazid
Ganciclovir
was found to be associated with only a slightly increased Anesthetics and analgesics
likelihood of epilepsy. Nonetheless, most epileptologists Meperidine
know of patients who have partial seizures within hours Tramadol
or days of a mild head injury and subsequently develop Local anesthetics
chronic seizures of the same type; such cases may repre- Dietary supplements
sent rare examples of chronic epilepsy resulting from Ephedra (ma huang)
mild head injury. Gingko
SECTION III

Immunomodulatory drugs
The causes of seizures in older adults include cerebrovas-
Cyclosporine
cular disease, trauma (including subdural hematoma), CNS OKT3 (monoclonal antibodies to T cells)
tumors, and degenerative diseases. Cerebrovascular disease Tacrolimus
may account for ~50% of new cases of epilepsy in patients Interferons
older than 65 years. Acute seizures (i.e., occurring at the Psychotropics
time of the stroke) are seen more often with embolic Antidepressants
Diseases of the Central Nervous System

rather than hemorrhagic or thrombotic stroke. Chronic Antipsychotics

Lithium
seizures typically appear months to years after the initial
Radiographic contrast agents
event and are associated with all forms of stroke. Theophylline
Metabolic disturbances such as electrolyte imbalance, Sedative-hypnotic drug withdrawal
hypo- or hyperglycemia, renal failure, and hepatic fail- Alcohol
ure may cause seizures at any age. Similarly, endocrine Barbiturates (short-acting)
disorders, hematologic disorders, vasculitides, and many Benzodiazepines (short-acting)
other systemic diseases may cause seizures over a broad Drugs of abuse
Amphetamine
age range. A wide variety of medications and abused
Cocaine
substances are known to precipitate seizures as well Phencyclidine
(Table 20-5). Methylphenidate
Flumazenila

BASIC MECHANISMS a
In benzodiazepine-dependent patients.
MECHANISMS OF SEIZURE INITIATION AND
PROPAGATION
Partial seizure activity can begin in a very discrete
region of cortex and then spread to neighboring from a sufcient number of neurons result in a so-called
regions, i.e., there is a seizure initiation phase and a seizure spike discharge on the EEG.
propagation phase.The initiation phase is characterized by Normally, the spread of bursting activity is prevented
two concurrent events in an aggregate of neurons: (1) by intact hyperpolarization and a region of surrounding
high-frequency bursts of action potentials and (2) inhibition created by inhibitory neurons. With suf-
hypersynchronization. The bursting activity is caused by cient activation there is a recruitment of surrounding
a relatively long-lasting depolarization of the neuronal neurons via a number of mechanisms. Repetitive dis-
membrane due to inux of extracellular calcium (Ca2+), charges lead to the following: (1) an increase in extracel-
which leads to the opening of voltage-dependent lular K+, which blunts hyperpolarization and depolarizes
sodium (Na+) channels, inux of Na+, and generation of neighboring neurons; (2) accumulation of Ca2+ in presy-
repetitive action potentials. This is followed by a hyper- naptic terminals, leading to enhanced neurotransmitter
polarizing afterpotential mediated by -aminobutyric release; and (3) depolarization-induced activation of the
acid (GABA) receptors or potassium (K+) channels, N-methyl-D-aspartate (NMDA) subtype of the excita-
depending on the cell type. The synchronized bursts tory amino acid receptor, which causes Ca2+ inux and
neuronal activation. The recruitment of a sufcient MECHANISMS OF EPILEPTOGENESIS 231
number of neurons leads to a loss of the surrounding
Epileptogenesis refers to the transformation of a normal
inhibition and propagation of seizure activity into con-
neuronal network into one that is chronically hyperex-
tiguous areas via local cortical connections, and to more
citable.There is often a delay of months to years between
distant areas via long commissural pathways such as the
an initial CNS injury such as trauma, stroke, or infection
corpus callosum.
and the rst seizure. The injury appears to initiate a
Many factors control neuronal excitability, and thus
process that gradually lowers the seizure threshold in the
there are many potential mechanisms for altering a neu-
affected region until a spontaneous seizure occurs. In
rons propensity to have bursting activity. Mechanisms
many genetic and idiopathic forms of epilepsy, epilepto-
intrinsic to the neuron include changes in the conduc-
genesis is presumably determined by developmentally
tance of ion channels, response characteristics of mem-
regulated events.
brane receptors, cytoplasmic buffering, second-messenger
Pathologic studies of the hippocampus from patients
systems, and protein expression as determined by gene
with temporal lobe epilepsy have led to the suggestion that
transcription, translation, and posttranslational modica-
some forms of epileptogenesis are related to structural
tion. Mechanisms extrinsic to the neuron include changes
changes in neuronal networks. For example, many patients
in the amount or type of neurotransmitters present at the
with MTLE have a highly selective loss of neurons that
synapse, modulation of receptors by extracellular ions

CHAPTER 20
may contribute to inhibition of the main excitatory neu-
and other molecules, and temporal and spatial properties
rons within the dentate gyrus. There is also evidence that,
of synaptic and nonsynaptic input. Nonneural cells, such
in response to the loss of neurons, there is reorganization or
as astrocytes and oligodendrocytes, have an important
sprouting of surviving neurons in a way that affects the
role in many of these mechanisms as well.
excitability of the network. Some of these changes can be
Certain recognized causes of seizures are explained
seen in experimental models of prolonged electrical
by these mechanisms. For example, accidental ingestion
seizures or traumatic brain injury. Thus, an initial injury

Seizures and Epilepsy

of domoic acid, which is an analogue of glutamate (the
such as head injury may lead to a very focal, conned
principal excitatory neurotransmitter in the brain),
region of structural change that causes local hyperexcitabil-
causes profound seizures via direct activation of excita-
ity. The local hyperexcitability leads to further structural
tory amino acid receptors throughout the CNS.
changes that evolve over time until the focal lesion pro-
Penicillin, which can lower the seizure threshold in
duces clinically evident seizures. Similar models have also
humans and is a potent convulsant in experimental
provided strong evidence for long-term alterations in intrin-
models, reduces inhibition by antagonizing the effects
sic, biochemical properties of cells within the network, such as
of GABA at its receptor.The basic mechanisms of other
chronic changes in glutamate or GABA receptor function.
precipitating factors of seizures, such as sleep depriva-
tion, fever, alcohol withdrawal, hypoxia, and infection,
are not as well understood but presumably involve
GENETIC CAUSES OF EPILEPSY
analogous perturbations in neuronal excitability. Simi-
larly, the endogenous factors that determine an indi- The most important recent progress in epilepsy
viduals seizure threshold may relate to these properties research has been the identication of genetic muta-
as well. tions associated with a variety of epilepsy syndromes
Knowledge of the mechanisms responsible for initia- (Table 20-2). Although all of the mutations identied to
tion and propagation of most generalized seizures date cause rare forms of epilepsy, their discovery has led to
(including tonic-clonic, myoclonic, and atonic types) extremely important conceptual advances. For example, it
remains rudimentary and reects the limited understand- appears that many of the inherited, idiopathic epilepsies
ing of the connectivity of the brain at a systems level. (i.e., the relatively pure forms of epilepsy in which
Much more is understood about the origin of general- seizures are the phenotypic abnormality and brain struc-
ized spike-and-wave discharges in absence seizures.These ture and function are otherwise normal) are due to muta-
appear to be related to oscillatory rhythms normally gen- tions affecting ion channel function. These syndromes are
erated during sleep by circuits connecting the thalamus therefore part of the larger group of channelopathies caus-
and cortex. This oscillatory behavior involves an interac- ing paroxysmal disorders such as cardiac arrhythmias,
tion between GABAB receptors, T-type Ca2+ channels, episodic ataxia, periodic weakness, and familial hemiplegic
and K+ channels located within the thalamus. Pharmaco- migraine. In contrast, gene mutations observed in sympto-
logic studies indicate that modulation of these receptors matic epilepsies (i.e., disorders in which other neurologic
and channels can induce absence seizures, and there is abnormalities, such as cognitive impairment, coexist with
speculation that the genetic forms of absence epilepsy seizures) are proving to be associated with pathways inu-
may be associated with mutations of components of this encing CNS development or neuronal homeostasis.
system. A current challenge is to identify the multiple susceptibility
 232 genes that underlie the more common forms of idiopathic HISTORY AND EXAMINATION
epilepsies.
The rst goal is to determine whether the event was
MECHANISMS OF ACTION OF truly a seizure. An in-depth history is essential, for in
ANTIEPILEPTIC DRUGS many cases the diagnosis of a seizure is based solely on clinical
groundsthe examination and laboratory studies are often
Antiepileptic drugs appear to act primarily by blocking normal. Questions should focus on the symptoms before,
the initiation or spread of seizures.This occurs through a during, and after the episode in order to differentiate a
variety of mechanisms that modify the activity of ion seizure from other paroxysmal events (see Differential
channels or neurotransmitters, and in most cases the Diagnosis of Seizures later). Seizures frequently occur
drugs have pleiotropic effects. The mechanisms include out-of-hospital, and the patient may be unaware of the
inhibition of Na+-dependent action potentials in a ictal and immediate postictal phases; thus, witnesses to
frequency-dependent manner (e.g., phenytoin, carba- the event should be interviewed carefully.
mazepine, lamotrigine, topiramate, zonisamide), inhibi- The history should also focus on risk factors and pre-
tion of voltage-gated Ca2+ channels (phenytoin), decrease disposing events. Clues for a predisposition to seizures
of glutamate release (lamotrigine), potentiation of GABA include a history of febrile seizures, earlier auras or brief
receptor function (benzodiazepines and barbiturates), seizures not recognized as such, and a family history of
increase in the availability of GABA (valproic acid,
SECTION III

seizures. Epileptogenic factors such as prior head trauma,

gabapentin, tiagabine), and modulation of release of stroke, tumor, or infection of the nervous system should
synaptic vesicles (levetiracetam). The two most effective be identied. In children, a careful assessment of devel-
drugs for absence seizures, ethosuximide and valproic opmental milestones may provide evidence for underly-
acid, probably act by inhibiting T-type Ca2+ channels in ing CNS disease. Precipitating factors such as sleep
thalamic neurons. deprivation, systemic diseases, electrolyte or metabolic
In contrast to the relatively large number of antiepileptic derangements, acute infection, drugs that lower the
Diseases of the Central Nervous System

drugs that can attenuate seizure activity, there are currently seizure threshold (Table 20-5), or alcohol or illicit drug
no drugs known to prevent the formation of a seizure use should also be identied.
focus following CNS injury.The eventual development of The general physical examination includes a search for
such antiepileptogenic drugs will provide an important signs of infection or systemic illness. Careful examina-
means of preventing the emergence of epilepsy following tion of the skin may reveal signs of neurocutaneous dis-
injuries such as head trauma, stroke, and CNS infection. orders, such as tuberous sclerosis or neurobromatosis, or
chronic liver or renal disease. A nding of organomegaly
may indicate a metabolic storage disease, and limb asym-
metry may provide a clue to brain injury early in devel-
Approach to the Patient: opment. Signs of head trauma and use of alcohol or
SEIZURE
illicit drugs should be sought. Auscultation of the heart
When a patient presents shortly after a seizure, the and carotid arteries may identify an abnormality that
rst priorities are attention to vital signs, respiratory predisposes to cerebrovascular disease.
and cardiovascular support, and treatment of seizures All patients require a complete neurologic examina-
if they resume (see Rx: Seizures and Epilepsy). Life- tion, with particular emphasis on eliciting signs of cere-
threatening conditions such as CNS infection, meta- bral hemispheric disease (Chap. 1). Careful assessment of
bolic derangement, or drug toxicity must be recognized mental status (including memory, language function, and
and managed appropriately. abstract thinking) may suggest lesions in the anterior
When the patient is not acutely ill, the evaluation frontal, parietal, or temporal lobes.Testing of visual elds
will initially focus on whether there is a history of ear- will help screen for lesions in the optic pathways and
lier seizures (Fig. 20-2). If this is the rst seizure, then occipital lobes. Screening tests of motor function such as
the emphasis will be to (1) establish whether the pronator drift, deep tendon reexes, gait, and coordina-
reported episode was a seizure rather than another tion may suggest lesions in motor (frontal) cortex, and
paroxysmal event, (2) determine the cause of the seizure cortical sensory testing (e.g., double simultaneous stimu-
by identifying risk factors and precipitating events, and lation) may detect lesions in the parietal cortex.
(3) decide whether anticonvulsant therapy is required in
addition to treatment for any underlying illness.
In the patient with prior seizures or a known his- LABORATORY STUDIES
tory of epilepsy, the evaluation is directed toward Routine blood studies are indicated to identify the more
(1) identication of the underlying cause and precipi- common metabolic causes of seizures, such as abnormali-
tating factors, and (2) determination of the adequacy ties in electrolytes, glucose, calcium, or magnesium, and
of the patients current therapy. hepatic or renal disease. A screen for toxins in blood and
 233
Adult Patient with a Seizure

History
Physical examination
Exclude
Syncope
Transient ischemic attack
Migraine
Acute psychosis
Other causes of episodic cerebral dysfunction

History of epilepsy; currently treated No history of epilepsy

with antiepileptics

Laboratory studies
Assess: adequacy of antiepileptic therapy CBC
Side effects Electrolytes, calcium, magnesium
Serum levels Serum glucose
Liver and renal function tests

CHAPTER 20
Urinalysis
Consider Toxicology screen
Electrolytes
CBC
Liver and renal function tests
Toxicology screen
Positive metabolic screen Negative
or symptoms/signs metabolic screen
suggesting a metabolic
Normal Abnormal or change in or infectious disorder

Seizures and Epilepsy

neurologic exam MRI scan or
EEG
Further work-up
Subtherapeutic Therapeutic Treat identifiable Lumbar puncture
antiepileptic antiepileptic metabolic abnormalities Cultures Focal features of
levels levels Assess cause of Endocrine studies seizures
neurologic change CT Focal abnormalities
MRI if focal on clinical or lab
features present examination
Appropriate Increase antiepileptic Other evidence of
increase or therapy to maximum neurologic
resumption tolerated dose; dysfunction
of dose consider alternative Treat underlying
antiepileptic drugs metabolic abnormality

Consider: Antiepileptic therapy

Yes No

Consider: Mass lesion; stroke; CNS infection; Idiopathic seizures

trauma; degenerative disease

Consider: Antiepileptic therapy

Treat underlying disorder

Consider: Antiepileptic therapy

FIGURE 20-2
Evaluation of the adult patient with a seizure. CBC, com- resonance imaging; EEG, electroencephalogram; CNS,
plete blood count; CT, computed tomography; MRI, magnetic central nervous system.

urine should also be obtained from all patients in appro- ELECTROPHYSIOLOGIC STUDIES
priate risk groups, especially when no clear precipitating All patients who have a possible seizure disorder should
factor has been identied. A lumbar puncture is indicated be evaluated with an EEG as soon as possible. Details
if there is any suspicion of meningitis or encephalitis, and about the EEG are covered in Chap. 3.
it is mandatory in all patients infected with HIV, even in In the evaluation of a patient with suspected epilepsy,
the absence of symptoms or signs suggesting infection. the presence of electrographic seizure activity during the
 234 clinically evident eventi.e., abnormal, repetitive, rhyth- conditions, such as head injury or brain tumor, will go
mic activity having an abrupt onset and termination on to develop epilepsy, because in such circumstances
clearly establishes the diagnosis. The absence of electro- epileptiform activity is commonly encountered regardless
graphic seizure activity does not exclude a seizure disorder, of whether seizures occur.
however, because simple or complex seizures may origi-
nate from a region of the cortex that is not within range
BRAIN IMAGING
of the scalp electrodes. The EEG is always abnormal
during generalized tonic-clonic seizures. Since seizures Almost all patients with new-onset seizures should have a
are typically infrequent and unpredictable, it is often not brain imaging study to determine whether there is an
possible to obtain the EEG during a clinical event. underlying structural abnormality that is responsible. The
Continuous monitoring for prolonged periods in video- only potential exception to this rule is children who have
EEG telemetry units for hospitalized patients or the use an unambiguous history and examination suggestive of a
of portable equipment to record the EEG continuously benign, generalized seizure disorder such as absence
on cassettes for 24 h in ambulatory patients has made it epilepsy. MRI has been shown to be superior to CT for
easier to capture the electrophysiologic accompaniments the detection of cerebral lesions associated with epilepsy.
of clinical events. In particular, video-EEG telemetry is In some cases MRI will identify lesions such as tumors,
now a routine approach for the accurate diagnosis of vascular malformations, or other pathologies that need
SECTION III

epilepsy in patients with poorly characterized events or immediate therapy.The use of newer MRI methods, such
seizures that are difcult to control. as uid-attenuated inversion recovery (FLAIR), has
Magnetoencephalography (MEG) provides another increased the sensitivity for detection of abnormalities of
way of looking noninvasively at cortical activity. Instead cortical architecture, including hippocampal atrophy asso-
of measuring electrical activity of the brain, it measures ciated with mesial temporal sclerosis, as well as abnormal-
the small magnetic elds that are generated by this ities of cortical neuronal migration. In such cases the
Diseases of the Central Nervous System

activity. Epileptiform activity seen on the MEG can be ndings may not lead to immediate therapy, but they do
analyzed, and its source in the brain can be estimated provide an explanation for the patients seizures and point
using a variety of mathematical techniques.These source to the need for chronic anticonvulsant therapy or possible
estimates can then be plotted on an anatomic image of surgical resection.
the brain, such as an MRI (discussed later), to generate a In the patient with a suspected CNS infection or mass
magnetic source image (MSI). MSI can be useful to lesion, CT scanning should be performed emergently
localize potential seizure foci. when MRI is not immediately available. Otherwise, it is
The EEG may also be helpful in the interictal period usually appropriate to obtain an MRI study within a few
by showing certain abnormalities that are highly support- days of the initial evaluation. Functional imaging proce-
ive of the diagnosis of epilepsy. Such epileptiform activity dures such as positron emission tomography (PET) and
consists of bursts of abnormal discharges containing spikes single photon emission computed tomography (SPECT)
or sharp waves. The presence of epileptiform activity is are also used to evaluate certain patients with medically
not specic for epilepsy, but it has a much greater preva- refractory seizures (discussed below).
lence in patients with epilepsy than in normal individuals.
However, even in an individual who is known to have
epilepsy, the initial routine interictal EEG may be normal DIFFERENTIAL DIAGNOSIS
up to 60% of the time. Thus, the EEG cannot establish OF SEIZURES
the diagnosis of epilepsy in many cases.
The EEG is also used for classifying seizure disorders Disorders that may mimic seizures are listed in Table 20-6.
and aiding in the selection of anticonvulsant medications. In most cases seizures can be distinguished from other
For example, episodic generalized spike-wave activity is conditions by meticulous attention to the history and
usually seen in patients with typical absence epilepsy and relevant laboratory studies. On occasion, additional stud-
may be seen with other generalized epilepsy syndromes. ies, such as video-EEG monitoring, sleep studies, tilt-
Focal interictal epileptiform discharges would support table analysis, or cardiac electrophysiology, may be required
the diagnosis of a partial seizure disorder such as tempo- to reach a correct diagnosis. Two of the more common
ral lobe epilepsy or frontal lobe seizures, depending on nonepileptic syndromes in the differential diagnosis are
the location of the discharges. detailed below.
The routine scalp-recorded EEG may also be used to
assess the prognosis of seizure disorders; in general, a nor-
mal EEG implies a better prognosis, whereas an abnormal SYNCOPE
background or profuse epileptiform activity suggests a (See also Chap. 8) The diagnostic dilemma encountered
poor outlook. Unfortunately, the EEG has not proved to most frequently is the distinction between a generalized
be useful in predicting which patients with predisposing seizure and syncope. Observations by the patient and
TABLE 20-6 syncopal episode can induce a full tonic-clonic seizure. In 235
DIFFERENTIAL DIAGNOSIS OF SEIZURES such cases the evaluation must focus on both the cause of
the syncopal event as well as the possibility that the patient
Syncope
Vasovagal syncope
has a propensity for recurrent seizures.
Cardiac arrhythmia
Valvular heart disease PSYCHOGENIC SEIZURES
Cardiac failure
Orthostatic hypotension Psychogenic seizures are nonepileptic behaviors that resem-
Psychological disorders ble seizures. They are often part of a conversion reaction
Psychogenic seizure precipitated by underlying psychological distress. Certain
Hyperventilation
behaviors, such as side-to-side turning of the head, asym-
Panic attack
Metabolic disturbances
metric and large-amplitude shaking movements of the
Alcoholic blackouts limbs, twitching of all four extremities without loss of
Delirium tremens consciousness, and pelvic thrusting are more commonly
Hypoglycemia associated with psychogenic rather than epileptic seizures.
Hypoxia Psychogenic seizures often last longer than epileptic
Psychoactive drugs (e.g., hallucinogens) seizures and may wax and wane over minutes to hours.

CHAPTER 20
Migraine However, the distinction is sometimes difcult on clinical
Confusional migraine
Basilar migraine
grounds alone, and there are many examples of diagnostic
Transient ischemic attack (TIA) errors made by experienced epileptologists. This is espe-
Basilar artery TIA cially true for psychogenic seizures that resemble complex
Sleep disorders partial seizures, since the behavioral manifestations of
Narcolepsy/cataplexy complex partial seizures (especially of frontal lobe origin)

Seizures and Epilepsy

Benign sleep myoclonus can be extremely unusual, and in both cases the routine
Movement disorders surface EEG may be normal. Video-EEG monitoring is
Tics
very useful when historic features are nondiagnostic. Gen-
Nonepileptic myoclonus
Paroxysmal choreoathetosis eralized tonic-clonic seizures always produce marked EEG
Special considerations in children abnormalities during and after the seizure. For suspected
Breath-holding spells complex partial seizures of temporal lobe origin, the use of
Migraine with recurrent abdominal pain and cyclic additional electrodes beyond the standard scalp locations
vomiting (e.g., sphenoidal electrodes) may be required to localize a
Benign paroxysmal vertigo seizure focus. Measurement of serum prolactin levels may
Apnea
also help to distinguish between organic and psychogenic
Night terrors
Sleepwalking
seizures, since most generalized seizures and many com-
plex partial seizures are accompanied by rises in serum
prolactin (during the immediate 30-min postictal period),
whereas psychogenic seizures are not. The diagnosis of
psychogenic seizures does not exclude a concurrent diag-
bystanders that can help differentiate between the two are nosis of epilepsy, since the two often coexist.
listed in Table 20-7. Characteristics of a seizure include
the presence of an aura, cyanosis, unconsciousness, motor
manifestations lasting >30 s, postictal disorientation, mus-
cle soreness, and sleepiness. In contrast, a syncopal episode Treatment:
is more likely if the event was provoked by acute pain or SEIZURES AND EPILEPSY
anxiety or occurred immediately after arising from the lying
Therapy for a patient with a seizure disorder is almost
or sitting position. Patients with syncope often describe a
always multimodal and includes treatment of underly-
stereotyped transition from consciousness to unconscious-
ing conditions that cause or contribute to the seizures,
ness that includes tiredness, sweating, nausea, and tunneling
avoidance of precipitating factors, suppression of recur-
of vision, and they experience a relatively brief loss of
rent seizures by prophylactic therapy with antiepileptic
consciousness. Headache or incontinence usually suggests
medications or surgery, and addressing a variety of psy-
a seizure but may on occasion also occur with syncope.
chological and social issues. Treatment plans must be
A brief period (i.e., 110 s) of convulsive motor activity is
individualized, given the many different types and
frequently seen immediately at the onset of a syncopal
causes of seizures as well as the differences in efcacy
episode, especially if the patient remains in an upright pos-
and toxicity of antiepileptic medications for each
ture after fainting (e.g., in a dentists chair) and therefore
patient. In almost all cases a neurologist with experience
has a sustained decrease in cerebral perfusion. Rarely, a
 236 TABLE 20-7
FEATURES THAT DISTINGUISH GENERALIZED TONIC-CLONIC SEIZURE FROM SYNCOPE

FEATURES SEIZURE SYNCOPE

Immediate precipitating factors Usually none Emotional stress, Valsalva, orthostatic

hypotension, cardiac etiologies
Premonitory symptoms None or aura Tiredness, nausea, diaphoresis,
(e.g., odd odor) tunneling of vision
Posture at onset Variable Usually erect
Transition to unconsciousness Often immediate Gradual over secondsa
Duration of unconsciousness Minutes Seconds
Duration of tonic or clonic 3060 s Never more than 15 s
movements
Facial appearance during event Cyanosis, frothing Pallor
at mouth
Disorientation and sleepiness Many minutes <5 min
after event to hours
Aching of muscles after event Often Sometimes
Biting of tongue Sometimes Rarely
SECTION III

Incontinence Sometimes Sometimes

Headache Sometimes Rarely

a
May be sudden with certain cardiac arrhythmias.
Diseases of the Central Nervous System

in the treatment of epilepsy should design and oversee benet from surgical removal of the epileptic brain
implementation of the treatment strategy. Furthermore, region (see later).
patients with refractory epilepsy or those who require
polypharmacy with antiepileptic drugs should remain AVOIDANCE OF PRECIPITATING FACTORS
under the regular care of a neurologist. Unfortunately, little is known about the specic factors
that determine precisely when a seizure will occur in a
TREATMENT OF UNDERLYING CONDITIONS patient with epilepsy. Some patients can identify partic-
If the sole cause of a seizure is a metabolic disturbance ular situations that appear to lower their seizure thresh-
such as an abnormality of serum electrolytes or glucose, old; these situations should be avoided. For example, a
then treatment is aimed at reversing the metabolic patient who has seizures in the setting of sleep depriva-
problem and preventing its recurrence. Therapy with tion should obviously be advised to maintain a normal
antiepileptic drugs is usually unnecessary unless the sleep schedule. Many patients note an association
metabolic disorder cannot be corrected promptly and between alcohol intake and seizures, and they should
the patient is at risk of having further seizures. If the be encouraged to modify their drinking habits accord-
apparent cause of a seizure was a medication (e.g., theo- ingly. There are also relatively rare cases of patients with
phylline) or illicit drug use (e.g., cocaine), then appropri- seizures that are induced by highly specic stimuli such
ate therapy is avoidance of the drug; there is usually no as a video game monitor, music, or an individuals voice
need for antiepileptic medications unless subsequent (reex epilepsy). If there is an association between
seizures occur in the absence of these precipitants. stress and seizures, stress reduction techniques such as
Seizures caused by a structural CNS lesion such as a physical exercise, meditation, or counseling may be
brain tumor, vascular malformation, or brain abscess helpful.
may not recur after appropriate treatment of the under-
lying lesion. However, despite removal of the structural ANTIEPILEPTIC DRUG THERAPY Antiepilep-
lesion, there is a risk that the seizure focus will remain in tic drug therapy is the mainstay of treatment for most
the surrounding tissue or develop de novo as a result of patients with epilepsy. The overall goal is to completely
gliosis and other processes induced by surgery, radia- prevent seizures without causing any untoward side
tion, or other therapies. Most patients are therefore effects, preferably with a single medication and a dosing
maintained on an antiepileptic medication for at least schedule that is easy for the patient to follow. Seizure
1 year, and an attempt is made to withdraw medications classication is an important element in designing the
only if the patient has been completely seizure-free. If treatment plan, since some antiepileptic drugs have dif-
seizures are refractory to medication, the patient may ferent activities against various seizure types. However,
there is considerable overlap between many antiepilep- Selection of Antiepileptic Drugs Antiepileptic 237
tic drugs, such that the choice of therapy is often deter- drugs available in the United States are shown in
mined more by the patients specic needs, especially Table 20-8, and the main pharmacologic characteristics
his/her assessment of side effects. of commonly used drugs are listed in Table 20-9. World-
wide, older medications such as phenytoin, valproic
When to Initiate Antiepileptic Drug Therapy acid, carbamazepine, and ethosuximide are generally
Antiepileptic drug therapy should be started in any used as rst-line therapy for most seizure disorders
patient with recurrent seizures of unknown etiology or a since, overall, they are as effective as recently marketed
known cause that cannot be reversed.Whether to initiate drugs and signicantly less expensive. Most of the new
therapy in a patient with a single seizure is controversial. drugs that have become available in the past decade are
Patients with a single seizure due to an identied lesion used as add-on or alternative therapy, although some
such as a CNS tumor, infection, or trauma, in which there are now being used as rst-line monotherapy.
is strong evidence that the lesion is epileptogenic, In addition to efcacy, factors inuencing the choice
should be treated. The risk of seizure recurrence in a of an initial medication include the convenience of dos-
patient with an apparently unprovoked or idiopathic ing (e.g., once daily versus three or four times daily) and
seizure is uncertain, with estimates ranging from 31 to potential side effects. In this regard, a number of the

CHAPTER 20
71% in the rst 12 months after the initial seizure. This newer drugs have the advantage of a relative lack of
uncertainty arises from differences in the underlying drug-drug interactions and easier dosing. Almost all of
seizure types and etiologies in various published epi- the commonly used antiepileptic drugs can cause simi-
demiologic studies. Generally accepted risk factors asso- lar, dose-related side effects such as sedation, ataxia, and
ciated with recurrent seizures include the following: diplopia. Close follow-up is required to ensure these are
(1) an abnormal neurologic examination, (2) seizures pre- promptly recognized and reversed. Most of the older
senting as status epilepticus, (3) postictal Todds paraly- drugs and some of the newer ones can also cause idio-

Seizures and Epilepsy

sis, (4) a strong family history of seizures, or (5) an abnor- syncratic toxicity such as rash, bone marrow suppres-
mal EEG. Most patients with one or more of these risk sion, or hepatotoxicity. Although rare, these side effects
factors should be treated. Issues such as employment or should be considered during drug selection, and
driving may inuence the decision whether to start med- patients must be instructed about symptoms or signs
ications as well. For example, a patient with a single, idio- that should signal the need to alert their health care
pathic seizure whose job depends on driving may prefer provider. For some drugs, laboratory tests (e.g., com-
taking antiepileptic drugs rather than risk a seizure recur- plete blood count and liver function tests) are recom-
rence and the potential loss of driving privileges. mended prior to the institution of therapy (to establish

TABLE 20-8
SELECTION OF ANTIEPILEPTIC DRUGS

PRIMARY ATYPICAL
GENERALIZED ABSENCE,
TONIC-CLONIC PARTIALa ABSENCE MYOCLONIC, ATONIC

First-Line
Valproic acid Carbamazepine Valproic acid Valproic acid
Lamotrigine Phenytoin Ethosuximide Lamotrigine
Topiramate Lamotrigine Topiramate
Oxcarbazepine
Valproic acid
Alternatives
Zonisamideb Levetiracetamb Lamotrigine Clonazepam
Phenytoin Topiramate Clonazepam Felbamate
Carbamazepine Tiagabineb
Oxcarbazepine Zonisamideb
Phenobarbital Gabapentinb
Primidone Phenobarbital
Felbamate Primidone
Felbamate

a
Includes simple partial, complex partial, and secondarily generalized seizures.
b
As adjunctive therapy.
 238 TABLE 20-9
DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS

ADVERSE EFFECTS
GENERIC TRADE PRINCIPAL TYPICAL DOSE; THERAPEUTIC DRUG
NAME NAME USES DOSE INTERVAL HALF-LIFE RANGE NEUROLOGIC SYSTEMIC INTERACTIONS

Phenytoin Dilantin Tonic-clonic 300400 mg/d 24 h (wide 1020 g/mL Dizziness Gum Level increased
(diphenyl- (grand (36 mg/kg, variation, Diplopia hyperplasia by isoniazid,
hydantoin mal) adult; 48 mg/kg, dose- Ataxia Lymphade- sulfonamides,
Focal-onset child); qd-bid dependent) Incoordination nopathy uoxetine
Confusion Hirsutism Level decreased
Osteomalacia by enzyme-
Facial inducing drugsa
coarsening Altered folate
Skin rash metabolism
Carba Tegretol Tonic-clonic 6001800 mg/d 1017 h 612 g/mL Ataxia Aplastic Level decreased
mazepine Carbatrol Focal-onset (1535 mg/kg, Dizziness anemia by enzyme-
child); bid-qid Diplopia Leukopenia inducing drugsa
Vertigo Gastrointesti- Level increased
nal irritation by erythromycin,
SECTION III

Hepatotoxicity propoxyphene,
Hyponatremia isoniazid, cimeti-
dine, uoxetine
Valproic Depakene Tonic-clonic 7502000 mg/d 15 h 50125 g/mL Ataxia Hepatotoxicity Level decreased
acid Depakote Absence (2060 mg/kg); Sedation Thrombocyto- by enzyme-
Depakote Atypical bid-qid Tremor penia inducing drugsa
ER absence Gastrointesti-
Myoclonic nal irritation
Diseases of the Central Nervous System

Focal-onset Weight gain

Transient
alopecia
Hyperamm-
onemia
Lamotrigine Lamictal Focal-onset 150500 mg/d; 25 h Not established Dizziness Skin rash Level decreased
Tonic-clonic bid 14 h (with Diplopia Stevens- by enzyme-
Atypical enzyme- Sedation Johnson inducing drugsa
absence inducers) Ataxia syndrome and oral
Myoclonic 59 h (with val- Headache contraceptives
Lennox- proic acid) Level increased
Gastaut by valproic acid
syndrome
Ethosuxi Zarontin Absence 7501250 mg/d 60 h, adult 40100 g/mL Ataxia Gastrointesti-
mide (petit mal) (20-40 mg/kg); 30 h, child Lethargy nal irritation
qd-bid Headache Skin rash
Bone marrow
suppression
Gabapentin Neurontin Focal-onset 9002400 mg/d; 59 h Not established Sedation Gastrointesti- No known
tid-qid Dizziness nal irritation signicant
Ataxia Weight gain interactions
Fatigue Edema
Topiramate Topamax Focal-onset 200400 mg/d; 2030 h Not established Psychomotor Renal stones Level decreased
Tonic-clonic bid slowing (avoid use by enzyme-
Lennox- Sedation with other inducing
Gastaut Speech or carbonic drugsa
syndrome language anhydrase
problems inhibitors)
Fatigue Glaucoma
Paresthesias Weight loss
Hypohydrosis
Tiagabine Gabitril Focal-onset 3256 mg/d; 79 h Not established Confusion Gastrointesti- Level decreased
Tonic-clonic bid-qid Sedation nal irritation by enzyme-
Depression inducing
Dizziness drugsa
Speech or
language
problems
Paresthesias
Psychosis
TABLE 20-9 (CONTINUED) 239
DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS

ADVERSE EFFECTS
GENERIC TRADE PRINCIPAL TYPICAL DOSE; THERAPEUTIC DRUG
NAME NAME USES DOSE INTERVAL HALF-LIFE RANGE NEUROLOGIC SYSTEMIC INTERACTIONS

Phenobar Luminol Tonic-clonic 60180 mg/d 90 h (70 h in 1040 g/mL Sedation Skin rash Level increased
bital Focal-onset (14 mg/kg, children) Ataxia by valproic acid,
adult); (36 mg/kg, Confusion phenytoin
child); qd Dizziness
Decreased
libido
Depression
Primidone Mysoline Tonic-clonic 7501000 mg/d Primidone, Primidone, Same as
Focal-onset (1025 mg/kg); 815 h 412 g/mL phenobarbital
bid-tid Phenobarbital, Phenobarbital,
90 h 1040 g/mL
Clonazepam Klonopin Absence 112 mg/d 2448 h 1070 ng/mL Ataxia Anorexia Level decreased
Atypical (0.10.2 mg/kg); Sedation by enzyme-
absence qd-tid Lethargy inducing

CHAPTER 20
Myoclonic drugsa
Felbamate Felbatol Focal-onset 24003600 mg/d, 1622 h Not Insomnia Aplastic Increases
Lennox- (45 mg/kg, child); established Dizziness anemia phenytoin,
Gastaut tid-qid Sedation Hepatic valproic acid,
syndrome Headache failure active
Weight loss carbamazepine
Gastrointesti- metabolite
nal irritation

Seizures and Epilepsy

Levetirace- Keppra Focal-onset 10003000 68 h Not Sedation Anemia None known
tam mg/d; bid established Fatigue Leukopenia
Incoordination
Psychosis
Zonisamide Zonegran Focal-onset 200400 mg/d; 5068 h Not Sedation Anorexia Level decreased
qd-bid established Dizziness Renal stones by enzyme-
Confusion Hypohydrosis inducing
Headache drugsa
Psychosis
Oxcarbaz- Trileptal Focal-onset 9002400 mg/d 1017 h (for Not Fatigue
epine (3045 mg/kg, active established Ataxia See carba- Level decreased
child); bid metabolite) Dizziness mazepine by enzyme-
Diplopia inducing
Vertigo drugsa
Headache May increase
phenytoin

a
Phenytoin, carbamazepine, phenobarbital.

baseline values) and during initial dosing and titration other drugs. However, phenytoin shows properties of
of the agent. saturation kinetics, such that small increases in pheny-
toin doses above a standard maintenance dose can pre-
Antiepileptic Drug Selection for Partial cipitate marked side effects. This is one of the main
Seizures Carbamazepine (or a related drug, oxcar- causes of acute phenytoin toxicity. Long-term use of
bazepine), phenytoin, lamotrigine and topiramate are phenytoin is associated with untoward cosmetic effects
currently the drugs of choice approved for the initial (e.g., hirsutism, coarsening of facial features, and gingival
treatment of partial seizures, including those that secon- hypertrophy), and effects on bone metabolism, so it is
darily generalize. Overall they have very similar efcacy, often avoided in young patients who are likely to
but differences in pharmacokinetics and toxicity are the require the drug for many years. An advantage of carba-
main determinants for use in a given patient. For exam- mazepine (which is also available in an extended-
ple, phenytoin has a relatively long half-life and offers release form) is that its metabolism follows rst-order
the advantage of once or twice daily dosing in compari- pharmacokinetics, and the relationship between drug
son with two or three times daily dosing for many of the dose, serum levels, and toxicity is linear. Carbamazepine
 240 can cause leukopenia, aplastic anemia, or hepatotoxicity treatment of primary generalized, tonic-clonic seizures.
and would therefore be contraindicated in patients with Phenytoin, followed by topiramate, carbamazepine, and
predispositions to these problems. Asian individuals car- zonisamide are suitable alternatives. Valproic acid is also
rying the HLA allele HLA-B*1502 are at particularly high particularly effective in absence, myoclonic, and atonic
risk of developing fatal skin reactions including Stevens seizures and is therefore the drug of choice in patients
Johnson syndrome and should be tested for this allele with generalized epilepsy syndromes having mixed
prior to initiation of carbamazepine. Oxcarbazepine has seizure types. Importantly, both carbamazepine and
the advantage of being metabolized in a way that phenytoin can worsen certain types of generalized
avoids an intermediate metabolite associated with seizures, including absence, myoclonic, tonic, and atonic
some of the side effects of carbamazepine. Oxcar- seizures. Ethosuximide is a particularly effective drug for
bazepine also has fewer drug interactions than carba- the treatment of uncomplicated absence seizures, but it
mazepine. Lamotrigine tends to be well-tolerated in is not useful for tonic-clonic or partial seizures. Ethosux-
terms of side effects. However, patients need to be par- imide rarely causes bone marrow suppression, so that
ticularly vigilant about the possibility of a skin rash dur- periodic monitoring of blood cell counts is required.
ing the initiation of therapy. This can be extremely Lamotrigine appears to be particularly effective in
severe and lead to Stevens-Johnson syndrome if unrec- epilepsy syndromes with mixed, generalized seizure
ognized and if the medication is not discontinued types such as JME and Lennox-Gastaut syndrome. Topi-
SECTION III

immediately. This risk can be reduced by slow introduc- ramate, zonisamide, and felbamate may have similar
tion and titration. Lamotrigine must be started slowly broad efcacy.
when used as add-on therapy with valproic acid, since
valproic acid inhibits lamotrigine metabolism, thereby Initiation and Monitoring of Therapy Because
substantially prolonging its half-life. Topiramate has the response to any antiepileptic drug is unpredictable,
recently been approved as monotherapy for partial and patients should be carefully educated about the
Diseases of the Central Nervous System

primary generalized seizures. Similar to some of the approach to therapy. The goal is to prevent seizures and
other antiepileptic drugs, topiramate can cause signi- minimize the side effects of therapy; determination of
cant psychomotor slowing and other cognitive prob- the optimal dose is often a matter of trial and error. This
lems, and it should not be used in patients at risk for the process may take months or longer if the baseline
development of glaucoma or renal stones. seizure frequency is low. Most anticonvulsant drugs
Valproic acid is an effective alternative for some need to be introduced relatively slowly to minimize side
patients with partial seizures, especially when the seizures effects, and patients should expect that minor side
secondarily generalize. Gastrointestinal side effects are effects such as mild sedation, slight changes in cogni-
fewer when using the valproate semisodium formulation tion, or imbalance will typically resolve within a few
(Depakote). Valproic acid also rarely causes reversible days. Starting doses are usually the lowest value listed
bone marrow suppression and hepatotoxicity, and labora- under the dosage column in Table 20-9. Subsequent
tory testing is required to monitor toxicity. This drug increases should be made only after achieving a steady
should generally be avoided in patients with preexisting state with the previous dose (i.e., after an interval of ve
bone marrow or liver disease. Irreversible, fatal hepatic fail- or more half-lives).
ure appearing as an idiosyncratic rather than dose-related Monitoring of serum antiepileptic drug levels can be
side effect is a relatively rare complication; its risk is high- very useful for establishing the initial dosing schedule.
est in children <2 years, especially those taking other However, the published therapeutic ranges of serum
antiepileptic drugs or with inborn errors of metabolism. drug concentrations are only an approximate guide for
Levetiracetam, tiagabine, zonisamide, and gabapentin determining the proper dose for a given patient. The
are additional drugs currently used for the treatment of key determinants are the clinical measures of seizure
partial seizures with or without secondary generaliza- frequency and presence of side effects, not the labora-
tion. Phenobarbital and other barbiturate compounds tory values. Conventional assays of serum drug levels
were commonly used in the past as rst-line therapy for measure the total drug (i.e., both free and protein-
many forms of epilepsy. However, the barbiturates fre- bound). However, it is the concentration of free drug
quently cause sedation in adults, hyperactivity in chil- that reects extracellular levels in the brain and corre-
dren, and other more subtle cognitive changes; thus, lates best with efcacy. Thus, patients with decreased
their use should be limited to situations in which no levels of serum proteins (e.g., decreased serum albumin
other suitable treatment alternatives exist. due to impaired liver or renal function) may have an
increased ratio of free to bound drug, yet the concentra-
Antiepileptic Drug Selection for General- tion of free drug may be adequate for seizure control.
ized Seizures Valproic acid and lamotrigine are These patients may have a subtherapeutic drug level,
currently considered the best initial choice for the but the dose should be changed only if seizures remain
uncontrolled, not just to achieve a therapeutic level. It of clonazepam, and those with absence seizures may 241
is also useful to monitor free drug levels in such respond to a combination of valproic acid and ethosux-
patients. In practice, other than during the initiation or imide. The same principles concerning the monitoring
modication of therapy, monitoring of antiepileptic of therapeutic response, toxicity, and serum levels for
drug levels is most useful for documenting compliance. monotherapy apply to polypharmacy, and potential
If seizures continue despite gradual increases to the drug interactions need to be recognized. If there is no
maximum tolerated dose and documented compliance, improvement, a third drug can be added while the rst
then it becomes necessary to switch to another two are maintained. If there is a response, the less effec-
antiepileptic drug. This is usually done by maintaining tive or less well-tolerated of the rst two drugs should
the patient on the rst drug while a second drug is be gradually withdrawn.
added. The dose of the second drug should be adjusted
to decrease seizure frequency without causing toxicity. SURGICAL TREATMENT OF REFRACTORY
Once this is achieved, the rst drug can be gradually EPILEPSY Approximately 2030% of patients with
withdrawn (usually over weeks unless there is signicant epilepsy are resistant to medical therapy despite efforts
toxicity). The dose of the second drug is then further to nd an effective combination of antiepileptic drugs.
optimized based on seizure response and side effects. For some, surgery can be extremely effective in substan-

CHAPTER 20
Monotherapy should be the goal whenever possible. tially reducing seizure frequency and even providing
complete seizure control. Understanding the potential
When to Discontinue Therapy Overall, about
value of surgery is especially important when, at the time
70% of children and 60% of adults who have their
of diagnosis, a patient has an epilepsy syndrome that is
seizures completely controlled with antiepileptic drugs
considered likely to be drug-resistant. Rather than sub-
can eventually discontinue therapy. The following patient
mitting the patient to years of unsuccessful medical ther-
prole yields the greatest chance of remaining seizure-
apy and the psychosocial trauma and increased mortal-

Seizures and Epilepsy

free after drug withdrawal: (1) complete medical control
ity associated with ongoing seizures, the patient should
of seizures for 15 years; (2) single seizure type, either par-
have an efcient but relatively brief attempt at medical
tial or generalized; (3) normal neurologic examination,
therapy and then be referred for surgical evaluation.
including intelligence; and (4) normal EEG. The appropri-
The most common surgical procedure for patients
ate seizure-free interval is unknown and undoubtedly
with temporal lobe epilepsy involves resection of the
varies for different forms of epilepsy. However, it seems
anteromedial temporal lobe (temporal lobectomy) or a
reasonable to attempt withdrawal of therapy after 2 years
more limited removal of the underlying hippocampus
in a patient who meets all of the above criteria, is moti-
and amygdala (amygdalohippocampectomy). Focal
vated to discontinue the medication, and clearly under-
seizures arising from extratemporal regions may be
stands the potential risks and benets. In most cases it is
abolished by a focal neocortical resection with precise
preferable to reduce the dose of the drug gradually over
removal of an identied lesion (lesionectomy). When
23 months. Most recurrences occur in the rst 3 months
the cortical region cannot be removed, multiple subpial
after discontinuing therapy, and patients should be
transection, which disrupts intracortical connections, is
advised to avoid potentially dangerous situations such as
sometimes used to prevent seizure spread. Hemi-
driving or swimming during this period.
spherectomy or multilobar resection is useful for some
Treatment of Refractory Epilepsy Approxi- patients with severe seizures due to hemispheric abnor-
mately one-third of patients with epilepsy do not malities such as hemimegalencephaly or other dysplas-
respond to treatment with a single antiepileptic drug, tic abnormalities, and corpus callosotomy has been
and it becomes necessary to try a combination of drugs shown to be effective for disabling tonic or atonic
to control seizures. Patients who have focal epilepsy seizures, usually when they are part of a mixed-seizure
related to an underlying structural lesion or those with syndrome (e.g., Lennox-Gastaut syndrome).
multiple seizure types and developmental delay are par- Presurgical evaluation is designed to identify the
ticularly likely to require multiple drugs. There are cur- functional and structural basis of the patients seizure
rently no clear guidelines for rational polypharmacy, disorder. Inpatient video-EEG monitoring is used to
although in theory a combination of drugs with differ- dene the anatomic location of the seizure focus and to
ent mechanisms of action may be most useful. In most correlate the abnormal electrophysiologic activity with
cases the initial combination therapy combines rst-line behavioral manifestations of the seizure. Routine scalp
drugs, i.e., carbamazepine, phenytoin, valproic acid, and or scalp-sphenoidal recordings are usually sufcient for
lamotrigine. If these drugs are unsuccessful, then the localization, and advances in neuroimaging have made
addition of a newer drug such as levetiracetam or topi- the use of invasive electrophysiologic monitoring such
ramate is indicated. Patients with myoclonic seizures as implanted depth electrodes or subdural electrodes
resistant to valproic acid may benet from the addition less common. A high-resolution MRI scan is routinely
 242 used to identify structural lesions, and this is sometimes associated increased seizure threshold. Adverse effects
augmented with MEG. Functional imaging studies such of the surgery are rare, and stimulation-induced side
as SPECT and PET are adjunctive tests that may help ver- effects, including transient hoarseness, cough, and dysp-
ify the localization of an apparent epileptogenic region. nea, are usually mild.
Once the presumed location of the seizure onset is Although still in development, there are some addi-
identied, additional studies, including neuropsycho- tional therapies that will likely be of benet to patients
logical testing and the intracarotid amobarbital test with medically refractory epilepsy. Preliminary studies
(Wada test) may be used to assess language and mem- suggest that stereotactic radiosurgery may be effective
ory localization and to determine the possible func- in certain partial seizure disorders. There has also been
tional consequences of surgical removal of the epilepto- great interest in the development of implantable
genic region. In some cases, the exact extent of the devices that can detect the onset of a seizure (in some
resection to be undertaken is determined by perform- instances, before the seizure becomes clinically appar-
ing cortical mapping at the time of the surgical proce- ent) and deliver either an electrical stimulation or drug
dure, allowing for a tailored resection. This involves elec- directly to the seizure focus to abort the event.
trocorticographic recordings made with electrodes on
the surface of the brain to identify the extent of epilep-
tiform disturbances. If the region to be resected is
SECTION III

within or near brain regions suspected of having senso- STATUS EPILEPTICUS

rimotor or language function, electrical cortical stimula-
Status epilepticus refers to continuous seizures or repeti-
tion mapping is performed on the awake patient to
tive, discrete seizures with impaired consciousness in the
determine the function of cortical regions in question in
interictal period. Status epilepticus has numerous sub-
order to avoid resection of so-called eloquent cortex
types, including generalized convulsive status epilepticus
and thereby minimize postsurgical decits.
Diseases of the Central Nervous System

(GCSE) (e.g., persistent, generalized electrographic

Advances in presurgical evaluation and microsurgical
seizures, coma, and tonic-clonic movements), and non-
techniques have led to a steady increase in the success
convulsive status epilepticus (e.g., persistent absence
of epilepsy surgery. Clinically signicant complications
seizures or partial seizures, confusion or partially impaired
of surgery are <5%, and the use of functional mapping
consciousness, and minimal motor abnormalities). The
procedures has markedly reduced the neurologic
duration of seizure activity sufcient to meet the deni-
sequelae due to removal or sectioning of brain tissue.
tion of status epilepticus has traditionally been specied
For example, about 70% of patients treated with tempo-
as 1530 min. However, a more practical denition is to
ral lobectomy will become seizure-free, and another
consider status epilepticus as a situation in which the
1525% will have at least a 90% reduction in seizure fre-
duration of seizures prompts the acute use of anticon-
quency. Marked improvement is also usually seen in
vulsant therapy. For GCSE, this is typically when
patients treated with hemispherectomy for catastrophic
seizures last beyond 5 min.
seizure disorders due to large hemispheric abnormali-
GCSE is an emergency and must be treated immediately,
ties. Postoperatively, patients generally need to remain
since cardiorespiratory dysfunction, hyperthermia, and
on antiepileptic drug therapy, but the marked reduction
metabolic derangements can develop as a consequence
of seizures following resective surgery can have a very
of prolonged seizures, and these can lead to irreversible
benecial effect on quality of life. Recently, focal radio-
neuronal injury. Furthermore, CNS injury can occur
surgery as emerged as a potential alternative to resec-
even when the patient is paralyzed with neuromuscular
tive procedures.
blockade but continues to have electrographic seizures.
Not all medically refractory patients are suitable can-
The most common causes of GCSE are anticonvulsant
didates for resective surgery. For example, some
withdrawal or noncompliance, metabolic disturbances,
patients have seizures arising from more than one site,
drug toxicity, CNS infection, CNS tumors, refractory
making the risk of ongoing seizures or potential harm
epilepsy, and head trauma.
from the surgery unacceptably high. Vagus nerve stimu-
GCSE is obvious when the patient is having overt
lation (VNS) may be useful in some of these cases,
convulsions. However, after 3045 min of uninterrupted
although the benet for most patients seems to be very
seizures, the signs may become increasingly subtle.
limited; i.e., the efcacy of VNS appears to be no greater
Patients may have mild clonic movements of only the
than trying another drug, which rarely works if a patient
ngers or ne, rapid movements of the eyes. There may
has proved to be refractory to the rst two to three
be paroxysmal episodes of tachycardia, hypertension, and
drugs. The precise mechanism of action of VNS is
pupillary dilation. In such cases, the EEG may be the
unknown, although experimental studies have shown
only method of establishing the diagnosis. Thus, if the
that stimulation of vagal nuclei leads to widespread
patient stops having overt seizures, yet remains comatose,
activation of cortical and subcortical pathways and an
an EEG should be performed to rule out ongoing status
 243
Lorazepam 0.10.15 mg/kg IV over 12 min Additional emergent drug therapy
(repeat x 1 if no response after 5 min) may not be required if seizures
stop and the etiology of status
epilepticus is rapidly corrected

Fosphenytoin 20 mg/kg PE IV @ 150 mg/min

or Phenytoin 20 mg/kg IV @ 50 mg/min

Seizures continuing
Consider valproate
25 mg/kg IV in pts. Fosphenytoin 710 mg/kg PE IV @ 150 mg/min
normally taking or Phenytoin 710 mg/kg IV @ 50 mg/min
valproate and who may
be subtherapeutic Seizures continuing
Consider valproate
25 mg/kg IV
No immediate access to ICU

Phenobarbital 20 mg/kg IV @ 60 mg/min

Admit Seizures continuing FIGURE 20-3

to ICU Pharmacologic treatment of generalized

CHAPTER 20
Phenobarbital 10 mg/kg IV @ 60 mg/min
tonic-clonic status epilepticus in adults.
The horizontal bars indicate the approximate
IV anesthesia with propofol or
midazolam or pentobarbital duration of drug infusions. IV, intravenous; PE,
phenytoin equivalents.

Seizures and Epilepsy

epilepticus.This is obviously also essential when a patient productive lives. In contrast, patients with seizures sec-
with GCSE has been paralyzed with neuromuscular ondary to developmental abnormalities or acquired
blockade in the process of protecting the airway. brain injury may have impaired cognitive function and
The rst step in the management of a patient in GCSE other neurologic decits. Frequent interictal EEG
is to attend to any acute cardiorespiratory problems or abnormalities have been shown to be associated with
hyperthermia, perform a brief medical and neurologic subtle dysfunction of memory and attention. Patients
examination, establish venous access, and send samples for with many seizures, especially those emanating from the
laboratory studies to identify metabolic abnormalities. temporal lobe, often note an impairment of short-term
Anticonvulsant therapy should then begin without delay; memory that may progress over time.
a treatment approach is shown in Fig. 20-3. Patients with epilepsy are at risk of developing a vari-
The treatment of nonconvulsive status epilepticus is ety of psychiatric problems, including depression, anxiety,
somewhat less urgent than GCSE, since the ongoing and psychosis.This risk varies considerably depending on
seizures are not accompanied by the severe metabolic many factors, including the etiology, frequency, and
disturbances seen with GCSE. However, evidence sug- severity of seizures and the patients age and previous
gests that nonconvulsive status epilepticus, especially that history. Depression occurs in ~20% of patients, and the
caused by ongoing, focal seizure activity, is associated incidence of suicide is higher in epileptic patients than
with cellular injury in the region of the seizure focus, so in the general population. Depression should be treated
that the condition should be treated as promptly as pos- through counseling or medication. The selective sero-
sible using the general approach described for GCSE. tonin reuptake inhibitors typically have no effect on
seizures, while the tricyclic antidepressants may lower
the seizure threshold. Anxiety can appear as a manifesta-
BEYOND SEIZURES: OTHER tion of a seizure, and anxious or psychotic behavior can
MANAGEMENT ISSUES sometimes be observed as part of a postictal delirium.
Postictal psychosis is a rare phenomenon that typically
INTERICTAL BEHAVIOR
occurs after a period of increased seizure frequency.
The adverse effects of epilepsy often go beyond the There is usually a brief lucid interval lasting up to a
occurrence of clinical seizures, and the extent of these week, followed by days to weeks of agitated, psychotic
effects largely depends on the etiology of the seizure behavior. The psychosis will usually resolve sponta-
disorder, the degree to which the seizures are controlled, neously but may require treatment with antipsychotic or
and the presence of side effects from antiepileptic ther- anxiolytic medications.
apy. Many patients with epilepsy are completely normal There is ongoing controversy as to whether some
between seizures and able to live highly successful and patients with epilepsy (especially temporal lobe epilepsy)
 244 have a stereotypical interictal personality. The predomi- (unless the seizures are not associated with impairment of
nant view is that the unusual or abnormal personality consciousness or motor control). In general, most states
traits observed in such patients are, in most cases, not due allow patients to drive after a seizure-free interval (on or
to epilepsy but result from an underlying structural brain off medications) of between 3 months and 2 years.
lesion, the effects of antiepileptic drugs, or psychosocial Patients with incompletely controlled seizures must
factors related to suffering from a chronic disease. also contend with the risk of being in situations where
an impairment of consciousness or loss of motor control
could lead to major injury or death.Thus, depending on
MORTALITY OF EPILEPSY the type and frequency of seizures, many patients need
Patients with epilepsy have a risk of death that is to be instructed to avoid working at heights or with
roughly two to three times greater than expected in a machinery, or to have someone close by for activities
matched population without epilepsy. Most of the such as bathing and swimming.
increased mortality is due to the underlying etiology of
epilepsy, e.g., tumors or strokes in older adults. However,
a signicant number of patients die from accidents, sta- SPECIAL ISSUES RELATED
tus epilepticus, and a syndrome known as sudden unex- TO WOMEN AND EPILEPSY
pected death in epileptic patients (SUDEP), which usually
SECTION III

affects young people with convulsive seizures and tends CATAMENIAL EPILEPSY
to occur at night. The cause of SUDEP is unknown; it
Some women experience a marked increase in seizure
may result from brainstem-mediated effects of seizures
frequency around the time of menses.This is thought to
on cardiac rhythms or pulmonary function.
reect either the effects of estrogen and progesterone
on neuronal excitability or changes in antiepileptic
drug levels due to altered protein binding. Acetazo-
Diseases of the Central Nervous System

PSYCHOSOCIAL ISSUES
lamide (250500 mg/d) may be effective as adjunctive
There continues to be a cultural stigma about epilepsy, therapy in some cases when started 710 days prior to
although it is slowly declining in societies with effective the onset of menses and continued until bleeding stops.
health education programs. Many patients with epilepsy Some patients may benet from increases in antiepilep-
harbor fears, such as the fear of becoming mentally tic drug dosages during this time or from control of the
retarded or dying during a seizure. These issues need to menstrual cycle through the use of oral contraceptives.
be carefully addressed by educating the patient about Natural progestins may be of benet to a subset of
epilepsy and by ensuring that family members, teachers, women.
fellow employees, and other associates are equally well
informed. The Epilepsy Foundation of America (1-800-
EFA-1000) is a patient advocacy organization and a use- PREGNANCY
ful source of educational material. Most women with epilepsy who become pregnant will
have an uncomplicated gestation and deliver a normal
baby. However, epilepsy poses some important risks to a
EMPLOYMENT, DRIVING, AND OTHER
pregnancy. Seizure frequency during pregnancy will
ACTIVITIES
remain unchanged in ~50% of women, increase in 30%,
Many patients with epilepsy face difculty in obtaining or and decrease in 20%. Changes in seizure frequency are
maintaining employment, even when their seizures are attributed to endocrine effects on the CNS, variations in
well controlled. Federal and state legislation is designed to antiepileptic drug pharmacokinetics (such as acceleration
prevent employers from discriminating against patients of hepatic drug metabolism or effects on plasma protein
with epilepsy, and patients should be encouraged to binding), and changes in medication compliance. It is use-
understand and claim their legal rights. Patients in these ful to see patients at frequent intervals during pregnancy
circumstances also benet greatly from the assistance of and monitor serum antiepileptic drug levels. Measure-
health providers who act as strong patient advocates. ment of the unbound drug concentrations may be useful
Loss of driving privileges is one of the most disruptive if there is an increase in seizure frequency or worsening
social consequences of epilepsy. Physicians should be very of side effects of antiepileptic drugs.
clear about local regulations concerning driving and The overall incidence of fetal abnormalities in children
epilepsy, since the laws vary considerably among states born to mothers with epilepsy is 56%, in comparison
and countries. In all cases, it is the physicians responsibil- with 23% in healthy women. Part of the higher inci-
ity to warn patients of the danger imposed on themselves dence is due to teratogenic effects of antiepileptic drugs,
and others while driving if their seizures are uncontrolled and the risk increases with the number of medications
used (e.g., 10% risk of malformations with three drugs).A BREAST-FEEDING 245
syndrome comprising facial dysmorphism, cleft lip, cleft
Antiepileptic medications are excreted into breast milk to
palate, cardiac defects, digital hypoplasia, and nail dysplasia
a variable degree. The ratio of drug concentration in
was originally ascribed to phenytoin therapy, but it is now
breast milk relative to serum is ~80% for ethosuximide,
known to occur with other rst-line antiepileptic drugs
4060% for phenobarbital, 40% for carbamazepine, 15%
(i.e., valproic acid and carbamazepine) as well. Also, val-
for phenytoin, and 5% for valproic acid. Given the overall
proic acid and carbamazepine are associated with a 12%
benets of breast-feeding and the lack of evidence for
incidence of neural tube defects compared with a baseline
long-term harm to the infant by being exposed to
of 0.51%. Little is currently known about the safety of
antiepileptic drugs, mothers with epilepsy can be encour-
newer drugs, although very recent reports suggest a
aged to breast-feed.This should be reconsidered, however,
higher than expected incidence of cleft lip with the use of
if there is any evidence of drug effects on the infant, such
lamotrigine during pregnancy.
as lethargy or poor feeding.
Because the potential harm of uncontrolled seizures on
the mother and fetus is considered greater than the ter-
atogenic effects of antiepileptic drugs, it is currently rec- FURTHER READINGS
ommended that pregnant women be maintained on BARBARO NM et al: A multicenter, prospective pilot study of gamma
effective drug therapy.When possible, it seems prudent to knife radiosurgery for mesial temporal lobe epilepsy: Seizure response,

CHAPTER 20
have the patient on monotherapy at the lowest effective adverse events, and verbal memory.Ann Neurol 65:167, 2009.
dose, especially during the rst trimester. Patients should CHANG B, LOWENSTEIN DH: Mechanisms of disease: Epilepsy. N
also take folate (14 mg/d), since the antifolate effects of Engl J Med 349:1257, 2003
CHOI H et al: Epilepsy surgery for pharmacoresistant temporal lobe
anticonvulsants are thought to play a role in the develop-
epilepsy:A decision analysis. JAMA 300:2497, 2008
ment of neural tube defects, although the benets of this DUNCAN JS et al: Adult epilepsy. Lancet 367:1087, 2006
treatment remain unproved in this setting. ENSRUD KE et al: Antiepileptic drug use and rates of hip bone loss in

Seizures and Epilepsy

Enzyme-inducing drugs such as phenytoin, phenobar- older men: A prospective study. Neurology 71:723, 2008
bital, and primidone cause a transient and reversible de- FRENCH JA, PEDLEY TA: Clinical practice. Initial management of
ciency of vitamin Kdependent clotting factors in ~50% epilepsy. 359:166, 2008
of newborn infants. Although neonatal hemorrhage is HARDEN CL et al: Management issues for women with epilepsy-
Focus on pregnancy (an evidence-based review): I-III. Teratoge-
uncommon, the mother should be treated with oral vita-
nesis and perinatal outcomes: Report of the Quality Standards
min K (20 mg/d) in the last 2 weeks of pregnancy, and Subcommittee and Therapeutics and Technology Subcommittee
the infant should receive vitamin K (1 mg) at birth. of the American Academy of Neurology and the American
Epilepsy Society. Epilepsia 50:1229, 2009
CONTRACEPTION KARCESKI S et al: Treatment of epilepsy in adults: Expert opinion,
2005. Epilepsy Behav 7(Suppl 1):S1, 2005
Special care should be taken when prescribing antiepilep- LOCHARERNKUL C et al: Carbamazepine- and phenytoin-induced
tic medications for women who are taking oral contracep- Stevens-Johnson syndrome is associated with HLA-B1502 allele
tive agents. Drugs such as carbamazepine, phenytoin, phe- in Thai population. Epilepsia 49:2087, 2008
nobarbital, and topiramate can signicantly antagonize the LOWENSTEIN DH: Treatment options for status epilepticus. Curr
Opin Pharmocol 5:334, 2005
effects of oral contraceptives via enzyme induction and
LUCIANO AL, SHORVON SD: Results of treatment changes in patients
other mechanisms. Patients should be advised to consider with apparently drug-resistant chronic epilepsy. Ann Neurol
alternative forms of contraception, or their contraceptive 62:375, 2007
medications should be modied to offset the effects of the TAN NC et al: Genetic dissection of the common epilepsies. Curr
antiepileptic medications. Opin Neurol 19:157, 2006
 CHAPTER 21

CEREBROVASCULAR DISEASES

Wade S. Smith I Joey D. English I S. Claiborne Johnston

I Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 I Intracranial Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275

Pathophysiology of Ischemic Stroke . . . . . . . . . . . . . . . . . . . 247 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Etiology of Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Emergency Management . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Less Common Causes of Stroke . . . . . . . . . . . . . . . . . . . . . 258 Intraparenchymal Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . 276
Transient Ischemic Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . 259 I Vascular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
Risk Factors for Ischemic Stroke and TIA . . . . . . . . . . . . . . . 260 Congenital Vascular Malformations . . . . . . . . . . . . . . . . . . . . 280
Primary and Secondary Prevention of Stroke and TIA . . . . . . 260 Acquired Vascular Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Stroke Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

Cerebrovascular diseases include some of the most com- and the patients symptoms are only transient: this is
mon and devastating disorders: ischemic stroke, hemor- called a transient ischemic attack (TIA).The standard den-
rhagic stroke, and cerebrovascular anomalies such as ition of TIA requires that all neurologic signs and symp-
intracranial aneurysms and arteriovenous malformations toms resolve within 24 h regardless of whether there is
(AVMs). They cause ~200,000 deaths each year in the imaging evidence of new permanent brain injury; stroke
United States and are a major cause of disability. The has occurred if the neurologic signs and symptoms last
incidence of cerebrovascular diseases increases with age, for >24 h. However, a newly proposed denition classi-
and the number of strokes is projected to increase as the es those with new brain infarction as ischemic strokes
elderly population grows, with a doubling in stroke regardless of whether symptoms persist. A generalized
deaths in the United States by 2030. Most cerebrovascu- reduction in cerebral blood ow due to systemic
lar diseases are manifest by the abrupt onset of a focal hypotension (e.g., cardiac arrhythmia, myocardial infarc-
neurologic decit, as if the patient was struck by the tion, or hemorrhagic shock) usually produces syncope
hand of God. A stroke, or cerebrovascular accident, is (Chap. 8). If low cerebral blood ow persists for a longer
dened by this abrupt onset of a neurologic decit that duration, then infarction in the border zones between
is attributable to a focal vascular cause. Thus, the deni- the major cerebral artery distributions may develop. In
tion of stroke is clinical, and laboratory studies including more severe instances, global hypoxia-ischemia causes
brain imaging are used to support the diagnosis. The widespread brain injury; the constellation of cognitive
clinical manifestations of stroke are highly variable sequelae that ensues is called hypoxic-ischemic encephalopa-
because of the complex anatomy of the brain and its thy (Chap. 22). Focal ischemia or infarction, on the other
vasculature. Cerebral ischemia is caused by a reduction in hand, is usually caused by thrombosis of the cerebral
blood ow that lasts longer than several seconds. Neuro- vessels themselves or by emboli from a proximal arterial
logic symptoms are manifest within seconds because source or the heart. Intracranial hemorrhage is caused by
neurons lack glycogen, so energy failure is rapid. If the bleeding directly into or around the brain; it produces
cessation of ow lasts for more than a few minutes, neurologic symptoms by producing a mass effect on
infarction or death of brain tissue results. When blood neural structures, from the toxic effects of blood itself, or
ow is quickly restored, brain tissue can recover fully by increasing intracranial pressure.

246
 ALGORITHM FOR STROKE AND TIA MANAGEMENT 247
Approach to the Patient:
Stroke or TIA
CEREBROVASCULAR DISEASE
Rapid evaluation is essential for use of time-sensitive ABCs, glucose
treatments such as thrombolysis. However, nearly half
of patients with acute stroke often do not seek medical Ischemic stroke/ Obtain brain Hemorrhage
TIA, 85% imaging 15%
assistance on their own, both because they are rarely in
pain, as well as because they may lose the appreciation Consider thrombolysis/ Consider BP
that something is wrong (anosognosia); it is often a thrombectomy lowering

family member or a bystander who calls for help.

Therefore, patients and their family members should Establish cause Establish cause

be counseled to call emergency medical services

immediately if they experience or witness the sudden Atrial Carotid
Other, Aneurysmal Hyperten- Other,
onset of any of the following: loss of sensory and/or fibrillation, disease,
64% SAH, 4% sive ICH, 7% 4%
17% 4%
motor function on one side of the body (nearly 85%
of ischemic stroke patients have hemiparesis); change in Consider Treat Treat
Consider Clip or coil Consider
vision, gait, or ability to speak or understand; or if they CEA or specific specific

CHAPTER 21
warfarin (Chap. 22) surgery
stent cause cause
experience a sudden, severe headache.
There are several common causes of sudden-onset
neurologic symptoms that may mimic stroke, including Deep venous thrombosis prophylaxis
Physical, occupational, speech therapy
seizure, intracranial tumor, migraine, and metabolic Evaluate for rehab, discharge planning
encephalopathy. An adequate history from an observer Secondary prevention based on disease

that no convulsive activity occurred at the onset reason-

Cerebrovascular Diseases
ably excludes seizure. Tumors may present with acute FIGURE 21-1
neurologic symptoms due to hemorrhage, seizure, or Medical management of stroke and TIA. Rounded boxes
hydrocephalus. Surprisingly, migraine can mimic stroke, are diagnoses; rectangles are interventions. Numbers are
percentages of stroke overall. TIA, transient ischemic attack;
even in patients without a signicant migraine history.
ABCs, airway, breathing, circulation; BP, blood pressure;
When it develops without head pain (acephalgic migraine),
CEA, carotid endarterectomy, SAH, subarachnoid hemor-
the diagnosis may remain elusive. Patients without any
rhage; ICH, intracerebral hemorrhage.
prior history of migraine may develop acephalgic
migraine even older than 65 years.A sensory disturbance
is often prominent, and the sensory decit, as well as any
motor decits, tends to migrate slowly across a limb over endovascular mechanical thrombectomy may be bene-
minutes rather than seconds as with stroke.The diagno- cial in restoring cerebral perfusion (see Rx: Acute
sis of migraine becomes more secure as the cortical dis- Ischemic Stroke). Medical management to reduce the
turbance begins to cross vascular boundaries or if typical risk of complications becomes the next priority, followed
visual symptoms are present, such as scintillating sco- by plans for secondary prevention. For ischemic stroke,
tomata (Chap. 6). At times it may be difcult to make several strategies can reduce the risk of subsequent stroke
the diagnosis until multiple episodes have occurred leav- in all patients, while other strategies are effective for
ing behind no residual symptoms and with a normal patients with specic causes of stroke such as cardiac
MRI study of the brain. Classically, metabolic embolus and carotid atherosclerosis. For hemorrhagic
encephalopathies produce uctuating mental status stroke, aneurysmal subarachnoid hemorrhage (SAH) and
without focal neurologic ndings. However, in the set- hypertensive intracranial hemorrhage are two important
ting of prior stroke or brain injury, a patient with fever causes. The treatment and prevention of hypertensive
or sepsis may manifest hemiparesis, which clears rapidly intracranial hemorrhage are discussed later in this
when the infection is remedied. The metabolic process chapter. SAH is discussed in Chap. 22.
serves to unmask a prior decit.
Once the diagnosis of stroke is made, a brain imaging
study is necessary to determine if the cause of stroke is ISCHEMIC STROKE
ischemia or hemorrhage (Fig. 21-1). CT imaging of the
brain is the standard imaging modality to detect the pres- PATHOPHYSIOLOGY OF ISCHEMIC STROKE
ence or absence of intracranial hemorrhage (see Imaging
Acute occlusion of an intracranial vessel causes reduction
Studies, later). If the stroke is ischemic, administration of
in blood ow to the brain region it supplies.The magni-
recombinant tissue plasminogen activator (rtPA) or
tude of ow reduction is a function of collateral blood
 248 CASCADE OF CEREBRAL ISCHEMIA
Arterial occlusion

Thrombolysis
Ischemia Reperfusion
Thrombectomy
Inflammatory
Energy failure PARP response
Glutamate
release
Mitochondrial
Leukocyte
damage
adhesion

Glutamate
Ca2+/Na+ influx Apoptosis Arachidonic acid
receptors
production
Lipolysis
Proteolysis
iNOS Free radical
formation

Membrane and FIGURE 21-2

cytoskeletal breakdown Phospholipase Major steps in the cascade of cerebral
SECTION III

ischemia. See text for details. PARP, poly-A

Cell death ribose polymerase; iNOS, inducible nitric
oxide synthase.
Diseases of the Central Nervous System

ow and this depends on individual vascular anatomy as are seen within the ischemic penumbra, favor apop-
and the site of occlusion. A fall in cerebral blood ow to totic cellular death causing cells to die days to weeks
zero causes death of brain tissue within 410 min; values later. Fever dramatically worsens ischemia, as does hyper-
<1618 mL/100 g tissue per min cause infarction within glycemia [glucose >11.1 mmol/L (200 mg/dL)], so it is
an hour; and values <20 mL/100 g tissue per min cause reasonable to suppress fever and prevent hyperglycemia as
ischemia without infarction unless prolonged for several much as possible. Induced moderate hypothermia to mit-
hours or days. If blood ow is restored prior to a signi- igate stroke is the subject of continuing clinical research.
cant amount of cell death, the patient may experience
only transient symptoms, i.e., a TIA. Tissue surrounding
the core region of infarction is ischemic but reversibly Treatment:
dysfunctional and is referred to as the ischemic penumbra. ACUTE ISCHEMIC STROKE
The penumbra may be imaged by using perfusion- After the clinical diagnosis of stroke is made, an orderly
diffusion imaging with MRI (see later and Fig. 21-16). process of evaluation and treatment should follow
The ischemic penumbra will eventually infarct if no (Fig. 21-1). The rst goal is to prevent or reverse brain
change in ow occurs, and hence saving the ischemic injury. Attend to the patients airway, breathing, circula-
penumbra is the goal of revascularization therapies. tion, and treat hypoglycemia or hyperglycemia if identi-
Focal cerebral infarction occurs via two distinct path- ed. Perform an emergency noncontrast head CT scan in
ways (Fig. 21-2): (1) a necrotic pathway in which cellu- order to differentiate between ischemic stroke and hem-
lar cytoskeletal breakdown is rapid, due principally to orrhagic stroke; there are no reliable clinical ndings that
energy failure of the cell; and (2) an apoptotic pathway in conclusively separate ischemia from hemorrhage,
which cells become programmed to die. Ischemia pro- although a more depressed level of consciousness,
duces necrosis by starving neurons of glucose, which in higher initial blood pressure, or worsening of symptoms
turn results in failure of mitochondria to produce ATP. after onset favor hemorrhage, and a decit that remits
Without ATP, membrane ion pumps stop functioning suggests ischemia. Treatments designed to reverse or
and neurons depolarize, allowing intracellular calcium to lessen the amount of tissue infarction and improve clini-
rise. Cellular depolarization also causes glutamate release cal outcome fall within six categories: (1) medical sup-
from synaptic terminals; excess extracellular glutamate port (2) intravenous thrombolysis, (3) endovascular
produces neurotoxicity by activating postsynaptic gluta- techniques, (4) antithrombotic treatment, (5) neuropro-
mate receptors that increase neuronal calcium inux. tection, and (6) stroke centers and rehabilitation.
Free radicals are produced by membrane lipid degrada-
MEDICAL SUPPORT When ischemic stroke occurs,
tion and mitochondrial dysfunction. Free radicals cause
catalytic destruction of membranes and likely damage the immediate goal is to optimize cerebral perfusion in
other vital functions of cells. Lesser degrees of ischemia, the surrounding ischemic penumbra. Attention is also
directed toward preventing the common complications 60 min) vs. placebo in patients with ischemic stroke 249
of bedridden patientsinfections (pneumonia, urinary within 3 h of onset. Half of the patients were treated
tract, and skin) and deep venous thrombosis (DVT) with within 90 min. Symptomatic intracerebral hemorrhage
pulmonary embolism. Many physicians use pneumatic occurred in 6.4% of patients on rtPA and 0.6% on
compression stockings to prevent DVT; subcutaneous placebo. There was a nonsignificant 4% reduction in
heparin appears to be safe as well and can be used mortality in patients on rtPA (21% on placebo and
concomitantly. 17% on rtPA); there was a significant 12% absolute
Because collateral blood ow within the ischemic increase in the number of patients with only minimal
brain is blood pressure dependent, there is controversy disability (32% on placebo and 44% on rtPA.) Thus,
about whether blood pressure should be lowered despite an increased incidence of symptomatic
acutely. Blood pressure should be lowered if there is intracerebral hemorrhage, treatment with IV rtPA
malignant hypertension or concomitant myocardial within 3 h of the onset of ischemic stroke improved
ischemia or if blood pressure is >185/110 mmHg and clinical outcome.
thrombolytic therapy is anticipated. When faced with Results of other trials of rtPA have been negative, per-
the competing demands of myocardium and brain, low- haps because of the dose of rtPA and timing of its deliv-
ering the heart rate with a 1-adrenergic blocker (such ery. The European Cooperative Acute Stroke Study

CHAPTER 21
as esmolol) can be a rst step to decrease cardiac work (ECASS) I used a higher dose of rtPA (1.2 mg/kg), and
and maintain blood pressure. Fever is detrimental and ECASS-II tested the NINDS dose of rtPA (0.9 mg/kg; max-
should be treated with antipyretics and surface cooling. imum dose, 90 mg) but allowed patients to receive drug
Serum glucose should be monitored and kept at <6.1 up to the sixth hour. No signicant benet was found,
mmol/L (110 mg/dL) using an insulin infusion. but improvement was found in post hoc analyses.
Between 5 and 10% of patients develop enough ATLANTIS tested the NINDS dosing of rtPA between 3
cerebral edema to cause obtundation or brain hernia- and 5 h and found no benet. Because of the marked

Cerebrovascular Diseases
tion. Edema peaks on the second or third day but can differences in trial design, including drug and dose used,
cause mass effect for ~10 days. The larger the infarct, the time to thrombolysis, and severity of stroke, the precise
greater the likelihood that clinically signicant edema efcacy of IV thrombolytics for acute ischemic stroke
will develop. Water restriction and IV mannitol may be remains unclear. The risk of intracranial hemorrhage
used to raise the serum osmolarity, but hypovolemia appears to rise with larger strokes, longer times from
should be avoided as this may contribute to hypoten- onset of symptoms, and higher doses of rtPA adminis-
sion and worsening infarction. Combined analysis of tered. The established dose of 0.9 mg/kg administered
three randomized European trials of hemicraniectomy IV within 3 h of stroke onset appears safe. The ECASS-III
(craniotomy and temporary removal of part of the skull) trial established efcacy of IV tPA in a 4.5-h window,
shows that this procedure markedly reduces mortality, although with less robust results compared to 3-hour
and the clinical outcomes of survivors are acceptable. trials. When data from all randomized IV rtPA trails are
Special vigilance is warranted for patients with cere- combined, efcacy is conrmed in the <3-h time win-
bellar infarction. Such strokes may mimic labyrinthitis dow, and efcacy likely extends to 4.5 h. One may be
because of prominent vertigo and vomiting; the pres- able to select patients beyond the usual time windows
ence of head or neck pain should alert the physician to who will benet from thrombolysis using advanced
consider cerebellar stroke from vertebral artery dissec- neuroimaging (see neuroimaging section later), but this
tion. Even small amounts of cerebellar edema can is currently investigational. The drug is now approved in
acutely increase intracranial pressure (ICP) or directly the United States, Canada, and Europe for acute stroke
compress the brainstem. The resulting brainstem com- when given within 3 h from the time the stroke symp-
pression can result in coma and respiratory arrest and toms began, and efforts should be made to give it as
require emergency surgical decompression. Prophylac- early in this 3-h window as possible. The time of stroke
tic suboccipital decompression of large cerebellar onset is dened as the time the patients symptoms
infarcts before brainstem compression, although not began or the time the patient was last seen as normal.
tested rigorously in a clinical trial, is practiced at most Patients who awaken with stroke have the onset
stroke centers. defined as when they went to bed. Table 21-1 summa-
rizes eligibility criteria and instructions for administra-
INTRAVENOUS THROMBOLYSIS The National tion of IV rtPA.
Institute of Neurological Disorders and Stroke (NINDS)
recombinant tPA (rtPA) Stroke Study showed a clear ENDOVASCULAR TECHNIQUES Ischemic stroke
benefit for IV rtPA in selected patients with acute from large-vessel intracranial occlusion results in high
stroke. The NINDS study used IV rtPA (0.9 mg/kg to a rates of mortality and morbidity. Occlusions in such
90-mg max; 10% as a bolus, then the remainder over large vessels [middle cerebral artery (MCA), internal
 250 TABLE 21-1
ADMINISTRATION OF INTRAVENOUS RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR
(rtPA) FOR ACUTE ISCHEMIC STROKEa

INDICATION CONTRAINDICATION

Clinical diagnosis of stroke Sustained BP >185/110 despite treatment

Onset of symptoms to time Platelets <100,000; HCT <25%; glucose <50 or
of drug administration 3 h >400 mg/dL
CT scan showing no hemorrhage Use of heparin within 48 h and prolonged PTT,
or edema of >1/3 of the MCA territory or elevated INR
Age 18 years Rapidly improving symptoms
Consent by patient or surrogate Prior stroke or head injury within 3 months; prior
intracranial hemorrhage
Major surgery in preceding 14 days
Minor stroke symptoms
Gastrointestinal bleeding in preceding 21 days
Recent myocardial infarction
Coma or stupor
SECTION III

Administration of rtPA

Intravenous access with two peripheral IV lines (avoid arterial or central line placement)
Review eligibility for rtPA
Administer 0.9 mg/kg intravenously (maximum 90 mg) IV as 10% of total dose by bolus,
followed by remainder of total dose over 1 h
Frequent cuff blood pressure monitoring
No other antithrombotic treatment for 24 h
Diseases of the Central Nervous System

For decline in neurologic status or uncontrolled blood pressure, stop infusion, give
cryoprecipitate, and reimage brain emergently
Avoid urethral catheterization for 2 h

a
See Activase (tissue plasminogen activator) package insert for complete list of contraindications and dosing.
Note: BP, blood pressure; HCT, hematocrit; INR, international normalized ratio; MCA, middle cerebral artery;
PTT, partial thromboplastin time.

carotid artery, and the basilar artery] generally involve a device to restore patency of occluded intracranial ves-
large clot volume and often fail to open with IV rtPA sels within 8 h of ischemic stroke symptoms. Recanal-
alone. Therefore, there is growing interest in using ization of the target vessel occurred in 48% of treated
thrombolytics via an intraarterial route to increase the patients and in 60% following use of adjuvant endovas-
concentration of drug at the clot and minimize systemic cular methods, and successful recanalization at 90 days
bleeding complications. The Prolyse in Acute Cerebral correlated well with favorable outcome. Based upon
Thromboembolism (PROACT) II trial found benet for these nonrandomized data, the FDA approved this
intraarterial pro-urokinase for acute MCA occlusions up device for revascularization of occluded vessels in acute
to the sixth hour following onset of stroke. Intra-arterial ischemic stroke within 8 h of symptom onset. Recent
treatment of basilar artery occlusions may also be trials have shown that it is safe to use this technique
benecial for selected patients. Intra-arterial administration even in patients who have been given IV rtPA yet have
of a thrombolytic agent for acute ischemic stroke is not failed to recanalize. Such a strategy allows primary
approved by the U.S. Food and Drug Administration stroke centers to administer rtPA to eligible patients,
(FDA); however, many stroke centers offer this treatment then rapidly refer such patients to comprehensive
based on these data. stroke centers that have endovascular capability.
Endovascular mechanical thrombectomy has
recently shown promise as an alternative treatment of ANTITHROMBOTIC TREATMENT
acute stroke in patients who are ineligible for, or have Platelet Inhibition Aspirin is the only antiplatelet
contraindications to, thrombolytics or in those who have agent that has been proven effective for the acute
failed to have vascular recanalization with IV throm- treatment of ischemic stroke; there are several
bolytics (Fig. 21-15). The MERCI (Mechanical Embolus antiplatelet agents proven for the secondary prevention
Removal in Cerebral Ischemia) single-arm trial investi- of stroke (see later). Two large trials, the International
gated the ability of a novel endovascular thrombectomy Stroke Trial (IST) and the Chinese Acute Stroke Trial
(CAST), found that the use of aspirin within 48 h of STROKE CENTERS AND REHABILITATION 251
stroke onset reduced both stroke recurrence risk and Patient care in comprehensive stroke units followed by
mortality minimally. Among 19,435 patients in IST, those rehabilitation services improves neurologic outcomes
allocated to aspirin, 300 mg/d, had slightly fewer deaths and reduces mortality. Use of clinical pathways and staff
within 14 days (9.0 vs. 9.4%), signicantly fewer dedicated to the stroke patient can improve care. Stroke
recurrent ischemic strokes (2.8 vs. 3.9%), no excess of teams that provide emergency 24-h evaluation of acute
hemorrhagic strokes (0.9 vs. 0.8%), and a trend toward stroke patients for acute medical management and
a reduction in death or dependence at 6 months (61.2 consideration of thrombolysis or endovascular treatments
vs. 63.5%). In CAST, 21,106 patients with ischemic stroke are important.
received 160 mg/d of aspirin or a placebo for up to Proper rehabilitation of the stroke patient includes
4 weeks. There were very small reductions in the aspirin early physical, occupational, and speech therapy. It is
group in early mortality (3.3 vs. 3.9%), recurrent ischemic directed toward educating the patient and family about
strokes (1.6 vs. 2.1%), and dependency at discharge or the patients neurologic decit, preventing the compli-
death (30.5 vs. 31.6%). These trials demonstrate that the cations of immobility (e.g., pneumonia, DVT and pulmonary
use of aspirin in the treatment of acute ischemic stroke embolism, pressure sores of the skin, and muscle con-
is safe and produces a small net benet. For every 1000 tractures), and providing encouragement and instruc-

CHAPTER 21
acute strokes treated with aspirin, about 9 deaths or tion in overcoming the decit. The goal of rehabilitation
nonfatal stroke recurrences will be prevented in the rst is to return the patient to home and to maximize recov-
few weeks and ~13 fewer patients will be dead or ery by providing a safe, progressive regimen suited to
dependent at 6 months. the individual patient. Additionally, the use of restraint
The glycoprotein IIb/IIIa receptor inhibitor abciximab therapy (immobilizing the unaffected side) has been
held promise as an acute treatment, but a recent clinical shown to improve hemiparesis following stroke, even
trial was stopped because of excess intracranial hemor- years following the stroke, suggesting that physical ther-

Cerebrovascular Diseases
rhage. apy can recruit unused neural pathways. This nding
suggests that the human nervous system is more adapt-
Anticoagulation Numerous clinical trials have able than originally thought and has stimulated active
failed to demonstrate any benet of anticoagulation in research into physical and pharmacologic strategies
the primary treatment of atherothrombotic cerebral that can enhance long-term neural recovery.
ischemia. Several trials have investigated antiplatelet
versus anticoagulant medications given within 1224 h
of the initial event. The U.S. Trial of Organon 10172 in
Acute Stroke Treatment (TOAST), an investigational low- ETIOLOGY OF ISCHEMIC STROKE
molecular-weight heparin, failed to show any benet
(Figs. 21-1 and 21-3 and Table 21-2) Although the
over aspirin. Use of SC unfractionated heparin versus
initial management of acute ischemic stroke often does
aspirin was tested in IST. Heparin given SC afforded no
not depend on the etiology, establishing a cause is essen-
additional benet over aspirin and increased bleeding
tial in reducing the risk of recurrence. Particular focus
rates. Several trials of low-molecular-weight heparins
should be on atrial brillation and carotid atherosclero-
have also shown no consistent benet in acute ischemic
sis, as these etiologies have proved secondary prevention
stroke. Furthermore, trials generally have shown an
strategies. The clinical presentation and examination
excess risk of brain and systemic hemorrhage with acute
ndings often establish the cause of stroke or narrow the
anticoagulation. Therefore, trials do not support the use
possibilities to a few. Judicious use of laboratory testing
of heparin or other anticoagulants for patients with
and imaging studies completes the initial evaluation.
atherothrombotic stroke.
Nevertheless, nearly 30% of strokes remain unexplained
NEUROPROTECTION Neuroprotection is the con-
despite extensive evaluation.
cept of providing a treatment that prolongs the brains
Clinical examination should focus on the peripheral
tolerance to ischemia. Drugs that block the excitatory
and cervical vascular system (carotid auscultation for
amino acid pathways have been shown to protect
bruits, blood pressure, and pressure comparison between
neurons and glia in animals, but despite multiple clinical
arms), the heart (dysrhythmia, murmurs), extremities
trials, they have not yet been proven to be benecial in
(peripheral emboli), and retina [effects of hypertension
humans. Hypothermia is a powerful neuroprotective
and cholesterol emboli (Hollenhorst plaques)]. A com-
treatment in patients with cardiac arrest (Chap. 22) and
plete neurologic examination is performed to localize
is neuroprotective in animal models of stroke, but it has
the site of stroke. An imaging study of the brain is nearly
not been adequately studied in patients with ischemic
always indicated and is required for patients being con-
stroke.
sidered for thrombolysis; it may be combined with CT-
or MRI-based angiography to interrogate the neck and
 252 Intracranial Penetrating
atherosclerosis artery disease

Carotid Flow
plaque with reducing
arteriogenic carotid
emboli stenosis Internal
carotid

External
carotid

Common
Atrial fibrillation carotid
Cardiogenic
emboli
Valve disease
SECTION III

A B C
Left ventricular
thrombi
FIGURE 21-3
Pathophysiology of ischemic stroke. A. Diagram illustrat- major intracranial arteries; (3) hypoperfusion caused by ow-
Diseases of the Central Nervous System

ing the three major mechanisms that underlie ischemic limiting stenosis of a major extracranial (e.g., internal carotid)
stroke: (1) occlusion of an intracranial vessel by an embolus or intracranial vessel, often producing watershed ischemia.
that arises at a distant site (e.g., cardiogenic sources such as B and C. Diagram and reformatted CT angiogram of the
atrial brillation or artery-to-artery emboli from carotid ather- common, internal, and external carotid arteries. High-grade
osclerotic plaque), often affecting the large intracranial ves- stenosis of the internal carotid artery, which may be associ-
sels; (2) in situ thrombosis of an intracranial vessel, typically ated with either cerebral emboli or ow-limiting ischemia,
affecting the small penetrating arteries that arise from the was identied in this patient.

intracranial vessels (see Imaging Studies, later). A chest the ischemic territory. This is usually of no clinical sig-
x-ray, electrocardiogram (ECG), urinalysis, complete nicance and should be distinguished from frank
blood count, erythrocyte sedimentation rate, serum intracranial hemorrhage into a region of ischemic stroke
electrolytes, blood urea nitrogen, creatinine, blood sugar, where the mass effect from the hemorrhage can cause a
serologic test for syphilis, serum lipid prole, prothrom- decline in neurologic function.
bin time, and partial thromboplastin time (PTT) are Emboli from the heart most often lodge in the MCA,
often useful and should be considered in all patients. An the posterior cerebral artery (PCA), or one of their
ECG may demonstrate arrhythmias or reveal evidence branches; infrequently, the anterior cerebral artery (ACA)
of recent myocardial infarction (MI). territory is involved. Emboli large enough to occlude the
stem of the MCA (34 mm) lead to large infarcts that
involve both deep gray and white matter and some por-
Cardioembolic Stroke
tions of the cortical surface and its underlying white
Cardioembolism is responsible for ~20% of all ischemic matter.A smaller embolus may occlude a small cortical or
strokes. Stroke caused by heart disease is primarily due penetrating arterial branch. The location and size of an
to embolism of thrombotic material forming on the infarct within a vascular territory depend on the extent
atrial or ventricular wall or the left heart valves. These of the collateral circulation.
thrombi then detach and embolize into the arterial cir- The most signicant causes of cardioembolic stroke
culation. The thrombus may fragment or lyse quickly, in most of the world are nonrheumatic (often called
producing only a TIA. Alternatively, the arterial occlu- nonvalvular) atrial brillation, MI, prosthetic valves,
sion may last longer, producing stroke. Embolic strokes rheumatic heart disease, and ischemic cardiomyopathy
tend to be sudden in onset, with maximum neurologic (Table 21-2). Cardiac disorders causing brain embolism
decit at once. With reperfusion following more pro- are discussed in the respective chapters on heart diseases.
longed ischemia, petechial hemorrhage can occur within A few pertinent aspects are highlighted here.
 TABLE 21-2 253
CAUSES OF ISCHEMIC STROKE

COMMON CAUSES UNCOMMON CAUSES

Thrombosis Hypercoagulable disorders

Lacunar stroke (small vessel) Protein C deciency
Large vessel thrombosis Protein S deciency
Dehydration Antithrombin III deciency
Embolic occlusion Antiphospholipid syndrome
Artery-to-artery Factor V Leiden mutationa
Carotid bifurcation Prothrombin G20210 mutationa
Aortic arch Systemic malignancy
Arterial dissection Sickle cell anemia
Cardioembolic -Thalassemia
Atrial brillation Polycythemia vera
Mural thrombus Systemic lupus erythematosus
Myocardial infarction Homocysteinemia
Dilated cardiomyopathy Thrombotic thrombocytopenic purpura

CHAPTER 21
Valvular lesions Disseminated intravascular coagulation
Mitral stenosis Dysproteinemias
Mechanical valve Nephrotic syndrome
Bacterial endocarditis Inammatory bowel disease
Paradoxical embolus Oral contraceptives
Atrial septal defect Venous sinous thrombosisb
Patent foramen ovale Fibromuscular dysplasia
Atrial septal aneurysm Vasculitis

Cerebrovascular Diseases
Spontaneous echo contrast Systemic vasculitis (PAN, Wegeners,
Takayasus, giant cell arteritis)
Primary CNS vasculitis
Meningitis (syphilis, tuberculosis,
fungal, bacterial, zoster)
Cardiogenic
Mitral valve calcication
Atrial myxoma
Intracardiac tumor
Marantic endocarditis
Libman-Sacks endocarditis
Subarachnoid hemorrhage vasospasm
Drugs: cocaine, amphetamine
Moyamoya disease
Eclampsia

a
Chiey cause venous sinus thrombosis.
b
May be associated with any hypercoagulable disorder.
Note: CNS, central nervous system; PAN, polyarteritis nodosa.

Nonrheumatic atrial brillation is the most common formation of atrial thrombi. Rheumatic heart disease usu-
cause of cerebral embolism overall. The presumed stroke ally causes ischemic stroke when there is prominent mitral
mechanism is thrombus formation in the brillating stenosis or atrial brillation. Guidelines for the use of war-
atrium or atrial appendage, with subsequent embolization. farin and aspirin for secondary prevention are based on
Patients with atrial brillation have an average annual risk risk factors (Table 21-3).
of stroke of ~5%.The risk varies according to the presence Recent MI may be a source of emboli, especially
of certain risk factors, including older age, hypertension, when transmural and involving the anteroapical ventric-
poor left ventricular function, prior cardioembolism, mitral ular wall, and prophylactic anticoagulation following MI
stenosis, prosthetic heart valve, or diabetes. Patients <65 has been shown to reduce stroke risk. Mitral valve pro-
years with none of these risk factors have an annual risk lapse is not usually a source of emboli unless the prolapse
for stroke of ~0.5%, while those with most of the factors is severe.
have a rate of ~15% per year. Left atrial enlargement and Paradoxical embolization occurs when venous thrombi
congestive heart failure are additional risk factors for migrate to the arterial circulation, usually via a patent
 254 TABLE 21-3 acutely thrombose; the resulting blockage causes stroke
CONSENSUS RECOMMENDATION FOR ANTITHROMBOTIC by producing ischemia within the region of brain it sup-
PROPHYLAXIS IN ATRIAL FIBRILLATION plied. Unlike the myocardial vessels, artery-to-artery
embolism, rather than local thrombosis, appears to be
AGE RISK FACTORSa RECOMMENDATION
the dominant vascular mechanism causing ischemia. Any
65 years 1 Warfarin INR 23 diseased vessel may be a source, including the aortic
0 Aspirin arch, common carotid, internal carotid, vertebral, and
6575 years 1 Warfarin INR 23 basilar arteries. Carotid bifurcation atherosclerosis is the
0 Warfarin INR 23 or aspirin
>75 years Warfarin INR 23
most common source of artery-to-artery embolus, and
specic treatments have proven efcacy in reducing risk.
a
Risk factors include previous transient ischemic attack or stroke,
hypertension, heart failure, diabetes, systemic embolism, mitral steno-
Carotid Atherosclerosis
sis, or prosthetic heart valve. Atherosclerosis within the carotid artery occurs most
Source: Modied from DE Singer et al: Antithrombotic therapy in frequently within the common carotid bifurcation and
atrial brillation. Chest 126:429S, 2004; with permission. proximal internal carotid artery. Additionally, the carotid
siphon (portion within the cavernous sinus) is also vul-
nerable to atherosclerosis. Male gender, older age, smok-
SECTION III

foramen ovale or atrial septal defect. Bubble-contrast ing, hypertension, diabetes, and hypercholesterolemia are
echocardiography (IV injection of agitated saline coupled risk factors for carotid disease, as they are for stroke in
with either transthoracic or transesophageal echocardiog- general (Table 21-4). Carotid atherosclerosis produces
raphy) can demonstrate a right-to-left cardiac shunt, an estimated 10% of ischemic stroke.
revealing the conduit for paradoxical embolization. Alter- Carotid disease can be classied by whether the
natively, a right-to-left shunt is implied if immediately stenosis is symptomatic or asymptomatic and by the
Diseases of the Central Nervous System

following IV injection of agitated saline, the ultrasound degree of stenosis (percent narrowing of the narrowest
signature of bubbles is observed during transcranial segment compared to a more distal internal carotid seg-
Doppler insonation of the MCA; pulmonary AVMs ment). Symptomatic carotid disease implies that the
should be considered if this test is positive yet an echocar- patient has experienced a stroke or TIA within the vas-
diogram fails to reveal an intracardiac shunt. Both tech- cular distribution of the artery, and it is associated with a
niques are highly sensitive for detection of right-to-left greater risk of subsequent stroke than asymptomatic
shunts. Besides venous clot, fat and tumor emboli, bacte- stenosis, in which the patient is symptom free and the
rial endocarditis, IV air, and amniotic uid emboli at stenosis is detected through screening. Greater degrees
childbirth may occasionally be responsible for paradoxi- of arterial narrowing are generally associated with a
cal embolization. The importance of right-to-left shunt greater risk of stroke, except that those with near occlu-
as a cause of stroke is debated, particularly because such sions are at lower risk of stroke.
shunts are present in ~15% of the general population.
Some studies have suggested that the risk is only ele-
vated in the presence of a coexisting atrial septal
aneurysm. The presence of a venous source of embolus,
most commonly a deep venous thrombus, may provide Treatment:
CAROTID ATHEROSCLEROSIS
conrmation of the importance of a right-to-left shunt
in a particular case. Carotid atherosclerosis can be removed surgically
Bacterial endocarditis can cause valvular vegetations (endarterectomy) or mitigated with endovascular stent-
that can give rise to septic emboli. The appearance of ing with or without balloon angioplasty.
multifocal symptoms and signs in a patient with stroke SURGICAL THERAPY Symptomatic carotid stenosis
makes bacterial endocarditis more likely. Infarcts of was studied in the North American Symptomatic
microscopic size occur, and large septic infarcts may Carotid Endarterectomy Trial (NASCET) and the
evolve into brain abscesses or cause hemorrhage into the European Carotid Surgery Trial (ECST). Both showed a
infarct, which generally precludes use of anticoagulation substantial benet for surgery in patients with a stenosis
or thrombolytics. Mycotic aneurysms caused by septic of 70%. In NASCET, the average cumulative ipsilateral
emboli give rise to SAH or intracerebral hemorrhage. stroke risk at 2 years was 26% for patients treated
medically and 9% for those receiving the same medical
Artery-to-Artery Embolic Stroke treatment plus a carotid endarterectomy. This 17%
absolute reduction in the surgical group is a 65% relative
Thrombus formation on atherosclerotic plaques may
risk reduction favoring surgery (Table 21-4). NASCET also
embolize to intracranial arteries producing an artery-to-
showed a signicant, although less robust, benet for
artery embolic stroke. Alternatively, a diseased vessel may
 TABLE 21-4 255
RISK FACTORS FOR STROKE

NUMBER NEEDED TO TREATa

RELATIVE RISK REDUCTION PRIMARY SECONDARY

RISK FACTOR RELATIVE RISK WITH TREATMENT PREVENTION PREVENTION

Hypertension 25 38% 100300 50100

Atrial brillation 1.82.9 68% warfarin, 21% aspirin 2083 13
Diabetes 1.86 No proven effect
Smoking 1.8 50% at 1 year, baseline risk at
5 years post cessation
Hyperlipidemia 1.82.6 1630% 560 230
Asymptomatic carotid 2.0 53% 85 N/A
stenosis
Symptomatic carotid 65% at 2 years N/A 12
stenosis (7099%)
Symptomatic carotid 29% at 5 years N/A 77
stenosis (5069%)

CHAPTER 21
a
Number needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here.
Note: N/A, not applicable.

patients with 5070% stenosis. ECST found harm for risk reduction is only 5.9% over 5 years, or 1.2% annually

Cerebrovascular Diseases
patients with stenosis <30% treated surgically. (Table 21-4). Nearly half of the strokes in the surgery
A patients risk of stroke and possible benet from group were caused by preoperative angiograms. The
surgery are related to the presence of retinal versus recently published ACST randomized 3120 asympto-
hemispheric symptoms, degree of arterial stenosis, matic patients with >60% carotid stenosis to
extent of associated medical conditions (of note, endarterectomy or medical therapy. The 5-year risk of
NASCET and ECST excluded high-risk patients with stroke in the surgical group (including perioperative
signicant cardiac, pulmonary, or renal disease), institu- stroke or death) was 6.4%, in comparison with 11.8% in
tional surgical morbidity and mortality, timing of the medically treated group (46% relative risk reduction
surgery relative to symptoms, and other factors. A recent and 5.4% absolute risk reduction).
meta-analysis of the NASCET and ECST trials demon- In both ACAS and ACST, the perioperative complication
strated that endarterectomy is most benecial when rate was higher in women, perhaps negating any benet
performed within 2 weeks of symptom onset. In addi- in the reduction of stroke risk within 5 years. It is possible
tion, benet is more pronounced in patients >75 years, that with longer follow-up, a clear benet in women will
and men appear to benet more than women. emerge. At present, carotid endarterectomy in asympto-
In summary, a patient with recent symptomatic hemi- matic women remains particularly controversial.
spheric ischemia, high-grade stenosis in the appropriate In summary, the natural history of asymptomatic
internal carotid artery, and an institutional perioperative stenosis is a ~2% per year stroke rate, while sympto-
morbidity and mortality rate of 6% generally should matic patients experience a 13% per year risk of stroke.
undergo carotid endarterectomy. If the perioperative Whether to recommend carotid revascularization for an
stroke rate is >6% for any particular surgeon, however, asymptomatic patient is somewhat controversial and
the benets of carotid endarterectomy are questionable. depends on many factors, including patient preference,
The indications for surgical treatment of asympto- degree of stenosis, age, gender, and comorbidities. Med-
matic carotid disease have been claried by the results of ical therapy for reduction of atherosclerosis risk factors,
the Asymptomatic Carotid Atherosclerosis Study (ACAS) including cholesterol-lowering agents and antiplatelet
and the Asymptomatic Carotid Surgery Trial (ACST). medications, is generally recommended for patients
ACAS randomized asymptomatic patients with 60% with asymptomatic carotid stenosis. As with atrial bril-
stenosis to medical treatment with aspirin or the same lation, it is imperative to counsel the patient about TIAs
medical treatment plus carotid endarterectomy. The sur- so that therapy can be revised if symptoms develop.
gical group had a risk over 5 years for ipsilateral stroke
(and any perioperative stroke or death) of 5.1%, com- ENDOVASCULAR THERAPY Balloon angioplasty
pared to a risk in the medical group of 11%. While this coupled with stenting is being used with increasing
demonstrates a 53% relative risk reduction, the absolute frequency to open stenotic carotid arteries and maintain
 256 their patency. These techniques can treat carotid of patients on aspirin experienced major hemorrhage,
stenosis not only at the bifurcation but also near the compared to 8.3% of patients taking warfarin.
skull base and in the intracranial segments.The SAPPHIRE Given the worrisome natural history of symptomatic
trial (Stenting and Angioplasty with Protection in intracranial atherosclerosis (in the aspirin arm of the
Patients at High Risk for Endarterectomy) randomized WASID trial, 15% of patients experienced a stroke
high-risk patients (dened as patients with clinically within the rst year, despite current standard aggressive
signicant coronary or pulmonary disease, contralateral medical therapy), some centers treat symptomatic lesions
carotid occlusion, restenosis after endarterectomy, with intracranial angioplasty and stenting.This interven-
contralateral laryngeal-nerve palsy, prior radical neck tion has not been compared with medical therapy for
surgery or radiation, or age >80) with symptomatic stroke prevention in this patient population, but such
carotid stenosis >50% or asymptomatic stenosis >80% clinical trials will likely be conducted in the near future.
to either stenting combined with a distal emboli- Likewise, it is unclear whether EC-IC bypass, or other
protection device or endarterectomy. The risk of death, grafting procedures of extracranial blood supply to the
stroke, or MI within 30 days and ipsilateral stroke or pial arteries, is of value in such patients.
death within 1 year was 12.2% in the stenting group Dissection of the internal carotid or vertebral arteries
and 20.1% in the endarterectomy group (p = .055), or even vessels beyond the circle of Willis is a common
suggesting that stenting is at the very least comparable source of embolic stroke in young (<60 years) patients.
SECTION III

to endarterectomy as a treatment option for this patient The dissection is usually painful and precedes the stroke
group at high risk of surgery. However, the outcomes by several hours or days. Extracranial dissections do not
with both interventions may not have been better than cause hemorrhage because of the tough adventitia of
leaving the carotid stenoses untreated, particularly for these vessels. Intracranial dissections, on the other hand,
the asymptomatic patients, and much of the benet may produce SAH because the adventitia of intracranial
seen in the stenting group was due to a reduction in vessels is thin and pseudoaneurysms may form, requiring
Diseases of the Central Nervous System

peri-procedure MI. Multicenter trials are currently treatment to prevent rerupture. Treating asymptomatic
underway comparing stenting with endarterectomy in pseudoaneurysms following dissection is controversial.
lower-risk patients, the population previously studied in The cause of dissection is usually unknown and recur-
the NASCET, ECST, ACAS, and ACST trials (see above). rence is rare. Ehlers-Danlos type IV, Marfans disease,
cystic medial necrosis, and bromuscular dysplasia are
BYPASS SURGERY Extracranial-to-intracranial (EC-IC) associated with dissections. Trauma (usually a motor
bypass surgery has been proven ineffective for atheroscle- vehicle accident or a sports injury) can cause carotid and
rotic stenoses that are inaccessible to conven-tional vertebral artery dissections. Spinal manipulative therapy
carotid endarterectomy. However, a trial is underway to is independently associated with vertebral artery dissec-
evaluate whether patients with decreased brain tion and stroke. Most dissections heal spontaneously, and
perfusion based on positron emission tomography (PET) stroke or TIA is uncommon beyond 2 weeks. Although
imaging will benet from EC-IC bypass. there are no trials comparing anticoagulation to
antiplatelet agents, many physicians treat acutely with
anticoagulants for 36 months then convert to 69
months of antiplatelet therapy after demonstration of
Other Causes of Artery-to-Artery vascular recanalization; a recent observational study ques-
Embolic Stroke tioned the superiority of anticoagulants versus antiplatelets
Intracranial atherosclerosis produces stroke either by an in carotid dissection.
embolic mechanism or by in situ thrombosis of a diseased
vessel. It is more common in patients of Asian and
Small-Vessel Stroke
African-American descent. The WASID (Warfarin-
Aspirin Symptomatic Intracranial Disease) trial random- The term lacunar infarction refers to infarction following
ized patients with symptomatic stenosis (5099%) of a atherothrombotic or lipohyalinotic occlusion of a small
major intracranial vessel to either high-dose aspirin (1300 artery (30300 m) in the brain. The term small-vessel
mg/d) or warfarin (target INR, 2.03.0), with a com- stroke denotes occlusion of such a small penetrating
bined primary endpoint of ischemic stroke, brain hemor- artery and is now the preferred term. Small-vessel
rhage, or death from vascular cause other than stroke.The strokes account for ~20% of all strokes.
trial was terminated early because of an increased risk of
adverse events related to warfarin anticoagulation. With a Pathophysiology
mean follow-up of 1.8 years, the primary endpoint was The MCA stem, the arteries comprising the circle of
seen in 22.1% in the aspirin group and 21.8% of the war- Willis (A1 segment, anterior and posterior communicat-
farin group. Death from any cause was seen in 4.3% of ing arteries, and P1 segment), and the basilar and vertebral
the aspirin group and 9.7% of the warfarin group; 3.2% arteries all give rise to 30- to 300-m branches that
 Deep branches of the 257
Anterior cerebral a. middle cerebral a.

Anterior cerebral a.

Internal
carotid a.

Middle cerebral a.
Internal carotid a. Middle cerebral a.

CHAPTER 21
Cerebrovascular Diseases
Basilar a.
Vertebral a.

Basilar a.
Deep branches
Vertebral a. of the basilar a.
FIGURE 21-4
Diagrams and reformatted CT angiograms in the coronal posterior circulation, similar arteries arise directly from the
section illustrating the deep penetrating arteries involved in vertebral and basilar arteries to supply the brainstem (lower
small-vessel strokes. In the anterior circulation, small pene- panels). Occlusion of a single penetrating artery gives rise to
trating arteries called lenticulostriates arise from the proximal a discrete area of infarct (pathologically termed a lacune, or
portion of the anterior and middle cerebral arteries and lake). Note that these vessels are too small to be visualized
supply deep subcortical structures (upper panels). In the on CT angiography.

penetrate the deep gray and white matter of the cere- stroke from an infarct in the ventral thalamus; (3) ataxic
brum or brainstem (Fig. 21-4). Each of these small hemiparesis from an infarct in the ventral pons or internal
branches can occlude either by atherothrombotic disease capsule; (4) and dysarthria and a clumsy hand or arm due
at its origin or by the development of lipohyalinotic to infarction in the ventral pons or in the genu of the
thickening. Thrombosis of these vessels causes small internal capsule.
infarcts that are referred to as lacunes (Latin for lake of Transient symptoms (small vessel TIAs) may herald a
uid noted at autopsy).These infarcts range in size from small-vessel infarct; they may occur several times a day
3 mm to 2 cm in diameter. Hypertension and age are and last only a few minutes. Recovery from small-vessel
the principal risk factors. strokes tends to be more rapid and complete than recov-
ery from large-vessel strokes; in some cases, however,
Clinical Manifestations there is severe permanent disability. Often, institution of
The most common lacunar syndromes are the following: combined antithrombotic treatments does not prevent
(1) Pure motor hemiparesis from an infarct in the posterior eventual stroke in stuttering lacunes.
limb of the internal capsule or basis pontis; the face, A large-vessel source (either thrombosis or embolism)
arm, and leg are almost always involved; (2) pure sensory may manifest initially as a lacunar syndrome with
 258 small-vessel infarction. Therefore, the search for embolic Doppler ultrasonography. In children who are identied
sources (carotid and heart) should not be completely to have high velocities, treatment with aggressive exchange
abandoned in the evaluation of these patients. Secondary transfusion dramatically reduces risk of stroke, and if
prevention of lacunar stroke involves risk factor modi- exchange transfusion is ceased, their stroke rate increases
cation, specically reduction in blood pressure (see Primary again along with MCA velocities.
and Secondary Prevention, later). Fibromuscular dysplasia affects the cervical arteries and
occurs mainly in women.The carotid or vertebral arter-
ies show multiple rings of segmental narrowing alter-
LESS COMMON CAUSES OF STROKE
nating with dilatation. Occlusion is usually incomplete.
(Table 21-2) Hypercoagulable disorders primarily cause The process is often asymptomatic but occasionally is
increased risk of venous thrombosis and therefore may associated with an audible bruit, TIAs, or stroke.
cause venous sinus thrombosis. Protein S deciency and Involvement of the renal arteries is common and may
homocysteinemia may cause arterial thromboses as result in hypertension. The cause and natural history of
well. Systemic lupus erythematosus with Libman-Sacks bromuscular dysplasia are unknown. TIA or stroke
endocarditis can be a cause of embolic stroke. These generally occurs only when the artery is severely nar-
conditions overlap with the antiphospholipid syndrome, rowed or dissects. Anticoagulation or antiplatelet ther-
which probably requires long-term anticoagulation to apy may be helpful.
SECTION III

prevent further stroke. Temporal (giant cell) arteritis is a relatively common

Venous sinus thrombosis of the lateral or sagittal sinus or afiction of elderly persons in which the external
of small cortical veins (cortical vein thrombosis) occurs carotid system, particularly the temporal arteries,
as a complication of oral contraceptive use, pregnancy becomes the site of a subacute granulomatous inam-
and the postpartum period, inammatory bowel disease, mation with giant cells. Occlusion of posterior ciliary
intracranial infections (meningitis), and dehydration. It is arteries derived from the ophthalmic artery results in
Diseases of the Central Nervous System

also seen with increased incidence in patients with labo- blindness in one or both eyes and can be prevented with
ratory-conrmed thrombophilia (Table 21-2) including glucocorticoids. It rarely causes stroke as the internal
polycythemia, sickle cell anemia, deciencies of proteins carotid artery is usually not inamed. Idiopathic giant
C and S, factor V Leiden mutation (resistance to acti- cell arteritis involving the great vessels arising from the
vated protein C), antithrombin III deciency, homocys- aortic arch (Takayasus arteritis) may cause carotid or ver-
teinemia, and the prothrombin G20210 mutation. tebral thrombosis; it is rare in the western hemisphere.
Women who take oral contraceptives and have the pro- Necrotizing (or granulomatous) arteritis, occurring alone
thrombin G20210 mutation may be at particularly high or in association with generalized polyarteritis nodosa or
risk for sinus thrombosis. Patients present with headache Wegeners granulomatosis, involves the distal small
and may also have focal neurologic signs (especially branches (<2 mm diameter) of the main intracranial
paraparesis) and seizures. Often, CT imaging is normal arteries and produces small ischemic infarcts in the brain,
unless an intracranial venous hemorrhage has occurred, optic nerve, and spinal cord. The cerebrospinal uid
but the venous sinus occlusion is readily visualized using (CSF) often shows pleocytosis, and the protein level is
magnetic resonance (MR) venography or conventional elevated. Primary central nervous system vasculitis is rare; small
x-ray angiography. With greater degrees of sinus throm- or medium-sized vessels are usually affected, without
bosis, the patient may develop signs of increased ICP apparent systemic vasculitis. Brain biopsy or high-resolution
and coma. Intravenous heparin, regardless of the pres- conventional x-ray angiography is usually required to make
ence of intracranial hemorrhage, has been shown to the diagnosis (Fig. 21-5).The differential diagnosis includes
reduce morbidity and mortality, and the long-term out- infection (tubercular, fungal), atherosclerosis, emboli,
come is generally good. Heparin prevents further connective tissue disease, sarcoidosis, angiocentric lym-
thrombosis and reduces venous hypertension and phoma, carcinomatous meningitis, vasospasm, and drug-
ischemia. If an underlying hypercoagulable state is not associated causes. Some cases follow the postpartum
found, many physicians treat with warfarin sodium for period and are self-limited. Patients with any form of
36 months then convert to aspirin, depending on the vasculitis may present with insidious progression of com-
degree of resolution of the venous sinus thrombus. Anti- bined white and gray matter infarctions, prominent
coagulation is often continued indenitely if throm- headache, and cognitive decline. Aggressive immunosup-
bophilia is diagnosed. pression with glucocorticoids, and often cyclophos-
Sickle cell anemia (SS disease) is a common cause of phamide, is usually necessary to prevent progression; a
stroke in children. A subset of homozygous carriers of diligent investigation for infectious causes such as tuber-
this hemoglobin mutation develop stroke in childhood culosis is essential prior to immunosuppression. Depend-
and this may be predicted by documenting high- ing upon the duration of the disease, many patients can
velocity blood ow within the MCAs using transcranial make an excellent recovery.
 Reversible posterior leukoencephalopathy can occur in 259
head injury, migraine, sympathomimetic drug use,
eclampsia, and the postpartum period. The etiology is
unclear but likely involves widespread cerebral segmen-
tal vasoconstriction and cerebral edema. Patients com-
plain of headache and manifest uctuating neurologic
symptoms and signs, especially visual symptoms. Some-
times cerebral infarction ensues, but typically the clinical
and imaging ndings suggest that ischemia reverses
completely. Conventional x-ray angiography is the only
means of establishing the diagnosis, but MRI ndings
are characteristic.
Leukoariosis, or periventricular white matter disease, is the
result of multiple small-vessel infarcts within the subcor-
tical white matter. It is readily seen on CT or MRI
scans as areas of white matter injury surrounding the
ventricles and within the corona radiata. Areas of lacunar

CHAPTER 21
infarction are often seen also.The pathophysiologic basis
FIGURE 21-5 of the disease is lipohyalinosis of small penetrating arter-
Cerebral angiogram from a 32-year-old male with central ies within the white matter, likely produced by chronic
nervous system vasculitis. Dramatic beading (arrow) typical hypertension. Patients with periventricular white matter
of vasculitis is seen. disease may develop a subcortical dementia syndrome,
depending on the amount of white matter infarction.

Cerebrovascular Diseases
CADASIL (cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy) is an
Drugs, in particular amphetamines and perhaps inherited disorder that presents as small-vessel strokes,
cocaine, may cause stroke on the basis of acute hyper- progressive dementia, and extensive symmetric white
tension or drug-induced vasculitis. Abstinence appears matter changes visualized by MRI.Approximately 40% of
to be the best treatment, as no data exist on use of any patients have migraine with aura, often manifest as tran-
treatment. Phenylpropanolamine has been linked with sient motor or sensory decits. Onset is usually in the
intracranial hemorrhage, as has cocaine, perhaps related fourth or fth decade of life. This autosomal dominant
to a drug-induced vasculitis. Arteritis can also occur as a condition is caused by one of several mutations in Notch-
consequence of bacterial, tuberculous, and syphilitic 3, a member of a highly conserved gene family character-
meningitis. ized by epidermal growth factor repeats in its extracellular
Moyamoya disease is a poorly understood occlusive dis- domain. Other monogenic ischemic stroke syndromes
ease involving large intracranial arteries, especially the dis- include cerebral autosomal recessive arteriopathy with
tal internal carotid artery and the stem of the MCA and subcortical infarcts and leukoencephalopathy (CARASIL)
ACA.Vascular inammation is absent. The lenticulostriate and hereditary endotheliopathy, retinopathy, nephropathy,
arteries develop a rich collateral circulation around the and stroke (HERNS). Fabrys disease also produces both
occlusive lesion, which gives the impression of a puff of large-vessel arteriopathy and small-vessel infarcts by an
smoke (moyamoya in Japanese) on conventional x-ray unknown mechanism.
angiography. Other collaterals include transdural anasto-
moses between the cortical surface branches of the
TRANSIENT ISCHEMIC ATTACKS
meningeal and scalp arteries.The disease occurs mainly in
Asian children or young adults, but the appearance may be TIAs are episodes of stroke symptoms that last only
identical in adults who have atherosclerosis, particularly briey; the standard denition of duration is <24 h, but
in association with diabetes.The etiology of the childhood most TIAs last <1 h.The causes of TIA are similar to the
form is unknown. Because of the occurrence of intracra- causes of ischemic stroke, but because TIAs may herald
nial hemorrhage from rupture of the transdural and pial stroke they are an important risk factor that should be
anastomotic channels, anticoagulation is risky. Breakdown considered separately.TIAs may arise from emboli to the
of dilated lenticulostriate arteries may produce parenchy- brain or from in situ thrombosis of an intracranial vessel.
mal hemorrhage, and progressive occlusion of large surface With a TIA, the occluded blood vessel reopens and neu-
arteries can occur, producing large-artery distribution rologic function is restored. However, infarcts of the
strokes. Bypass of extracranial carotid arteries to the dura brain do occur in 1550% of TIAs even though neuro-
or MCAs may prevent stroke and hemorrhage. logic signs and symptoms are absent. Newer denitions
 260 of TIA categorize those with new infarct as having thrombotic stroke, diabetes mellitus, hypertension,
ischemic stroke rather than TIA regardless of symptom tobacco smoking, abnormal blood cholesterol [particu-
duration, but the vast majority of studies have used the larly, low high-density lipoprotein (HDL) and/or high
standard, time-based denition. low-density lipoprotein (LDL)], and other factors are
In addition to the stroke syndromes discussed later, either proven or probable risk factors for ischemic
one specic TIA symptom should receive special notice. stroke, largely by their link to atherosclerosis. Risk of
Amaurosis fugax, or transient monocular blindness, occurs stroke is much greater in those with prior stroke or TIA.
from emboli to the central retinal artery of one eye.This Many cardiac conditions predispose to stroke, including
may indicate carotid stenosis as the cause or local oph- atrial brillation and recent MI. Oral contraceptives and
thalmic artery disease. hormone replacement therapy increase stroke risk, and
The risk of stroke after a TIA is ~1015% in the rst certain inherited and acquired hypercoagulable states
3 months, with most events occurring in the rst 2 days. predispose to stroke. Hypertension is the most signi-
Therefore, urgent evaluation and treatment are justied. cant of the risk factors; in general, all hypertension
Since etiologies for stroke and TIA are identical, evalua- should be treated.The presence of known cerebrovascu-
tion for TIA should parallel that of stroke (Figs. 21-1 lar disease is not a contraindication to treatment aimed
and 21-3). The improvement characteristic of TIA is a at achieving normotension. Also, the value of treating
contraindication to thrombolysis. However, since the systolic hypertension in older patients has been clearly
SECTION III

risk of subsequent stroke in the rst few days after a TIA established. Lowering blood pressure to levels below
is high, the opportunity to give rtPA more frequently those traditionally dening hypertension appears to
and rapidly if a stroke occurs probably justies hospital reduce the risk of stroke even further. Data are particu-
admission for most patients. Acute antiplatelet therapy larly strong in support of thiazide diuretics, angiotensin-
has not been tested specically after TIA but is likely to converting enzyme inhibitors, and angiotensin receptor
be effective and is recommended. No large-scale trial blockers.
Diseases of the Central Nervous System

has evaluated acute anticoagulation after TIA, a setting Several trials have conrmed that statin drugs reduce
in which the risk of hemorrhage may be lower than for the risk of stroke even in patients without elevated LDL
other categories of stroke. or low HDL. The recently reported SPARCL (Stroke
Prevention by Aggressive Reduction in Cholesterol
Levels) trial showed benet in secondary stroke reduc-
RISK FACTORS FOR ISCHEMIC tion for patients with recent stroke or TIA who were
STROKE AND TIA prescribed atorvastatin, 80 mg/d. Although studies
specically targeting primary prevention of stroke are
Identication and control of modiable risk factors is
still underway, results for patients with cardiovascular
the best strategy to reduce the burden of stroke, and the
risk factors or dyslipidemia have been compelling, with
total number of strokes could be reduced substantially
a 1630% relative risk reduction for stroke. Therefore, a
by these means (Table 21-4).
statin should be considered in all patients with prior
ischemic stroke.Tobacco smoking should be discouraged
PRIMARY AND SECONDARY PREVENTION in all patients. Whether tight control of blood sugar in
OF STROKE AND TIA patients with diabetes lowers stroke risk is uncertain, but
statins, more aggressive blood pressure control, and piogli-
General Principles
tazone (an agonist of peroxisome proliferator-activated
A number of medical and surgical interventions, as well receptor gamma) are effective.
as lifestyle modications, are available for preventing
stroke. Some of these can be widely applied because of
Antiplatelet Agents
their low cost and minimal risk; others are expensive
and carry substantial risk but may be valuable for Platelet antiaggregation agents can prevent atherothrom-
selected high-risk patients. botic events, including TIA and stroke, by inhibiting the
Evaluation of a patients clinical risk prole can help formation of intraarterial platelet aggregates. These can
determine which preventive treatments to offer. In addi- form on diseased arteries, induce thrombus formation,
tion to known risk factors for ischemic stroke (above), and occlude the artery or embolize into the distal circu-
certain clinical characteristics also contribute to an lation. Aspirin, clopidogrel, and the combination of aspirin
increased risk of stroke (Table 21-4). plus extended-release dipyridamole are the antiplatelet
agents most commonly used for this purpose. Ticlopi-
dine has been largely abandoned because of its adverse
Atherosclerosis Risk Factors
effects.
There are a number of factors that are associated with Aspirin is the most widely studied antiplatelet
the risk of atherosclerosis. Older age, family history of agent. Aspirin acetylates platelet cyclooxygenase, which
irreversibly inhibits the formation in platelets of phosphodiesterases, dipyridamole also potentiates the 261
thromboxane A2, a platelet aggregating and vasocon- antiaggregatory effects of prostacyclin and nitric oxide
stricting prostaglandin. This effect is permanent and produced by the endothelium and acts by inhibiting
lasts for the usual 8-day life of the platelet. Paradoxi- platelet phosphodiesterase, which is responsible for the
cally, aspirin also inhibits the formation in endothelial breakdown of cyclic AMP. The resulting elevation in
cells of prostacyclin, an antiaggregating and vasodilat- cyclic AMP inhibits aggregation of platelets. Dipyri-
ing prostaglandin. This effect is transient. As soon as damole is erratically absorbed depending on stomach
aspirin is cleared from the blood, the nucleated pH, but a newer formulation combines timed-release
endothelial cells again produce prostacyclin. Aspirin in dipyridamole, 200 mg, with aspirin, 25 mg, and has better
low doses given once daily inhibits the production of oral bioavailability. This combination drug was studied
thromboxane A2 in platelets without substantially in two trials. The European Stroke Prevention Study
inhibiting prostacyclin formation. Higher doses of (ESPS) II showed efcacy of both 50 mg/d of aspirin
aspirin have not been proven to be more effective than and extended-release dipyridamole in preventing
lower doses, and 50325 mg/d of aspirin is generally stroke, and a signicantly better risk reduction when
recommended for stroke prevention. the two agents were combined. The ESPRIT (Euro-
Ticlopidine and clopidogrel block the ADP receptor pean/Australasian Stroke Prevention in Reversible
on platelets and thus prevent the cascade resulting in Ischaemia Trial) trial conrmed the ESPS-II results.

CHAPTER 21
activation of the glycoprotein IIb/IIIa receptor that This was an open-label, academic trial in which 2739
leads to brinogen binding to the platelet and conse- patients with stroke or TIA treated with aspirin were
quent platelet aggregation. Ticlopidine is more effective randomized to dipyridamole, 200 mg twice daily, or no
than aspirin; however, it has the disadvantage of causing dipyridamole. Primary outcome was the composite of
diarrhea, skin rash, and, in rare instances, neutropenia death from all vascular causes, non-fatal stroke, non-fatal
and thrombotic thrombocytopenic purpura. Clopidogrel MI, or major bleeding complication. After 3.5 years of

Cerebrovascular Diseases
is not associated with these important side effects. How- follow-up, 13% patients on aspirin and dipyridamole
ever, the CAPRIE (Clopidogrel versus Aspirin in and 16% on aspirin alone (hazard ratio 0.80, 95% CI
Patients at Risk of Ischemic Events) trial, which led to 0.660.98) met the primary outcome. A meta-analysis
FDA approval, found that it was only marginally more of all dypridamole data on secondary stroke prevention
effective than aspirin in reducing risk of stroke. The found an overall risk ratio for the composite of vascular
MATCH (Management of Atherothrombosis with death, stroke, or MI of 0.82 (95% CI 0.740.91). The
Clopidogrel in High-Risk Patients) trial was a large principal side effect of the drug is headache. A combina-
multicenter, randomized double-blind study that com- tion capsule of extended-release dipyridamole and aspirin
pared clopidogrel in combination with aspirin to clopi- is approved for prevention of stroke.
dogrel alone in the secondary prevention of TIA or Many large clinical trials have demonstrated clearly
stroke.The MATCH trial found no difference in TIA or that most antiplatelet agents reduce the risk of all impor-
stroke prevention with this combination, but did show a tant vascular atherothrombotic events (i.e., ischemic
small but signicant increase in major bleeding compli- stroke, MI, and death due to all vascular causes) in patients
cations (3% vs. 1%). In the CHARISMA (Clopidogrel at risk for these events. The overall relative reduction in
for High Atherothrombotic Risk and Ischemic Stabiliza- risk of nonfatal stroke is about 2530% and of all vascular
tion, Management, and Avoidance) trial, which included events is about 25%.The absolute reduction varies consid-
a subgroup of patients with prior stroke or TIA along erably, depending on the particular patients risk. Individ-
with other groups at high risk of cardiovascular events, uals at very low risk for stroke seem to experience the
there was no benet of clopidogrel combined with same relative reduction, but their risk may be so low that
aspirin compared to aspirin alone. Thus, the use of the benet is meaningless. On the other hand, individ-
clopidogrel in combination with aspirin is not generally uals with a 1015% risk of vascular events per year expe-
recommended for stroke prevention. However, these tri- rience a reduction to about 7.511%.
als did not enroll patients immediately after the stroke or Aspirin is inexpensive, can be given in low doses, and
TIA, and the benets of combination therapy were could be recommended for all adults to prevent both
greater among those treated earlier, so it is possible that stroke and MI. However, it causes epigastric discomfort,
clopidogrel combined with aspirin may be benecial in gastric ulceration, and gastrointestinal hemorrhage,
this acute period. Ongoing studies are currently address- which may be asymptomatic or life-threatening. Con-
ing this question. sequently, not every 40- or 50-year-old should be
Dipyridamole is an antiplatelet agent that inhibits the advised to take aspirin regularly because the risk of
uptake of adenosine by a variety of cells, including atherothrombotic stroke is extremely low and is out-
those of the vascular endothelium. The accumulated weighed by the risk of adverse side effects. Conversely,
adenosine is an inhibitor of aggregation. At least in every patient who has experienced an atherothrom-
part through its effects on platelet and vessel wall botic stroke or TIA and has no contraindication should
 262 be taking an antiplatelet agent regularly because the persists. Warfarin is currently being studied in patients
average annual risk of another stroke is 810%; another with congestive heart failure.
few percent will experience a MI or vascular death. Stroke secondary to thromboembolism is one of the
Clearly, the likelihood of benet far outweighs the risks most serious complications of prosthetic heart valve
of treatment. implantation. The intensity of anticoagulation and/or
The choice of antiplatelet agent and dose must bal- antiplatelet therapy is dictated by the type of prosthetic
ance the risk of stroke, the expected benet, and the risk valve and its location. The Seventh American College of
and cost of treatment. However, there are no denitive Chest Physicians Conference on Antithrombotic Therapy
data, and opinions vary. Many authorities believe low- for Valvular Heart Disease published the following guide-
dose (3075 mg/d) and high-dose (6501300 mg/d) lines in 2004: (1) for St. Jude Medical bileaet valves in
aspirin are about equally effective. Some advocate very the aortic position, long-term warfarin with a target INR
low doses to avoid adverse effects, and still others advo- of 2.5 (range 2.03.0), (2) for tilting disk valves and
cate very high doses to be sure the benet is maximal. bileaet mechanical valves in the mitral position, long-
Most physicians in North America recommend 81325 term warfarin with a target INR of 3.0; (range 2.53.5);
mg/d, while most in Europe recommend 50100 mg. (3) for caged ball or caged disk valves, long-term warfarin
Similarly, the choice of aspirin, clopidogrel, or dipyri- with target INR of 3.0 (range 2.53.5) in combination
damole plus aspirin must balance the fact that the latter with aspirin (75100 mg/d); (4) for bioprosthetic valves,
SECTION III

are more effective than aspirin but the cost is higher, and warfarin anticoagulation with target INR 2.5 for 3
this is likely to affect long-term patient adherence. The months, followed by long-term aspirin alone (75100
Prevention Regimen for Effectively Avoiding Second mg/d), assuming there is no history of atrial brillation.
Strokes (PRoFESS) study was a large randomized sec- If the embolic source cannot be eliminated, anticoag-
ondary prevention trial of over 20,000 patients that ulation should in most cases be continued indenitely.
demonstrated equal efcacy of clopidogrel and the Many neurologists recommend combining antiplatelet
Diseases of the Central Nervous System

combination of low-dose aspirin and extended-release agents with anticoagulants for patients who fail anti-
dipyridamole, suggesting that either is a reasonable coagulation (i.e., have another stroke or TIA).
choice for secondary stroke prevention.

Anticoagulation Therapy and

Anticoagulation Therapy and Noncardiogenic Stroke
Embolic Stroke
Data do not support the use of long-term warfarin for
Several trials have shown that anticoagulation (INR
preventing atherothrombotic stroke, for either intracra-
range, 23) in patients with chronic nonvalvular (non-
nial or extracranial cerebrovascular disease. The WARSS
rheumatic) atrial brillation prevents cerebral embolism
(Warfarin-Aspirin Reinfarction Stroke Study) study
and is safe. For primary prevention and for patients who
found no benet of warfarin sodium (INR, 1.42.8)
have experienced stroke or TIA, anticoagulation with
over aspirin, 325 mg, for secondary prevention of stroke
warfarin reduces the risk by about 67%, which clearly
but did nd a slightly higher bleeding rate in the war-
outweighs the 1% risk per year of a major bleeding
farin group. A recent European study conrmed this
complication. In those patients who cannot tolerate
nding.The WASID study (see earlier) demonstrated no
warfarin, the combination of aspirin and clopidogrel
benet of warfarin (INR, 23) over aspirin in patients
appears superior to aspirin alone.
with symptomatic intracranial atherosclerosis, and also
The decision to use anticoagulation for primary pre-
found higher bleeding complications.
vention is based primarily on risk factors (Table 21-3).
The presence of any risk factor tips the balance in favor
of anticoagulation. Other Causes of Stroke
Because of the high annual stroke risk in untreated
rheumatic heart disease, primary prophylaxis against Carotid Disease
stroke has not been studied in a double-blind fashion. Surgical or endovascular repair of carotid atherosclerosis
These patients generally should receive long-term anti- is preferred over medical therapy for symptomatic
coagulation. carotid artery disease (see earlier section). Anticoagula-
Anticoagulation also reduces the risk of embolism in tion has not been directly compared with antiplatelet
acute MI. Most clinicians recommend a 3-month course therapy for carotid disease.
of anticoagulation when there is anterior Q-wave infarc-
tion, substantial left ventricular dysfunction, congestive Dural Sinus Thrombosis
heart failure, mural thrombosis, or atrial brillation. Limited evidence exists to support short-term usage of
Warfarin is recommended long-term if atrial brillation anticoagulants, regardless of the presence of intracranial
hemorrhage for venous infarction following sinus 263
thrombosis.

STROKE SYNDROMES
Internal
A careful history and neurologic examination can often capsule
localize the region of brain dysfunction; if this region
corresponds to a particular arterial distribution, the pos-
sible causes responsible for the syndrome can be nar- Claustrum
Caudate
rowed.This is of particular importance when the patient
presents with a TIA and a normal examination. For
example, if a patient develops language loss and a right Anterior Putamen
homonymous hemianopia, a search for causes of left cerebral a.
middle cerebral emboli should be performed. A nding
of an isolated stenosis of the right internal carotid artery
Uncus
in that patient, for example, suggests an asymptomatic Internal carotid a.
carotid stenosis, and the search for other causes of stroke Middle cerebral a.

CHAPTER 21
should continue. The following sections describe the
KEY
clinical ndings of cerebral ischemia associated with
cerebral vascular territories depicted in Figs. 21-4, and Ant. cerebral a.
21-6 through 21-14. Stroke syndromes are divided into: Middle cerebral a.
(1) large-vessel stroke within the anterior circulation, (2)
Deep branches of middle cerebral a.
large-vessel stroke within the posterior circulation, and

Cerebrovascular Diseases
(3) small-vessel disease of either vascular bed. Post cerebral a.
Deep branches of ant. cerebral a.
Stroke within the Anterior Circulation
FIGURE 21-6
The internal carotid artery and its branches comprise the Diagram of a cerebral hemisphere in coronal section
anterior circulation of the brain. These vessels can be showing the territories of the major cerebral vessels that
occluded by intrinsic disease of the vessel (e.g., atheroscle- branch from the internal carotid arteries.
rosis or dissection) or by embolic occlusion from a proxi-
mal source as discussed earlier. Occlusion of each major
intracranial vessel has distinct clinical manifestations.
and inferior divisions (M2 branches). Branches of the
Middle Cerebral Artery inferior division supply the inferior parietal and tempo-
Occlusion of the proximal MCA or one of its major ral cortex, and those from the superior division supply
branches is most often due to an embolus (artery-to- the frontal and superior parietal cortex (Fig. 21-7).
artery, cardiac, or of unknown source) rather than If the entire MCA is occluded at its origin (blocking
intracranial atherothrombosis.Atherosclerosis of the proxi- both its penetrating and cortical branches) and the distal
mal MCA may cause distal emboli to the middle cerebral collaterals are limited, the clinical ndings are contralat-
territory or, less commonly, may produce low-ow TIAs. eral hemiplegia, hemianesthesia, homonymous hemianopia,
Collateral formation via leptomeningeal vessels often pre- and a day or two of gaze preference to the ipsilateral side.
vents MCA stenosis from becoming symptomatic. Dysarthria is common because of facial weakness. When
The cortical branches of the MCA supply the lateral the dominant hemisphere is involved, global aphasia is
surface of the hemisphere except for (1) the frontal pole present also, and when the nondominant hemisphere is
and a strip along the superomedial border of the frontal affected, anosognosia, constructional apraxia, and neglect
and parietal lobes supplied by the ACA, and (2) the are found (Chap. 15).
lower temporal and occipital pole convolutions supplied Complete MCA syndromes occur most often when
by the PCA (Figs. 21-6, 21-7, 21-8, and 21-9). an embolus occludes the stem of the artery. Cortical
The proximal MCA (M1 segment) gives rise to pen- collateral blood ow and differing arterial congurations
etrating branches (termed lenticulostriate arteries) that sup- are probably responsible for the development of many
ply the putamen, outer globus pallidus, posterior limb of partial syndromes. Partial syndromes may also be due to
the internal capsule, the adjacent corona radiata, and emboli that enter the proximal MCA without complete
most of the caudate nucleus (Fig. 21-6). In the sylvian occlusion, occlude distal MCA branches, or fragment
ssure, the MCA in most patients divides into superior and move distally.
 264 Ant. parietal a.

Rolandic a.

Post. parietal a.

Prerolandic a.
Angular a.
Lateral
orbitofrontal a.

Sup. division
middle cerebral a.
Post. temporal a.

Temporopolar a.

Visual radiation
Inf. division
middle cerebral a.
SECTION III

Ant. temporal a.

KEY

Broca's area Sensory cortex Auditory area Motor cortex

Contraversive Wernicke's Visual cortex

eye center aphasia area
Diseases of the Central Nervous System

FIGURE 21-7
Diagram of a cerebral hemisphere, lateral aspect, showing Conduction aphasia: Central speech area (parietal
the branches and distribution of the middle cerebral artery and operculum)
the principal regions of cerebral localization. Note the bifurcation Apractognosia of the nondominant hemisphere, anosog-
of the middle cerebral artery into a superior and inferior division. nosia, hemiasomatognosia, unilateral neglect, agnosia for
Signs and symptoms: Structures involved the left half of external space, dressing apraxia, construc-
Paralysis of the contralateral face, arm, and leg; sensory tional apraxia, distortion of visual coordinates, inaccurate
impairment over the same area (pinprick, cotton touch, localization in the half eld, impaired ability to judge dis-
vibration, position, two-point discrimination, stereognosis, tance, upside-down reading, visual illusions (e.g., it may
tactile localization, barognosis, cutaneographia): Somatic appear that another person walks through a table): Non-
motor area for face and arm and the bers descending from dominant parietal lobe (area corresponding to speech area
the leg area to enter the corona radiata and corresponding in dominant hemisphere); loss of topographic memory is
somatic sensory system usually due to a nondominant lesion, occasionally to a domi-
Motor aphasia: Motor speech area of the dominant hemi- nant one
sphere Homonymous hemianopia (often homonymous inferior
Central aphasia, word deafness, anomia, jargon speech, quadrantanopia): Optic radiation deep to second temporal
sensory agraphia, acalculia, alexia, nger agnosia, right-left convolution
confusion (the last four comprise the Gerstmann syndrome): Paralysis of conjugate gaze to the opposite side: Frontal
Central, suprasylvian speech area and parietooccipital cortex contraversive eye eld or projecting bers
of the dominant hemisphere

Partial syndromes due to embolic occlusion of a single the dominant hemisphere is probably involved. Jargon
branch include hand, or arm and hand, weakness alone speech and an inability to comprehend written and spo-
(brachial syndrome) or facial weakness with nonuent ken language are prominent features, often accompanied
(Broca) aphasia (Chap. 15), with or without arm weakness by a contralateral, homonymous superior quadrantanopia.
(frontal opercular syndrome). A combination of sensory Hemineglect or spatial agnosia without weakness indi-
disturbance, motor weakness, and nonuent aphasia sug- cates that the inferior division of the MCA in the non-
gests that an embolus has occluded the proximal superior dominant hemisphere is involved.
division and infarcted large portions of the frontal and Occlusion of a lenticulostriate vessel produces small-ves-
parietal cortices (Fig. 21-7). If a uent (Wernickes) apha- sel (lacunar) stroke within the internal capsule (Fig. 21-6).
sia occurs without weakness, the inferior division of the This produces pure motor stroke or sensory-motor stroke
MCA supplying the posterior part (temporal cortex) of contralateral to the lesion. Ischemia within the genu of
the internal capsule causes primarily facial weakness fol- hypothalamus, and the inferior part of the head of the 265
lowed by arm then leg weakness as the ischemia moves caudate nucleus (Fig. 21-6).
posterior within the capsule. Alternatively, the contralat- Occlusion of the proximal ACA is usually well toler-
eral hand may become ataxic and dysarthria will be ated because of collateral ow through the anterior
prominent (clumsy hand, dysarthria lacunar syndrome). communicating artery and collaterals through the MCA
Lacunar infarction affecting the globus pallidus and and PCA. Occlusion of a single A2 segment results in
putamen often has few clinical signs, but parkinsonism the contralateral symptoms noted in Fig. 21-8. If both
and hemiballismus have been reported. A2 segments arise from a single anterior cerebral stem
(contralateral A1 segment atresia), the occlusion may
affect both hemispheres. Profound abulia (a delay in ver-
Anterior Cerebral Artery
bal and motor response) and bilateral pyramidal signs
The ACA is divided into two segments: the precommunal
with paraparesis and urinary incontinence result.
(A1) circle of Willis, or stem, which connects the internal
carotid artery to the anterior communicating artery, and
the postcommunal (A2) segment distal to the anterior Anterior Choroidal Artery
communicating artery (Figs. 21-4, 21-6, and 21-8). The This artery arises from the internal carotid artery and
A1 segment gives rise to several deep penetrating branches supplies the posterior limb of the internal capsule and

CHAPTER 21
that supply the anterior limb of the internal capsule, the white matter posterolateral to it, through which pass
the anterior perforate substance, amygdala, anterior some of the geniculocalcarine bers (Fig. 21-9). The

Medial

Cerebrovascular Diseases
Motor rolandic a.
cortex
Post.
Secondary Pericallosal a. Sensory parietal a.
motor area cortex
Medial Splenial a.
prerolandic a.
Lateral posterior
Callosomarginal a. choroidal a.
Post. thalamic a.

Frontopolar a. Parietooccipital a.

Visual
cortex
Ant. cerebral a.
Striate area
along calcarine
sulcus
Medial orbitofrontal a. Calcarine a.
Post. communicating a. Post. temporal a.

Medial posterior choroidal a.

Penetrating
thalamosubthalamic Post. Hippocampal As.
Ant.
paramedian As. cerebral temporal a.
stem
FIGURE 21-8
Diagram of a cerebral hemisphere, medial aspect, Contralateral grasp reex, sucking reex, gegenhalten
showing the branches and distribution of the anterior (paratonic rigidity): Medial surface of the posterior frontal
cerebral artery and the principal regions of cerebral lobe; likely supplemental motor area
localization. Abulia (akinetic mutism), slowness, delay, intermittent
Signs and symptoms: Structures involved interruption, lack of spontaneity, whispering, reex distrac-
Paralysis of opposite foot and leg: Motor leg area tion to sights and sounds: Uncertain localizationprobably
A lesser degree of paresis of opposite arm: Arm area of cingulate gyrus and medial inferior portion of frontal, pari-
cortex or bers descending to corona radiata etal, and temporal lobes
Cortical sensory loss over toes, foot, and leg: Sensory Impairment of gait and stance (gait apraxia): Frontal
area for foot and leg cortex near leg motor area
Urinary incontinence: Sensorimotor area in paracentral Dyspraxia of left limbs, tactile aphasia in left limbs:
lobule Corpus callosum
 266 Ant. cerebral a.
Internal
carotid a. Post.
communicating a.

Post. cerebral a.

Ant.
choroidal a. Medial posterior
choroidal a.

Mesencephalic
paramedian As.
Ant. temporal a.
Splenial a.

Parietooccipital a. Hippocampal a.

Calcarine a.
Post. temporal a.
SECTION III

Post. thalamic a.
Visual
cortex Lateral posterior
choroidal a.
FIGURE 21-9
Inferior aspect of the brain with the branches and distribu- visual spread, palinopsia, distortion of outlines, central pho-
Diseases of the Central Nervous System

tion of the posterior cerebral artery and the principal tophobia: Calcarine cortex. Complex hallucinations: Usually
anatomic structures shown. nondominant hemisphere.
Signs and symptoms: Structures involved Central territory. Thalamic syndrome: sensory loss (all
Peripheral territory (see also Fig. 21-12). Homonymous modalities), spontaneous pain and dysesthesias, choreoa-
hemianopia (often upper quadrantic): Calcarine cortex or thetosis, intention tremor, spasms of hand, mild hemipare-
optic radiation nearby. Bilateral homonymous hemianopia, sis: Posteroventral nucleus of thalamus; involvement of the
cortical blindness, awareness or denial of blindness; tactile adjacent subthalamus body or its afferent tracts. Thalamop-
naming, achromatopia (color blindness), failure to see erforate syndrome: crossed cerebellar ataxia with ipsilateral
to-and-fro movements, inability to perceive objects not third nerve palsy (Claudes syndrome): Dentatothalamic
centrally located, apraxia of ocular movements, inability to tract and issuing third nerve. Webers syndrome: Third nerve
count or enumerate objects, tendency to run into things palsy and contralateral hemiplegia: Third nerve and cere-
that the patient sees and tries to avoid: Bilateral occipital bral peduncle. Contralateral hemiplegia: Cerebral peduncle.
lobe with possibly the parietal lobe involved. Verbal dyslexia Paralysis or paresis of vertical eye movement, skew devia-
without agraphia, color anomia: Dominant calcarine lesion tion, sluggish pupillary responses to light, slight miosis and
and posterior part of corpus callosum. Memory defect: ptosis (retraction nystagmus and tucking of the eyelids
Hippocampal lesion bilaterally or on the dominant side only. may be associated): Supranuclear bers to third nerve,
Topographic disorientation and prosopagnosia: Usually with interstitial nucleus of Cajal, nucleus of Darkschewitsch, and
lesions of nondominant, calcarine, and lingual gyrus. Simul- posterior commissure. Contralateral rhythmic, ataxic action
tanagnosia, hemivisual neglect: Dominant visual cortex, tremor; rhythmic postural or holding tremor (rubral
contralateral hemisphere. Unformed visual hallucinations, tremor): Dentatothalamic tract.
peduncular hallucinosis, metamorphopsia, teleopsia, illusory

complete syndrome of anterior choroidal artery occlu- Internal Carotid Artery

sion consists of contralateral hemiplegia, hemianesthesia The clinical picture of internal carotid occlusion varies
(hypesthesia), and homonymous hemianopia. However, depending on whether the cause of ischemia is propagated
because this territory is also supplied by penetrating ves- thrombus, embolism, or low ow. The cortex supplied
sels of the proximal MCA and the posterior communi- by the MCA territory is affected most often. With a
cating and posterior choroidal arteries, minimal decits competent circle of Willis, occlusion may go unnoticed.
may occur, and patients frequently recover substantially. If the thrombus propagates up the internal carotid artery
Anterior choroidal strokes are usually the result of in situ into the MCA or embolizes it, symptoms are identical
thrombosis of the vessel, and the vessel is particularly vul- to proximal MCA occlusion (see earlier). Sometimes
nerable to iatrogenic occlusion during surgical clipping there is massive infarction of the entire deep white mat-
of aneurysms arising from the internal carotid artery. ter and cortical surface. When the origins of both the
ACA and MCA are occluded at the top of the carotid PCA syndromes usually result from atheroma forma- 267
artery, abulia or stupor occurs with hemiplegia, hemi- tion or emboli that lodge at the top of the basilar
anesthesia, and aphasia or anosognosia. When the PCA artery; posterior circulation disease may also be caused
arises from the internal carotid artery (a conguration by dissection of either vertebral artery and bromuscu-
called a fetal posterior cerebral artery), it may also become lar dysplasia.
occluded and give rise to symptoms referable to its Two clinical syndromes are commonly observed with
peripheral territory (Figs. 21-8 and 21-9). occlusion of the PCA: (1) P1 syndrome: midbrain, sub-
In addition to supplying the ipsilateral brain, the inter- thalamic, and thalamic signs, which are due to disease of
nal carotid artery perfuses the optic nerve and retina via the proximal P1 segment of the PCA or its penetrating
the ophthalmic artery. In ~25% of symptomatic internal branches (thalamogeniculate, Percheron, and posterior
carotid disease, recurrent transient monocular blindness choroidal arteries); and (2) P2 syndrome: cortical tempo-
(amaurosis fugax) warns of the lesion. Patients typically ral and occipital lobe signs, due to occlusion of the P2
describe a horizontal shade that sweeps down or up across segment distal to the junction of the PCA with the pos-
the eld of vision. They may also complain that their terior communicating artery.
vision was blurred in that eye or that the upper or lower
half of vision disappeared. In most cases, these symptoms P1 Syndromes
last only a few minutes. Rarely, ischemia or infarction of

CHAPTER 21
Infarction usually occurs in the ipsilateral subthalamus
the ophthalmic artery or central retinal arteries occurs at and medial thalamus and in the ipsilateral cerebral
the time of cerebral TIA or infarction. peduncle and midbrain (Figs. 21-9 and 21-14). A third
A high-pitched prolonged carotid bruit fading into nerve palsy with contralateral ataxia (Claudes syn-
diastole is often associated with tightly stenotic lesions. drome) or with contralateral hemiplegia (Webers syn-
As the stenosis grows tighter and ow distal to the drome) may result. The ataxia indicates involvement of
stenosis becomes reduced, the bruit becomes fainter and the red nucleus or dentatorubrothalamic tract; the hemi-

Cerebrovascular Diseases
may disappear when occlusion is imminent. plegia is localized to the cerebral peduncle (Fig. 21-14).
If the subthalamic nucleus is involved, contralateral
Common Carotid Artery hemiballismus may occur. Occlusion of the artery of
All symptoms and signs of internal carotid occlusion Percheron produces paresis of upward gaze and drowsi-
may also be present with occlusion of the common ness, and often abulia. Extensive infarction in the mid-
carotid artery. Bilateral common carotid artery occlu- brain and subthalamus occurring with bilateral proximal
sions at their origin may occur in Takayasus arteritis. PCA occlusion presents as coma, unreactive pupils, bilat-
eral pyramidal signs, and decerebrate rigidity.
Occlusion of the penetrating branches of thalamic
Stroke within the Posterior Circulation and thalamogeniculate arteries produces less extensive
thalamic and thalamocapsular lacunar syndromes. The
The posterior circulation is composed of the paired ver- thalamic Djerine-Roussy syndrome consists of contralateral
tebral arteries, the basilar artery, and the paired posterior hemisensory loss followed later by an agonizing, searing
cerebral arteries. The vertebral arteries join to form the or burning pain in the affected areas. It is persistent and
basilar artery at the pontomedullary junction.The basilar responds poorly to analgesics. Anticonvulsants (carba-
artery divides into two posterior cerebral arteries in the mazepine or gabapentin) or tricyclic antidepressants may
interpeduncular fossa (Figs. 21-4, 21-8, and 21-9).These be benecial.
major arteries give rise to long and short circumferential
branches and to smaller deep penetrating branches that
supply the cerebellum, medulla, pons, midbrain, subthal- P2 Syndromes
amus, thalamus, hippocampus, and medial temporal and (See also Figs. 21-8 and 21-9) Occlusion of the distal
occipital lobes. Occlusion of each vessel produces its PCA causes infarction of the medial temporal and
own distinctive syndrome. occipital lobes. Contralateral homonymous hemianopia
with macula sparing is the usual manifestation. Occa-
sionally, only the upper quadrant of visual eld is
Posterior Cerebral Artery involved. If the visual association areas are spared and
In 75% of cases, both PCAs arise from the bifurcation of only the calcarine cortex is involved, the patient may be
the basilar artery; in 20%, one has its origin from the aware of visual defects. Medial temporal lobe and hip-
ipsilateral internal carotid artery via the posterior com- pocampal involvement may cause an acute disturbance
municating artery; in 5%, both originate from the in memory, particularly if it occurs in the dominant
respective ipsilateral internal carotid arteries (Figs. 21-8 hemisphere. The defect usually clears because memory
and 21-9).The precommunal, or P1, segment of the true has bilateral representation. If the dominant hemisphere
posterior cerebral artery is atretic in such cases. is affected and the infarct extends to involve the splenium
 268 of the corpus callosum, the patient may demonstrate threatens the origin of the other, the collateral circulation,
alexia without agraphia.Visual agnosia for faces, objects, which may also include retrograde ow down the basilar
mathematical symbols, and colors and anomia with artery, is often insufcient (Figs. 21-4 and 21-9). In this
paraphasic errors (amnestic aphasia) may also occur in setting, low-ow TIAs may occur, consisting of syncope,
this setting, even without callosal involvement. Occlu- vertigo, and alternating hemiplegia; this state also sets
sion of the posterior cerebral artery can produce pedun- the stage for thrombosis. Disease of the distal fourth seg-
cular hallucinosis (visual hallucinations of brightly colored ment of the vertebral artery can promote thrombus for-
scenes and objects). mation manifest as embolism or with propagation as
Bilateral infarction in the distal PCAs produces corti- basilar artery thrombosis. Stenosis proximal to the origin
cal blindness (blindness with preserved pupillary light of the PICA can threaten the lateral medulla and poste-
reaction). The patient is often unaware of the blindness rior inferior surface of the cerebellum.
or may even deny it (Antons syndrome). Tiny islands of If the subclavian artery is occluded proximal to the
vision may persist, and the patient may report that vision origin of the vertebral artery, there is a reversal in the
uctuates as images are captured in the preserved por- direction of blood ow in the ipsilateral vertebral artery.
tions. Rarely, only peripheral vision is lost and central Exercise of the ipsilateral arm may increase demand on
vision is spared, resulting in gun-barrel vision. Bilateral vertebral ow, producing posterior circulation TIAs, or
visual association area lesions may result in Balints syn- subclavian steal.
SECTION III

drome, a disorder of the orderly visual scanning of the Although atheromatous disease rarely narrows the
environment (Chap. 15), usually resulting from infarc- second and third segments of the vertebral artery, this
tions secondary to low ow in the watershed between region is subject to dissection, bromuscular dysplasia,
the distal PCA and MCA territories, as occurs after car- and, rarely, encroachment by osteophytic spurs within
diac arrest. Patients may experience persistence of a the vertebral foramina.
visual image for several minutes despite gazing at Embolic occlusion or thrombosis of a V4 segment
Diseases of the Central Nervous System

another scene (palinopia) or an inability to synthesize the causes ischemia of the lateral medulla. The constellation
whole of an image (asimultanagnosia). Embolic occlusion of vertigo, numbness of the ipsilateral face and contralat-
of the top of the basilar artery can produce any or all of eral limbs, diplopia, hoarseness, dysarthria, dysphagia,
the central or peripheral territory symptoms. The hall- and ipsilateral Horners syndrome is called the lateral
mark is the sudden onset of bilateral signs, including medullary (or Wallenbergs) syndrome (Fig. 21-10). Most
ptosis, pupillary asymmetry or lack of reaction to light, cases result from ipsilateral vertebral artery occlusion; in
and somnolence. the remainder, PICA occlusion is responsible. Occlusion
of the medullary penetrating branches of the vertebral
Vertebral and Posterior Inferior artery or PICA results in partial syndromes. Hemiparesis
Cerebellar Arteries is not a feature of vertebral artery occlusion, however, quadri-
The vertebral artery, which arises from the innominate paresis may result from occlusion of the anterior spinal artery.
artery on the right and the subclavian artery on the left, Rarely, a medial medullary syndrome occurs with infarc-
consists of four segments.The rst (V1) extends from its tion of the pyramid and contralateral hemiparesis of the
origin to its entrance into the sixth or fth transverse arm and leg, sparing the face. If the medial lemniscus
vertebral foramen. The second segment (V2) traverses and emerging hypoglossal nerve bers are involved,
the vertebral foramina from C6 to C2. The third (V3) contralateral loss of joint position sense and ipsilateral
passes through the transverse foramen and circles around tongue weakness occur.
the arch of the atlas to pierce the dura at the foramen Cerebellar infarction with edema can lead to sudden
magnum. The fourth (V4) segment courses upward to respiratory arrest due to raised ICP in the posterior fossa.
join the other vertebral artery to form the basilar artery; Drowsiness, Babinski signs, dysarthria, and bifacial weak-
only the fourth segment gives rise to branches that sup- ness may be absent, or present only briey, before respi-
ply the brainstem and cerebellum.The posterior inferior ratory arrest ensues. Gait unsteadiness, headache, dizziness,
cerebellar artery (PICA) in its proximal segment supplies nausea, and vomiting may be the only early symptoms
the lateral medulla and, in its distal branches, the inferior and signs and should arouse suspicion of this impending
surface of the cerebellum. complication, which may require neurosurgical decom-
Atherothrombotic lesions have a predilection for V1 pression, often with an excellent outcome. Separating
and V4 segments of the vertebral artery. The rst seg- these symptoms from those of viral labrynthitis can be a
ment may become diseased at the origin of the vessel challenge, but headache, neck stiffness, and unilateral
and may produce posterior circulation emboli; collateral dysmetria favor stroke.
ow from the contralateral vertebral artery or the ascend-
ing cervical, thyrocervical, or occipital arteries is usually Basilar Artery
sufcient to prevent low-ow TIAs or stroke. When one Branches of the basilar artery supply the base of the
vertebral artery is atretic and an atherothrombotic lesion pons and superior cerebellum and fall into three groups:
 Medial lemniscus
Pyramid 269
12th n.

Spinothalamic tract
Inferior olive
Ventral
spinocerebellar tract
10th n. Medulla
Dorsal
spinocerebellar tract Descending
sympathetic
Nucleus ambiguus tract
motor 9 +10
Restiform
Descending nucleus body
and tract - 5th n.
Olivocerebellar
Tractus solitarus fibers
with nucleus Cerebellum
Vestibular
nucleus 12th n.
Medial longitudinal fasciculus
nucleus
Medullary syndrome:

CHAPTER 21
Lateral Medial

FIGURE 21-10
Axial section at the level of the medulla, depicted Horners syndrome (miosis, ptosis, decreased
schematically on the left, with a corresponding MR image on sweating): Descending sympathetic tract
the right. Note that in Figs. 21-10 through 21-14, all drawings Dysphagia, hoarseness, paralysis of palate, paraly-
are oriented with the dorsal surface at the bottom, matching sis of vocal cord, diminished gag reex: Issuing

Cerebrovascular Diseases
the orientation of the brainstem that is commonly seen in all bers ninth and tenth nerves
modern neuroimaging studies. Approximate regions involved Loss of taste: Nucleus and tractus solitarius
in medial and lateral medullary stroke syndromes are shown. Numbness of ipsilateral arm, trunk, or leg: Cuneate
Signs and symptoms: Structures involved and gracile nuclei
1. Medial medullary syndrome (occlusion of vertebral Weakness of lower face: Genuected upper motor
artery or of branch of vertebral or lower basilar artery) neuron bers to ipsilateral facial nucleus
On side of lesion On side opposite lesion
Paralysis with atrophy of half the tongue: Ipsilateral Impaired pain and thermal sense over half the body,
twelfth nerve sometimes face: Spinothalamic tract
On side opposite lesion 3. Total unilateral medullary syndrome (occlusion of ver-
Paralysis of arm and leg, sparing face; impaired tac- tebral artery): Combination of medial and lateral syn-
tile and proprioceptive sense over half the body: dromes
Contralateral pyramidal tract and medial lemnis- 4. Lateral pontomedullary syndrome (occlusion of verte-
cus bral artery): Combination of lateral medullary and lat-
2. Lateral medullary syndrome (occlusion of any of ve eral inferior pontine syndrome
vessels may be responsiblevertebral, posterior inferior 5. Basilar artery syndrome (the syndrome of the lone ver-
cerebellar, superior, middle, or inferior lateral medullary tebral artery is equivalent): A combination of the vari-
arteries) ous brainstem syndromes plus those arising in the
On side of lesion posterior cerebral artery distribution.
Pain, numbness, impaired sensation over half the Bilateral long tract signs (sensory and motor; cerebel-
face: Descending tract and nucleus fth nerve lar and peripheral cranial nerve abnormalities): Bilat-
Ataxia of limbs, falling to side of lesion: Uncertain eral long tract; cerebellar and peripheral cranial
restiform body, cerebellar hemisphere, cerebellar nerves
bers, spinocerebellar tract (?) Paralysis or weakness of all extremities, plus all bulbar
Nystagmus, diplopia, oscillopsia, vertigo, nausea, musculature: Corticobulbar and corticospinal tracts
vomiting: Vestibular nucleus bilaterally

(1) paramedian, 710 in number, which supply a wedge rior cerebellar and anterior inferior cerebellar arteries),
of pons on either side of the midline; (2) short circum- which course around the pons to supply the cerebellar
ferential, 57 in number, which supply the lateral two- hemispheres.
thirds of the pons and middle and superior cerebellar Atheromatous lesions can occur anywhere along the
peduncles; and (3) bilateral long circumferential (supe- basilar trunk but are most frequent in the proximal
 270 basilar and distal vertebral segments. Typically, lesions emerge with ischemia, reecting involvement of the
occlude either the proximal basilar and one or both ver- corticospinal and corticobulbar tracts, ascending sensory
tebral arteries. The clinical picture varies depending on tracts, and cranial nerve nuclei (Figs. 21-11, 21-12,
the availability of retrograde collateral ow from the 21-13, and 21-14).
posterior communicating arteries. Rarely, dissection of a The symptoms of transient ischemia or infarction in
vertebral artery may involve the basilar artery and, the territory of the basilar artery often do not indicate
depending on the location of true and false lumen, may whether the basilar artery itself or one of its branches is
produce multiple penetrating artery strokes. diseased, yet this distinction has important implications
Although atherothrombosis occasionally occludes the for therapy. The picture of complete basilar occlusion, however,
distal portion of the basilar artery, emboli from the heart is easy to recognize as a constellation of bilateral long tract signs
or proximal vertebral or basilar segments are more com- (sensory and motor) with signs of cranial nerve and cerebellar
monly responsible for top of the basilar syndromes. dysfunction. A locked-in state of preserved conscious-
Because the brainstem contains many structures in ness with quadriplegia and cranial nerve signs suggests
close apposition, a diversity of clinical syndromes may complete pontine and lower midbrain infarction. The
SECTION III

Corticospinal and
Spinothalamic corticobulbar tract
tract Medial lemniscus

6th n. Middle cerebellar

Descending tract peduncle 7th and 8th
and nucleus of cranial
5th n. Inferior pons nerves
Diseases of the Central Nervous System

7th n.
8th n.

Dorsal
cochlear
nucleus

7th n. nucleus
Restiform body Medial longitudinal Cerebellum
fasciculus
Vestibular nucleus
6th n. nucleus
complex
Inferior pontine syndrome:

Lateral Medial

FIGURE 21-11
Axial section at the level of the inferior pons, depicted Impaired tactile and proprioceptive sense over half
schematically on the left, with a corresponding MR image on of the body: Medial lemniscus
the right. Approximate regions involved in medial and lateral 2. Lateral inferior pontine syndrome (occlusion of anterior
inferior pontine stroke syndromes are shown. inferior cerebellar artery)
Signs and symptoms: Structures involved On side of lesion
1. Medial inferior pontine syndrome (occlusion of para- Horizontal and vertical nystagmus, vertigo, nausea,
median branch of basilar artery) vomiting, oscillopia: Vestibular nerve or nucleus
On side of lesion Facial paralysis: Seventh nerve
Paralysis of conjugate gaze to side of lesion (preser- Paralysis of conjugate gaze to side of lesion: Center
vation of convergence): Center for conjugate lat- for conjugate lateral gaze
eral gaze Deafness, tinnitus: Auditory nerve or cochlear nucleus
Nystagmus: Vestibular nucleus Ataxia: Middle cerebellar peduncle and cerebellar
Ataxia of limbs and gait: Likely middle cerebellar hemisphere
peduncle Impaired sensation over face: Descending tract and
Diplopia on lateral gaze: Abducens nerve nucleus fth nerve
On side opposite lesion On side opposite lesion
Paralysis of face, arm, and leg: Corticobulbar and Impaired pain and thermal sense over half the body
corticospinal tract in lower pons (may include face): Spinothalamic tract
 Corticospinal and
corticopontine tracts
271

Medial
lemniscus
Temporal lobe
5th n.
Mid-pons
Lateral
lemniscus 5th cranial
nerve

Middle
cerebellar
peduncle

Spinothalamic
tract

5th n. motor nucleus

Cerebellum
5th n. sensory nucleus

Superior cerebellar

CHAPTER 21
peduncle Medial longitudinal
fasciculus

Midpontine syndrome:

Lateral Medial

FIGURE 21-12
Axial section at the level of the mid pons, depicted schemati- Variable impaired touch and proprioception when

Cerebrovascular Diseases
cally on the left, with a corresponding MR image on the right. lesion extends posteriorly: Medial lemniscus
Approximate regions involved in medial and lateral midpon- 2. Lateral midpontine syndrome (short circumferential
tine stroke syndromes are shown. artery)
Signs and symptoms: Structures involved On side of lesion
1. Medial midpontine syndrome (paramedian branch of Ataxia of limbs: Middle cerebellar peduncle
midbasilar artery) Paralysis of muscles of mastication: Motor bers or
On side of lesion nucleus of fth nerve
Ataxia of limbs and gait (more prominent in bilateral Impaired sensation over side of face: Sensory bers
involvement): Pontine nuclei or nucleus of fth nerve
On side opposite lesion On side opposite lesion
Paralysis of face, arm, and leg: Corticobulbar and Impaired pain and thermal sense on limbs and
corticospinal tract trunk: Spinothalamic tract

therapeutic goal is to identify impending basilar occlusion suggests intermittent reduction of ow. Many neurolo-
before devastating infarction occurs. A series of TIAs and gists treat with heparin to prevent clot propagation.
a slowly progressive, uctuating stroke are extremely sig- Atherothrombotic occlusion of the basilar artery with
nicant, as they often herald an atherothrombotic occlu- infarction usually causes bilateral brainstem signs. A gaze
sion of the distal vertebral or proximal basilar artery. paresis or internuclear ophthalmoplegia associated with
TIAs in the proximal basilar distribution may produce ipsilateral hemiparesis may be the only manifestation of
vertigo (often described by patients as swimming,sway- bilateral brainstem ischemia. More often, unequivocal
ing, moving, unsteadiness, or light-headedness). signs of bilateral pontine disease are present. Complete
Other symptoms that warn of basilar thrombosis include basilar thrombosis carries a high mortality.
diplopia, dysarthria, facial or circumoral numbness, and Occlusion of a branch of the basilar artery usually
hemisensory symptoms. In general, symptoms of basilar causes unilateral symptoms and signs involving motor,
branch TIAs affect one side of the brainstem, whereas sensory, and cranial nerves. As long as symptoms remain
symptoms of basilar artery TIAs usually affect both sides, unilateral, concern over pending basilar occlusion should
though a herald hemiparesis has been emphasized as be reduced.
an initial symptom of basilar occlusion. Most often TIAs, Occlusion of the superior cerebellar artery results in
whether due to impending occlusion of the basilar severe ipsilateral cerebellar ataxia, nausea and vomiting,
artery or a basilar branch, are short-lived (530 min) and dysarthria, and contralateral loss of pain and temperature
repetitive, occurring several times a day. The pattern sensation over the extremities, body, and face (spino- and
 272 Pontine nuclei and
Corticospinal tract
pontocerebellar fibers
Temporal lobe
Medial
lemniscus
Basilar artery

Central
tegmental
bundle

Lateral
lemniscus

Spinothalamic Superior
tract pons
Medial longitudinal Superior cerebellar
fasciculus peduncle

Superior pontine syndrome:

SECTION III

Lateral Medial

FIGURE 21-13
Axial section at the level of the superior pons, depicted 2. Lateral superior pontine syndrome (syndrome of supe-
schematically on the left, with a corresponding MR image on rior cerebellar artery)
the right. Approximate regions involved in medial and lateral On side of lesion
Diseases of the Central Nervous System

superior pontine stroke syndromes are shown. Ataxia of limbs and gait, falling to side of lesion:
Signs and symptoms: Structures involved Middle and superior cerebellar peduncles, supe-
1. Medial superior pontine syndrome (paramedian rior surface of cerebellum, dentate nucleus
branches of upper basilar artery) Dizziness, nausea, vomiting; horizontal nystagmus:
On side of lesion Vestibular nucleus
Cerebellar ataxia (probably): Superior and/or middle Paresis of conjugate gaze (ipsilateral): Pontine con-
cerebellar peduncle tralateral gaze
Internuclear ophthalmoplegia: Medial longitudinal Skew deviation: Uncertain
fasciculus Miosis, ptosis, decreased sweating over face (Horners
Myoclonic syndrome, palate, pharynx, vocal cords, syndrome): Descending sympathetic bers
respiratory apparatus, face, oculomotor appara- Tremor: Localization unclearDentate nucleus,
tus, etc.: Localization uncertaincentral tegmen- superior cerebellar peduncle
tal bundle, dentate projection, inferior olivary On side opposite lesion
nucleus Impaired pain and thermal sense on face, limbs,
On side opposite lesion and trunk: Spinothalamic tract
Paralysis of face, arm, and leg: Corticobulbar and Impaired touch, vibration, and position sense, more
corticospinal tract in leg than arm (there is a tendency to incongruity
Rarely touch, vibration, and position are affected: of pain and touch deficits): Medial lemniscus
Medial lemniscus (lateral portion)

trigeminothalamic tract). Partial deafness, ataxic tremor vertigo, nausea and vomiting, nystagmus, tinnitus,
of the ipsilateral upper extremity, Horners syndrome, and cerebellar ataxia, Horners syndrome, and paresis of
palatal myoclonus may occur rarely. Partial syndromes conjugate lateral gaze; and (2) contralateral loss of pain
occur frequently (Fig. 21-13).With large strokes, swelling and temperature sensation. An occlusion close to the
and mass effects may compress the midbrain or produce origin of the artery may cause corticospinal tract signs
hydrocephalus; these symptoms may evolve rapidly. Neu- (Fig. 21-11).
rosurgical intervention may be lifesaving in such cases. Occlusion of one of the short circumferential
Occlusion of the anterior inferior cerebellar artery branches of the basilar artery affects the lateral two-thirds
produces variable degrees of infarction because the of the pons and middle or superior cerebellar peduncle,
size of this artery and the territory it supplies vary whereas occlusion of one of the paramedian branches
inversely with those of the PICA.The principal symp- affects a wedge-shaped area on either side of the medial
toms include: (1) ipsilateral deafness, facial weakness, pons (Figs. 21-11 through 21-13).
 3rd n. 273
Internal
Red nucleus Basilar artery carotid
Crus cerebri
artery

Substantia
nigra

Medial
lemniscus

Spinothalamic
tract
3rd nerve Midbrain
nucleus Periaqueductal
gray matter

Cerebral aqueduct
Superior colliculus

Midbrain syndrome:

CHAPTER 21
Lateral Medial

FIGURE 21-14
Axial section at the level of the midbrain, depicted Paralysis of face, arm, and leg: Corticobulbar and
schematically on the left, with a corresponding MR image on corticospinal tract descending in crus cerebri
the right. Approximate regions involved in medial and lateral 2. Lateral midbrain syndrome (syndrome of small pene-
midbrain stroke syndromes are shown. trating arteries arising from posterior cerebral artery)

Cerebrovascular Diseases
Signs and symptoms: Structures involved On side of lesion
1. Medial midbrain syndrome (paramedian branches of Eye down and out secondary to unopposed
upper basilar and proximal posterior cerebral arteries) action of fourth and sixth cranial nerves, with
On side of lesion dilated and unresponsive pupil: Third nerve bers
Eye down and out secondary to unopposed and/or third nerve nucleus
action of fourth and sixth cranial nerves, with On side opposite lesion
dilated and unresponsive pupil: Third nerve bers Hemiataxia, hyperkinesias, tremor: Red nucleus,
On side opposite lesion dentatorubrothalamic pathway

IMAGING STUDIES the coronary arteries in one imaging session. Carotid dis-
ease and intracranial vascular occlusions are readily identi-
See also Chap. 2. ed with this method (Fig. 21-3). After an IV bolus of
contrast, decits in brain perfusion produced by vascular
CT Scans occlusion can also be demonstrated (Fig. 21-15) and used
CT radiographic images identify or exclude hemor- to predict the region of infarcted brain and the brain at
rhage as the cause of stroke, and they identify extra- risk of further infarction (i.e., the ischemic penumbra). CT
parenchymal hemorrhages, neoplasms, abscesses, and imaging is also sensitive for detecting SAH (though by
other conditions masquerading as stroke. Scans obtained itself does not rule it out), and CTA can readily identify
in the rst several hours after an infarction generally intracranial aneurysms (Chap. 22). Because of its speed and
show no abnormality, and the infarct may not be seen wide availability, noncontrast head CT is the imaging
reliably for 2448 h. CT may fail to show small ischemic modality of choice in patients with acute stroke (Fig. 21-1),
strokes in the posterior fossa because of bone artifact; and CTA and CT perfusion imaging may also be useful
small infarcts on the cortical surface may also be missed. and convenient adjuncts.
Contrast-enhanced CT scans add specicity by show-
MRI
ing contrast enhancement of subacute infarcts and allow
visualization of venous structures. Coupled with newer MRI reliably documents the extent and location of
generation multi-detector scanners, CT angiography infarction in all areas of the brain, including the posterior
(CTA) can be performed with administration of IV iodi- fossa and cortical surface. It also identies intracranial
nated contrast allowing visualization of the cervical and hemorrhage and other abnormalities but is less sensitive
intracranial arteries, intracranial veins, aortic arch, and even than CT for detecting acute blood. MRI scanners with
 274

FIGURE 21-15
Acute left middle cerebral artery (MCA)
A B stroke with right hemiplegia but preserved
language. A. CT perfusion mean-transit
time map showing delayed perfusion of
the left MCA distribution (blue). B. Pre-
SECTION III

dicted region of infarct (red) and penumbra

(green) based on CT perfusion data. C.
Conventional angiogram showing occlu-
sion of the left internal carotidMCA bifur-
cation (left panel), and revascularization of
C the vessels following successful thrombec-
tomy 8 h after stroke symptom onset (right
Diseases of the Central Nervous System

panel). D. The clot removed with a thrombec-

tomy device (L5, Concentric Medical, Inc).
E. CT scan of the brain 2 days later; note
infarction in the region predicted in B but
preservation of the penumbral region by suc-
D E cessful revascularization.

magnets of higher eld strength produce more reliable limitations. However, MRI may be useful outside the
and precise images. Diffusion-weighted imaging is more acute period by more clearly dening the extent of tissue
sensitive for early brain infarction than standard MR injury and discriminating new from old regions of brain
sequences or CT (Fig. 21-16), as is FLAIR (uid- infarction. MRI may have particular utility in patients
attenuated inversion recovery) imaging (Chap. 2). Using with TIA: it is also more likely to identify new infarction,
IV administration of gadolinium contrast, MR perfusion which is a strong predictor of subsequent stroke.
studies can be performed. Brain regions showing poor
perfusion but no abnormality on diffusion are considered
Cerebral Angiography
equivalent to the ischemic penumbra (see Pathophysiol-
ogy of Ischemic Stroke, earlier and Fig. 21-16), and Conventional x-ray cerebral angiography is the gold
patients showing large regions of mismatch may be standard for identifying and quantifying atherosclerotic
better candidates for acute revascularization. MR angiog- stenoses of the cerebral arteries and for identifying and
raphy is highly sensitive for stenosis of extracranial inter- characterizing other pathologies, including aneurysms,
nal carotid arteries and of large intracranial vessels. With vasospasm, intraluminal thrombi, bromuscular dysplasia,
higher degrees of stenosis, MR angiography tends to arteriovenous stula, vasculitis, and collateral channels of
overestimate the degree of stenosis when compared to blood ow. Endovascular techniques, which are evolving
conventional x-ray angiography. MRI with fat saturation rapidly, can be used to deploy stents within delicate intracra-
is an imaging sequence used to visualize extra- or nial vessels, to perform balloon angioplasty of stenotic
intracranial arterial dissection. This sensitive technique lesions, to treat intracranial aneurysms by embolization, and
images clotted blood within the dissected vessel wall. to open occluded vessels in acute stroke with mechanical
MRI is less sensitive for acute blood products than CT thrombectomy devices. Recent studies have also docu-
and is more expensive and time consuming and less read- mented that intraarterial delivery of thrombolytic agents
ily available. Claustrophobia also limits its application. to patients with acute MCA stroke can effectively recanal-
Most acute stroke protocols use CT because of these ize vessels and improve clinical outcomes.Although its use
 that combines a B-mode ultrasound image with a 275
Doppler ultrasound assessment of ow velocity (duplex
ultrasound). Transcranial Doppler (TCD) assessment of
MCA, ACA, and PCA ow and of vertebrobasilar ow
is also useful. This latter technique can detect stenotic
lesions in the large intracranial arteries because such
lesions increase systolic ow velocity. In many cases, MR
angiography combined with carotid and transcranial
ultrasound studies eliminates the need for conventional
x-ray angiography in evaluating vascular stenosis. Alter-
A B natively, CT angiography of the entire head and neck
can be performed during the initial imaging of acute
stroke. Because this images the entire arterial system rel-
evant to stroke, with the exception of the heart, much of
the clinicians stroke workup can be completed with
one imaging study.

CHAPTER 21
Perfusion Techniques
Both xenon techniques (principally xenon-CT) and PET
can quantify cerebral blood ow. These tools are gener-
ally used for research (Chap. 2) but can be useful for
C D
determining the signicance of arterial stenosis and
FIGURE 21-16

Cerebrovascular Diseases
planning for revascularization surgery. Single photon emis-
MRI of acute stroke. A. Perfusion defect within the right sion tomography (SPECT) and MR perfusion techniques
hemisphere (bright signal) imaged after administration of an
report relative cerebral blood ow. Since CT imaging is
IV bolus of gadolinium contrast. B. Cerebral blood ow mea-
used as the initial imaging modality for acute stroke,
sured at the same time as in A; darker signal reects
some centers now combine both CT angiography and
decreased blood ow. C. Diffusion-weighted image obtained
CT perfusion imaging together with the noncontrast CT
5 h after onset of a right middle cerebral artery stroke; bright
signal indicates regions of restricted diffusion that will
scan. CT perfusion imaging increases the sensitivity for
progress to infarction. The discrepancy between the region of
detecting ischemia, and can measure the ischemic
poor perfusion shown in A and B and the diffusion decit is penumbra (Fig. 21-15). Alternatively, MR perfusion can
called diffusion-perfusion mismatch and is a measure of the be combined with MR diffusion imaging to identify the
ischemic penumbra. Without specic therapy (as shown in ischemic penumbra as the mismatch between these two
Fig. 21-15) the region of infarction will expand to match the imaging sequences (Fig. 21-16).The ability to image the
perfusion decit, as shown in the diffusion weighted image in ischemic penumbra allows more judicious selection of
D obtained 5 days later. (Courtesy of Gregory Albers and patients who may or may not benet from acute inter-
Vincent Thijs, MD, Stanford University; with permission.) ventions such as thrombolysis, thrombectomy, or investi-
gational neuroprotective strategies.

is investigational in many centers, cerebral angiography

coupled with endovascular techniques for cerebral revas- INTRACRANIAL HEMORRHAGE
cularization may become routine in the near future.
Hemorrhages are classied by their location and the
Centers capable of these techniques are termed compre-
underlying vascular pathology. Bleeding into subdural
hensive stroke centers to distinguish them from primary
and epidural spaces is principally produced by trauma.
stroke centers that can administer IV rtPA but not per-
SAHs are produced by trauma and rupture of intracra-
form endovascular therapy. Conventional angiography
nial aneurysms (Chap. 22). Intraparenchymal and intra-
carries risks of arterial damage, groin hemorrhage,
ventricular hemorrhage will be considered here.
embolic stroke, and renal failure from contrast nephropa-
thy, so it should be reserved for situations where less
invasive means are inadequate. DIAGNOSIS
Intracranial hemorrhage is often discovered on noncon-
Ultrasound Techniques
trast CT imaging of the brain during the acute evalua-
Stenosis at the origin of the internal carotid artery can tion of stroke. Since CT is more sensitive than routine
be identied and quantied reliably by ultrasonography MRI for acute blood, CT imaging is the preferred
 276 TABLE 21-5
CAUSES OF INTRACRANIAL HEMORRHAGE

CAUSE LOCATION COMMENTS

Head trauma Intraparenchymal: frontal lobes, Coup and contracoup injury during brain
anterior temporal lobes; subarachnoid deceleration
Hypertensive hemorrhage Putamen, globus pallidus, thalamus, Chronic hypertension produces
cerebellar hemisphere, pons hemorrhage from small (~100 m) vessels
in these regions
Transformation of prior Basal ganglion, subcortical Occurs in 16% of ischemic strokes with
ischemic infarction regions, lobar predilection for large hemispheric
infarctions
Metastatic brain tumor Lobar Lung, choriocarcinoma, melanoma, renal
cell carcinoma, thyroid, atrial myxoma
Coagulopathy Any Uncommon cause; often associated with
prior stroke or underlying vascular anomaly
Drug Lobar, subarachnoid Cocaine, amphetamine,
phenylpropranolamine
Arteriovenous malformation Lobar, intraventricular, subarachnoid Risk is ~24% per year for bleeding
SECTION III

Aneurysm Subarachnoid, intraparenchymal, Mycotic and nonmycotic forms of aneurysms

rarely subdural
Amyloid angiopathy Lobar Degenerative disease of intracranial vessels;
linkage to Alzheimers disease, rare in
patients <60
Cavernous angioma Intraparenchymal Multiple cavernous angiomas linked to
mutations in KRIT1, CCM2, and PDCD10
Diseases of the Central Nervous System

genes
Dural arteriovenous stula Lobar, subarachnoid Produces bleeding by venous hypertension
Capillary telangiectasias Usually brainstem Rare cause of hemorrhage

method for acute stroke evaluation (Fig. 21-1). The elevation of the head of the bed while surgical consulta-
location of the hemorrhage narrows the differential tion is obtained (Chap. 22).
diagnosis to a few entities. Table 21-5 lists the causes
and anatomic spaces involved in hemorrhages. INTRAPARENCHYMAL HEMORRHAGE

EMERGENCY MANAGEMENT Intraparenchymal hemorrhage is the most common type

of intracranial hemorrhage. It accounts for ~10% of all
Close attention should be paid to airway management strokes and is associated with a 50% case fatality rate.
since a reduction in the level of consciousness is com- Incidence rates are particularly high in Asians and
mon and often progressive. The initial blood pressure African Americans. Hypertension, trauma, and cerebral
should be maintained until the results of the CT scan amyloid angiopathy cause the majority of these hemor-
are reviewed. There is growing evidence that intra- rhages. Advanced age and heavy alcohol consumption
parenchymal hemorrhage may be exacerbated by increase the risk, and cocaine use is one of the most
acutely elevated blood pressure, and current recommen- important causes in the young.
dations are to lower mean arterial blood pressure to
<130 mmHg. Blood pressure should be lowered with
nonvasodilating IV drugs such as nicardipine, labetalol, Hypertensive Intraparenchymal Hemorrhage
or esmolol. Patients with cerebellar hemorrhages or Pathophysiology
with depressed mental status and radiographic evidence Hypertensive intraparenchymal hemorrhage (hyperten-
of hydrocephalus should undergo urgent neurosurgical sive hemorrhage or hypertensive intracerebral hemor-
evaluation. Based on the clinical examination and CT rhage) usually results from spontaneous rupture of a small
ndings, further imaging studies may be necessary, penetrating artery deep in the brain. The most common
including MRI or conventional x-ray angiography. Stu- sites are the basal ganglia (especially the putamen), thala-
porous or comatose patients generally are treated pre- mus, cerebellum, and pons. When hemorrhages occur in
sumptively for elevated ICP, with tracheal intubation other brain areas or in nonhypertensive patients, greater
and hyperventilation, mannitol administration, and consideration should be given to hemorrhagic disorders,
neoplasms, vascular malformations, and other causes. worsen until the affected limbs become accid or 277
The small arteries in these areas seem most prone to extend rigidly. When hemorrhages are large, drowsiness
hypertension-induced vascular injury. The hemorrhage gives way to stupor as signs of upper brainstem com-
may be small or a large clot may form and compress adja- pression appear. Coma ensues, accompanied by deep,
cent tissue, causing herniation and death. Blood may dissect irregular, or intermittent respiration, a dilated and xed
into the ventricular space, which substantially increases ipsilateral pupil, and decerebrate rigidity. In milder cases,
morbidity and may cause hydrocephalus. edema in adjacent brain tissue may cause progressive
Most hypertensive intraparenchymal hemorrhages deterioration over 1272 h.
develop over 3090 min, whereas those associated with Thalamic hemorrhages also produce a contralateral
anticoagulant therapy may evolve for as long as 2448 h. hemiplegia or hemiparesis from pressure on, or dissection
Within 48 h macrophages begin to phagocytize the hem- into, the adjacent internal capsule. A prominent sensory
orrhage at its outer surface.After 16 months, the hemor- decit involving all modalities is usually present. Aphasia,
rhage is generally resolved to a slitlike orange cavity lined often with preserved verbal repetition, may occur after
with glial scar and hemosiderin-laden macrophages. hemorrhage into the dominant thalamus, and construc-
tional apraxia or mutism occurs in some cases of non-
Clinical Manifestations dominant hemorrhage.There may also be a homonymous
Although not particularly associated with exertion, visual eld defect. Thalamic hemorrhages cause several

CHAPTER 21
intracerebral hemorrhages almost always occur while the typical ocular disturbances by virtue of extension inferi-
patient is awake and sometimes when stressed.The hem- orly into the upper midbrain.These include deviation of
orrhage generally presents as the abrupt onset of focal the eyes downward and inward so that they appear to be
neurologic decit. Seizures are uncommon. The focal looking at the nose, unequal pupils with absence of light
decit typically worsens steadily over 3090 min and is reaction, skew deviation with the eye opposite the hem-
associated with a diminishing level of consciousness and orrhage displaced downward and medially, ipsilateral

Cerebrovascular Diseases
signs of increased ICP, such as headache and vomiting. Horners syndrome, absence of convergence, paralysis of
The putamen is the most common site for hyperten- vertical gaze, and retraction nystagmus. Patients may later
sive hemorrhage, and the adjacent internal capsule is develop a chronic, contralateral pain syndrome (Djerine-
usually damaged (Fig. 21-17). Contralateral hemiparesis Roussy syndrome).
is therefore the sentinel sign. When mild, the face sags In pontine hemorrhages, deep coma with quadriple-
on one side over 530 min, speech becomes slurred, the gia usually occurs over a few minutes. There is often
arm and leg gradually weaken, and the eyes deviate away prominent decerebrate rigidity and pin-point (1 mm)
from the side of the hemiparesis. The paralysis may pupils that react to light. There is impairment of reex
horizontal eye movements evoked by head turning
(dolls-head or oculocephalic maneuver) or by irrigation
of the ears with ice water (Chap. 14). Hyperpnea, severe
hypertension, and hyperhidrosis are common. Death
often occurs within a few hours, but small hemorrhages
are compatible with survival.
Cerebellar hemorrhages usually develop over several
hours and are characterized by occipital headache,
repeated vomiting, and ataxia of gait. In mild cases there
may be no other neurologic signs other than gait ataxia.
Dizziness or vertigo may be prominent. There is often
paresis of conjugate lateral gaze toward the side of the
hemorrhage, forced deviation of the eyes to the opposite
side, or an ipsilateral sixth nerve palsy. Less frequent ocu-
lar signs include blepharospasm, involuntary closure of
one eye, ocular bobbing, and skew deviation. Dysarthria
and dysphagia may occur. As the hours pass, the patient
often becomes stuporous and then comatose from brain-
stem compression or obstructive hydrocephalus; imme-
diate surgical evacuation before brainstem compression
FIGURE 21-17 occurs may be lifesaving. Hydrocephalus from fourth
Hypertensive hemorrhage. Transaxial noncontrast CT scan ventricle compression can be relieved by external ven-
through the region of the basal ganglia reveals a hematoma tricular drainage, but denitive hematoma evacuation is
involving the left putamen in a patient with rapidly progres- essential for survival. If the deep cerebellar nuclei are
sive onset of right hemiparesis. spared, full recovery is common.
 278 Lobar Hemorrhage Intracranial hemorrhages associated with anticoagulant
therapy can occur at any location; they are often lobar or
Symptoms and signs appear over several minutes. Most
subdural. Anticoagulant-related intracerebral hemor-
lobar hemorrhages are small and cause a restricted clinical
rhages may evolve slowly, over 2448 h. Coagulopathy
syndrome that simulates an embolus to an artery supply-
and thrombocytopenia should be reversed rapidly, as dis-
ing one lobe. For example, the major neurologic decit
cussed below. Intracerebral hemorrhage associated with
with an occipital hemorrhage is hemianopia; with a left
hematologic disorders (leukemia, aplastic anemia, thrombo-
temporal hemorrhage, aphasia and delirium; with a parietal
cytopenic purpura) can occur at any site and may pre-
hemorrhage, hemisensory loss; and with frontal hemor-
sent as multiple intracerebral hemorrhages. Skin and
rhage, arm weakness. Large hemorrhages may be associ-
mucous membrane bleeding is usually evident and offers
ated with stupor or coma if they compress the thalamus
a diagnostic clue.
or midbrain. Most patients with lobar hemorrhages have
Hemorrhage into a brain tumor may be the rst mani-
focal headaches, and more than half vomit or are drowsy.
festation of neoplasm. Choriocarcinoma, malignant
Stiff neck and seizures are uncommon.
melanoma, renal cell carcinoma, and bronchogenic car-
cinoma are among the most common metastatic tumors
Other Causes of Intracerebral Hemorrhage associated with intracerebral hemorrhage. Glioblastoma
multiforme in adults and medulloblastoma in children
SECTION III

Cerebral amyloid angiopathy is a disease of the elderly in may also have areas of intracerebral hemorrhage.
which arteriolar degeneration occurs and amyloid is Hypertensive encephalopathy is a complication of malig-
deposited in the walls of the cerebral arteries. Amyloid nant hypertension. In this acute syndrome, severe hyper-
angiopathy causes both single and recurrent lobar hem- tension is associated with headache, nausea, vomiting,
orrhages and is probably the most common cause of convulsions, confusion, stupor, and coma. Focal or later-
lobar hemorrhage in the elderly. It accounts for some alizing neurologic signs, either transitory or permanent,
Diseases of the Central Nervous System

intracranial hemorrhages associated with IV thromboly- may occur but are infrequent and therefore suggest
sis given for MI. This disorder can be suspected in some other vascular disease (hemorrhage, embolism, or
patients who present with multiple hemorrhages (and atherosclerotic thrombosis). There are retinal hemor-
infarcts) over several months or years, or in patients with rhages, exudates, papilledema (hypertensive retinopathy),
micro-bleeds seen on brain MRI sequences sensitive and evidence of renal and cardiac disease. In most cases
for hemosiderin, but it is denitively diagnosed by ICP and CSF protein levels are elevated. The hyperten-
pathologic demonstration of Congo red staining of sion may be essential or due to chronic renal disease,
amyloid in cerebral vessels. The 2 and 4 allelic varia- acute glomerulonephritis, acute toxemia of pregnancy,
tions of the apolipoprotein E gene are associated with pheochromocytoma, or other causes. Lowering the
increased risk of recurrent lobar hemorrhage and may blood pressure reverses the process, but stroke can occur,
therefore be markers of amyloid angiopathy. Currently, especially if blood pressure is lowered too rapidly. Neu-
there is no specic therapy, though antiplatelet and anti- ropathologic examination reveals multifocal to diffuse
coagulating agents are typically avoided. cerebral edema and hemorrhages of various sizes from
Cocaine is a frequent cause of stroke in young (<45 petechial to massive. Microscopically, there are necrosis
years) patients. Intracerebral hemorrhage, ischemic stroke, of arterioles, minute cerebral infarcts, and hemorrhages.
and SAH are all associated with cocaine use.Angiographic The term hypertensive encephalopathy should be reserved
ndings vary from completely normal arteries to large- for this syndrome and not for chronic recurrent
vessel occlusion or stenosis, vasospasm, or changes consis- headaches, dizziness, recurrent TIAs, or small strokes that
tent with vasculitis. The mechanism of cocaine-related often occur in association with high blood pressure.
stroke is not known, but cocaine enhances sympathetic Primary intraventricular hemorrhage is rare. It usually
activity causing acute, sometimes severe, hypertension, begins within the substance of the brain and dissects
and this may lead to hemorrhage. Slightly more than half into the ventricular system without leaving signs of
of cocaine-related intracranial hemorrhages are intracere- intraparenchymal hemorrhage. Alternatively, bleeding
bral, and the rest are subarachnoid. In cases of SAH, a can arise from periependymal veins. Vasculitis, usually
saccular aneurysm is usually identied. Presumably, acute polyarteritis nodosa or lupus erythematosus, can pro-
hypertension causes aneurysmal rupture. duce hemorrhage into any region of the central nervous
Head injury often causes intracranial bleeding. The system; most hemorrhages are associated with hyperten-
common sites are intracerebral (especially temporal and sion, but the arteritis itself may cause bleeding by dis-
inferior frontal lobes) and into the subarachnoid, sub- rupting the vessel wall. Sepsis can cause small petechial
dural, and epidural spaces.Trauma must be considered in hemorrhages throughout the cerebral white matter.
any patient with an unexplained acute neurologic decit Moyamoya disease, mainly an occlusive arterial disease
(hemiparesis, stupor, or confusion), particularly if the that causes ischemic symptoms, may on occasion pro-
decit occurred in the context of a fall (Chap. 31). duce intraparenchymal hemorrhage, particularly in the
young. Hemorrhages into the spinal cord are usually the warfarin sodium, more rapid reversal of coagulopathy 279
result of an AVM or metastatic tumor. Epidural spinal can be achieved by infusing prothrombin complex
hemorrhage produces a rapidly evolving syndrome of concentrates followed by fresh-frozen plasma and
spinal cord or nerve root compression (Chap. 30). Spinal vitamin K. When intracerebral hemorrhage is associated
hemorrhages usually present with sudden back pain and with thrombocytopenia (platelet count <50,000/L),
some manifestation of myelopathy. transfusion of fresh platelets is indicated. At present, little
can be done about the hemorrhage itself. Hematomas
Laboratory and Imaging Evaluation may expand for several hours following the initial
hemorrhage, so treating severe hypertension seems
Patients should have routine blood chemistries and hema-
reasonable to prevent hematoma progression. Preliminary
tologic studies. Specic attention to the platelet count
data suggested that treatment with recombinant factor
and PT/PTT are important to identify coagulopathy.
VIIa, even in patients without coagulopathy, may decrease
CT imaging reliably detects acute focal hemorrhages in
risk of hematoma expansion and improve clinical
the supratentorial space. Small pontine hemorrhages may
outcome; however, a multicenter randomized trial of this
not be identied because of motion and bone-induced
approach did not show clinical benet despite a decrease
artifact that obscure structures in the posterior fossa.
in hematoma expansion.
After the rst 2 weeks, x-ray attenuation values of clot-

CHAPTER 21
Evacuation of supratentorial hematomas does not
ted blood diminish until they become isodense with
appear to improve outcome. The International Surgical
surrounding brain. Mass effect and edema may remain.
Trial in Intracerebral Hemorrhage (STICH) randomized
In some cases, a surrounding rim of contrast enhance-
1033 patients with supratentorial intracerebral hemor-
ment appears after 24 weeks and may persist for
rhage to either early surgical evacuation or initial med-
months. MRI, though more sensitive for delineating
ical management. No benet was found in the early
posterior fossa lesions, is generally not necessary in most
surgery arm, though analysis was complicated by the

Cerebrovascular Diseases
instances. Images of owing blood on MRI scan may
fact that 26% of patients in the initial medical manage-
identify AVMs as the cause of the hemorrhage. MRI,
ment group ultimately had surgery for neurologic deteri-
CT angiography, and conventional x-ray angiography
oration. Overall, these data do not support routine surgi-
are used when the cause of intracranial hemorrhage is
cal evacuation of supratentorial hemorrhages; however,
uncertain, particularly if the patient is young or not
many centers operate on patients with progressive neu-
hypertensive and the hematoma is not in one of the
rologic deterioration. Surgical techniques continue to
four usual sites for hypertensive hemorrhage. For exam-
evolve, and minimally invasive endoscopic hematoma
ple, hemorrhage into the temporal lobe suggests rupture
evacuation may prove benecial in future trials.
of a MCA saccular aneurysm.
For cerebellar hemorrhages, a neurosurgeon should
Since patients typically have focal neurologic signs
be consulted immediately to assist with the evaluation;
and obtundation, and often show signs of increased ICP,
most cerebellar hematomas >3 cm in diameter will
a lumbar puncture should be avoided as it may induce
require surgical evacuation. If the patient is alert without
cerebral herniation.
focal brainstem signs and if the hematoma is <1 cm in
diameter, surgical removal is usually unnecessary.
Patients with hematomas between 1 and 3 cm require
careful observation for signs of impaired consciousness
Treatment: and precipitous respiratory failure.
INTRACRANIAL HEMORRHAGE Tissue surrounding hematomas is displaced and
compressed but not necessarily infarcted. Hence, in sur-
ACUTE MANAGEMENT Nearly 50% of patients vivors, major improvement commonly occurs as the
with a hypertensive intracerebral hemorrhage die, but hematoma is reabsorbed and the adjacent tissue
others may have a good to complete recovery if they regains its function. Careful management of the patient
survive the initial hemorrhage. The volume and location during the acute phase of the hemorrhage can lead to
of the hematoma determine the prognosis. In general, considerable recovery.
supratentorial hematomas with volumes <30 mL have a Surprisingly, ICP is often normal even with large intra-
good prognosis; 3060 mL, an intermediate prognosis; parenchymal hemorrhages. However, if the hematoma
and >60 mL, a poor prognosis during initial hospitalization. causes marked midline shift of structures with conse-
Extension into the ventricular system worsens the quent obtundation, coma, or hydrocephalus, osmotic
prognosis, as does advanced age, location within the agents coupled with induced hyperventilation can be
posterior fossa, and depressed level of consciousness at instituted to lower ICP (Chap. 22). These maneuvers will
initial presentation. Any identied coagulopathy should provide enough time to place a ventriculostomy or ICP
be reversed as soon as possible. For patients taking monitor. Once ICP is recorded, further hyperventilation
 280 and osmotic therapy can be tailored to the individual Headache (without bleeding) may be hemicranial and
patient. For example, if ICP is found to be high, CSF can throbbing, like migraine, or diffuse. Focal seizures, with
be drained from the ventricular space and osmotic ther- or without generalization, occur in ~30% of cases. Half
apy continued; persistent or progressive elevation in ICP of AVMs become evident as intracerebral hemorrhages.
may prompt surgical evacuation of the clot or with-
In most, the hemorrhage is mainly intraparenchymal
drawal of support. Alternately, if ICP is normal or only
with extension into the subarachnoid space in some
mildly elevated, induced hyperventilation can be
cases. Blood is usually not deposited in the basal cisterns,
reversed and osmotic therapy tapered. Since hyperven-
and symptomatic cerebral vasospasm is rare. The risk of
tilation may actually produce ischemia by cerebral vaso-
rerupture is ~24% per year and is particularly high in
the rst few weeks. Hemorrhages may be massive, lead-
constriction, induced hyperventilation should be limited
ing to death, or may be as small as 1 cm in diameter,
to acute resuscitation of the patient with presumptive
leading to minor focal symptoms or no decit. The
high ICP and eliminated once other treatments (osmotic
AVM may be large enough to steal blood away from
therapy or surgical treatments) have been instituted.
adjacent normal brain tissue or to increase venous pres-
Glucocorticoids are not helpful for the edema from
sure signicantly to produce venous ischemia locally and
intracerebral hematoma.
in remote areas of the brain.This is seen most often with
large AVMs in the territory of the MCA.
PREVENTION Hypertension is the leading cause of
SECTION III

Large AVMs of the anterior circulation may be associ-

primary intracerebral hemorrhage. Prevention is aimed
ated with a systolic and diastolic bruit (sometimes self-audi-
at reducing hypertension, excessive alcohol use, and use
ble) over the eye, forehead, or neck and a bounding carotid
of illicit drugs such as cocaine and amphetamines.
pulse. Headache at the onset of AVM rupture is not gener-
ally as explosive as with aneurysmal rupture. MRI is better
than CT for diagnosis, although noncontrast CT scanning
Diseases of the Central Nervous System

sometimes detects calcication of the AVM and contrast

VASCULAR ANOMALIES may demonstrate the abnormal blood vessels. Once identi-
ed, conventional x-ray angiography is the gold standard
Vascular anomalies can be divided into congenital vascu- for evaluating the precise anatomy of the AVM.
lar malformations and acquired vascular lesions. Surgical treatment of symptomatic AVMs, often with
preoperative embolization to reduce operative bleeding,
is usually indicated for accessible lesions. Stereotaxic
CONGENITAL VASCULAR MALFORMATIONS
radiation, an alternative to surgery, can produce a slow
True arteriovenous malformations (AVMs), venous anom- sclerosis of arterial channels over 23 years.
alies, and capillary telangiectasias are lesions that usually Patients with asymptomatic AVMs have about a ~24%
remain clinically silent through life. Although most per year risk for hemorrhage. Several angiographic features
AVMs are congenital, cases of acquired lesions have been of the AVM can be used to help predict future bleeding
reported. risk. Paradoxically, smaller lesions seem to have a higher
True AVMs are congenital shunts between the arterial hemorrhage rate.The impact of recurrent hemorrhage on
and venous systems that may present as headache, disability is relatively modest, so the indication for surgery
seizures, and intracranial hemorrhage. AVMs consist of a in asymptomatic AVMs is debated. A large-scale random-
tangle of abnormal vessels across the cortical surface or ized trial is currently addressing this question.
deep within the brain substance. AVMs vary in size from Venous anomalies are the result of development of
a small blemish a few millimeters in diameter to a large anomalous cerebral, cerebellar, or brainstem drainage.
mass of tortuous channels composing an arteriovenous These structures, unlike AVMs, are functional venous
shunt of sufcient magnitude to raise cardiac output. channels. They are of little clinical signicance and
The blood vessels forming the tangle interposed between should be ignored if found incidentally on brain imag-
arteries and veins are usually abnormally thin and do ing studies. Surgical resection of these anomalies may
not have a normal structure. AVMs occur in all parts of result in venous infarction and hemorrhage. Venous
the cerebral hemispheres, brainstem, and spinal cord, but anomalies may be associated with cavernous malforma-
the largest ones are most frequently in the posterior half tions (see below), which do carry some bleeding risk. If
of the hemispheres, commonly forming a wedge-shaped resection of a cavernous malformation is attempted, the
lesion extending from the cortex to the ventricle. venous anomaly should not be disturbed.
Although the lesion is thought to be present from Capillary telangiectasias are true capillary malformations
birth in most patients, bleeding or other symptoms are that often form extensive vascular networks through an
most common between 10 and 30 years of age, occa- otherwise normal brain structure. The pons and deep
sionally as late as the 50s. AVMs are more frequent in cerebral white matter are typical locations, and these capil-
men, and rare familial cases have been described. lary malformations can be seen in patients with hereditary
hemorrhagic telangiectasia (Osler-Rendu-Weber) syn- Cardiology Council, Cardiovascular Radiology and Intervention 281
drome. If bleeding does occur, it rarely produces mass Council, and the Atherosclerotic Peripheral Vascular Disease and
effect or signicant symptoms. No treatment options exist. Quality of Care Outcomes in Research Interdisciplinary Work-
ing Groups. The American Academy of Neurology afrms the
value of this guideline as an educational tool for neurologists.
ACQUIRED VASCULAR LESIONS Stroke 38:1655, 2007
Cavernous angiomas are tufts of capillary sinusoids that form ALBERTS MJ et al: Recommendations for comprehensive stroke centers:
A consensus statement from the Brain Attack Coalition. Stroke
within the deep hemispheric white matter and brainstem
36:1597, 2005
with no normal intervening neural structures.The patho- CHOI JH, MOHR JP: Brain arteriovenous malformations in adults.
genesis is unclear. Familial cavernous angiomas have been Lancet Neurol 4:299, 2005
mapped to several different chromosomal loci: KRIT1 CONNOLLY SJ et al: Effect of clopidogrel added to aspirin in patients
(7q21-q22), CCM2 (7p13), and PDCD10 (3q26.1). Both with atrial brillation. N Engl J Med. 360:2066, 2009
KRIT1 and CCM2 are instrumental in blood vessel for- GEORGIADIS D et al: Aspirin vs anticoagulation in carotid artery
mation while PDCD10 is an apoptotic gene. Cavernous dissection. Neurology 72:1810, 2009
angiomas are typically <1 cm in diameter and are often GOLDSTEIN LB et al: Primary prevention of ischemic stroke: A
guideline from the American Heart Association/American
associated with a venous anomaly. Bleeding is usually of Stroke Association Stroke Council: cosponsored by the Ather-
small volume, causing slight mass effect only.The bleeding osclerotic Peripheral Vascular Disease Interdisciplinary Work-

CHAPTER 21
risk for single cavernous malformations is 0.71.5% per ing Group; Cardiovascular Nursing Council; Clinical Cardiol-
year and may be higher for patients with prior clinical ogy Council; Nutrition, Physical Activity, and Metabolism
hemorrhage or multiple malformations. Seizures may Council; and the Quality of Care and Outcomes Research
occur if the malformation is located near the cerebral cor- Interdisciplinary Working Group: The American Academy of
tex. Surgical resection eliminates bleeding risk and may Neurology affirms the value of this guideline. Stroke 37:1583,
2006
reduce seizure risk, but it is reserved for those malforma-
HACKE W et al: Thrombolysis with Alteplase 3 to 4.5 Hours after
tions that form near the brain surface. Radiation treatment

Cerebrovascular Diseases
Acute Ischemic Stroke. N Engl J Med 359:1317, 2008
has not been shown to be of benet. HOWARD VJ et al: Care seeking after stroke symptoms. Ann Neurol
Dural arteriovenous stulas are acquired connections 63:466, 2008
usually from a dural artery to a dural sinus. Patients may Ikram MA et al: Genome-wide association studies of stroke. N Engl J
complain of a pulse-synchronous cephalic bruit (pul- Med 360:1718, 2009
satile tinnitus) and headache. Depending on the magni- JOHNSTON SC et al: National Stroke Association guidelines for the
management of transient ischemic attacks. Ann Neurol 60:301,
tude of the shunt, venous pressures may rise high
2006
enough to cause cortical ischemia or venous hyperten- MAYER SA et al: Efcacy and safety of recombinant activated factor
sion and hemorrhage, particularly subarachnoid hemor- VII for acute intracerebral hemorrhage. N Engl J Med 358:2127,
rhage. Surgical and endovascular techniques are usually 2008
curative. These stulas may form because of trauma, but MENDELOW AD et al: Early surgery versus initial conservative treat-
most are idiopathic. There is an association between s- ment in patients with spontaneous supratentorial intracerebral
tulas and dural sinus thrombosis. Fistulas have been haematomas in the International Surgical Trial in Intracerebral
observed to appear months to years following venous Haemorrhage (STICH): A randomised trial. Lancet 365:387,
2005
sinus thrombosis, suggesting that angiogenesis factors MOHR JP et al: A comparison of warfarin and aspirin for the preven-
elaborated from the thrombotic process may cause these tion of recurrent ischemic stroke. N Engl J Med. 345:1444, 2001
anomalous connections to form. Alternatively, dural ROTHWELL PM et al: Endarterectomy for symptomatic carotid steno-
arteriovenous stulas can produce venous sinus occlu- sis in relation to clinical subgroups and timing of surgery. Lancet
sion over time, perhaps from the high pressure and high 363:915, 2004
ow through a venous structure. SACCO RL et al: Guidelines for Prevention of Stroke in Patients with
Ischemic Stroke and Transient Ischemic Attack: A Statement for
Healthcare Professionals From the American Heart Association/
FURTHER READINGS
American Stroke Association Council on Stroke. Stroke 37:577,
ADAMS HP JR. et al: Guidelines for the Early Management of Adults 2006
with Ischemic Stroke. A Guideline from the American Heart _______ et al: Aspirin and extended-release dipyridamole versus
Association/American Stroke Association Stroke Council, Clinical clopidogrel for recurrent stroke. N Engl J Med 359:1317, 2008
 CHAPTER 22
NEUROLOGIC CRITICAL CARE, INCLUDING
HYPOXIC-ISCHEMIC ENCEPHALOPATHY
AND SUBARACHNOID HEMORRHAGE
J. Claude Hemphill, III Wade S. Smith

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Wernickes Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290

Critical Care Disorders of the Central Nervous System . . . . . 287 Critical Care Disorders of the Peripheral Nervous System . . . . 291
Hypoxic-Ischemic Encephalopathy . . . . . . . . . . . . . . . . . . . . 287 Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Delayed Postanoxic Encephalopathy . . . . . . . . . . . . . . . . . . 289 Disorders of Neuromuscular Transmission . . . . . . . . . . . . . . 292
Metabolic Encephalopathies . . . . . . . . . . . . . . . . . . . . . . . . . 289 Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Septic Encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Subarachnoid Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Central Pontine Myelinolysis . . . . . . . . . . . . . . . . . . . . . . . . . 290 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Life-threatening neurologic illness may be caused by a Early astrocytic swelling is a hallmark of ischemia. Brain
primary disorder affecting any region of the neuraxis or edema that is clinically signicant usually represents a
may occur as a consequence of a systemic disorder such combination of vasogenic and cellular components.
as hepatic failure, multisystem organ failure, or cardiac Edema can lead to increased ICP as well as tissue shifts
arrest (Table 22-1). Neurologic critical care focuses on and brain displacement from focal processes (Chap. 14).
preservation of neurologic tissue and prevention of sec- These tissue shifts can cause injury by mechanical dis-
ondary brain injury caused by ischemia, edema, and ele- traction and compression in addition to the ischemia of
vated intracranial pressure (ICP). impaired perfusion consequent to the elevated ICP.

Ischemic Cascade and Cellular Injury

PATHOPHYSIOLOGY
When delivery of substrates, principally oxygen and glu-
Brain Edema
cose, is inadequate to sustain cellular function, a series of
Swelling, or edema, of brain tissue occurs with many interrelated biochemical reactions known as the ischemic
types of brain injury. The two principal types of edema cascade is initiated (see Fig. 21-2).The release of excitatory
are vasogenic and cytotoxic. Vasogenic edema refers to the amino acids, especially glutamate, leads to inux of cal-
inux of uid and solutes into the brain through an cium and sodium ions, which disrupt cellular homeostasis.
incompetent blood-brain barrier (BBB). In the normal An increased intracellular calcium concentration may acti-
cerebral vasculature, endothelial tight junctions associ- vate proteases and lipases, which then lead to lipid peroxi-
ated with astrocytes create an impermeable barrier (the dation and free radicalmediated cell membrane injury.
BBB), through which access into the brain interstitium Cytotoxic edema ensues, and ultimately necrotic cell death
is dependent upon specific transport mechanisms and tissue infarction occur.This pathway to irreversible cell
(Chap. 19).The BBB may be compromised in ischemia, death is common to ischemic stroke, global cerebral
trauma, infection, and metabolic derangements. Typi- ischemia, and traumatic brain injury. Penumbra refers to
cally, vasogenic edema develops rapidly following injury. ischemic brain tissue that has not yet undergone irre-
Cytotoxic edema refers to cellular swelling and occurs in a versible infarction, implying that the region is potentially
variety of settings including brain ischemia and trauma. salvageable if ischemia can be reversed. Factors that may
282
 TABLE 22-1 283
NEUROLOGIC DISORDERS IN CRITICAL ILLNESS

LOCALIZATION
ALONG NEUROAXIS SYNDROME

Central Nervous System

Brain: Cerebral hemispheres Global encephalopathy
Sepsis
Organ failurehepatic, renal
Medication related
Sedatives/hypnotics/analgesics
H2 blockers, antihypertensives
Drug overdose
Electrolyte disturbancehyponatremia, hypoglycemia
Hypotension/hypoperfusion
Hypoxia
Meningitis
Subarachnoid hemorrhage

CHAPTER 22
Wernickes disease
Seizurepostictal or nonconvulsive status
Hypertensive encephalopathy
Hypothyroidismmyxedema
Focal decits
Ischemic stroke
Tumor

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

Abscess, subdural empyema
Subdural/epidural hematoma
Brainstem Mass effect and compression
Ischemic stroke, intraparenchymal hemorrhage
Hypoxia
Spinal cord Mass effect and compression
Disc herniation
Epidural hematoma
Ischemiahypotension/embolic
Subdural empyema
Trauma, central cord syndrome
Peripheral Nervous System
Peripheral nerve Critical illness polyneuropathy
Axonal Possible neuromuscular blocking agent complication
Metabolic disturbances, uremia, hyperglycemia
Medication effectschemotherapeutic, antiretroviral
Demyelinating Guillian-Barr syndrome
Chronic inammatory demyelinating polyneuropathy
Neuromuscular junction Prolonged effect of neuromuscular blockade
Medication effectsaminoglycosides
Myasthenia-gravis, Lambert-Eaton syndrome
Muscle Critical illness myopathy
Septic myopathy
Cachectic myopathywith or without disuse atrophy
Electrolyte disturbanceshypokalemia/hyperkalemia, hypophosphatemia
Acute quadriplegic myopathy

exacerbate ischemic brain injury include systemic to exacerbation of the primary brain injury. Prevention,
hypotension and hypoxia, which further reduce substrate identication, and treatment of secondary brain insults are
delivery to vulnerable brain tissue, and fever, seizures, and fundamental goals of management.
hyperglycemia, which can increase cellular metabolism An alternative pathway of cellular injury is apoptosis.
outstripping compensatory processes. Clinically, these This process implies programmed cell death, which may
events are known as secondary brain insults because they lead occur in the setting of ischemic stroke, global cerebral
 284 ischemia, traumatic brain injury, and possibly intracerebral and decreases with hypocapnia and alkalosis. This forms
hemorrhage. Apoptotic cell death can be distinguished the basis for the use of hyperventilation to lower ICP,
histologically from the necrotic cell death of ischemia and and this effect on ICP is mediated through a decrease in
is mediated through a different set of biochemical path- intracranial blood volume. Cerebral autoregulation is
ways. At present, interventions for prevention and treat- critical to the normal homeostatic functioning of the
ment of apoptotic cell death remain less well dened than brain, and this process may be disordered focally and
those for ischemia. Excitotoxicity and mechanisms of cell unpredictably in disease states such as traumatic brain
death are discussed in more detail in Chap. 19. injury and severe focal cerebral ischemia.

Cerebral Perfusion and Autoregulation Cerebrospinal Fluid and Intracranial Pressure

Brain tissue requires constant perfusion in order to The cranial contents consist essentially of brain, cere-
ensure adequate delivery of substrate. The hemodynamic brospinal uid (CSF), and blood. CSF is produced prin-
response of the brain has the capacity to preserve perfu- cipally in the choroid plexus of each lateral ventricle,
sion across a wide range of systemic blood pressures. exits the brain via the foramina of Luschka and Magendi,
Cerebral perfusion pressure (CPP), dened as the mean and ows over the cortex to be absorbed into the venous
systemic arterial pressure (MAP) minus the ICP, provides system along the superior sagittal sinus. Approximately
SECTION III

the driving force for circulation across the capillary beds 150 mL of CSF are contained within the ventricles and
of the brain. Autoregulation refers to the physiologic surrounding the brain and spinal cord; the cerebral blood
response whereby cerebral blood ow (CBF) remains volume is also ~150 mL. The bony skull offers excellent
relatively constant over a wide range of blood pressures as protection for the brain but allows little tolerance for
a consequence of alterations of cerebrovascular resistance additional volume. Signicant increases in volume even-
(Fig. 22-1). If systemic blood pressure drops, cerebral tually result in increased ICP. Obstruction of CSF out-
Diseases of the Central Nervous System

perfusion is preserved through vasodilatation of arterioles ow, edema of cerebral tissue, or increases in volume
in the brain; likewise, arteriolar vasoconstriction occurs at from tumor or hematoma may increase ICP. Elevated
high systemic pressures to prevent hyperperfusion. At the ICP diminishes cerebral perfusion and can lead to tissue
extreme limits of MAP or CPP (high or low), ow ischemia. Ischemia in turn may lead to vasodilatation via
becomes directly related to perfusion pressure. These autoregulatory mechanisms designed to restore cerebral
autoregulatory changes occur in the microcirculation and perfusion. However, vasodilatation also increases cerebral
are mediated by vessels below the resolution of those seen blood volume, which in turn then increases ICP, lowers
on angiography. CBF is also strongly inuenced by pH CPP, and provokes further ischemia (Fig. 22-2). This
and PCO2. CBF increases with hypercapnia and acidosis vicious cycle is commonly seen in traumatic brain injury,
massive intracerebral hemorrhage, and large hemispheric
infarcts with signicant tissue shifts.

125 PaCO2

PaO2 Spontaneous
Dehydration
SABP Pharmacologic
CBF, mL/100g per min

Mechanical
Metabolism
75 CPP

CMR-O2/Metabolism
Edema Viscosity
ICP Vasodilatation O2 delivery
CSF
Hypercapnia
25 Pharmacologic

CBV
25 75 125 175 FIGURE 22-2
BP, mmHg Ischemia and vasodilatation. Reduced cerebral perfusion
FIGURE 22-1 pressure (CPP) leads to increased ischemia, vasodilatation,
Autoregulation of cerebral blood ow (solid line). Cerebral increased intracranial pressure (ICP), and further reductions
perfusion is constant over a wide range of systemic blood in CPP, a cycle leading to further neurologic injury. CBV, cere-
pressure. Perfusion is increased in the setting of hypoxia or bral blood volume; CMR, cerebral metabolic rate; CSF, cere-
hypercarbia. BP, blood pressure; CBF, cerebral blood ow. brospinal uid; SABP, systolic arterial blood pressure.
(Reprinted with permission from Anesthesiology 43:447, (Adapted from MJ Rosner et al: J Neurosurg 83:949, 1995;
1975. Copyright 1975, Lippincott Company.) with permission.)
 metabolic encephalopathy typically reveals generalized 285
Approach to the Patient:
SEVERE CNS DYSFUNCTION
slowing. One of the most important uses of EEG is to
help exclude inapparent seizures, especially nonconvul-
Critically ill patients with severe central nervous system sive status epilepticus. Untreated continuous or fre-
dysfunction require rapid evaluation and intervention quently recurrent seizures may cause neuronal injury,
in order to limit primary and secondary brain injury. making the diagnosis and treatment of seizures crucial in
Initial neurologic evaluation should be performed con- this patient group. Lumbar puncture (LP) may be neces-
current with stabilization of basic respiratory, cardiac, sary to exclude infectious processes, and an elevated
and hemodynamic parameters. Signicant barriers opening pressure may be an important clue to cerebral
may exist to neurologic assessment in the critical care venous sinus thrombosis. In patients with coma or pro-
unit, including endotracheal intubation and the use of found encephalopathy, it is preferable to perform a neu-
sedative or paralytic agents to facilitate procedures. roimaging study prior to LP. If bacterial meningitis is
An impaired level of consciousness is common in suspected, an LP may be performed rst or antibiotics
critically ill patients. The essential rst task in assess- may be empirically administered before the diagnostic
ment is to determine whether the cause of dysfunc- studies are completed. Standard laboratory evaluation of
tion is related to a diffuse, usually metabolic, process critically ill patients should include assessment of serum
or whether a focal, usually structural, process is impli-

CHAPTER 22
electrolytes (especially sodium and calcium), glucose,
cated. Examples of diffuse processes include meta- renal and hepatic function, complete blood count, and
bolic encephalopathies related to organ failure, drug coagulation. Serum or urine toxicology screens should
overdose, or hypoxia-ischemia. Focal processes include be performed in patients with encephalopathy of
ischemic and hemorrhagic stroke and traumatic unknown cause. EEG, LP, and other specic laboratory
brain injury, especially with intracranial hematomas. tests are most useful when the mechanism of the altered
Since these two categories of disorders have funda- level of consciousness is uncertain; they are not routinely

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

mentally different causes, treatments, and prognoses, performed in clear-cut cases of stroke or traumatic brain
the initial focus is on making this distinction rapidly injury.
and accurately. The approach to the comatose Monitoring of ICP can be an important tool in
patient is discussed in Chap. 14; etiologies are listed in selected patients. In general, patients who should be
Table 14-1. considered for ICP monitoring are those with pri-
Minor focal decits may be present on the neuro- mary neurologic disorders, such as stroke or traumatic
logic examination in patients with metabolic brain injury, who are at signicant risk for secondary
encephalopathies. However, the nding of prominent brain injury due to elevated ICP and decreased CPP.
focal signs such as pupillary asymmetry, hemiparesis, Included are patients with the following: severe trau-
gaze palsy, or paraplegia should suggest the possibility matic brain injury [Glasgow Coma Scale (GCS) score
of a structural lesion. All patients with a decreased 8 (Table 31-2)]; large tissue shifts from supratentorial
level of consciousness associated with focal ndings ischemic or hemorrhagic stroke; or hydrocephalus
should undergo an urgent neuroimaging procedure, from subarachnoid hemorrhage (SAH), intraventricu-
as should all patients with coma of unknown etiology. lar hemorrhage, or posterior fossa stroke.An additional
CT scanning is usually the most appropriate initial disorder in which ICP monitoring can add important
study because it can be performed quickly in criti- information is fulminant hepatic failure, in which ele-
cally ill patients and demonstrates hemorrhage, hydro- vated ICP may be treated with barbiturates or, eventu-
cephalus, and intracranial tissue shifts well. MRI may ally, liver transplantation. In general, ventriculostomy is
provide more specic information in some situations, preferable to ICP monitoring devices that are placed
such as acute ischemic stroke (diffusion-weighted in the brain parenchyma, because ventriculostomy
imaging, DWI) and cerebral venous sinus thrombosis allows CSF drainage as a method of treating elevated
(magnetic resonance venography, MRV). Any sugges- ICP. However, parenchymal ICP monitoring is most
tion of trauma from the history or examination appropriate for patients with diffuse edema and small
should alert the examiner to the possibility of cervical ventricles (which may make ventriculostomy place-
spine injury and prompt an imaging evaluation using ment more difcult) or any degree of coagulopathy
plain x-rays, MRI, or CT. (in which ventriculostomy carries a higher risk of
Other diagnostic studies are best utilized in specic hemorrhagic complications) (Fig 22-3).
circumstances, usually when neuroimaging studies fail to
reveal a structural lesion and the etiology of the altered TREATMENT OF ELEVATED ICP Elevated ICP
mental state remains uncertain. Electroencephalography may occur in a wide range of disorders including
(EEG) can be important in the evaluation of critically ill head trauma, intracerebral hemorrhage, SAH with
patients with severe brain dysfunction. The EEG of hydrocephalus, and fulminant hepatic failure. Because
 286 TABLE 22-2
Lateral ventricle
STEPWISE APPROACH TO TREATMENT OF
Brain tissue
Ventriculostomy
oxygen probe ELEVATED INTRACRANIAL PRESSUREa
Insert ICP monitorventriculostomy versus parenchymal
device
General goals: maintain ICP <20 mmHg and CPP
60 mmHg
For ICP > 2025 mmHg for >5 min:
Fiberoptic 1. Drain CSF via ventriculostomy (if in place)
intraparenchymal 2. Elevate head of the bed; midline head position
ICP monitor
3. Osmotherapymannitol 25100 g q4h as needed
(maintain serum osmolality <320 mosmol) or hyper-
tonic saline (30 mL, 23.4% NaCl bolus)
4. Glucocorticoidsdexamethasone 4 mg q6h for
vasogenic edema from tumor, abscess (avoid
FIGURE 22-3 glucocorticoids in head trauma, ischemic and
Intracranial pressure and brain tissue oxygen monitoring. hemorrhagic stroke)
A ventriculostomy allows for drainage of cerebrospinal uid 5. Sedation (e.g., morphine, propofol, or midazolam);
SECTION III

to treat elevated intracranial pressure (ICP). Fiberoptic ICP add neuromuscular paralysis if necessary (patient will
and brain tissue oxygen monitors are usually secured using a require endotracheal intubation and mechanical venti-
screwlike skull bolt. Cerebral blood ow and microdialysis lation at this point, if not before)
probes (not shown) may be placed in a manner similar to the 6. Hyperventilationto Paco2 3035 mmHg
brain tissue oxygen probe. 7. Pressor therapyphenylephrine, dopamine, or
norepinephrine to maintain adequate MAP to ensure
CPP 60 mmHg (maintain euvolemia to minimize
deleterious systemic effects of pressors)
Diseases of the Central Nervous System

8. Consider second-tier therapies for refractory elevated

CSF and blood volume can be redistributed initially, ICP
by the time elevated ICP occurs intracranial compli- a. High-dose barbiturate therapy (pentobarb coma)
ance is severely impaired. At this point, any small b. Aggressive hyperventilation to Paco2 <30 mmHg
c. Hypothermia
increase in the volume of CSF, intravascular blood,
d. Hemicraniectomy
edema, or a mass lesion may result in a signicant
increase in ICP and a decrease in cerebral perfusion. a
Throughout ICP treatment algorithm, consider repeat head CT to
This is a fundamental mechanism of secondary identify mass lesions amenable to surgical evacuation.
ischemic brain injury and constitutes an emergency Note: CPP, cerebral perfusion pressure; CSF, cerebrospinal uid;
that requires immediate attention. In general, ICP MAP, mean arterial pressure; Paco2, arterial partial pressure of carbon
should be maintained at <20 mm Hg and CPP dioxide.
should be maintained at >60 mm Hg.
Interventions to lower ICP are ideally based on the
underlying mechanism responsible for the elevated
ICP (Table 22-2). For example, in hydrocephalus studies may reveal evidence of edema and mass effect.
from SAH, the principal cause of elevated ICP is Hypotonic IV uids should be avoided, and elevation
impairment of CSF drainage. In this setting, ventricu- of the head of the bed is recommended. Patients must
lar drainage of CSF is likely to be sufcient and most be carefully observed for risk of aspiration and com-
appropriate. In head trauma and stroke, cytotoxic promise of the airway as the level of alertness
edema may be most responsible, and the use of declines. Coma and unilateral pupillary changes are
osmotic diuretics such as mannitol becomes an late signs and require immediate intervention. Emer-
appropriate early step. As described above, elevated gent treatment of elevated ICP is most quickly
ICP may cause tissue ischemia, and, if cerebral achieved by intubation and hyperventilation, which
autoregulation is intact, the resulting vasodilatation causes vasoconstriction and reduces cerebral blood
can lead to a cycle of worsening ischemia. Paradoxi- volume. In order to avoid provoking or worsening
cally, administration of vasopressor agents to increase cerebral ischemia, hyperventilation is best used for
mean arterial pressure may actually lower ICP by short periods of time until a more denitive treat-
improving perfusion, thereby allowing autoregulatory ment can be instituted. Furthermore, the effects of
vasoconstriction as ischemia is relieved and ultimately hyperventilation on ICP are short-lived, often lasting
decreasing intracranial blood volume. only for several hours because of the buffering capac-
Early signs of elevated ICP include drowsiness and ity of the cerebral interstitium, and rebound eleva-
a diminished level of consciousness. Neuroimaging tions of ICP may accompany abrupt discontinuation
of hyperventilation. As the level of consciousness CRITICAL CARE DISORDERS OF THE 287
declines to coma, the ability to follow the neurologic CENTRAL NERVOUS SYSTEM
status of the patient by examination deteriorates and
measurement of ICP assumes greater importance. If a HYPOXIC-ISCHEMIC ENCEPHALOPATHY
ventriculostomy device is in place, direct drainage of This occurs from lack of delivery of oxygen to the brain
CSF to reduce ICP is possible. Finally, high-dose bar- because of hypotension or respiratory failure. Causes
biturates, decompressive hemicraniectomy, or hypother- include myocardial infarction, cardiac arrest, shock, asphyx-
mia are sometimes used for refractory elevations of iation, paralysis of respiration, and carbon monoxide or
ICP, although these have signicant side effects and cyanide poisoning. In some circumstances, hypoxia may
have not been proven to improve outcome. predominate. Carbon monoxide and cyanide poisoning
are termed histotoxic hypoxia since they cause a direct
SECONDARY BRAIN INSULTS Patients with impairment of the respiratory chain.
primary brain injuries, whether due to trauma or
stroke, are at risk for ongoing secondary ischemic brain
injury. Because secondary brain injury can be a major Clinical Manifestations
determinant of a poor outcome, strategies for minimiz- Mild degrees of pure hypoxia, such as occur at high alti-

CHAPTER 22
ing secondary brain insults are an integral part of the tudes, cause impaired judgment, inattentiveness, motor
critical care of all patients.While elevated ICP may lead incoordination, and, at times, euphoria. However, with
to secondary ischemia, most secondary brain injury is hypoxia-ischemia, such as occurs with circulatory arrest,
mediated through other clinical events that exacerbate consciousness is lost within seconds. If circulation is
the ischemic cascade already initiated by the primary restored within 35 min, full recovery may occur, but if
brain injury. Episodes of secondary brain insults are hypoxia-ischemia lasts beyond 35 min, some degree of
usually not associated with apparent neurologic wors-

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

permanent cerebral damage is the rule. Except in
ening. Rather, they lead to cumulative injury, which extreme cases, it may be difcult to judge the precise
manifests as higher mortality or worsened long-term degree of hypoxia-ischemia, and some patients make a
functional outcome. Thus, close monitoring of vital relatively full recovery after even 810 min of global
signs is important, as is early intervention to prevent cerebral ischemia.The distinction between pure hypoxia
secondary ischemia. Avoiding hypotension and hypoxia and hypoxia-ischemia is important, since a Pao2 as low as
is critical, as signicant hypotensive events (systolic 20 mmHg (2.7 kPa) can be well tolerated if it develops
blood pressure <90 mm Hg) as short as 10 min in gradually and normal blood pressure is maintained, but
duration have been shown to adversely inuence out- short durations of very low or absent cerebral circula-
come after traumatic brain injury. Even in patients with tion may result in permanent impairment.
stroke or head trauma who do not require ICP moni- Clinical examination at different time points after a
toring, close attention to adequate cerebral perfusion is hypoxic-ischemic insult (especially cardiac arrest) is useful
warranted. Hypoxia (pulse oximetry saturation < 90%), in assessing prognosis for long-term neurologic outcome.
particularly in combination with hypotension, also leads The prognosis is better for patients with intact brainstem
to secondary brain injury. Likewise, fever and hyper- function, as indicated by normal pupillary light responses
glycemia both worsen experimental ischemia and have and intact oculocephalic (dolls-eyes), oculovestibular
been associated with worsened clinical outcome after (caloric), and corneal reexes (Fig. 22-4). Absence of
stroke and head trauma.Aggressive control of fever with these reexes and the presence of persistently dilated
a goal of normothermia is warranted but may be dif- pupils that do not react to light are grave prognostic signs.
cult to achieve with antipyretic medications and cool- A uniformly dismal prognosis from hypoxic-ischemic
ing blankets.The value of newer surface or intravascular coma is conveyed by an absent pupillary light reex or
temperature control devices for the management of extensor or absent motor response to pain on day 3 fol-
refractory fever is under investigation. The use of IV lowing the injury. Electrophysiologically, the bilateral absence
insulin infusion is encouraged for control of hyper- of the N20 component of the somatosensory evoked
glycemia as this allows better regulation of serum glu- response (SSEPs) in the rst several days also conveys a
cose levels than subcutaneous insulin. A reasonable goal poor prognosis.A very elevated serum level (>33 g/L) of
is to maintain the serum glucose level at <7.8 mmol/L the biochemical marker neuron-specic enolase (NSE) is
(<140 mg/dL), although some have suggested that even indicative of brain damage after resuscitation from cardiac
tighter control is warranted. New cerebral monitoring arrest and predicts a poor outcome. However, at present,
tools that allow continuous evaluation of brain tissue SSEPs and NSE levels may be difcult to obtain in a
oxygen tension, CBF, and metabolism (via microdialysis) timely fashion, with SSEP testing requiring substantial
may further improve the management of secondary expertise in interpretation and NSE measurements not yet
brain injury. standardized.Whether administration of mild hypothermia
 288
Coma

Exclude major confounders

No brain stem reflexes at Yes Brain death

any time (pupil, cornea,
testing
oculocephalic, cough)
or
Yes FPR
Day 1 Poor
0%
Myoclonus, status epilepticus outcome
(08.8)
or
Day 13 Yes FPR
Poor
SSEP 0.7%
outcome
absent N20 responses (03.7)
or

Day 13 Yes FPR

Poor
Serum NSE > 33 g/L outcome
0%
(03)
or
SECTION III

Day 3
Absent pupil or corneal Yes FPR
Poor
0%
FIGURE 22-5
reflexes; extensor or absent outcome
motor response (03) Cortical laminar necrosis in hypoxic-ischemic encephalopa-
no
thy. T1-weighted postcontrast MRI shows cortical enhance-
ment in a watershed distribution consistent with laminar
Indeterminate outcome
necrosis.
Diseases of the Central Nervous System

FIGURE 22-4
Prognostication of outcome in comatose survivors of car-
diopulmonary resuscitation. Numbers in parentheses are 95% or brainstem. In some cases, extensive bilateral thalamic
condence intervals. Confounders could include use of scarring may affect pathways that mediate arousal, and
sedatives or neuromuscular blocking agents, hypothermia this pathology may be responsible for the persistent veg-
therapy, organ failure, or shock. Tests denoted with an * may etative state. A specic form of hypoxic-ischemic
not be available in a timely and standardized manner. SSEP, encephalopathy, so-called watershed infarcts, occurs at
somatosensory evoked potentials; NSE, neuron-specic the distal territories between the major cerebral arteries
enolase; FPR, false-positive rate. (From Wijdicks et al, with and can cause cognitive decits, including visual agnosia,
permission.) and weakness that is greater in proximal than in distal
muscle groups.

Diagnosis
after cardiac arrest (see Treatment) will alter the usefulness Diagnosis is based upon the history of a hypoxic-
of these clinical and electrophysiologic predictors is ischemic event such as cardiac arrest. Blood pressure
unknown. Long-term consequences of hypoxic-ischemic <70 mmHg systolic or Pao2 <40 mmHg is usually nec-
encephalopathy include persistent coma or a vegetative essary, although both absolute levels as well as duration
state (Chap. 14), dementia, visual agnosia (Chap. 15), of exposure are important determinants of cellular
parkinsonism, choreoathetosis, cerebellar ataxia, myoclonus, injury. Carbon monoxide intoxication can be conrmed
seizures, and an amnestic state, which may be a conse- by measurement of carboxyhemoglobin and is suggested
quence of selective damage to the hippocampus. by a cherry red color of the skin, although the latter is
an inconsistent clinical nding.
Pathology
Principal histologic ndings are extensive multifocal or Treatment:
diffuse laminar cortical necrosis (Fig. 22-5), with almost HYPOXIC-ISCHEMIC ENCEPHALOPATHY
invariable involvement of the hippocampus. The hip-
Treatment should be directed at restoration of normal
pocampal CA1 neurons are vulnerable to even brief
cardiorespiratory function. This includes securing a clear
episodes of hypoxia-ischemia, perhaps explaining why
airway, ensuring adequate oxygenation and ventilation,
selective persistent memory decits may occur after brief
and restoring cerebral perfusion, whether by cardiopul-
cardiac arrest. Scattered small areas of infarction or neuronal
monary resuscitation, uid, pressors, or cardiac pacing.
loss may be present in the basal ganglia, hypothalamus,
 Hypothermia may target the neuronal cell injury cascade disturbance. This is often attributed to medication 289
and has substantial neuroprotective properties in experi- effects, sleep deprivation, pain, and anxiety. The term
mental models of brain injury. In two trials, mild ICU psychosis has been used to describe a mental state
hypothermia (33C) improved functional outcome in with profound agitation occurring in this setting. The
patients who remained comatose after resuscitation presence of family members in the ICU may help to
from a cardiac arrest. Treatment was initiated within min- calm and orient agitated patients, and in severe cases,
utes of cardiac resuscitation and continued for 12 h in low doses of neuroleptics (e.g., haloperidol 0.51 mg)
one study and 24 h in the other. Potential complications can be useful. Ultimately, the psychosis resolves with
of hypothermia include coagulopathy and an increased improvement in the underlying illness and a return to
risk of infection. Based upon these studies, the Interna- familiar surroundings.
tional Liaison Committee on Resuscitation issued the fol- In the ICU setting, several metabolic causes of an
lowing advisory statement in 2003: Unconscious adult altered level of consciousness predominate. Hypercarbic
patients with spontaneous circulation after out-of-hospital encephalopathy can present with headache, confusion,
cardiac arrest should be cooled to 3234C for 1224 h stupor, or coma. Hypoventilation syndrome occurs most
when the initial rhythm was ventricular brillation. frequently in patients with a history of chronic CO2
Severe carbon monoxide intoxication may be treated retention who are receiving oxygen therapy for emphy-
sema or chronic pulmonary disease. The elevated Paco2

CHAPTER 22
with hyperbaric oxygen. Anticonvulsants may be needed
to control seizures, although these are not usually given leading to CO2 narcosis may have a direct anesthetic
prophylactically. Posthypoxic myoclonus may respond to effect, and cerebral vasodilatation from increased Paco2
oral administration of clonazepam at doses of 1.510 mg can lead to increased ICP. Hepatic encephalopathy is
daily or valproate at doses of 3001200 mg daily in suggested by asterixis and can occur in chronic liver fail-
divided doses. Myoclonic status epilepticus within 24 h ure or acute fulminant hepatic failure. Both hyper-
after a primary circulatory arrest portends a universally glycemia and hypoglycemia can cause encephalopathy, as

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

poor prognosis, even if seizures are controlled. can hypernatremia and hyponatremia. Confusion, impair-
ment of eye movements, and gait ataxia are the hallmarks
of acute Wernickes disease (see later in the chapter).

SEPTIC ENCEPHALOPATHY
DELAYED POSTANOXIC ENCEPHALOPATHY
Pathogenesis
Delayed postanoxic encephalopathy is an uncommon
phenomenon in which patients appear to make an ini- In patients with sepsis, the systemic response to infectious
tial recovery from hypoxic-ischemic insult but then agents leads to the release of circulating inammatory
develop a relapse characterized by apathy, confusion, and mediators that appear to contribute to encephalopathy.
agitation. Progressive neurologic decits may include Critical illness, in association with the systemic inamma-
shufing gait, diffuse rigidity and spasticity, persistent tory response syndrome (SIRS), can lead to multisystem
parkinsonism or myoclonus, and, on occasion, coma and organ failure. This syndrome can occur in the setting of
death after 12 weeks. Widespread cerebral demyelina- apparent sepsis, severe burns, or trauma, even without clear
tion may be present. identication of an infectious agent. Many patients with
Carbon monoxide and cyanide intoxication can also critical illness, sepsis, or SIRS develop encephalopathy
cause a delayed encephalopathy. Little clinical impairment without obvious explanation. This condition is broadly
is evident when the patient rst regains consciousness, termed septic encephalopathy. While the specic mediators
but a parkinsonian syndrome characterized by akinesia leading to neurologic dysfunction remain uncertain, it is
and rigidity without tremor may develop. Symptoms clear that the encephalopathy is not simply the result of
can worsen over months, accompanied by increasing metabolic derangements of multiorgan failure. The
evidence of damage in the basal ganglia as seen on both cytokines tumor necrosis factor , interleukin (IL) 1, IL-2,
CT and MRI. and IL-6 are thought to play a role in this syndrome.

METABOLIC ENCEPHALOPATHIES Diagnosis

Altered mental states, variously described as confusion, Septic encephalopathy presents clinically as a diffuse
delirium, disorientation, and encephalopathy, are present dysfunction of the brain without prominent focal nd-
in many patients with severe illness in an intensive care ings. Confusion, disorientation, agitation, and uctuations
unit (ICU). Older patients are particularly vulnerable to in level of alertness are typical. In more profound cases,
delirium, a confusional state characterized by disordered especially with hemodynamic compromise, the decrease
perception, frequent hallucinations, delusions, and sleep in level of alertness can be more prominent, at times
 290 resulting in coma. Hyperreexia and frontal release signs should aim for gradual correction, i.e., by 10 mmol/L
such as a grasp or snout reex (Chap. 15) can be seen. (10 meq/L) within 24 h and 20 mmol/L (20 meq/L)
Abnormal movements such as myoclonus, tremor, or within 48 h.
asterixis can occur. Septic encephalopathy is quite com-
mon, occurring in the majority of patients with sepsis
WERNICKES DISEASE
and multisystem organ failure. Diagnosis is often difcult
because of the multiple potential causes of neurologic Wernickes disease is a common and preventable disor-
dysfunction in critically ill patients and requires exclu- der due to a deciency of thiamine. In the United States,
sion of structural, metabolic, toxic, and infectious (e.g., alcoholics account for most cases, but patients with mal-
meningitis or encephalitis) causes. The mortality of nutrition due to hyperemesis, starvation, renal dialysis,
patients with septic encephalopathy severe enough to cancer, AIDS, or rarely gastric surgery are also at risk.
produce coma approaches 50%, although this principally The characteristic clinical triad is that of ophthalmople-
reects the severity of the underlying critical illness and gia, ataxia, and global confusion. However, only one-
is not a singular result of the septic encephalopathy. third of patients with acute Wernickes disease present
Patients dying from severe sepsis or septic shock may with the classic clinical triad. Most patients are profoundly
have elevated levels of the serum brain injury biomarker disoriented, indifferent, and inattentive, although rarely
S-100 and neuropathologic ndings of neuronal apop- they have an agitated delirium related to ethanol with-
SECTION III

tosis and cerebral ischemic injury. However, successful drawal. If the disease is not treated, stupor, coma, and
treatment of the underlying critical illness almost always death may ensue. Ocular motor abnormalities include
results in complete resolution of the encephalopathy, horizontal nystagmus on lateral gaze, lateral rectus palsy
with profound long-term cognitive disability being (usually bilateral), conjugate gaze palsies, and rarely pto-
uncommon. sis. Gait ataxia probably results from a combination of
polyneuropathy, cerebellar involvement, and vestibular
Diseases of the Central Nervous System

paresis. The pupils are usually spared, but they may

CENTRAL PONTINE MYELINOLYSIS
become miotic with advanced disease.
This disorder typically presents in a devastating fashion Wernickes disease is usually associated with other
as quadriplegia and pseudobulbar palsy. Predisposing fac- manifestations of nutritional disease, such as polyneu-
tors include severe underlying medical illness or nutri- ropathy. Rarely, amblyopia or myelopathy occurs.Tachy-
tional deciency; most cases are associated with rapid cor- cardia and postural hypotension may be related to
rection of hyponatremia or with hyperosmolar states. impaired function of the autonomic nervous system or
The pathology consists of demyelination without inam- to the coexistence of cardiovascular beriberi. Patients
mation in the base of the pons, with relative sparing of who recover show improvement in ocular palsies within
axons and nerve cells. MRI is useful in establishing the hours after the administration of thiamine, but horizon-
diagnosis (Fig. 22-6) and may also identify partial forms tal nystagmus may persist. Ataxia improves more slowly
that present as confusion, dysarthria, and/or disturbances than the ocular motor abnormalities. Approximately half
of conjugate gaze without quadriplegia. Occasional cases recover incompletely and are left with a slow, shufing,
present with lesions outside of the brainstem. Therapeu- wide-based gait and an inability to tandem walk. Apathy,
tic guidelines for the restoration of severe hyponatremia drowsiness, and confusion improve more gradually. As
these symptoms recede, an amnestic state with impair-
ment in recent memory and learning may become more
apparent (Korsakoffs psychosis). Korsakoff s psychosis is
frequently persistent; the residual mental state is charac-
terized by gaps in memory, confabulation, and disor-
dered temporal sequencing.

Pathology
Periventricular lesions surround the third ventricle,
aqueduct, and fourth ventricle, with petechial hemor-
rhages in occasional acute cases and atrophy of the
mammillary bodies in most chronic cases. There is fre-
quently endothelial proliferation, demyelination, and
FIGURE 22-6 some neuronal loss. These changes may be detected by
Central pontine myelinolysis. Axial T2-weighted MR scan MRI scanning (Fig. 22-7). The amnestic defect is
through the pons reveals a symmetric area of abnormal high related to lesions in the dorsal medial nuclei of the
signal intensity within the basis pontis (arrows). thalamus.
 (2) secondary PNS manifestations of systemic critical 291
illness, often involving multisystem organ failure. The
former include acute polyneuropathies such as Guillain-
Barr syndrome (Chap. 41), neuromuscular junction
disorders including myasthenia gravis (Chap. 42) and bot-
ulism, and primary muscle disorders such as polymyositis
(Chap. 44). The latter result either from the systemic dis-
ease itself or as a consequence of interventions.
General principles of respiratory evaluation in patients
with PNS involvement, regardless of cause, include assess-
ment of pulmonary mechanics, such as maximal inspiratory
force (MIF) and vital capacity (VC), and evaluation of
strength of bulbar muscles. Regardless of the cause of
weakness, endotracheal intubation should be considered
FIGURE 22-7 when the MIF falls to <25 cmH2O or the VC is <1 L.
Wernickes disease. Coronal T1-weighted postcontrast MRI Also, patients with severe palatal weakness may require
reveals abnormal enhancement of the mammillary bodies endotracheal intubation in order to prevent acute upper

CHAPTER 22
(arrows), typical of acute Wernickes encephalopathy.
airway obstruction or recurrent aspiration. Arterial blood
gases and oxygen saturation from pulse oximetry are used
to follow patients with potential respiratory compromise
Pathogenesis from PNS dysfunction. However, intubation and mechani-
cal ventilation should be undertaken based on clinical
Thiamine is a cofactor of several enzymes, including trans-
assessment rather than waiting until oxygen saturation
ketolase, pyruvate dehydrogenase, and -ketoglutarate

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

drops or CO2 retention develops from hypoventilation.
dehydrogenase. Thiamine deciency produces a diffuse
Noninvasive mechanical ventilation may be considered
decrease in cerebral glucose utilization and results in
initially in lieu of endotracheal intubation but is generally
mitochondrial damage. Glutamate accumulates owing to
insufcient in patients with severe bulbar weakness or
impairment of -ketoglutarate dehydrogenase activity
ventilatory failure with hypercarbia.
and, in combination with the energy deciency, may
result in excitotoxic cell damage.
NEUROPATHY
Although encephalopathy may be the most obvious
neurologic dysfunction in critically ill patients, dysfunc-
Treatment: tion of the PNS is also quite common. It is typically
WERNICKES DISEASE present in patients with prolonged critical illnesses last-
Wernickes disease is a medical emergency and requires ing several weeks and involving sepsis; clinical suspicion
immediate administration of thiamine, in a dose of 100 mg is aroused when there is failure to wean from mechani-
either IV or IM. The dose should be given daily until the cal ventilation despite improvement of the underlying
patient resumes a normal diet and should be begun sepsis and critical illness. Critical illness polyneuropathy
prior to treatment with IV glucose solutions. Glucose refers to the most common PNS complication related to
infusions may precipitate Wernickes disease in a previ- critical illness; it is seen in the setting of prolonged criti-
ously unaffected patient or cause a rapid worsening of cal illness, sepsis, and multisystem organ failure. Neuro-
an early form of the disease. For this reason, thiamine logic ndings include diffuse weakness, decreased reexes,
should be administered to all alcoholic patients requir- and distal sensory loss. Electrophysiologic studies demon-
ing parenteral glucose. strate a diffuse, symmetric, distal axonal sensorimotor
neuropathy, and pathologic studies have conrmed axonal
degeneration. The precise mechanism of critical illness
polyneuropathy remains unclear, but circulating factors
such as cytokines, which are associated with sepsis and
CRITICAL CARE DISORDERS OF THE SIRS, are thought to play a role. It has been reported
PERIPHERAL NERVOUS SYSTEM that up to 70% of patients with the sepsis syndrome
have some degree of neuropathy, although far fewer
Critical illness with disorders of the peripheral nervous have a clinical syndrome profound enough to cause
system (PNS) arises in two contexts: (1) primary neuro- severe respiratory muscle weakness requiring prolonged
logic diseases that require critical care interventions mechanical ventilation or resulting in failure to wean.
such as intubation and mechanical ventilation, and Recent studies suggest that aggressive glycemic control
 292 with insulin infusions decreases the risk of critical illness muscle biopsy may be normal initially but eventually
polyneuropathy. Treatment is supportive, with specic show abnormal spontaneous activity and panfascicular
intervention directed at treating the underlying illness. necrosis with an accompanying inammatory reaction.
While spontaneous recovery is usually seen, the time Both of these myopathic syndromes may be considered
course may extend over weeks to months and necessi- under the broader heading of critical illness myopathy.
tate long-term ventilatory support and care even after Acute quadriplegic myopathy describes a clinical syn-
the underlying critical illness has resolved. drome of severe weakness seen in the setting of glucocor-
ticoid and nd-NMBA use.The most frequent scenario in
which this is encountered is the asthmatic patient who
DISORDERS OF NEUROMUSCULAR
requires high-dose glucocorticoids and nd-NMBA to
TRANSMISSION
facilitate mechanical ventilation. This muscle disorder is
A defect in neuromuscular transmission may be a source not due to prolonged action of nd-NMBAs at the neu-
of weakness in critically ill patients. Myasthenia gravis romuscular junction but, rather, is an actual myopathy
may be a consideration; however, persistent weakness with muscle damage; it has occasionally been described
secondary to impaired neuromuscular junction transmis- with high-dose glucocorticoid use alone. Clinically this
sion is almost always due to administration of drugs. A syndrome is most often recognized when a patient fails
number of medications impair neuromuscular transmis- to wean from mechanical ventilation despite resolution
SECTION III

sion; these include antibiotics, especially aminoglycosides, of the primary pulmonary process. Pathologically, there
and beta-blocking agents. In the ICU, the nondepolariz- may be vacuolar changes in both type I and type II mus-
ing neuromuscular blocking agents (nd-NMBAs), also cle bers with evidence of regeneration. Acute quadri-
known as muscle relaxants, are most commonly respon- plegic myopathy has a good prognosis. If patients survive
sible. Included in this group of drugs are such agents as their underlying critical illness, the myopathy invariably
pancuronium, vecuronium, rocuronium, and atracurium. improves and most patients return to normal. However,
Diseases of the Central Nervous System

They are often used to facilitate mechanical ventilation because this syndrome is a result of true muscle damage,
or other critical care procedures, but with prolonged use not just prolonged blockade at the neuromuscular junc-
persistent neuromuscular blockade may result in weak- tion, this process may take weeks or months, and tra-
ness even after discontinuation of these agents hours or cheostomy with prolonged ventilatory support may be
days earlier. Risk factors for this prolonged action of necessary. Some patients do have residual long-term
neuromuscular blocking agents include female sex, meta- weakness, with atrophy and fatigue limiting ambulation.
bolic acidosis, and renal failure. At present, it is unclear how to prevent this myopathic
Prolonged neuromuscular blockade does not appear complication, except by avoiding use of nd-NMBAs, a
to produce permanent damage to the PNS. Once the strategy not always possible. Monitoring with a periph-
offending medications are discontinued, full strength is eral nerve stimulator can help to avoid the overuse of
restored, although this may take days. In general, the low- these agents. However, this is more likely to prevent the
est dose of neuromuscular blocking agent should be used complication of prolonged neuromuscular junction
to achieve the desired result, and, when these agents are blockade than it is to prevent this myopathy.
used in the ICU, a peripheral nerve stimulator should be
used to monitor neuromuscular junction function.
SUBARACHNOID HEMORRHAGE
MYOPATHY
Subarachnoid hemorrhage (SAH) renders the brain crit-
Critically ill patients, especially those with sepsis, fre- ically ill from both primary and secondary brain insults.
quently develop muscle wasting, often in the face of Excluding head trauma, the most common cause of
seemingly adequate nutritional support. The assumption SAH is rupture of a saccular aneurysm. Other causes
has been that this represents a catabolic myopathy include bleeding from a vascular malformation (arteri-
brought about as a result of multiple factors, including ovenous malformation or dural arterial-venous stula)
elevated cortisol and catecholamine release and other cir- and extension into the subarachnoid space from a pri-
culating factors induced by the SIRS. In this syndrome, mary intracerebral hemorrhage. Some idiopathic SAHs
known as cachectic myopathy, serum creatine kinase levels are localized to the perimesencephalic cisterns and are
and electromyography (EMG) are normal. Muscle biopsy benign; they probably have a venous or capillary source,
shows type II ber atrophy. Panfascicular muscle ber and angiography is unrevealing.
necrosis may also occur in the setting of profound sepsis.
This so-called septic myopathy is characterized clinically
Saccular (Berry) Aneurysm
by weakness progressing to a profound level over just a
few days. There may be associated elevations in serum Autopsy and angiography studies have found that about
creatine kinase and urine myoglobin. Both EMG and 2% of adults harbor intracranial aneurysms, for a prevalence
of 4 million persons in the United States; the aneurysm site of rupture (most often the dome) the wall thins, 293
will rupture, producing SAH, in 25,00030,000 cases and the tear that allows bleeding is often 0.5 mm
per year. For patients who arrive alive at hospital, the long. Aneurysm size and site are important in predicting
mortality rate over the next month is about 45%. Of risk of rupture. Those >7 mm in diameter and those at
those who survive, more than half are left with major the top of the basilar artery and at the origin of the
neurologic decits as a result of the initial hemorrhage, posterior communicating artery are at greater risk of
cerebral vasospasm with infarction, or hydrocephalus. If rupture.
the patient survives but the aneurysm is not obliterated,
the rate of rebleeding is about 20% in the rst 2 weeks, Clinical Manifestations
30% in the rst month, and about 3% per year afterwards. Most unruptured intracranial aneurysms are completely
Given these alarming gures, the major therapeutic asymptomatic. Symptoms are usually due to rupture
emphasis is on preventing the predictable early complica- and resultant SAH, although some present with mass
tions of the SAH. effect on cranial nerves or brain parenchyma. At the
Unruptured, asymptomatic aneurysms are much less moment of aneurysmal rupture with major SAH, the
dangerous than a recently ruptured aneurysm. The ICP suddenly rises. This may account for the sudden
annual risk of rupture for aneurysms <10 mm in size is transient loss of consciousness that occurs in nearly half
~0.1%, and for aneurysms 10 mm in size is ~0.51%; of patients. Sudden loss of consciousness may be pre-

CHAPTER 22
the surgical morbidity far exceeds these percentages. ceded by a brief moment of excruciating headache, but
Because of the longer length of exposure to risk of rup- most patients rst complain of headache upon regain-
ture, younger patients with aneurysms >10 mm in size ing consciousness. In 10% of cases, aneurysmal bleeding
may benet from prophylactic treatment. As with the is severe enough to cause loss of consciousness for sev-
treatment of asymptomatic carotid stenosis, this risk- eral days. In ~45% of cases, severe headache associated
benet strongly depends on the complication rate of with exertion is the presenting complaint. The patient

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

treatment. often calls the headache the worst headache of my
Giant aneurysms, those >2.5 cm in diameter, occur at life; however, the most important characteristic is sud-
the same sites (see later) as small aneurysms and account den onset. Occasionally these ruptures may present as
for 5% of cases. The three most common locations are headache of only moderate intensity or as a change in
the terminal internal carotid artery, middle cerebral the patients usual headache pattern. The headache is
artery (MCA) bifurcation, and top of the basilar artery. usually generalized, often with neck stiffness, and vom-
Their risk of rupture is ~6% in the rst year after identi- iting is common.
cation and may remain high indenitely. They often Although sudden headache in the absence of focal
cause symptoms by compressing the adjacent brain or neurologic symptoms is the hallmark of aneurysmal
cranial nerves. rupture, focal neurologic decits may occur. Anterior
Mycotic aneurysms are usually located distal to the communicating artery or MCA bifurcation aneurysms
rst bifurcation of major arteries of the circle of Willis. may rupture into the adjacent brain or subdural space
Most result from infected emboli due to bacterial endo- and form a hematoma large enough to produce mass
carditis causing septic degeneration of arteries and sub- effect. The common decits that result include hemi-
sequent dilatation and rupture. Whether these lesions paresis, aphasia, and abulia.
should be sought and repaired prior to rupture or left to Occasionally, prodromal symptoms suggest the loca-
heal spontaneously is controversial. tion of a progressively enlarging unruptured aneurysm.
A third cranial nerve palsy, particularly when associated
Pathophysiology with pupillary dilatation, loss of ipsilateral (but retained
Saccular aneurysms occur at the bifurcations of the contralateral) light reex, and focal pain above or behind
large to medium-sized intracranial arteries; rupture is the eye, may occur with an expanding aneurysm at the
into the subarachnoid space in the basal cisterns and junction of the posterior communicating artery and the
often into the parenchyma of the adjacent brain. internal carotid artery. A sixth nerve palsy may indicate
Approximately 85% of aneurysms occur in the anterior an aneurysm in the cavernous sinus, and visual eld
circulation, mostly on the circle of Willis. About 20% of defects can occur with an expanding supraclinoid
patients have multiple aneurysms, many at mirror sites carotid or anterior cerebral artery aneurysm. Occipital
bilaterally. As an aneurysm develops, it typically forms a and posterior cervical pain may signal a posterior infe-
neck with a dome. The length of the neck and the size rior cerebellar artery or anterior inferior cerebellar
of the dome vary greatly and are factors that are impor- artery aneurysm. Pain in or behind the eye and in the
tant in planning neurosurgical obliteration or endovas- low temple can occur with an expanding MCA
cular embolization. The arterial internal elastic lamina aneurysm.Thunderclap headache is a variant of migraine
disappears at the base of the neck.The media thins, and that simulates a SAH. Before concluding that a patient
connective tissue replaces smooth-muscle cells. At the with sudden, severe headache has thunderclap migraine,
 294 TABLE 22-3
GRADING SCALES FOR SUBARACHNOID HEMORRHAGE

WORLD FEDERATION OF NEUROSURGICAL

GRADE HUNT-HESS SCALE SOCIETIES (WFNS) SCALE

1 Mild headache, normal mental Glasgow Coma Scalea (GCS) score 15, no
status, no cranial nerve or motor motor decits
ndings
2 Severe headache, normal mental GCS 1314, no motor decits
status, may have cranial nerve
decit
3 Somnolent, confused, may have GCS 1314, with motor decits
cranial nerve or mild motor decit
4 Stupor, moderate to severe motor GCS 712, with or without motor decits
decit, may have intermittent
reex posturing
5 Coma, reex posturing or accid GCS 36, with or without motor decits

a
SECTION III

Glasgow Coma Scale: See Table 31-2.

a denitive workup for aneurysm or other intracranial hydrocephalus may develop weeks to months after
pathology is required. SAH and manifest as gait difculty, incontinence, or
Aneurysms can undergo small ruptures and leaks of impaired mentation. Subtle signs may be a lack of
initiative in conversation or a failure to recover
Diseases of the Central Nervous System

blood into the subarachnoid space, so-called sentinel

bleeds. Sudden unexplained headache at any location independence.
should raise suspicion of SAH and be investigated, 3. Vasospasm. Narrowing of the arteries at the base of
because a major hemorrhage may be imminent. the brain following SAH causes symptomatic
The initial clinical manifestations of SAH can be graded ischemia and infarction in ~30% of patients and is the
using the Hunt-Hess or World Federation of Neurosurgi- major cause of delayed morbidity and death. Signs of
cal Societies classication schemes (Table 22-3). For rup- ischemia appear 414 days after the hemorrhage,
tured aneurysms, prognosis for good outcomes falls as most often at 7 days.The severity and distribution of
the grade increases. For example it is unusual for a vasospasm determine whether infarction will occur.
Hunt-Hess grade 1 patient to die if the aneurysm is Delayed vasospasm is believed to result from
treated, but the mortality for grade 4 and 5 patients may direct effects of clotted blood and its breakdown
be as high as 80%. products on the arteries within the subarachnoid
space. In general, the more blood that surrounds the
Delayed Neurologic Decits arteries, the greater the chance of symptomatic
There are four major causes of delayed neurologic decits: vasospasm. Spasm of major arteries produces symp-
rerupture, hydrocephalus, vasospasm, and hyponatremia. toms referable to the appropriate vascular territory
(Chap. 21). All of these focal symptoms may present
1. Rerupture. The incidence of rerupture of an abruptly, uctuate, or develop over a few days. In
untreated aneurysm in the rst month following most cases, focal spasm is preceded by a decline in
SAH is ~30%, with the peak in the rst 7 days. mental status.
Rerupture is associated with a 60% mortality and Vasospasm can be detected reliably with conven-
poor outcome. Early treatment eliminates this risk. tional x-ray angiography, but this invasive procedure
2. Hydrocephalus. Acute hydrocephalus can cause stupor is expensive and carries the risk of stroke and other
and coma and can be mitigated by placement of an complications. TCD ultrasound is based on the
external ventricular drain. More often, subacute principle that the velocity of blood ow within an
hydrocephalus may develop over a few days or artery will rise as the lumen diameter is narrowed.
weeks and causes progressive drowsiness or slowed By directing the probe along the MCA and proxi-
mentation (abulia) with incontinence. Hydro- mal anterior cerebral artery (ACA), carotid termi-
cephalus is differentiated from cerebral vasospasm nus, and vertebral and basilar arteries on a daily or
with a CT scan, CT angiogram, transcranial Doppler every-other-day basis, vasospasm can be reliably
(TCD) ultrasound, or conventional x-ray angiogra- detected and treatments initiated to prevent cerebral
phy. Hydrocephalus may clear spontaneously or ischemia (see later). CT angiography is another
require temporary ventricular drainage. Chronic method that can detect vasospasm.
 Severe cerebral edema in patients with infarction blood to be visualized on a high-quality noncontrast 295
from vasospasm may increase the ICP enough to reduce CT scan obtained within 72 h. If the scan fails to estab-
cerebral perfusion pressure. Treatment may include lish the diagnosis of SAH and no mass lesion or
mannitol, hyperventilation, and hemicraniectomy; obstructive hydrocephalus is found, a lumbar puncture
moderate hypothermia may have a role as well. should be performed to establish the presence of sub-
4. Hyponatremia. Hyponatremia may be profound and arachnoid blood. Lysis of the red blood cells and subse-
can develop quickly in the rst 2 weeks following quent conversion of hemoglobin to bilirubin stains the
SAH. There is both natriuresis and volume deple- spinal uid yellow within 612 h. This xanthochromic
tion with SAH, so that patients become both spinal uid peaks in intensity at 48 h and lasts for 14
hyponatremic and hypovolemic. Both atrial natri- weeks, depending on the amount of subarachnoid
uretic peptide and brain natriuretic peptide have a blood.
role in producing this cerebral salt-wasting syn- The extent and location of subarachnoid blood on
drome. Typically it clears over the course of 12 noncontrast CT scan help locate the underlying
weeks and, in the setting of SAH, should not be aneurysm, identify the cause of any neurologic decit,
treated with free-water restriction as this may and predict delayed vasospasm.A high incidence of symp-
increase the risk of stroke (see later). tomatic vasospasm in the MCA and ACA has been found
when early CT scans show subarachnoid clots >5 3

CHAPTER 22
Laboratory Evaluation and Imaging mm in the basal cisterns or layers of blood >1 mm thick
(Fig. 22-8) The hallmark of aneurysmal rupture is in the cerebral ssures. CT scans less reliably predict
blood in the CSF. More than 95% of cases have enough vasospasm in the vertebral, basilar, or posterior cerebral
arteries.
Lumbar puncture prior to an imaging procedure is
indicated only if a CT scan is not available at the time of

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

the suspected SAH. Once the diagnosis of hemorrhage
from a ruptured saccular aneurysm is suspected, four-vessel
conventional x-ray angiography (both carotids and both
vertebrals) is generally performed to localize and dene
the anatomic details of the aneurysm and to determine if
other unruptured aneurysms exist (Fig. 22-8C). At some
centers, the ruptured aneurysm can be treated using
endovascular techniques at the time of the initial angiogram
as a way to expedite treatment and minimize the number
of invasive procedures. CT angiography is an alternative
A B method for locating the aneurysm and may be sufcient
to plan denitive therapy.
Close monitoring (daily or twice daily) of electrolytes is
important because hyponatremia can occur precipitously
during the rst 2 weeks following SAH (see above).
The electrocardiogram (ECG) frequently shows ST-
segment and T-wave changes similar to those associated
with cardiac ischemia. Prolonged QRS complex, increased
QT interval, and prominent peaked or deeply inverted
symmetric T waves are usually secondary to the intracra-
nial hemorrhage.There is evidence that structural myocar-
C D dial lesions produced by circulating catecholamines and
FIGURE 22-8 excessive discharge of sympathetic neurons may occur
Subarachnoid hemorrhage. A. CT angiography revealing an after SAH, causing these ECG changes and a reversible
aneurysm of the left superior cerebellar artery. B. Noncontrast cardiomyopathy sufcient to cause shock or congestive
CT scan at the level of the third ventricle revealing subarach- heart failure. Echocardiography reveals a pattern of
noid blood (bright) in the left sylvian ssure and within the left regional wall motion abnormalities that follow the distrib-
lateral ventricle. C. Conventional anteroposterior x-ray ution of sympathetic nerves rather than the major coro-
angiogram of the right vertebral and basilar artery showing nary arteries, with relative sparing of the ventricular wall
the large aneurysm. D. Conventional angiogram following coil apex. The sympathetic nerves themselves appear to be
embolization of the aneurysm, whereby the aneurysm body is injured by direct toxicity from the excessive catecholamine
lled with platinum coils delivered through a microcatheter release. An asymptomatic troponin elevation is common.
navigated from the femoral artery into the aneurysm neck. Serious ventricular dysrhythmias are unusual.
 296 depressed level of consciousness, ICP should be mea-
Treatment:
SUBARACHNOID HEMORRHAGE
sured and the cerebral perfusion pressure targeted to
6070 mm Hg.
Early aneurysm repair prevents rerupture and allows the Because rebleeding is common, all patients who are
safe application of techniques to improve blood ow not candidates for early aneurysm repair are put on bed
(e.g., induced hypertension and hypervolemia) should rest in a quiet room and are given stool softeners to
symptomatic vasospasm develop. An aneurysm can be prevent straining. If headache or neck pain is severe,
clipped by a neurosurgeon or coiled by an endovas- mild sedation and analgesia are prescribed. Extreme
cular surgeon. Surgical repair involves placing a metal sedation is avoided because it can obscure changes in
clip across the aneurysm neck, thereby immediately neurologic status. Adequate hydration is necessary to
eliminating the risk of rebleeding. This approach avoid a decrease in blood volume predisposing to brain
requires craniotomy and brain retraction, which is asso- ischemia.
ciated with neurologic morbidity. Endovascular tech- Seizures are uncommon at the onset of aneurysmal
niques involve placing platinum coils, or other embolic rupture. The quivering, jerking, and extensor posturing
material, within the aneurysm via a catheter that is that often accompany loss of consciousness with SAH
passed from the femoral artery. The aneurysm is packed are probably related to the sharp rise in ICP or, perhaps,
tightly to enhance thrombosis and over time is walled- acute generalized vasospasm rather than seizure. How-
SECTION III

off from the circulation (Fig. 22-8D).The only prospective ever, phenytoin is often given as prophylactic therapy
randomized trial of surgery versus endovascular treat- since a seizure may promote rebleeding.
ment for ruptured aneurysm, the International Sub- Glucocorticoids may help reduce the head and neck
arachnoid Aneurysm Trial (ISAT), was terminated early ache caused by the irritative effect of the subarachnoid
when 24% of patients treated with endovascular ther- blood. There is no good evidence that they reduce cere-
apy were dead or dependent at 1 year compared to 31% bral edema, are neuroprotective, or reduce vascular
Diseases of the Central Nervous System

treated with surgery, a signicant 23% relative reduc- injury, and their routine use therefore is not recom-
tion. Follow-up for these patients, now complete, reveals mended.
that the benet of endovascular therapy is durable. Antibrinolytic agents are not routinely prescribed
However, some aneurysms have a morphology that is but may be considered in patients in whom aneurysm
not amenable to endovascular treatment. Thus, surgery treatment cannot proceed immediately. They are associ-
remains an important treatment option. Centers that ated with a reduced incidence of aneurysmal rerupture
combine both endovascular and neurosurgical exper- but may also increase the risk of delayed cerebral infarc-
tise likely offer the best outcomes for patients, and there tion and deep vein thrombosis (DVT).
are good data showing that centers that specialize in Vasospasm remains the leading cause of morbidity
aneurysm treatment have improved mortality rates. and mortality following aneurysmal SAH. Treatment
The medical management of SAH focuses on protect- with the calcium channel antagonist nimodipine (60 mg
ing the airway, managing blood pressure before and PO every 4 h) improves outcome, perhaps by preventing
after aneurysm treatment, preventing rebleeding prior ischemic injury rather than reducing the risk of
to treatment, managing vasospasm, treating hydro- vasospasm. Nimodipine can cause signicant hypoten-
cephalus, treating hyponatremia, and preventing pul- sion in some patients, which may worsen cerebral
monary embolus. ischemia in patients with vasospasm. Symptomatic cere-
Intracranial hypertension following aneurysmal rup- bral vasospasm can also be treated by increasing the
ture occurs secondary to subarachnoid blood, parenchy- cerebral perfusion pressure by raising mean arterial
mal hematoma, acute hydrocephalus, or loss of vascular pressure through plasma volume expansion and the
autoregulation. Patients who are stuporous should judicious use of IV vasopressor agents, usually phenyle-
undergo emergent ventriculostomy to measure ICP and phrine or norepinephrine. Raised perfusion pressure has
to treat high ICP in order to prevent cerebral ischemia. been associated with clinical improvement in many
Medical therapies designed to combat raised ICP (e.g., patients, but high arterial pressure may promote
mild hyperventilation, mannitol, and sedation) can also rebleeding in unprotected aneurysms. Treatment with
be used as needed. High ICP refractory to treatment is a induced hypertension and hypervolemia generally
poor prognostic sign. requires monitoring of arterial and central venous pres-
Prior to denitive treatment of the ruptured sures; it is best to infuse pressors through a central
aneurysm, care is required to maintain adequate cere- venous line as well. Volume expansion helps prevent
bral perfusion pressure while avoiding excessive eleva- hypotension, augments cardiac output, and reduces
tion of arterial pressure. If the patient is alert, it is reason- blood viscosity by reducing the hematocrit. This method
able to lower the blood pressure to normal using is called triple-H (hypertension, hemodilution, and
nicardipine, labetolol, or esmolol. If the patient has a hypervolemic) therapy.
 If symptomatic vasospasm persists despite optimal has been treated and whether or not the patient has 297
medical therapy, intraarterial vasodilators and percuta- had a craniotomy. Systemic anticoagulation with heparin
neous transluminal angioplasty are considered. Vasodi- is contraindicated in patients with ruptured and
latation by direct angioplasty appears to be permanent, untreated aneurysms. It is a relative contraindication fol-
allowing triple-H therapy to be tapered sooner. The lowing craniotomy for several days or perhaps weeks,
pharmacologic vasodilators (verapamil and nicardipine) and it may delay thrombosis of a coiled aneurysm. Fol-
do not last more than 824 h, and therefore multiple lowing craniotomy, use of inferior vena cava lters is
treatments may be required until the subarachnoid preferred to prevent further pulmonary emboli, while
blood is reabsorbed. Although intraarterial papaverine is systemic anticoagulation with heparin is preferred fol-
an effective vasodilator, there is evidence that papaver- lowing successful endovascular treatment.
ine may be neurotoxic so its use should be reserved for
refractory cases.
Acute hydrocephalus can cause stupor or coma. It
may clear spontaneously or require temporary ventricu- FURTHER READINGS
lar drainage. When chronic hydrocephalus develops,
HERMANS G et al: Clinical review. Critical illness polyneuropathy
ventricular shunting is the treatment of choice.
and myopathy. Crit Care 12:238, 2008

CHAPTER 22
Free-water restriction is contraindicated in patients LIOU AK et al:To die or not to die for neurons in ischemia, traumatic
with SAH at risk for vasospasm because hypovolemia brain injury and epilepsy: A review on the stress-activated signal-
and hypotension may occur and precipitate cerebral ing pathways and apoptotic pathways. Prog Neurobiol 69:103,
ischemia. Many patients continue to experience a 2003
decline in serum sodium despite receiving parenteral MOLYNEUX A et al: International Subarachnoid Aneurysm Trial
uids containing normal saline. Frequently, supplemen- (ISAT) of neurosurgical clipping versus endovascular coiling in
2143 patients with ruptured intracranial aneurysms: A random-
tal oral salt coupled with normal saline will mitigate

Neurologic Critical Care, Including Hypoxic-Ischemic Encephalopathy and Subarachnoid Hemorrhage

ized trial. Lancet 360:1267, 2002
hyponatremia, but often patients also require hyper- PANDHARIPANDE PP et al: Effect of sedation with dexmedetomidine
tonic saline. Care must be taken not to correct serum versus lorazepam on acute brain dysfunction in mechanically
sodium too quickly in patients with marked hypona- ventilated patients: The MENDS randomized controlled trial.
tremia of several days duration, as central pontine JAMA 298:2654, 2007
myelinolysis may occur. PUTTGEN HA et al: Management of cardiac arrest patients to maxi-
All patients should have pneumatic compression mize neurologic outcome. Curr Opin Crit Care 15:118, 2009
POSNER JB et al: Plum and Posners Diagnosis of Stupor and Coma,
stockings applied to prevent pulmonary embolism.
4th ed. New York, Oxford University Press, 2007
Unfractionated heparin administered subcutaneously SAFE STUDY INVESTIGATORS et al: Saline or albumin for uid resusci-
for DVT prophylaxis can be initiated immediately follow- tation in patients with traumatic brain injury. N Engl J Med
ing endovascular treatment and within days following 357:874, 2007
craniotomy and surgical clipping and is a useful adjunct WOLF SJ et al: Blast injuries. Lancet 374:405, 2009
to pneumatic compression stockings. Treatment of WIJDICKS EFM et al: Practice parameter: Prediction of outcome in
pulmonary embolus depends on whether the aneurysm comatose survivors after cardiopulmonary resuscitation (an
evidence-based review). Neurology 67:203, 2006
 CHAPTER 23

AL ZHEIMERS DISEASE AND OTHER DEMENTIAS

Thomas D. Bird I Bruce L. Miller

I Functional Anatomy of the Dementias . . . . . . . . . . . . . . . . . . 298

The Causes of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
I Specic Dementias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Alzheimers Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Vascular Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Frontotemporal Dementia, Progressive Supranuclear
Palsy, and Corticobasal Degeneration . . . . . . . . . . . . . . . . . 311
Dementia with Lewy Bodies . . . . . . . . . . . . . . . . . . . . . . . . . 313
I Other Causes of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . 314
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Dementia, a syndrome with many causes, affects >4 mil- affected regions are factors that combine to cause the spe-
lion Americans and results in a total health care cost of cic disorder (Chap. 15). Behavior and mood are modu-
>$100 billion annually. It is dened as an acquired deteri- lated by noradrenergic, serotonergic, and dopaminergic
oration in cognitive abilities that impairs the successful pathways, while acetylcholine seems to be particularly
performance of activities of daily living. Memory is the important for memory. Therefore, the loss of cholinergic
most common cognitive ability lost with dementia; 10% neurons in Alzheimers disease (AD) may underlie the
of persons >70 years and 2040% of individuals >85 memory impairment, while in patients with non-AD
years have clinically identiable memory loss. In addition dementias, the loss of serotonergic and glutaminergic
to memory, other mental faculties are also affected in neurons causes primarily behavioral symptoms, leaving
dementia; these include language, visuospatial ability, cal- memory relatively spared. Neurotrophins (Chap. 19) are
culation, judgment, and problem solving. Neuropsychi- also postulated to play a role in memory function, in part
atric and social decits also develop in many dementia by preserving cholinergic neurons, and therefore represent
syndromes, resulting in depression, withdrawal, hallucina- a pharmacologic pathway toward slowing or reversing the
tions, delusions, agitation, insomnia, and disinhibition.The effects of AD.
most common forms of dementia are progressive, but Dementias have anatomically specic patterns of neu-
some dementing illnesses are static and unchanging or ronal degeneration that dictate the clinical symptoma-
uctuate dramatically from day to day. Most diagnoses of tology. AD begins in the entorhinal cortex, spreads to
dementia require some sort of memory decit, although the hippocampus, and then moves to posterior temporal
there are many dementias, such as frontotemporal demen- and parietal neocortex, eventually causing a relatively
tia, where memory loss is not a presenting feature. diffuse degeneration throughout the cerebral cortex.
Multi-infarct dementia is associated with focal damage in a
random patchwork of cortical regions. Diffuse white
FUNCTIONAL ANATOMY OF THE matter damage may disrupt intracerebral connections
DEMENTIAS and cause dementia syndromes similar to those associ-
ated with leukodystrophies, multiple sclerosis, and Bin-
Dementia results from the disruption of cerebral neuronal swangers disease (see later). Subcortical structures,
circuits; the quantity of neuronal loss and the location of including the caudate, putamen, thalamus, and substantia
298
nigra, also modulate cognition and behavior in ways that dementia. Other disorders listed in the table are uncom- 299
are not yet well understood. The effect that these pat- mon but important because many are reversible.The clas-
terns of cortical degeneration have on disease sympto- sication of dementing illnesses into two broad groups of
matology is clear: AD primarily presents as memory loss reversible and irreversible disorders is a useful approach to
and is often associated with aphasia or other distur- the differential diagnosis of dementia.
bances of language. In contrast, patients with frontal lobe In a study of 1000 persons attending a memory disor-
or subcortical dementias such as frontotemporal dementia ders clinic, 19% had a potentially reversible cause of the
(FTD) or Huntingtons disease (HD) are less likely to cognitive impairment and 23% had a potentially reversible
begin with memory problems and more likely to have concomitant condition.The three most common poten-
difculties with attention, judgment, awareness, and tially reversible diagnoses were depression, hydrocephalus,
behavior. and alcohol dependence (Table 23-1).
Lesions of specic cortical-subcortical pathways have Subtle cumulative decline in episodic memory is a
equally specic effects on behavior.The dorsolateral pre- natural part of aging. This frustrating experience, often
frontal cortex has connections with dorsolateral caudate, the source of jokes and humor, is referred to as benign
globus pallidus, and thalamus. Lesions of these pathways forgetfulness of the elderly. Benign means that it is not so
result in poor organization and planning, decreased cog- progressive or serious that it impairs reasonably success-
nitive exibility, and impaired judgment. The lateral ful and productive daily functioning, although the dis-

CHAPTER 23
orbital frontal cortex connects with the ventromedial tinction between benign and more signicant memory
caudate, globus pallidus, and thalamus. Lesions of these loss can be difcult to make. At 85 years, the average
connections cause irritability, impulsiveness, and dis- person is able to learn and recall approximately one-half
tractibility. The anterior cingulate cortex connects with the number of items (e.g., words on a list) that he or she
the nucleus accumbens, globus pallidus, and thalamus. could at 18 years. A cognitive problem that has begun to
Interruption of these connections produces apathy and subtly interfere with daily activities is referred to as mild

Alzheimers Disease and Other Dementias

poverty of speech or even akinetic mutism. cognitive impairment (MCI). A sizeable proportion of per-
The single strongest risk factor for dementia is sons with MCI will progress to frank dementia, usually
increasing age. The prevalence of disabling memory loss caused by AD. The conversion rate from MCI to AD is
increases with each decade after 50 years of age and is ~12% per year. It remains unclear why some individuals
associated most often with the microscopic changes of show progression and others do not. Factors that predict
AD at autopsy. Slow accumulation of mutations in neu- progression from MCI to AD include a memory decit
ronal mitochondria is also hypothesized to contribute to >1.5 standard deviations from the norm, family history
the increasing prevalence of dementia with age.Yet some of dementia, the presence of an apolipoprotein 4 (Apo
centenarians have intact memory function and no evi- 4), and small hippocampal volumes. There is optimism
dence of clinically signicant dementia.Whether demen- that new positron emission tomography (PET) imaging
tia is an inevitable consequence of normal human aging techniques that label amyloid or tau in vivo might aid in
remains controversial. early diagnosis of AD in the future.
The major degenerative dementias include AD, FTD
THE CAUSES OF DEMENTIA and related disorders, DLB, HD, and prion disorders
including Creutzfeldt-Jakob disease (CJD). These disor-
The many causes of dementia are listed in Table 23-1. ders are all associated with the abnormal aggregation of
The frequency of each condition depends on the age a specic protein: A42 in AD, tau or TDP-43 in FTD,
group under study, the access of the group to medical -synuclein in DLB, polyglutamine repeats in HD, and
care, the country of origin, and perhaps racial or ethnic prions in CJD (Table 23-2).
background. AD is the most common cause of dementia
in Western countries, representing more than half of
demented patients. Vascular disease is the second most
common cause of dementia in the United States, repre-
senting 1020%. In populations with limited access to Approach to the Patient:
medical care, where vascular risk factors are undertreated, DEMENTIA
the prevalence of vascular dementia can be much higher.
Three major issues should be kept in the forefront:
Dementia associated with Parkinsons disease (PD) is the
(1) What is the most accurate diagnosis? (2) Is there a
next most common category, and in many instances these
treatable or reversible component to the dementia?
patients suffer from dementia with Lewy bodies (DLB).
(3) Can the physician help to alleviate the burden on
In patients younger than 60 years, FTD rivals AD as the
caregivers? A broad overview of the approach to
most common cause of dementia. Chronic intoxications,
dementia is shown in Table 23-3. The major degen-
including those resulting from alcohol and prescription
erative dementias can usually be distinguished by the
drugs, are an important and often treatable cause of
 300 TABLE 23-1
DIFFERENTIAL DIAGNOSIS OF DEMENTIA

Most Common Causes of Dementia

Alzheimers disease Alcoholisma
Vascular dementia Parkinsons disease
Multi-infarct Drug/medication intoxicationa
Diffuse white matter disease (Binswangers)
Less Common Causes of Dementia
Vitamin deciencies Toxic disorders
Thiamine (B1): Wernickes encephalopathya Drug, medication, and narcotic poisoninga
B12 (pernicious anemia)a Heavy metal intoxicationa
Nicotinic acid (pellagra)a Dialysis dementia (aluminum)
Endocrine and other organ failure Organic toxins
Hypothyroidisma Psychiatric
Adrenal insufciency and Cushings syndromea Depression (pseudodementia)a
Hypo- and hyperparathyroidisma Schizophreniaa
Renal failurea Conversion reactiona
SECTION III

Liver failurea Degenerative disorders

Pulmonary failurea Huntingtons disease
Chronic infections Picks disease
HIV Dementia with Lewy bodies
Neurosyphilisa Progressive supranuclear palsy (Steel-Richardson syndrome)
Papovavirus (progressive multifocal Multisystem degeneration (Shy-Drager syndrome)
leukoencephalopathy) Hereditary ataxias (some forms)
Diseases of the Central Nervous System

Prion (Creutzfeldt-Jakob and Gerstmann- Motor neuron disease [amyotrophic lateral sclerosis (ALS);
Strussler-Scheinker diseases) some forms]
Tuberculosis, fungal, and protozoala Frontotemporal dementia
Whipples diseasea Cortical basal degeneration
Head trauma and diffuse brain damage Multiple sclerosis
Dementia pugilistica Adult Downs syndrome with Alzheimers
Chronic subdural hematomaa ALSParkinsonsDementia complex of Guam
Postanoxia Miscellaneous
Postencephalitis Sarcoidosisa
Normal-pressure hydrocephalusa Vasculitisa
Neoplastic CADASIL etc
Primary brain tumora Acute intermittent porphyriaa
Metastatic brain tumora Recurrent nonconvulsive seizuresa
Paraneoplastic limbic encephalitis Additional conditions in children or adolescents
Hallervorden-Spatz disease
Subacute sclerosing panencephalitis
Metabolic disorders (e.g., Wilsons and Leighs diseases,
leukodystrophies, lipid storage diseases, mitochondrial
mutations)

a
Potentially reversible dementia.

initial symptoms; neuropsychological, neuropsychi- loss over several years is likely to suffer from AD.
atric, and neurologic findings; and neuroimaging Nearly 75% of AD patients begin with memory
features (Table 23-4). symptoms, but other early symptoms include difculty
with managing money, driving, shopping, following
HISTORY The history should concentrate on the instructions, nding words, or navigating. A change in
onset, duration, and tempo of progression of the personality, disinhibition, and gain of weight or food
dementia. An acute or subacute onset of confusion obsession suggests FTD, not AD. FTD is also suggested
may represent delirium and should trigger the search by the nding of apathy, loss of executive function, or
for intoxication, infection, or metabolic derangement. progressive abnormalities in speech, or by a relative
An elderly person with slowly progressive memory sparing of memory or spatial abilities. The diagnosis
TABLE 23-2 301
THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA

MOLECULAR CAUSAL GENES AND SUSCEPTIBILITY

DEMENTIA BASIS (CHROMOSOME) GENES PATHOLOGY

AD A <2% carry these mutations. Apo 4 (19) Amyloid plaques, neurobrillary tangles
APP (21), PS-1 (14), PS-2 (1)
(most mutations are in PS-1)
FTD Tau Tau exon and intron mutations H1 tau Tau inclusions, Pick bodies,
(17) (about 10% of haplotypes neurobrillary tangles
familial cases)
Progranulin (17) (10% of
familial cases)
DLB -synuclein Very rare -synuclein (4) Unknown -synuclein inclusions
(dominant) (Lewy bodies)
CJD PrPSC Prion (20) (up to 15% of cases Codon 129 Tau inclusions, spongiform changes,
proteins carry these dominant homozygosity gliosis
mutations) for methionine
or valine

CHAPTER 23
Note: AD, Alzheimers disease; FTD, frontotemporal dementia; DLB, dementia with Lewy bodies; CJD, Creutzfeldt-Jakob disease.

Alzheimers Disease and Other Dementias

TABLE 23-3
EVALUATION OF THE PATIENT WITH DEMENTIA

OPTIONAL OCCASIONALLY
ROUTINE EVALUATION FOCUSED TESTS HELPFUL TESTS

History Psychometric testing EEG

Physical examination Chest x-ray Parathyroid function
Laboratory tests Lumbar puncture Adrenal function
Thyroid function (TSH) Liver function Urine heavy metals
Vitamin B12 Renal function RBC sedimentation rate
Complete blood count Urine toxin screen Angiogram
Electrolytes HIV Brain biopsy
CT/MRI Apolipoprotein E SPECT
RPR or VDRL PET
Diagnostic Categories

IRREVERSIBLE/
DEGENERATIVE PSYCHIATRIC
REVERSIBLE CAUSES DEMENTIAS DISORDERS

Examples Examples Depression

Hypothyroidism Alzheimers Schizophrenia
Thiamine deciency Frontotemporal dementia Conversion reaction
Vitamin B12 deciency Huntingtons
Normal-pressure hydrocephalus Dementia with Lewy bodies
Subdural hematoma Vascular
Chronic infection Leukoencephalopathies
Brain tumor Parkinsons
Drug intoxication
Associated Treatable Conditions
Depression Agitation
Seizures Caregiver burnout
Insomnia Drug side effects

Note: PET, positron emission tomography; RPR, rapid plasma reagin (test); SPECT, single photon emission CT;
VDRL, Venereal Disease Research Laboratory (test for syphilis).
 302 TABLE 23-4
CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS

DISEASE FIRST SYMPTOM MENTAL STATUS NEUROPSYCHIATRY NEUROLOGY IMAGING

AD Memory loss Episodic Initially normal Initially normal Entorhinal cortex and
memory loss hippocampal atrophy
FTD Apathy; poor Frontal/executive, Apathy, disinhibition, Due to PSP/CBD Frontal and/or temporal
judgment/insight, language; hyperorality, overlap; vertical atrophy; spares
speech/language; spares drawing euphoria, depression gaze palsy, axial posterior parietal lobe
hyperorality rigidity, dystonia,
alien hand
DLB Visual hallucina- Drawing and Visual hallucinations, Parkinsonism Posterior parietal
tions, REM sleep frontal/executive; depression, sleep atrophy; hippocampi
disorder, delirium, spares memory; disorder, delusions larger than in AD
Capgras delirium prone
syndrome,
parkinsonism
CJD Dementia, mood, Variable, frontal/ Depression, anxiety Myoclonus, rigidity, Cortical ribboning and
anxiety, executive, focal parkinsonism basal ganglia or
SECTION III

movement cortical, memory thalamus

disorders hyperintensity on
diffusion/are MRI
Vascular Often but not Frontal/executive, Apathy, delusions, Usually motor Cortical and/or
always sudden; cognitive slowing; anxiety slowing, subcortical
variable; apathy, can spare spasticity; infarctions,
falls, focal memory can be normal conuent white
Diseases of the Central Nervous System

weakness matter disease

Note: AD, Alzheimers disease; FTD, frontotemporal dementia; PSP, progressive supranuclear palsy; CBD, cortical basal degeneration; DLB,
dementia with Lewy bodies; CJD, Creutzfeldt-Jakob disease.

of DLB is suggested by the early presence of visual HIV. A history of recurrent head trauma could indi-
hallucinations; parkinsonism; delirium; REM sleep cate chronic subdural hematoma, dementia pugilis-
disorder (the merging of dream-states into wakeful- tica, or NPH. Alcoholism may suggest malnutrition
ness); or Capgras syndrome, the delusion that a famil- and thiamine deciency. A remote history of gastric
iar person has been replaced by an impostor. surgery resulting in loss of intrinsic factor can bring
A history of sudden stroke with irregular stepwise about vitamin B12 deciency. Certain occupations
progression suggests multi-infarct dementia. Multi- such as working in a battery or chemical factory
infarct dementia is also commonly seen in the setting might indicate heavy metal intoxication. Careful
of hypertension, atrial brillation, peripheral vascular review of medication intake, especially of sedatives
disease, and diabetes. In patients suffering from cere- and tranquilizers, may raise the issue of chronic drug
brovascular disease, it can be difcult to determine intoxication. A positive family of dementia is found in
whether the dementia is due to AD, multi-infarct HD and in forms of familial Alzheimers disease
dementia, or a mixture of the two as many of the risk (FAD), FTD, or prion disorders.The recent death of a
factors for vascular dementia, including diabetes, high loved one, or depressive signs such as insomnia or
cholesterol, elevated homocysteine and low exercise, weight loss, raises the possibility of pseudodementia
are also risk factors for AD. Rapid progression of the due to depression.
dementia in association with motor rigidity and
myoclonus suggests CJD. Seizures may indicate PHYSICAL AND NEUROLOGIC EXAMINATION
strokes or neoplasm. Gait disturbance is commonly A thorough general and neurologic examination is
seen with multi-infarct dementia, PD, or normal- essential to document dementia, look for other signs
pressure hydrocephalus (NPH). Multiple sex partners of nervous system involvement, and search for clues
or intravenous drug use should trigger a search for suggesting a systemic disease that might be responsi-
central nervous system (CNS) infection, especially for ble for the cognitive disorder. AD does not affect
motor systems until later in the course. In contrast, COGNITIVE AND NEUROPSYCHIATRIC 303
FTD patients often develop axial rigidity, supranu- EXAMINATION Brief screening tools such as the
clear gaze palsy, or features of amyotrophic lateral mini-mental state examination (MMSE) help to con-
sclerosis (ALS). In DLB, initial symptoms may be the rm the presence of cognitive impairment and to fol-
new onset of a parkinsonian syndrome (resting low the progression of dementia (Table 23-5). The
tremor, cogwheel rigidity, bradykinesia, festinating MMSE, an easily administered 30-point test of cogni-
gait) with the dementia following later, or vice versa. tive function, contains tests of orientation, working
Corticobasal degeneration (CBD) is associated with memory (e.g., spell world backwards), episodic mem-
dystonia, alien hand, and asymmetric extrapyramidal, ory (orientation and recall), language comprehension,
pyramidal, or sensory decits or myoclonus. Progres- naming, and copying. In most patients with MCI and
sive supranuclear palsy (PSP) is associated with unex- some with clinically apparent AD, the MMSE may be
plained falls, axial rigidity, dysphagia, and vertical gaze normal and a more rigorous set of neuropsychologi-
decits. CJD is suggested by the presence of diffuse cal tests will be required. Additionally, when the etiol-
rigidity, an akinetic state, and myoclonus. ogy for the dementia syndrome remains in doubt, a
Hemiparesis or other focal neurologic decits may specially tailored evaluation should be performed that
occur in multi-infarct dementia or brain tumor. includes tasks of working and episodic memory,

CHAPTER 23
Dementia with a myelopathy and peripheral neuropa- frontal executive function, language, and visuospatial
thy suggests vitamin B12 deciency. A peripheral neu- and perceptual abilities. In AD the decits involve
ropathy could also indicate an underlying vitamin episodic memory, category generation (name as
deciency or heavy metal intoxication. Dry, cool skin, many animals as you can in one minute), and visuo-
hair loss, and bradycardia suggest hypothyroidism. constructive ability. Decits in verbal or visual
Confusion associated with repetitive stereotyped move- episodic memory are often the rst neuropsychologi-
ments may indicate ongoing seizure activity. Hearing cal abnormalities seen with AD, and tasks that require

Alzheimers Disease and Other Dementias

impairment or visual loss may produce confusion and the patient to recall a long list of words or a series of
disorientation misinterpreted as dementia. Such sen- pictures after a predetermined delay will demonstrate
sory decits are common in the elderly but can be a decits in most AD patients. In FTD, the earliest
manifestation of mitochondrial disorders. decits often involve frontal executive or language

TABLE 23-5
THE MINI-MENTAL STATUS EXAMINATION

POINTS

Orientation
Name: season/date/day/month/year 5 (1 for each name)
Name: hospital/oor/town/state/country 5 (1 for each name)
Registration
Identify three objects by name and ask 3 (1 for each object)
patient to repeat
Attention and calculation
Serial 7s; subtract from 100 5 (1 for each subtraction)
(e.g., 9386797265)
Recall
Recall the three objects presented earlier 3 (1 for each object)
Language
Name pencil and watch 2 (1 for each object)
Repeat No ifs, ands, or buts 1
Follow a 3-step command (e.g., 3 (1 for each command)
Take this paper, fold it in half, and
place it on the table)
Write close your eyes and ask patient 1
to obey written command
Ask patient to write a sentence 1
Ask patient to copy a design 1
(e.g., intersecting pentagons)
Total 30
 304 (speech or naming) function. DLB patients have more discourage multiple tests. Nevertheless, even a test
severe decits in visuospatial function but do better with only a 12% positive rate is probably worth
on episodic memory tasks than patients with AD. undertaking if the alternative is missing a treatable
Patients with vascular dementia often demonstrate a cause of dementia. Table 23-3 lists most screening
mixture of frontal executive and visuospatial decits. tests for dementia. Recently the American Academy
In delirium, decits tend to fall in the area of atten- of Neurology recommended the routine measure-
tion, working memory, and frontal function. ment of thyroid function, a vitamin B12 level test, and
A functional assessment should also be performed. a neuroimaging study (CT or MRI).
The physician should determine the day-to-day Neuroimaging studies will identify primary and
impact of the disorder on the patients memory, com- secondary neoplasms, locate areas of infarction, diag-
munity affairs, hobbies, judgment, dressing, and eat- nose subdural hematomas, and suggest NPH or dif-
ing. Knowledge of the patients day-to-day function fuse white matter disease. They also lend support to
will help the clinician and the family to organize a the diagnosis of AD, especially if there is hippocampal
therapeutic approach. atrophy in addition to diffuse cortical atrophy. Focal
Neuropsychiatric assessment is important for diag- frontal and/or anterior temporal atrophy suggests
nosis, prognosis, and treatment. In the early stages of FTD. There is no specic pattern yet determined for
AD, mild depressive features, social withdrawal, and DLB, although these patients tend to have less hip-
SECTION III

denial of illness are the most prominent psychiatric pocampal atrophy than patients with AD. The use of
changes. However, patients often maintain their social diffusion-weighted imaging with MRI will detect
skills into the middle stages of the illness, when delu- abnormalities in the cortical ribbon and basal ganglia
sions, agitation, and sleep disturbance become more in the vast majority of patients with CJD. Large
common. In FTD, dramatic personality change, apa- white-matter abnormalities correlate with a vascular
thy, overeating, repetitive compulsions, disinhibition, etiology for dementia.The role of functional imaging
Diseases of the Central Nervous System

euphoria, and loss of empathy are common. DLB in the diagnosis of dementia is still under study. Single
shows visual hallucinations, delusions related to per- photon emission computed tomography (SPECT) and
sonal identity, and day-to-day uctuation. Vascular PET scanning will show temporal-parietal hypoper-
dementia can present with psychiatric symptoms such fusion or hypometabolism in AD and frontotemporal
as depression, delusions, disinhibition, or apathy. hypoperfusion or hypometabolism in FTD, but most
of these changes reect atrophy. Recently, amyloid
LABORATORY TESTS The choice of laboratory imaging has shown promise for the diagnosis of AD,
tests in the evaluation of dementia is complex. The and Pittsburgh Agent B appears to be a reliable agent
physician does not want to miss a reversible or treat- for detecting brain amyloid due to the accumulation
able cause, yet no single etiology is common; thus, a of A42 within plaques (Fig. 23-1). Similarly, MRI
screen must employ multiple tests, each of which has perfusion and brain activation studies using functional
a low yield. Cost/benet ratios are difcult to assess, and MRI are under active study as potential early diag-
many laboratory screening algorithms for dementia nostic tools.

A B C

FIGURE 23-1
PET images obtained with the amyloid-imaging agent have control-like levels of amyloid, some have AD-like lev-
Pittsburgh Compound-B ([11C]PIB) in a normal control (A); els of amyloid, and some have intermediate levels. PET,
three different patients with mild cognitive impairment positron emission tomography; MCI, mild cognitive impair-
(MCI, B); and a mild AD patient (C). Some MCI patients ment; AD, Alzheimers disease.
 Lumbar puncture need not be done routinely in However, ~20% of AD patients present with nonmem- 305
the evaluation of dementia, but it is indicated if CNS ory complaints such as word-nding, organizational, or
infection is a serious consideration. Cerebrospinal navigational difculty. In the early stages of the disease,
uid (CSF) levels of tau protein and A42 amyloid the memory loss may go unrecognized or be ascribed to
show differing patterns with the various dementias; benign forgetfulness. Once the memory loss begins to
however, the sensitivity and specicity of these mea- affect day-to-day activities or falls below 1.5 standard
sures are not sufciently high to warrant routine deviations from normal on standardized memory tasks,
measurement. Formal psychometric testing, though the disease is dened as MCI. Approximately 50% of
not necessary in every patient with dementia, helps to MCI individuals will progress to AD within 5 years.
document the severity of dementia, suggest psychogenic Slowly the cognitive problems begin to interfere with
causes, and provide a semiquantitative method for fol- daily activities, such as keeping track of nances, follow-
lowing the disease course. EEG is rarely helpful except ing instructions on the job, driving, shopping, and
to suggest CJD (repetitive bursts of diffuse high volt- housekeeping. Some patients are unaware of these dif-
age sharp waves) or an underlying nonconvulsive culties (anosognosia), while others have considerable insight.
seizure disorder (epileptiform discharges). Brain biopsy Change of environment may be bewildering, and the
(including meninges) is not advised except to diag- patient may become lost on walks or while driving an
automobile. In the middle stages of AD, the patient is

CHAPTER 23
nose vasculitis, potentially treatable neoplasms,
unusual infections, or systemic disorders such as vas- unable to work, is easily lost and confused, and requires
culitis or sarcoid, or in young persons where the daily supervision. Social graces, routine behavior, and
diagnosis is uncertain. Angiography should be consid- supercial conversation may be surprisingly intact. Lan-
ered when cerebral vasculitis is a possible cause of the guage becomes impairedrst naming, then compre-
dementia. hension, and nally uency. In some patients, aphasia is
an early and prominent feature.Word nding difculties

Alzheimers Disease and Other Dementias

and circumlocution may be a problem even when for-
mal testing demonstrates intact naming and uency.
Apraxia emerges, and patients have trouble performing
sequential motor tasks. Visuospatial decits begin to
SPECIFIC DEMENTIAS interfere with dressing, eating, solving simple puzzles,
and copying geometric gures. Patients may be unable
ALZHEIMERS DISEASE
to do simple calculations or tell time.
Approximately 10% of all persons older than 70 years In the late stages of the disease, some persons remain
have signicant memory loss and in more than one-half ambulatory but wander aimlessly. Loss of judgment, rea-
the cause is AD. It is estimated that the annual total cost son, and cognitive abilities is inevitable. Delusions are
of caring for a single AD patient in an advanced stage of common and usually simple in quality, such as delusions
the disease is >$50,000. The disease also exacts a heavy of theft, indelity, or misidentication. Approximately
emotional toll on family members and caregivers. AD 10% of AD patients develop Capgras syndrome, believing
can occur in any decade of adulthood, but it is the most that a caregiver has been replaced by an impostor. In
common cause of dementia in the elderly. AD most contrast to DLB, where Capgras syndrome is an early
often presents with subtle onset of memory loss fol- feature, in AD this syndrome emerges later in the course
lowed by a slowly progressive dementia that has a course of the illness. Loss of inhibitions and aggression may
of several years. Pathologically, there is diffuse atrophy of occur and alternate with passivity and withdrawal.
the cerebral cortex with secondary enlargement of the Sleep-wake patterns are prone to disruption, and night-
ventricular system. Microscopically, there are neuritic time wandering becomes disturbing to the household.
plaques containing A amyloid, silver-staining neurob- Some patients develop a shufing gait with generalized
rillary tangles (NFTs) in neuronal cytoplasm, and accu- muscle rigidity associated with slowness and awkward-
mulation of A42 amyloid in arterial walls of cerebral ness of movement. Patients often look parkinsonian
blood vessels (see Pathogenesis, later). The identication (Chap. 24) but rarely have a rapid, rhythmic, resting
of four different susceptibility genes for AD has provided tremor. In end-stage AD, patients become rigid, mute,
a foundation for rapid progress in understanding ADs incontinent, and bedridden. Help may be needed with
biologic basis. the simplest tasks, such as eating, dressing, and toilet
function. They may show hyperactive tendon reexes.
Myoclonic jerks (sudden brief contractions of various
Clinical Manifestations
muscles or the whole body) may occur spontaneously or
The cognitive changes with AD tend to follow a charac- in response to physical or auditory stimulation.
teristic pattern, beginning with memory impairment Myoclonus raises the possibility of CJD (Chap. 38), but
and spreading to language and visuospatial decits. the course of AD is much more prolonged. Generalized
 306 seizures may also occur. Often death results from malnu-
trition, secondary infections, pulmonary emboli, or heart
disease.The typical duration of AD is 810 years, but the
course can range from 1 to 25 years. For unknown rea-
sons, some AD patients show a steady downhill decline
in function, while others have prolonged plateaus with-
out major deterioration.

Differential Diagnosis
Early in the disease course, other etiologies of dementia
should be excluded. These include treatable entities such
A B
as thyroid disease, vitamin deciencies, brain tumor, drug
and medication intoxication, chronic infection, and
severe depression (pseudodementia). Neuroimaging stud-
ies (CT and MRI) do not show a single specic pattern
with AD and may be normal early in the course of the
SECTION III

disease. As AD progresses, diffuse cortical atrophy

becomes apparent, and MRI scans show atrophy of the
hippocampus (Fig. 23-2A, B). Imaging helps to exclude
other disorders, such as primary and secondary neo-
plasms, multiinfarct dementia, diffuse white matter dis-
ease, and NPH; it also helps to distinguish AD from other
Diseases of the Central Nervous System

degenerative disorders with distinctive imaging patterns C D

such as FTD or CJD. Functional imaging studies in AD FIGURE 23-2
reveal hypoperfusion or hypometabolism in the posterior Alzheimers disease. Axial T1weighted MR images through
temporal-parietal cortex (Fig. 23-2C, D). The EEG in the midbrain of a normal 86-year-old athlete (A) and a
AD is normal or shows nonspecic slowing. Routine 77-year-old male (B) with AD. Note that both individuals
spinal uid examination is also normal. CSF A amyloid have prominent sulci and slight dilatation of the lateral ventri-
levels are reduced, whereas levels of tau protein are cles. However, there is a reduction in the volume of the hip-
increased, but the considerable overlap of these levels pocampus of the patient with AD (arrows) compared with
with those of the normal aged population limits the use- that of the normal-for-age hippocampus (A). Fluorodeoxyglu-
fulness of these measurements in diagnosis. The use of cose PET scans of a normal control (C) and a patient with AD
blood Apo genotyping is discussed under Pathogenesis, (D). Note that the patient with AD has decreased activity in
later. Slowly progressive decline in memory and orientation, the parietal lobes bilaterally (arrows), a typical nding in this
normal results on laboratory tests, and an MRI or CT scan condition. AD, Alzheimers disease; PET, positron emission
showing only diffuse or posteriorly predominant cortical and hip- tomography. (Images courtesy of TF Budinger, University of
California; with permission.)
pocampal atrophy is highly suggestive of AD. A clinical diag-
nosis of AD reached after careful evaluation is conrmed
at autopsy about 90% of the time, with misdiagnosed
depression suggests pseudodementia (see later). A history
cases usually representing one of the other dementing
of treatment for insomnia, anxiety, psychiatric disturbance,
disorders described later in this chapter, a mixture of AD
or epilepsy suggests chronic drug intoxication. Rapid pro-
with vascular pathology, or DLB.
gression over a few weeks or months associated with
Relatively simple clinical clues are useful in the differ-
rigidity and myoclonus suggests CJD (Chap. 38). Promi-
ential diagnosis. Early prominent gait disturbance with
nent behavioral changes with intact memory and lobar
only mild memory loss suggests vascular dementia or,
atrophy on brain imaging are typical of FTD. A positive
rarely, NPH (see later). Resting tremor with stooped
family history of dementia suggests either one of the
posture, bradykinesia, and masked facies suggest PD
familial forms of AD or one of the other genetic disorders
(Chap. 24).The early appearance of parkinsonian features,
associated with dementia, such as HD (see later), FTD
visual hallucinations, delusional misidentication, or REM
(see later), familial forms of prion diseases, or rare forms
sleep disorders suggest DLB. Chronic alcoholism should
of hereditary ataxias (Chap. 26).
prompt the search for vitamin deciency. Loss of sensi-
bility to position and vibration stimuli accompanied
by Babinski responses suggests vitamin B12 deciency Epidemiology
(Chap. 30). Early onset of a seizure suggests a metastatic The most important risk factors for AD are old age and
or primary brain neoplasm (Chap. 32). A past history of a positive family history. The frequency of AD increases
with each decade of adult life, reaching 2040% of the 307
population older than 85 years. A positive family history
of dementia suggests a genetic cause of AD. Female gen-
der may also be a risk factor independent of the greater
longevity of women. Some AD patients have a past his-
tory of head trauma with concussion, but this appears to
be a relatively minor risk factor. AD is more common in
groups with very low educational attainment, but edu-
cation inuences test-taking ability, and it is clear that
AD can affect persons of all intellectual levels. One
study found that the capacity to express complex writ-
ten language in early adulthood correlated with a
decreased risk for AD. Numerous environmental factors, FIGURE 23-3
including aluminum, mercury, and viruses, have been Mature neuritic plaque with a dense central amyloid core
proposed as causes of AD, but none has been demon- surrounded by dystrophic neurites (thioavin S stain). (Image
strated to play a signicant role. Similarly, several studies courtesy of S DeArmond, University of California; with per-
suggest that the use of nonsteroidal anti-inammatory mission.)

CHAPTER 23
agents is associated with a decreased risk of AD, but this
has not been conrmed in large prospective studies.Vas-
cular disease, in particular stroke, seems to lower the
threshold for the clinical expression of AD. Also, in many phosphorylated tau () protein and appear as paired heli-
AD patients, amyloid angiopathy can lead to ischemic cal laments by electron microscopy. Tau is a micro-
infarctions or hemorrhages. Diabetes increases the risk tubule associated protein that may function to assemble

Alzheimers Disease and Other Dementias

of AD threefold. Elevated homocysteine and cholesterol and stabilize the microtubules that convey cell organelles,
levels; hypertension; diminished serum levels of folic glycoproteins, and other important materials throughout
acid; low dietary intake of fruits, vegetables, and red the neuron. The ability of tau protein to bind to micro-
wine; and low levels of exercise are all being explored as tubule segments is determined partly by the number of
potential risk factors for AD. phosphate groups attached to it. Increased phosphoryla-
tion of tau protein disturbs this normal process. Finally,
Pathology the co-association of AD with DLB and vascular pathol-
ogy is extremely common.
At autopsy, the most severe pathology is usually found in Biochemically, AD is associated with a decrease in the
the hippocampus, temporal cortex, and nucleus basalis of cerebral cortical levels of several proteins and neuro-
Meynert (lateral septum). The most important micro- transmitters, especially acetylcholine, its synthetic
scopic ndings are neuritic senile plaques and NFTs. enzyme choline acetyltransferase, and nicotinic choliner-
These lesions accumulate in small numbers during nor- gic receptors. Reduction of acetylcholine may be related
mal aging of the brain but occur in excess in AD.There in part to degeneration of cholinergic neurons in the
is increasing evidence to suggest that soluble amyloid nucleus basalis of Meynert that project to many areas of
brils called oligomers lead to the dysfunction of the cell cortex. There is also reduction in norepinephrine levels
and may be the rst biochemical injury in AD. Mis- in brainstem nuclei such as the locus coeruleus.
folded A42 molecules may be the most toxic form of
this protein. Accumulation of oligomers eventually leads
GENETIC CONSIDERATIONS
to formation of neuritic plaques (Fig. 23-3). The neu-
ritic plaques contain a central core that includes A Several genetic factors play important roles in the
amyloid, proteoglycans, Apo 4, 1 antichymotrypsin, pathogenesis of at least some cases of AD. One is
and other proteins. A amyloid is a protein of 3942 the APP gene on chromosome 21. Adults with tri-
amino acids that is derived proteolytically from a larger somy 21 (Downs syndrome) consistently develop the
transmembrane protein named amyloid precursor protein typical neuropathologic hallmarks of AD if they survive
(APP) when APP is cleaved by and secretases. The beyond age 40. Many develop a progressive dementia
normal function of A amyloid is unknown. APP has superimposed on their baseline mental retardation. APP
neurotrophic and neuroprotective activities. The plaque is a membrane-spanning protein that is subsequently
core is surrounded by the debris of degenerating neu- processed into smaller units, including A amyloid that is
rons, microglia, and macrophages. The accumulation of deposited in neuritic plaques. A peptide results from
A amyloid in cerebral arterioles is termed amyloid cleavage of APP by and secretases (Fig. 23-4). Pre-
angiopathy. NFTs are silverstaining, twisted neurola- sumably the extra dose of the APP gene on chromosome
ments in neuronal cytoplasm that represent abnormally 21 is the initiating cause of AD in adult Downs syndrome
 308 Step 1: Cleavage by either - or -secretase homologous to a cell-trafcking protein, sel 12, found in

the nematode Coenorhabditis elegans. Patients with muta-
APP
Cell tions in these genes have elevated plasma levels of A42
membrane
amyloid, and PS-1 mutations in cell cultures produce
increased A42 amyloid in the media. There is evidence
that PS-1 is involved in the cleavage of APP at the
gamma secretase site and mutations in either gene (PS-1
-Secretase product -Secretase product or APP) may disturb this function. Mutations in PS-1
have thus far proved to be the most common cause of
Step 2: Cleavage by -secretase
earlyonset FAD, representing perhaps 4070% of this rel-
atively rare syndrome. Mutations in PS-1 tend to produce
A42 A40 P3
AD with an earlier age of onset (mean onset 45 years)
Toxic Nontoxic Nontoxic
Amyloidogenic and a shorter, more rapidly progressive course (mean
FIGURE 23-4
duration 67 years) than the disease caused by mutations
Amyloid precursor protein (APP) is catabolized by -, -,
in PS-2 (mean onset 53 years; duration 11 years). Some
and -secretases. A key initial step is the digestion by either carriers of uncommon PS-2 mutations have had onset
-secretase (BASE) or -secretase [ADAM10 or ADAM17 of dementia after the age of 70. Mutations in the prese-
SECTION III

(TACE)], producing smaller nontoxic products. Cleavage of nilins are rarely involved in the more common sporadic
the -secretase product by -secretase (step 2) results in cases of late-onset AD occurring in the general popula-
either the toxic A42 or the nontoxic A40 peptide; cleavage tion. Molecular DNA blood testing for these uncom-
of the -secretase product by -secretase produces the non- mon mutations is now possible on a research basis, and
toxic P3 peptide. Excess production of A42 is a key initiator mutation analysis of PS-1 is commercially available.
of cellular damage in Alzheimers disease. Current AD research Such testing is likely to be positive only in early-onset
Diseases of the Central Nervous System

is focused on developing therapies designed to reduce accu- familial cases of AD. Any testing of asymptomatic per-
mulation of A42 by antagonizing - or -secretases, promot- sons at risk must be done in the context of formal,
ing -secretase, or clearing A42 that has already formed by thoughtful genetic counseling.
use of specic antibodies. A discovery of great importance has implicated the
Apo gene on chromosome 19 in the pathogenesis of
late onset familial and sporadic forms of AD. Apo is
involved in cholesterol transport and has three alleles: 2,
and results in an excess of cerebral amyloid. Furthermore, 3, and 4.The Apo 4 allele has a strong association with
a few families with early onset FAD have been discovered AD in the general population, including sporadic and
to have point mutations in the APP gene. Although very late-onset familial cases. Approximately 2430% of the
rare, these families were the rst examples of a single- nondemented white population has at least one 4 allele
gene autosomal dominant genetic transmission of AD. (1215% allele frequency), and about 2% are 4/4
Investigation of large families with multigenerational homozygotes. Approximately 4065% of AD patients
FAD led to the discovery of two additional AD genes, have at least one 4 allele, a highly signicant difference
termed the presenilins. Presenilin-1 (PS-1) is on chromo- compared with controls. On the other hand, many AD
some 14 and encodes a protein called S182. Mutations patients have no 4 allele, and individuals with 4 may
in this gene cause an early-onset AD (onset before age never develop AD. Therefore, 4 is neither necessary
60 and often before age 50) transmitted in an autosomal nor sufcient as a cause of AD. Nevertheless, it is clear
dominant, highly penetrant fashion. More than 100 dif- that the Apo 4 allele, especially in the homozygous 4/4
ferent mutations have been found in the PS-1 gene in state, is an important risk factor for AD. It appears to act
families from a wide range of ethnic backgrounds. Pre- as a dose-dependent modier of age of onset, with the
senilin-2 (PS-2) is on chromosome 1 and encodes a earliest onset associated with the 4/4 homozygous
protein called STM2. A mutation in the PS-2 gene was state. It is unknown how Apo functions as a risk factor
rst found in a group of American families with Volga modifying age of onset, but it may be involved with the
German ethnic background. Mutations in PS-1 are clearance of amyloid, less efciently in the case of Apo
much more common than those in PS-2.The two genes 4. Apo is present in the neuritic amyloid plaques of
(PS-1 and PS-2) are highly homologous and encode AD, and it may also be involved in neurobrillary tangle
similar proteins that at rst appeared to have seven trans- formation, because it binds to tau protein. Apo 4
membrane domains (hence the designation STM), but decreases neurite outgrowth in cultures of dorsal root
subsequent studies have suggested eight such domains, ganglion neurons, perhaps indicating a deleterious role
with a ninth submembrane region. Both S182 and in the brains response to injury. There is some evidence
STM2 are cytoplasmic neuronal proteins that are widely that the 2 allele may be protective, but that remains
expressed throughout the nervous system. They are to be claried.The use of Apo testing in the diagnosis
of AD is controversial. It is not indicated as a predictive The pharmacologic action of donepezil, rivastigmine, 309
test in normal persons because its precise predictive and galantamine is inhibition of cholinesterase, with a
value is unclear, and many individuals with the 4 allele resulting increase in cerebral levels of acetylcholine.
never develop dementia. However, some cognitively Memantine appears to act by blocking overexcited
normal 4 heterozygotes and homozygotes have been N-methyl-D-aspartate (NMDA) channels. Double-blind,
found by PET to have decreased cerebral cortical meta- placebo-controlled, crossover studies with cholinesterase
bolic rates, suggesting possible presymptomatic abnor- inhibitors and memantine have shown them to be asso-
malities compatible with the earliest stage of AD. In ciated with improved caregiver ratings of patients func-
demented persons who meet clinical criteria for AD, the tioning and with an apparent decreased rate of decline
nding of an 4 allele increases the reliability of diagno-
in cognitive test scores over periods of up to 3 years. The
sis. However, the absence of an 4 allele does not elimi-
average patient on an anticholinesterase compound
nate the diagnosis of AD. Furthermore, all patients with
maintains his or her MMSE score for close to a year,
dementia, including those with an 4 allele, require a
whereas a placebo-treated patient declines 23 points
search for reversible causes of their cognitive impair-
over the same time period. Memantine, used in conjunc-
ment. Nevertheless, Apo 4 remains the single most
tion with cholinesterase inhibitors or by itself, seems to
important biologic marker associated with risk for AD,
slow cognitive deterioration in patients with moderate
and studies of its functional role and diagnostic useful-

CHAPTER 23
to severe AD and is not approved for mild AD. These
ness are progressing rapidly. Its association (or lack
compounds have only modest efcacy for AD and offer
thereof) with other dementing illnesses needs to be fully
even less benet in the late stages. All the cholinesterase
evaluated. The 4 allele is not associated with FTD,
inhibitors are relatively easy to administer, and their
DLB, or CJD. Additional genes are also likely to be
major side effects are gastrointestinal symptoms (nau-
involved in AD, but none have been reliably identied.
sea, diarrhea, cramps), altered sleep with bad dreams,
bradycardia (usually benign), and sometimes muscle

Alzheimers Disease and Other Dementias

cramps.
In a prospective observational study, the use of estro-
gen replacement therapy appeared to protectby
Treatment: about 50%against development of AD in women. This
ALZHEIMERS DISEASE study seemed to confirm the results of two earlier
The management of AD is challenging and gratifying, case-controlled studies. Sadly, a prospective placebo-
despite the absence of a cure or a robust pharmaco- controlled study of a combined estrogen-progesterone
logic treatment. The primary focus is on long-term therapy for asymptomatic postmenopausal women
amelioration of associated behavioral and neurologic increased, rather than decreased, the prevalence of
problems. dementia. This study markedly dampened enthusiasm
Building rapport with the patient, family members, for hormone treatments for the prevention of dementia.
and other caregivers is essential to successful manage- Additionally, no benet has been found in the treatment
ment. In the early stages of AD, memory aids such as of AD with estrogen.
notebooks and posted daily reminders can be helpful. In patients with moderately advanced AD, a prospec-
Common sense and clinical studies show that family tive trial of the antioxidants selegiline, -tocopherol
members should emphasize activities that are pleasant (vitamin E), or both, slowed institutionalization and pro-
and deemphasize those that are unpleasant. Kitchens, gression to death. Because vitamin E has less potential
bathrooms, and bedrooms need to be made safe, and for toxicity than selegiline and is cheaper, the doses
eventually patients must stop driving. Loss of indepen- used in this study of 1000 IU twice daily are offered to
dence and change of environment may worsen confu- many patients with AD. However, the benecial effects
sion, agitation, and anger. Communication and repeated of vitamin E remain controversial, and most investiga-
calm reassurance are necessary. Caregiver burnout is tors no longer give it in these high doses because of
common, often resulting in nursing home placement of potential cardiovascular complications.
the patient, and respite breaks for the caregiver help to A randomized, double-blind, placebo-controlled trial
maintain successful long-term management of the of an extract of Ginkgo biloba found modest improve-
patient. Use of adult day-care centers can be most help- ment in cognitive function in subjects with AD and vas-
ful. Local and national support groups, such as the cular dementia. This study requires conrmation before
Alzheimers Association, are valuable resources. Ginkgo biloba is used as a treatment for dementia
Donepezil, rivastigmine, galantamine, memantine, because there was a high subject dropout rate and no
and tacrine are the drugs presently approved by the improvement on a clinicians judgment scale. A compre-
Food and Drug Administration (FDA) for treatment of hensive 6-year multicenter prevention study using
AD. Due to hepatotoxicity, tacrine is no longer used. Ginkgo biloba is underway.
 310 Vaccination against A42 has proved highly efca- several strokes may develop chronic cognitive decits,
cious in mouse models of AD; it helped to clear amyloid commonly called multi-infarct dementia. The strokes may
from the brain and prevent further accumulation of be large or small (sometimes lacunar) and usually involve
amyloid. However, in human trials this approach led to several different brain regions. The occurrence of
life-threatening complications, including meningoen- dementia depends partly on the total volume of dam-
cephalitis. Modications of the vaccine approach using aged cortex, but it is also more common in individuals
passive immunization with monoclonal antibodies are with left-hemisphere lesions, independent of any lan-
currently being evaluated in phase 3 trials. Another guage disturbance. Patients typically report a history of
experimental approach to the treatment of AD has been discrete episodes of sudden neurologic deterioration.
the use of and secretase inhibitors that diminish the Many multi-infarct dementia patients have a history of
production of A42. hypertension, diabetes, coronary artery disease, or other
Several retrospective studies suggest that nons- manifestations of widespread atherosclerosis. Physical
teroidal anti-inammatory agents and statins (HMG-CoA examination usually shows focal neurologic decits such
reductase inhibitors) may have a protective effect on as hemiparesis, a unilateral Babinski reex, a visual eld
dementia, and controlled prospective studies are being defect, or pseudobulbar palsy. Recurrent strokes result in
conducted. Similarly, prospective studies with the goal a stepwise progression of disease. Neuroimaging studies
of lowering serum homocysteine levels are underway, show multiple areas of infarction. Thus, the history and
SECTION III

suggesting an association of elevated homocysteine neuroimaging ndings differentiate this condition from
with dementia progression based on epidemiologic AD. However, both AD and multiple infarctions are
studies. Finally, there is now a strong interest in the rela- common and sometimes occur together. With normal
tionship between diabetes and AD, and insulin-regulat- aging, there is also an accumulation of amyloid in cere-
ing studies are being conducted. bral blood vessels, leading to a condition called cerebral
Mild to moderate depression is common in the early amyloid angiopathy of aging (not associated with demen-
Diseases of the Central Nervous System

stages of AD and responds to antidepressants or tia), which predisposes older persons to hemorrhagic
cholinesterase inhibitors. Selective serotonin reuptake lobar stroke. AD patients with amyloid angiopathy may
inhibitors (SSRIs) are commonly used due to their low be at increased risk for cerebral infarction.
anticholinergic side effects. Generalized seizures should Some individuals with dementia are discovered on
be treated with an appropriate anticonvulsant, such as MRI to have bilateral abnormalities of subcortical white
phenytoin or carbamazepine. Agitation, insomnia, hallu- matter, termed diffuse white matter disease, often occurring
cinations, and belligerence are especially troublesome
in association with lacunar infarctions (Fig. 23-5). The
characteristics of some AD patients, and these behaviors
dementia may be insidious in onset and progress slowly,
can lead to nursing home placement. The newer genera-
features that distinguish it from multi-infarct dementia,
tion of atypical antipsychotics, such as risperidone,
but other patients show a stepwise deterioration more
quetiapine, and olanzapine, are being used in low doses
typical of multi-infarct dementia. Early symptoms are
mild confusion, apathy, changes in personality, depres-
to treat these neuropsychiatric symptoms. The few con-
sion, psychosis, memory, and spatial or executive decits.
trolled studies comparing drugs against behavioral
Marked difculties in judgment and orientation and
intervention in the treatment of agitation suggest mild
dependence on others for daily activities develop later.
efcacy with signicant side effects related to sleep, gait,
Euphoria, elation, depression, or aggressive behaviors are
and cardiovascular complications. All of the antipsy-
common as the disease progresses. Both pyramidal and
chotics carry a black-box warning and are associated
cerebellar signs may be present in the same patient. A
with increased deaths in AD patients; therefore, they
gait disorder is present in at least half of these patients.
should be used with caution. However, careful, daily,
With advanced disease, urinary incontinence and dysarthria
nonpharmacologic behavior management is often not
with or without other pseudobulbar features (e.g., dys-
available, rendering medications necessary.
phagia, emotional lability) are frequent. Seizures and
myoclonic jerks appear in a minority of patients. This
disorder appears to result from chronic ischemia due to
occlusive disease of small, penetrating cerebral arteries
VASCULAR DEMENTIA
and arterioles (microangiopathy). Any disease-causing
Dementia associated with cerebral vascular disease can stenosis of small cerebral vessels may be the critical
be divided into two general categories: multi-infarct underlying factor, though most typically hypertension is
dementia and diffuse white matter disease (also called the main cause. The term Binswangers disease should be
leukoaraiosis, subcortical arteriosclerotic encephalopathy or Bin- used with caution, because it does not really identify a
swangers disease). Cerebral vascular disease appears to be single entity.
a more common cause of dementia in Asia than in Other rare causes of white matter disease also present
Europe and North America. Individuals who have had with dementia, such as adult metachromatic leukodystrophy
 FRONTOTEMPORAL DEMENTIA, 311
PROGRESSIVE SUPRANUCLEAR PALSY,
AND CORTICOBASAL DEGENERATION
Frontotemporal dementia (FTD) often begins when the
patient is in the fth to seventh decades, and in this age
group it is nearly as common as AD. Most studies suggest
that FTD is twice as common in men as it is in women.
Unlike AD, behavioral symptoms predominate in the early
stages of FTD. Genetics play a signicant role in a sizable
minority of cases. The clinical heterogeneity in familial
and sporadic forms of FTD is remarkable, with patients
demonstrating variable mixtures of disinhibition, demen-
tia, PSP, CBD, and motor neuron disease. The most
common genetic mutations that cause an autosomal
dominant form of FTD involve the tau or progranulin
genes, both on chromosome 17. Tau mutations lead to a

CHAPTER 23
change in the alternate splicing of tau or cause loss of
FIGURE 23-5
function in the tau molecule.With progranulin, a missense
Diffuse white matter disease (Binswangers disease). Axial
mutation in the coding sequence of the gene is the
T2-weighted MR image through the lateral ventricles reveals
multiple areas of abnormal high signal intensity involving the
underlying cause for the neurodegeneration. Progranulin
periventricular white matter as well as the corona radiata and
appears to be a rare example of an autosomal dominant
lentiform nuclei (arrows). While seen in some individuals with mutation leading to haploinsufciencytoo little of the
progranulin protein. Both tau and progranulin mutations

Alzheimers Disease and Other Dementias

normal cognition, this appearance is more pronounced in
patients with dementia of a vascular etiology. are associated with parkinsonian features, while ALS is
rare in the setting of these mutations. In contrast, familial
FTD with ALS has been linked to chromosome 9. Muta-
tions in the valosin (chromosome 9) and ESCRTII mol-
(arylsulfatase A deciency) and progressive multifocal ecules (chromosome 3) also lead to autosomal dominant
leukoencephalopathy (papovavirus infection). A domi- forms of familial FTD.
nantly inherited form of diffuse white matter disease is In FTD, early symptoms are divided among cognitive,
known as cerebral autosomal dominant arteriopathy with sub- behavioral, and sometimes motor abnormalities, reect-
cortical infarcts and leukoencephalopathy (CADASIL). Clini- ing degeneration of the anterior frontal and temporal
cally, there is a progressive dementia developing in the regions, basal ganglia, and motor neurons. Cognitive
fth to seventh decades in multiple family members testing typically reveals spared memory but impaired
who may also have a history of migraine and recurrent planning, judgment, or language. Poor business decisions
stroke without hypertension. Skin biopsy may show and difculty organizing work tasks are common, and
characteristic dense bodies in the media of arterioles. speech and language decits often emerge. Patients with
The disease is caused by mutations in the notch 3 gene, FTD often show an absence of insight into their condi-
and there is a commercially available genetic test. The tion. Common behavioral decits include apathy, disin-
frequency of this disorder is unknown, and there are no hibition, weight gain, food fetishes, compulsions, and
known treatments. euphoria.
Mitochondrial disorders can present with strokelike Findings at the bedside are dictated by the anatomic
episodes and can selectively injure basal ganglia or cor- localization of the disorder. Asymmetric left-frontal cases
tex. Many such patients show other ndings suggestive of present with nonuent aphasias, while left anterior tem-
a neurologic or systemic disorder such as ophthalmople- poral degeneration is characterized by loss of words and
gia, retinal degeneration, deafness, myopathy, neuropathy, concepts related to language (semantic dementia). Non-
or diabetes. Diagnosis is difcult but serumespecially uent patients quickly progress to mutism, while those
CSFlevels of lactate and pyruvate may be abnormal, with semantic dementia develop features of multimodal-
and biopsy of affected tissue is often diagnostic. ity agnosia, losing the ability to recognize faces, objects,
Treatment of vascular dementia must be focused on the words, and the emotions of others. Copying, calculating,
underlying causes, such as hypertension, atherosclerosis, and navigation often remain normal into later in the ill-
and diabetes. Recovery of lost cognitive function is not ness. Recently it has become apparent that many if
likely to occur, although uctuations with periods of not most patients with nonuent aphasia progress to
improvement are common. Anticholinesterase compounds clinical syndromes that overlap with PSP and CBD and
are being studied as a treatment for vascular dementia. show these pathologies at autopsy. This left-hemisphere
 312 presentation of FTD has been called primary progressive
aphasia. In contrast, right-frontal or temporal cases show
profound alterations in social conduct, with loss of
empathy, disinhibition, and antisocial behaviors predom-
inating. Memory and visuospatial skills are relatively
spared in most FTD patients. There is a striking overlap
among FTD, PSP, CBD, and motor neuron disease; oph-
thalmoplegia, dystonia, swallowing symptoms, and fasci-
culations are common at presentation of FTD or
emerge during the course of the illness.
The distinguishing anatomic hallmark of FTD is a
marked lobar atrophy of temporal and/or frontal lobes,
which can be visualized by neuroimaging studies and is
readily apparent at autopsy (Figs. 23-6 and 23-7). The
atrophy is sometimes asymmetric and may involve the
basal ganglia.Two major pathologies have been linked to FIGURE 23-7
the clinical syndrome, one associated with tau inclu- Voxel-based morphometry analysis showing differing pat-
SECTION III

terns of brain atrophy in the frontal variant of frontotemporal

sions, the other with inclusions that stain negatively for
dementia (red), temporal variant of frontotemporal dementia
tau but positively for ubiquitin and TDP-43. Micro-
(green), and Alzheimers disease (blue). This technique allows
scopic ndings that are seen across all FTD cases include
comparison of MRI gray matter volumes between groups of
gliosis, neuronal loss, and spongiosus.
subjects. (Image courtesy of M Gorno-Tempini, University of
Approximately one-half of all cases show swollen or California at San Francisco; with permission.
ballooned neurons containing cytoplasmic inclusions
Diseases of the Central Nervous System

that stain positively for tau. These aggregates sometimes

resemble those found in PSP and CBD, and tau plays a
major role in the pathogenesis of all three conditions. A cholinergic system is relatively spared in FTD, whereas
toxic gain of function related to tau underlies the patho- serotonergic and glutaminergic neurons are depleted in
genesis of many familial cases and is presumed to be a many patients.
factor in sporadic cases as well. Nearly 80% of FTD Historically, Picks disease was described as a progressive
patients show involvement of the basal ganglia at degenerative disorder characterized clinically by selective
autopsy, and 15% go on to develop motor neuron dis- involvement of the anterior frontal and temporal neo-
ease, underscoring the multisystem nature of this illness. cortex and pathologically by intracellular inclusions
Serotonergic losses are seen in many patients, and gluta- (Pick bodies). Classic Pick bodies stain positive with silver
minergic neurons are depleted. In contrast to AD, the (argyrophilic) and tau, but many of the tau-positive

A B
FIGURE 23-6
Frontotemporal dementia (FTD). Coronal MRI sections disinhibition and antisocial behavior. In the temporally pre-
from one patient with frontally predominant FTD (A) and dominant patient, severe atrophy in the left temporal lobe
another with temporally predominant FTD (B). Prominent (open arrows) and amygdala (white arrowheads) is present;
atrophy affecting the frontal gyri (white arrows) is present in this patient presented with progressive aphasia. (Images
frontally predominant FTD, particularly affecting the right courtesy of H Rosen and G Schauer, University of California
frontal region; note also the thinning of the corpus callosum at San Francisco; with permission.)
superior to the lateral ventricles. This patient presented with
 no other effective treatments exist. Death occurs within 313
510 years of onset. At autopsy, abnormal accumulation
of tau is found within neurons and glia, often in the
form of neurobrillary tangles (NFTs).These tangles are
found in multiple subcortical structures (including the
subthalamus, globus pallidus, substantia nigra, locus
coeruleus, periaqueductal gray, superior colliculi, and
oculomotor nuclei) as well as in the neocortex. The
NFTs have similar staining characteristics to those of
AD, but on electron microscopy they are generally seen
FIGURE 23-8 to consist of straight tubules rather than the paired heli-
Classic intraneuronal Pick body (tau2 stain). These con- cal laments found in AD.
sist of loosely arranged paired and straight-helical laments In addition to its overlap with FTD and CBD (see
and stain positive for tau. Classic Pick bodies are seen in below), PSP is often confused with idiopathic Parkinsons
~20% of all frontotemporal dementia cases. disease (PD). Although elderly Parkinsons patients may
have some difculty with upgaze, they do not develop
downgaze paresis or other abnormalities of voluntary

CHAPTER 23
inclusions in FTD cases are not labeled with silver stains eye movements typical of PSP. Dementia does occur in
(Fig. 23-8).Although the nomenclature for these patients ~20% of PD patients, often secondary to DLB. Further-
has remained controversial, the term FTD is increasingly more, the behavioral syndromes seen with DLB differ
used to describe the clinical syndrome, while Picks dis- from PSP (see later).The occurrence of dementia in PD
ease is used to classify patients in whom the pathology is more likely with increasing age, increasing severity of
shows classic Pick bodies (only a minority of patients extrapyramidal signs, a long duration of disease, and the

Alzheimers Disease and Other Dementias

with the clinical features of FTD). presence of depression.These patients also show cortical
The burden on caregivers of FTD patients is atrophy on brain imaging. Neuropathologically, there
extremely high. Treatment is symptomatic, and there are may be Alzheimer changes in the cortex (amyloid
currently no therapies known to slow progression or plaques and NFTs), neuronal Lewy body inclusions in
improve cognitive symptoms. Many of the behaviors both the substantia nigra and the cortex, or no specic
that accompany FTD, such as depression, hyperorality, microscopic changes other than gliosis and neuronal
compulsions, and irritability, can be ameliorated with loss. Progressive supranuclear palsy and Parkinsons dis-
serotonin-modifying antidepressants. The co-association ease are discussed in detail in Chap. 24.
with motor disorders necessitates the careful use of Cortical basal degeneration (CBD) is a slowly progres-
antipsychotics, which can exacerbate this problem. sive dementing illness associated with severe gliosis and
Progressive supranuclear palsy (PSP) is a degenerative neuronal loss in both the neocortex and basal ganglia
disease that involves the brainstem, basal ganglia, and (substantia nigra and striatum). Occasionally there is a
neocortex. Clinically, this disorder begins with falls and unilateral onset with rigidity, dystonia, and apraxia of
vertical supranuclear gaze paresis and progresses to sym- one arm and hand, sometimes called the alien hand,
metrical rigidity and dementia. A stiff, unstable posture while in other instances the disease presents as a pro-
with hyperextension of the neck and slow gait with fre- gressive frontal syndrome or as progressive symmetrical
quent falls is characteristic of PSP. Early in the disease, parkinsonism. Some patients begin with a progressive
patients have difculty with downgaze and lose vertical nonuent aphasia or a progressive motor disorder of
opticokinetic nystagmus on downward movement of a speech. Eventually CBD becomes bilateral and leads to
target. Frequent unexplained and sometimes spectacular dysarthria, slow gait, action tremor, and dementia. The
falls are common secondary to a combination of axial microscopic features include enlarged, achromatic neu-
rigidity, inability to look down, and bad judgment. rons in the cortex with tau inclusions. Glial plaques with
Although the patients have very limited voluntary eye tau inclusions are pathognomonic of CBD. The condi-
movements, their eyes still retain oculocephalic reexes tion is rarely familial, the cause is unknown, and there is
(dolls head maneuver); thus, the eye-movement disorder no specic treatment.
is supranuclear. The dementia is similar to FTD with
apathy, frontal/executive dysfunction, poor judgment,
slowed thought processes, impaired verbal uency, and
DEMENTIA WITH LEWY BODIES
difculty with sequential actions and with shifting from The parkinsonian dementia syndromes are under increas-
one task to another all common at the time of presenta- ing study, with many cases unied by the presence of
tion and often preceding the motor syndrome. Some Lewy bodies in both the substantia nigra and the cortex
patients begin with a nonuent aphasia and progress to at pathology. The clinical syndrome is characterized by
classical PSP.There is only a limited response to L-dopa; visual hallucinations, parkinsonism, uctuating alertness,
 314 falls, and often REM sleep behavior disorder. Dementia must be carefully titrated; tolerability may be improved
can precede or follow the appearance of parkinsonism. by concomitant AD medications.
Hence, one pathway to DLB occurs in patients with
longstanding PD without cognitive impairment who
slowly develop a dementia that is associated with visual OTHER CAUSES OF DEMENTIA
hallucinations, parkinsonism, and uctuating alertness. In
others, the dementia and neuropsychiatric syndrome Prion disorders such as Creutzfeldt-Jakob disease (CJD) are
precede the parkinsonism. DLB patients are highly sus- rare conditions (~1 per million population) that produce
ceptible to metabolic perturbations, and in some patients dementia. CJD is a rapidly progressive disorder associ-
the rst manifestation of illness is a delirium, often pre- ated with dementia, focal cortical signs, rigidity, and
cipitated by an infection or other systemic disturbance. myoclonus, causing death in <1 year from the rst
A delirium induced by L-dopa, prescribed for parkin- symptoms. The rapidity of progression seen with CJD is
sonian symptoms attributed to PD, may be the initial uncommon in AD so that distinction between the two
clue that the correct diagnosis is DLB. Even without an disorders is usually possible. However, CBD and DLB,
underlying precipitant, uctuations can be marked in more rapid degenerative dementias with prominent
DLB patients, with the occurrence of episodic confu- abnormalities in movement, are more likely to be mis-
sion admixed with lucid intervals. However, despite the taken for CJD.The differential diagnosis for CJD usually
SECTION III

uctuating pattern, the clinical features persist over a includes other rapidly progressive dementing conditions
long period of time, unlike delirium, which resolves such as viral or bacterial encephalitides, Hashimotos
following correction of the underlying precipitant. Cog- encephalitis, CNS vasculitis, lymphoma, or paraneoplas-
nitively, DLB patients tend to have relatively better tic syndromes. The markedly abnormal periodic EEG
memory but more severe visuospatial decits than indi- discharges and cortical and basal ganglia abnormalities
viduals with AD. on diffusion-weighted MRI are unique diagnostic fea-
Diseases of the Central Nervous System

The key neuropathologic feature is the presence of tures of CJD. Transmission from infected cattle to the
Lewy bodies throughout the cortex, amygdala, cingulate human population in the United Kingdom has caused a
cortex, and substantia nigra. Lewy bodies are intraneu- small epidemic of atypical CJD in young adults. Prion
ronal cytoplasmic inclusions that stain with periodic diseases are discussed in detail in Chap. 38.
acidSchiff (PAS) and ubiquitin. They are composed of Huntingtons disease (HD) (Chap. 25) is an autosomal
straight neurolaments 720 nm long with surrounding dominant, degenerative brain disorder. A DNA repeat
amorphous material. They contain epitopes recognized expansion (CAG repeat) of the mutant gene on chro-
by antibodies against phosphorylated and nonphospho- mosome 4 forms the basis of a diagnostic blood test for
rylated neurolament proteins, ubiquitin, and a presy- the disease gene.The clinical hallmarks of the disease are
naptic protein called -synuclein. Lewy bodies are tradi- chorea, behavioral disturbance, and frontal executive dis-
tionally found in the substantia nigra of patients with order. Onset is usually in the fourth or fth decade, but
idiopathic PD. A profound cholinergic decit is present there is a wide range in age of onset, from childhood to
in many patients with DLB and may be a factor respon- >70 years. Memory is frequently not impaired until late
sible for the uctuations and visual hallucinations pre- in the disease, but attention, judgment, awareness, and
sent in these patients. In patients without other pathologic executive functions may be seriously decient at an
features, the condition is referred to as diffuse Lewy body early stage. Depression, apathy, social withdrawal, irri-
disease. In patients whose brains also contain excessive tability, and intermittent disinhibition are common.
amounts of amyloid plaques and NFTs, the condition is Delusions and obsessive compulsive behavior may occur.
called the Lewy body variant of Alzheimers disease. The The disease duration is typically about 15 years but is
quantity of Lewy bodies required to establish the diag- quite variable. There is no specic treatment, but the
nosis is controversial, but a denite diagnosis requires adventitious movements may partially respond to rst-
pathology. At autopsy, 1030% of demented patients and second-generation antipsychotics. Treatment of
show cortical Lewy bodies. behavioral changes are discussed in General Sympto-
Due to the overlap with AD and the cholinergic matic Treatment of the Patient with Dementia, later.
decit in DLB, anticholinesterase compounds may be Asymptomatic adult children at risk for HD should
helpful. Exercise programs maximize the motor function receive careful genetic counseling prior to DNA testing,
of these patients. Similarly, antidepressants are often nec- because a positive result may have serious emotional and
essary to treat the depressive syndromes that accompany social consequences.
DLB. Atypical antipsychotics in low doses are sometimes Normal-pressure hydrocephalus (NPH) is a relatively
needed to alleviate psychosis, although even low doses uncommon syndrome with clinical, physiologic, and
can increase extrapyramidal syndromes and may rarely neuroimaging characteristics. Historically, many of the
lead to death. As noted above, patients with DLB are individuals who have been treated for NPH have suf-
extremely sensitive to dopaminergic medications, which fered from other dementias, particularly AD, multi-infarct
 315

CHAPTER 23
FIGURE 23-9
Normal-pressure hydrocephalus. A. Sagittal T1-weighted dilatation of the lateral, third, and fourth ventricles with a
MR image demonstrates dilatation of the lateral ventricle and patent aqueduct, typical of communicating hydrocephalus.
stretching of the corpus callosum (arrows), depression of the B. Axial T2-weighted MR images demonstrate dilatation of
oor of the third ventricle (single arrowhead), and enlarge- the lateral ventricles. This patient underwent successful ven-

Alzheimers Disease and Other Dementias

ment of the aqueduct (double arrowheads). Note the diffuse triculoperitoneal shunting.

dementia, and DLB. For NPH the clinical triad includes A number of attempts have been made to use various
an abnormal gait (ataxic or apractic), dementia (usually special studies to improve the diagnosis of NPH and pre-
mild to moderate), and urinary incontinence. Neu- dict the success of ventricular shunting. These include
roimaging studies reveal enlarged lateral ventricles radionuclide cisternography (showing a delay in CSF
(hydrocephalus) with little or no cortical atrophy. This absorption over the convexity) and various attempts to
syndrome is a communicating hydrocephalus with a monitor and alter CSF ow dynamics, including a con-
patent aqueduct of Sylvius (Fig. 23-9), in contrast to stant-pressure infusion test. None has proven to be spe-
congenital aqueductal stenosis, where the aqueduct is cic or consistently useful.There is sometimes a transient
small. In many cases, periventricular edema is present. improvement in gait or cognition following lumbar
Lumbar puncture opening pressure is in the high normal puncture (or serial punctures) with removal of 3050 mL
range, and the CSF protein, sugar concentrations, and cell of CSF, but this nding also has not proven to be consis-
count are normal. NPH is presumed to be caused by tently predictive of post-shunt improvement. AD often
obstruction to normal ow of CSF over the cerebral masquerades as NPH, because the gait may be abnormal
convexity and delayed absorption into the venous sys- in AD and cortical atrophy sometimes is difcult to
tem. The indolent nature of the process results in determine by CT or MRI early in the disease. Hip-
enlarged lateral ventricles but relatively little increase in pocampal atrophy on MRI is a clue favoring AD.
CSF pressure. There is presumed stretching and distor- Approximately 3050% of patients identied by careful
tion of white matter tracts in the corona radiata, but the diagnosis as having NPH will show improvement with a
exact physiologic cause of the clinical syndrome is ventricular shunting procedure. Gait may improve more
unclear. Some patients have a history of conditions pro- than memory. Transient, short-lasting improvement is
ducing scarring of the basilar meninges (blocking common. Patients should be carefully selected for this
upward ow of CSF) such as previous meningitis, sub- operation, because subdural hematoma and infection are
arachnoid hemorrhage, or head trauma. Others with known complications.
longstanding but asymptomatic congenital hydrocephalus Dementia can accompany chronic alcoholism (Chap. 50).
may have adult-onset deterioration in gait or memory This may be a result of associated malnutrition, especially
that is confused with NPH. In contrast to AD, the NPH of B vitamins and particularly thiamine. However, other
patient has an early and prominent gait disturbance poorly dened aspects of chronic alcohol ingestion may
and no evidence of cortical atrophy on CT or MRI. also produce cerebral damage. A rare idiopathic syndrome
 316 of dementia and seizures with degeneration of the corpus Deciency of nicotinic acid (pellagra) is associated
callosum has been reported primarily in male Italian with sun-exposed skin rash, glossitis, and angular stom-
drinkers of red wine (Marchiafava-Bignami disease). atitis. Severe dietary deciency of nicotinic acid along
Thiamine (vitamin B1) deciency causes Wernickes with other B vitamins such as pyridoxine may result in
encephalopathy (Chap. 22).The clinical presentation is a spastic paraparesis, peripheral neuropathy, fatigue, irri-
malnourished individual (frequently but not necessarily tability, and dementia. This syndrome has been seen in
alcoholic) with confusion, ataxia, and diplopia from prisoner-of-war and concentration camps. Low serum
ophthalmoplegia.Thiamine deciency damages the thal- folate levels appear to be a rough index of malnutrition,
amus, mammillary bodies, midline cerebellum, periaque- but isolated folate deciency has not been proven to be
ductal grey matter of the midbrain, and peripheral specic cause of dementia.
nerves. Damage to the dorsomedial thalamic region cor- Infections of the CNS usually cause delirium and other
relates most closely with the memory loss. Prompt acute neurologic syndromes (Chap. 13). However, some
administration of parenteral thiamine (100 mg intra- chronic CNS infections, particularly those associated with
venously for 3 days followed by daily oral dosage) may chronic meningitis (Chap. 36), may produce a dementing
reverse the disease if given in the rst days of symptom illness. The possibility of chronic infectious meningitis
onset. However, prolonged untreated thiamine de- should be suspected in patients presenting with a demen-
ciency can result in an irreversible dementia/amnestic tia or behavioral syndrome who also have headache,
SECTION III

syndrome (Korsakoff s psychosis) or even death. meningismus, cranial neuropathy, and/or radiculopathy.
In Korsakoffs syndrome, the patient is unable to recall Between 20 and 30% of patients in the advanced stages of
new information despite normal immediate memory, infection with HIV become demented (Chap. 37). Cardi-
attention span, and level of consciousness. Memory for nal features include psychomotor retardation, apathy, and
new events is seriously impaired, whereas memory of impaired memory. This syndrome may result from sec-
knowledge prior to the illness is relatively intact. Patients ondary opportunistic infections but can also be caused
Diseases of the Central Nervous System

are easily confused, disoriented, and incapable of recall- by direct infection of CNS neurons with HIV. CNS
ing new information for more than a brief interval. syphilis was a common cause of dementia in the prean-
Supercially, they may be conversant, entertaining, and tibiotic era; it is uncommon nowadays but can still be
able to perform simple tasks and follow immediate com- encountered in patients with multiple sex partners. Char-
mands. Confabulation is common, although not always acteristic CSF changes consist of pleocytosis, increased
present, and may result in obviously erroneous state- protein, and a positive venereal disease research laboratory
ments and elaborations. There is no specic treatment (VDRL) test.
because the previous thiamine deciency has produced Primary and metastatic neoplasms of the CNS (Chap. 32)
irreversible damage to the medial thalamic nuclei and usually produce focal neurologic ndings and seizures
mammillary bodies. Mammillary body atrophy may be rather than dementia. However, if tumor growth begins
visible on high-resolution MRI. in the frontal or temporal lobes, the initial manifesta-
Vitamin B12 deciency, as can occur in pernicious anemia, tions may be memory loss or behavioral changes. A
causes a macrocytic anemia and may also damage the ner- paraneoplastic syndrome of dementia associated with
vous system (Chap. 30). Neurologically, it most commonly occult carcinoma (often small cell lung cancer) is termed
produces a spinal cord syndrome (myelopathy) affecting the limbic encephalitis (Chap. 39). In this syndrome, confusion,
posterior columns (loss of position and vibratory sense) and agitation, seizures, poor memory, movement disorders,
corticospinal tracts (hyperactive tendon reexes with and frank dementia may occur in association with sen-
Babinski responses); it also damages peripheral nerves, sory neuropathy.
resulting in sensory loss with depressed tendon reexes. A nonconvulsive seizure disorder may underlie a syn-
Damage to cerebral myelinated bers may also cause drome of confusion, clouding of consciousness, and gar-
dementia.The mechanism of neurologic damage is unclear bled speech. Psychiatric disease is often suspected, but an
but may be related to a deciency of S-adenosylmethionine EEG demonstrates the seizure discharges. If recurrent or
(required for methylation of myelin phospholipids) due to persistent, the condition may be termed complex partial
reduced methionine synthase activity or accumulation of status epilepticus.The cognitive disturbance often responds
methylmalonate, homocysteine, and propionate, providing to anticonvulsant therapy. The etiology may be previous
abnormal substrates for fatty acids synthesis in myelin. small strokes or head trauma; some cases are idiopathic.
The neurologic signs of vitamin B12 deciency are usually It is important to recognize systemic diseases that indi-
associated with macrocytic anemia but on occasion may rectly affect the brain and produce chronic confusion or
occur in its absence.Treatment with parenteral vitamin B12 dementia. Such conditions include hypothyroidism; vas-
(1000 g intramuscularly daily for a week, weekly for a culitis; and hepatic, renal, or pulmonary disease. Hepatic
month, and monthly for life for pernicious anemia) stops encephalopathy may begin with irritability and confu-
progression of the disease if instituted promptly, but reversal sion and slowly progress to agitation, lethargy, and coma
of advanced nervous system damage will not occur. (Chaps. 14, 45).
 Isolated vasculitis of the CNS (CNS granulomatous vas- of bouts. Early in the condition, a personality change 317
culitis) (Chap. 21) occasionally causes a chronic associated with social instability and sometimes paranoia
encephalopathy associated with confusion, disorienta- and delusions occurs. Later, memory loss progresses to
tion, and cloudiness of consciousness. Headache is com- full dementia, often associated with parkinsonian signs
mon, and strokes and cranial neuropathies may occur. and ataxia or intention tremor. At autopsy, the cerebral
Brain imaging studies may be normal or nonspecically cortex may show changes similar to AD, although NFTs
abnormal. CSF studies reveal a mild pleocytosis or ele- are usually more prominent than amyloid plaques
vation in the protein level. Cerebral angiography often (which are usually diffuse rather than neuritic). There
shows multifocal stenosis and narrowing of vessels. A may also be loss of neurons in the substantia nigra.
few patients have only small-vessel disease that is not Chronic subdural hematoma (Chap. 31) is also occasion-
revealed on angiography.The angiographic appearance is ally associated with dementia, often in the context of
not specic and may be mimicked by atherosclerosis, underlying cortical atrophy from conditions such as AD
infection, or other causes of vascular disease. Brain or or HD. In these latter cases, evacuation of subdural
meningeal biopsy demonstrates abnormal arteries with hematoma will not alter the underlying degenerative
endothelial cell proliferation and inltrates of mononu- process.
clear cells.The prognosis is often poor, although the dis- Transient global amnesia (TGA) is characterized by the
order may remit spontaneously. Some patients respond sudden onset of a severe episodic memory decit, usu-

CHAPTER 23
to glucocorticoids or chemotherapy. ally occurring in persons >50 years. Often the memory
Chronic metal exposure may produce a dementing syn- loss occurs in the setting of an emotional stimulus or
drome.The key to diagnosis is to elicit a history of expo- physical exertion. During the attack, the individual is
sure at work or home, or even as a consequence of a alert and communicative, general cognition seems intact,
medical procedure such as dialysis. Chronic lead poison- and there are no other neurologic signs or symptoms.
ing from inadequately red glazed pottery has been The patient may seem confused and repeatedly ask

Alzheimers Disease and Other Dementias

reported. Fatigue, depression, and confusion may be asso- about present events.The ability to form new memories
ciated with episodic abdominal pain and peripheral returns after a period of hours, and the individual
neuropathy. Gray lead lines appear in the gums. There is returns to normal with no recall for the period of the
usually an anemia with basophilic stippling of red cells. attack. Frequently no cause is determined, but cere-
The clinical presentation can resemble that of acute brovascular disease, epilepsy (7% in one study), migraine,
intermittent porphyria, including elevated levels of urine or cardiac arrhythmias have all been implicated. A Mayo
porphyrins as a result of the inhibition of -aminole- Clinic review of 277 patients with TGA found a past
vulinic acid dehydrase.The treatment is chelation therapy history of migraine in 14% and cerebrovascular disease
with agents such as ethylenediamine tetraacetic acid in 11%, but these conditions were not temporally related
(EDTA). Chronic mercury poisoning produces demen- to the TGA episodes. Approximately one-quarter of the
tia, peripheral neuropathy, ataxia, and tremulousness that patients had recurrent attacks, but they were not at
may progress to a cerebellar intention tremor or choreoa- increased risk for subsequent stroke. Rare instances of
thetosis. The confusion and memory loss of chronic permanent memory loss after sudden onset have been
arsenic intoxication is also associated with nausea, weight reported, usually representing ischemic infarction of the
loss, peripheral neuropathy, pigmentation and scaling of hippocampi or medial thalamic nuclei bilaterally.
the skin, and transverse white lines of the ngernails The ALS/parkinsonian/dementia complex of Guam is a
(Mees lines).Treatment is chelation therapy with dimer- rare degenerative disease that has occurred in the
caprol (BAL). Aluminum poisoning has been best docu- Chamorro natives on the island of Guam. Individuals
mented with the dialysis dementia syndrome, in which may have any combination of parkinsonian features,
water used during renal dialysis was contaminated with dementia, and motor neuron disease. The most charac-
excessive amounts of aluminum. This poisoning resulted teristic pathologic features are the presence of NFTs in
in a progressive encephalopathy associated with confu- degenerating neurons of the cortex and substantia nigra
sion, nonuent aphasia, memory loss, agitation, and, later, and loss of motor neurons in the spinal cord. Epidemio-
lethargy and stupor. Speech arrest and myoclonic jerks logic evidence supports a possible environmental cause,
were common and associated with severe and general- such as exposure to a neurotoxin with a long latency
ized EEG changes.The condition has been eliminated by period. One interesting but unproven candidate neuro-
the use of deionized water for dialysis. toxin occurs in the seed of the false palm tree, which
Recurrent head trauma in professional boxers may Guamanians traditionally used to make our. The ALS
lead to a dementia sometimes called the punch drunk syndrome is decreasing in frequency in Guam, but a
syndrome, or dementia pugilistica. The symptoms can be dementing illness with rigidity continues to be seen.
progressive, beginning late in a boxers career or even Rarely, adult-onset leukodystrophies, neuronal storage
long after retirement.The severity of the syndrome cor- diseases, and other genetic disorders can present as
relates with the length of the boxing career and number dementia late in life. Metachromatic leukodystrophy can
 318 present as a dementia associated with large frontal white third decades) than most dementing illnesses, and is
matter lesions.This syndrome is diagnosed by measuring associated with intact memory.The delusions and hallu-
arylsulfatase A enzyme activity in white blood cells. Adult cinations of schizophrenia are usually more complex and
presentations of adrenal leukodystrophy have been bizarre than those of dementia. Some chronic schizo-
reported, and in these cases involvement of the spinal cord phrenics develop an unexplained progressive dementia
and posterior white matter is common. Adrenoleukodys- late in life that is not related to AD. Conversely, FTD,
trophy is diagnosed with measurement of plasma very HD, vascular dementia, DLB, AD, or leukoencephalopa-
long-chain fatty acids. CADASIL is another genetic thy can begin with schizophrenia-like features, leading
syndrome associated with white matter disease, often to the misdiagnosis of a psychiatric condition. The later
frontally and temporally predominant. Diagnosis is made age of onset, presence of signicant decits on cognitive
with biopsy of skin which shows osmophilic granules in testing, or the presence of abnormal neuroimaging nd-
arterioles; genetic testing for mutations in notch 3 is also ings point toward a degenerative condition. Memory
possible (see earlier). The neuronal cerebrolipofuscinoses loss may also be part of a conversion reaction. In this sit-
are a genetically heterogeneous group of disorders asso- uation, patients commonly complain bitterly of memory
ciated with myoclonus, seizures, and progressive demen- loss, but careful cognitive testing either does not con-
tia. Diagnosis is made by nding curvilinear inclusions rm the decits or demonstrates inconsistent or unusual
within white blood cells or neuronal tissue. patterns of cognitive problems. The patients behavior
SECTION III

Psychogenic amnesia for personally important memo- and wrong answers to questions often indicate that he
ries is common, although whether this results from or she understands the question and knows the correct
deliberate avoidance of unpleasant memories or from answer.
unconscious repression is currently unknown. The Clouding of cognition by chronic drug or medication use,
event-specic amnesia is more likely to occur after vio- often prescribed by physicians, is an important cause of
lent crimes such as homicide of a close relative or friend dementia. Sedatives, tranquilizers, and analgesics used to
Diseases of the Central Nervous System

or sexual abuse. It may also develop in association with treat insomnia, pain, anxiety, or agitation may cause con-
severe drug or alcohol intoxication and sometimes with fusion, memory loss, and lethargy, especially in the
schizophrenia. More prolonged psychogenic amnesia elderly. Discontinuation of the offending medication
occurs in fugue states that also commonly follow severe often improves mentation.
emotional stress. The patient with a fugue state suffers
from a sudden loss of personal identity and may be
found wandering far from home. In contrast to organic
amnesia, fugue states are associated with amnesia for personal Treatment:
identity and events closely associated with the personal past. At DEMENTIA
the same time, memory for other recent events and the The major goals of management are to treat any cor-
ability to learn and use new information are preserved. rectable causes of the dementia and to provide comfort
The episodes usually last hours or days and occasionally and support to the patient and caregivers. Treatment of
weeks or months while the patient takes on a new iden- underlying causes might include thyroid replacement
tity. On recovery, there is a residual amnesia gap for the for hypothyroidism; vitamin therapy for thiamine or B12
period of the fugue.Very rarely, selective loss of autobio- deciency or for elevated serum homocysteine; antibi-
graphic information represents a focal injury in the otics for opportunistic infections; ventricular shunting
brain areas involved with these functions. for NPH; and appropriate surgical, radiation, and/or
Psychiatric diseases may mimic dementia. Severely chemotherapeutic treatment for CNS neoplasms. Removal
depressed individuals may appear demented, a phenom- of sedating or cognition-impairing drugs and medica-
enon called pseudodementia. Memory and language are tions is often benecial. If the patient is depressed rather
usually intact when carefully tested in depressed persons, than demented (pseudodementia), the depression
and a signicant memory disturbance usually suggests an should be vigorously treated. Patients with degenerative
underlying dementia, even if the patient is depressed. diseases may also be depressed, and that portion of
The pseudodemented patient may feel confused and their condition may respond to antidepressant therapy.
unable to accomplish routine tasks.Vegetative symptoms, Antidepressants that are low in cognitive side effects,
such as insomnia, lack of energy, poor appetite, and con- such as SSRIs (Chap. 49), are advisable when treatment is
cern with bowel function, are common. The onset is necessary. Anticonvulsants are used to control seizures.
often abrupt, and the psychosocial milieu may suggest Agitation, hallucinations, delusions, and confusion are
prominent reasons for depression. Such patients respond difcult to treat. These behavioral problems represent
to treatment of the depression. Schizophrenia is usually major causes for nursing home placement and institu-
not difcult to distinguish from dementia, but occasion-
tionalization. Before treating these behaviors with med-
ally the distinction can be problematic. Schizophrenia
ications, a thorough search for potentially modiable
generally has a much earlier age of onset (second and
environmental or metabolic factors should be sought. with complaints, depression, or anger. Hostile responses 319
Hunger, lack of exercise, toothache, constipation, urinary on the part of the caretaker are useless and sometimes
tract infection, or drug toxicity all represent easily harmful. Explanation, reassurance, distraction, and calm
correctable factors that can be treated without psy- statements are more productive responses in this set-
choactive drugs. Drugs such as phenothiazines and ben- ting. Eventually, tasks such as nances and driving must
zodiazepines may ameliorate the behavior problems be assumed by others, and the patient will conform and
but have untoward side effects such as sedation, rigidity, adjust. Safety is an important issue that includes not
and dyskinesias. Despite their unfavorable side-effect only driving but the environment of the kitchen, bath-
prole, second-generation antipsychotics such as queti- room, and sleeping area. These areas need to be moni-
apine (25 mg qd starting dose) are increasingly being tored, supervised, and made as safe as possible. A move
used for patients with agitation, aggression, and psy- to a retirement home, assisted-living center, or nursing
chosis. When patients do not respond to treatment, it is home can initially increase confusion and agitation.
usually a mistake to advance to higher doses or to use Repeated reassurance, reorientation, and careful intro-
anticholinergics or sedatives (such as barbiturates or duction to the new personnel will help to smooth the
benzodiazepines). It is important to recognize and treat process. Provision of activities that are known to be
depression; initial treatment can be with a low dose of enjoyable to the patient can be of considerable bene-

CHAPTER 23
an SSRI (e.g., escitalopram 10 mg/d) while monitoring fit. Attention should also be paid to frustration and
for efcacy and toxicity. Sometimes apathy, visual hallu- depression in family members and caregivers. Caregiver
cinations, depression, and other psychiatric symptoms guilt and burnout are common. Family members often
respond to the cholinesterase inhibitors, obviating the feel overwhelmed and helpless and may vent their
need for other more toxic therapies. frustrations on the patient, each other, and health
Cholinesterase inhibitors are being used to treat AD, care providers. Caregivers should be encouraged to
and other drugs, such as anti-inammatory agents, are take advantage of day-care facilities and respite breaks.

Alzheimers Disease and Other Dementias

being investigated in the treatment or prevention of AD. Education and counseling about dementia are impor-
Depression should be recognized and treated, initially tant. Local and national support groups can be of con-
with a low dose of an SSRI (Lexapro 10 mg), closely mon- siderable help, such as the Alzheimers Association
itoring for efcacy and toxicity. These approaches are (www.alz.org).
reviewed in the treatment section for AD, earlier.
A proactive strategy has been shown to reduce the
occurrence of delirium in hospitalized patients. This FURTHER READINGS
strategy includes frequent orientation, cognitive activi-
ties, sleep-enhancement measures, vision and hearing BALLARD C et al: The dementia antipsychotic withdrawal trial
(DART-AD): Long-term follow-up of a randomised placebo-
aids, and correction of dehydration.
controlled trial. Lancet Neurol 8:151, 2009
Nondrug behavior therapy has an important place in CASELLI RJ et al: Longitudinal Modeling of Age-Related Memory
the management of dementia. The primary goal is to Decline and the APOE 4 Effect. N Engl J Med 361:255, 2009
make the demented patients life comfortable, uncom- KNOPMAN DS et al: Incidence and causes of nondegenerative nonva-
plicated, and safe. Preparing lists, schedules, calendars, scular dementia: A population-based study. Arch Neurol 63:218,
and labels can be helpful. It is also useful to stress famil- 2006
iar routines, short-term tasks, walks, and simple physical ROBERSON ED, MUCKE L: 100 years and counting: Prospects for
defeating Alzheimers disease. Science 314:781, 2006
exercises. For many demented patients, memory for
SAVVA GM et al: Age, neuropathology, and dementia. N Engl J Med
facts is worse than that for routine activities, and they 360:2302, 2009
may still be able to take part in preserved physical activ- SEELEY WW et al: Early frontotemporal dementia targets neurons
ities such as walking, bowling, dancing, and golf. unique to apes and humans.Ann Neurol 60:660, 2006
Demented patients usually object to losing control over SMALL GW et al: PET of brain amyloid and tau in mild cognitive
familiar tasks such as driving, cooking, and handling impairment. N Engl J Med 355:2652, 2007
nances. Attempts to help or take over may be greeted VAN OIJEN M et al: Atherosclerosis and risk for dementia. Ann
Neurol 61:403, 2007
 CHAPTER 24
PARKINSONS DISEASE AND OTHER
EXTRAPYRAMIDAL MOVEMENT DISORDERS
Mahlon R. DeLong Jorge L. Juncos

Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Differential Diagnosis and Screening Evaluation . . . . . . . . . . . 325

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Dementia in Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . 334
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 Other Parkinsonian Disorders . . . . . . . . . . . . . . . . . . . . . . . . 334
Motor Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Parkinsonian Disorders Associated with Abnormal
Non-motor Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322 Metabolism of -Synuclein (-Synucleinopathies) . . . . . . . 334
Neuropsychiatric Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . 322 Parkinsonian Disorders Associated with Abnormalities
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 of Tau Metabolism (Tauopathies) . . . . . . . . . . . . . . . . . . . . . 335
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Secondary Parkinsonism . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

autosomal dominant and recessive forms of PD (now

PARKINSONS DISEASE numbering >10) comprise ~5% of cases (Table 24-1).These
Parkinsons disease (PD) is the most common form of a are generally characterized by an earlier age of onset (typ-
group of progressive neurodegenerative disorders charac- ically <45 years) and a longer course than cases of spo-
terized by the clinical features of parkinsonism, including radic PD, although one genetic form, LLRK-2, causes
bradykinesia (a paucity and slowness of movement), rest PD in the same age range as sporadic PD. Although most
tremor, muscular rigidity, shufing gait, and exed pos- patients with PD appear to have no strong genetic deter-
ture. Although dened clinically as a movement disorder, minant, epidemiologic evidence points to a complex inter-
it is now widely appreciated that PD can be accompa- action between genetic vulnerability and environmental
nied by a variety of non-motor symptoms, including factors. Risk factors include a positive family history, male
autonomic, sensory, sleep, cognitive, and psychiatric dis- gender, head injury, exposure to pesticides, consumption
turbances. Nearly all forms of parkinsonism result from a of well water, and rural living. Factors associated with a
reduction of dopaminergic transmission within the basal reduced incidence of PD include coffee drinking, smok-
ganglia. The discovery of dopamine in the brain, the ing, use of nonsteroidal anti-inammatory drugs, and
demonstration of its depletion in PD, and the success of estrogen replacement in postmenopausal women.
dopamine replacement therapy by its precursor, lev-
odopa, are all major landmarks in the eld of neurology. CLINICAL FEATURES
A diagnosis of PD can be made with some condence in
patients who present with at least two of the three cardinal
EPIDEMIOLOGY signsrest tremor, rigidity, and bradykinesia.Tremor is par-
PD aficts ~1 million individuals in the United States ticularly important, as it is present in 85% of patients with
(~1% of those older than 55 years). Its peak age of onset is true PD; a diagnosis of PD is particularly difcult when
in the early 60s (range 3585 years), and the course of the tremor is absent.A unilateral and gradual onset of symptoms
illness ranges between 10 and 25 years. PD accounts further supports the diagnosis. Masked facies, decreased eye
for ~75% of all cases of parkinsonism; the remaining blinking, stooped posture, and decreased arm swing com-
cases result from other neurodegenerative disorders, cere- plete the early picture. The onset may also be heralded by
brovascular disease, and drugs. Familial forms of known vague feelings of weakness, fatigue, aching, and discomfort.
320
TABLE 24-1 321
GENETICALLY BASED PARKINSONS DISEASE

LOCUS GENE PROTEIN FUNCTION INHERITANCE

PARK1 SNCA -Synuclein Uncertain; vesicle trafcking AD

PARK2 PRKN Parkin E3 ubiquitin ligase AR
PARK4 SNCA -Synuclein (triplication Uncertain; vesicle trafcking AD
or duplication)
PARK5 UCH-L1 UCH-L1 (Ubiquitin carboxy- Proteosomal processing AD
terminal hydroxylase L1)
PARK6 PINK1 PINK1 Mitochondrial kinase AR
PARK7 DJ-1 DJ-1 Oxidative stress response AR
PARK8 LRRK2 Dardarin Cytosolic kinase AD

Note: See text for details. AD, autosomal dominant; AR, autosomal recessive.

CHAPTER 24
MOTOR FEATURES changes in the posture of the ngers, hand, and arm. Pos-
tural instability is one of the most disabling features of
The most disabling motor feature of PD is bradykinesia, advanced PD, contributing to falls and injuries and lead-
which interferes with all aspects of daily living including ing to major morbidity and mortality. It can be tested in
rising from a chair, walking, turning in bed, and dress- the ofce with the pull test (Fig. 24-1). The develop-
ing. Fine motor control is also impaired, as evidenced by ment of postural instability and falls in the rst years of
decreased manual dexterity and micrographia. Soft the illness, however, strongly suggest a diagnosis of atypical

Parkinsons Disease and Other Extrapyramidal Movement Disorders

speech (hypophonia) and sialorrhea are other troubling PD. Patients are also at risk for hip fractures, which are
manifestations of (bulbar) bradykinesia. Rest tremor, at a associated with osteoporosis and vitamin D deciency.
frequency of 46 Hz, typically appears unilaterally, rst
distally, involving the digits and wrist, where it may have
a pill-rolling character. Tremor usually spreads proxi-
mally and occasionally to the ipsilateral leg before
appearing on the other side after a year or more. It may Testing for Postural Instability
appear later in the lips, tongue, and jaw but spares the
I. Practice session
head and neck. Rigidity is felt as a uniform resistance to
Explanation must be given that the patient will be pulled
passive movement about a joint throughout the full
forcefully backward to test balance and that the patient
range of motion, accompanied by a characteristic plastic must prevent himself or herself from falling, if necessary,
quality to the movement. Brief, regular interruptions of by taking a step backward after he or she is pulled. At
resistance during passive movement, due to subclinical least one good practice session is carried out before the
tremor, may give rise to a cogwheeling sensation. Dys- final test.
tonia involving the distal arm or leg may occur early in
the disease, unrelated to treatment, especially in younger II. Patient stance
patients. It can also be provoked by antiparkinsonian Patient must be upright and cannot lean forward in any
drug therapy. way unless axial flexion prevents upright posture. Patient
must not be pulled while off balance from a previous pull.
Gait disturbance with shufing short steps and a ten-
Stance should be with feet comfortably apart.
dency to turn en bloc is a prominent feature of PD. Fes-
tinating gait, a classic sign of parkinsonism, results from III. Pull
the combination of exed posture and loss of postural Patient is pulled briskly and forcefully enough to trigger
reexes, which cause the patient to accelerate in an one step back.
effort to catch up with the bodys center of gravity.
Freezing of gait, a feature of more advanced PD, occurs IV. Examiners response
commonly at the onset of locomotion (start hesitation), Examiner is ready to catch the patient but allows enough
when attempting to change direction or turn around, space to move backward with the patient for at least three
and upon entering a crowded room or narrow space steps of recovery. The test is to be performed in a space
such as a doorway. long enough to differentiate between persistent but
Abnormalities of balance and posture tend to increase recovering retropulsion and no recovery.
as the disease progresses. Flexion of the head, stooping FIGURE 24-1
and tilting of the upper trunk, and a tendency to hold the Testing for postural instability. (From: RP Munhox et al.
arm in a exed posture while walking are common, as are Neurology 62:125, 2004; with permission.)
 322 NON-MOTOR FEATURES somatic and vegetative symptoms of PD and depression.
As a result, depression may go unrecognized and untreated.
Non-motor aspects of PD include depression and anxi-
There is compelling evidence that depression in PD is an
ety, cognitive impairment, sleep disturbances, sensory
intrinsic part of the illness and not simply a reaction to
abnormalities and pain, loss of smell (anosmia), and dis-
disability. Recognizing even mild depression is particularly
turbances of autonomic function. Together these may
important since it can account for otherwise unexplained
contribute as much to the burden of the disease as the
albeit reversible worsening of parkinsonian motor symp-
more obvious motor abnormalities. Some of these non-
toms, new somatic symptoms, and sleep disruption.
motor disturbances may be present long before the onset
Depression can also be induced or aggravated iatrogeni-
of motor signs. The physiologic basis of the non-motor
cally by antiparkinsonian and psychotropic agents used to
signs and symptoms are explained in part by widespread
treat other symptoms. Finally, other causes for depressive
involvement of brainstem, olfactory, thalamic, and corti-
symptoms and refractory depression should always be
cal structures, as discussed later in the chapter.
considered, including hypothyroidism, hypogonadism, and
Sensory symptoms often manifest as a distressing sensa-
vitamin B12 deciency.
tion of inner restlessness presumed to be a form of
Anxiety disorders in PD can appear in isolation or as
akathisia. Aching pain and discomfort in the extremities
an accompaniment of depression or progressive cogni-
can be a prominent presenting symptom or develop when
tive impairment. They can also be due to an akathisia
SECTION III

antiparkinsonian medications are wearing off. Some

equivalent provoked in part by undertreatment of motor
patients may develop a subjective shortness of breath in
symptoms. The development of drug-induced motor
the absence of any underlying cardiorespiratory pathology.
uctuations can compound the problem by precipitating
Sleep disorders and impaired daytime alertness are com-
anxiety during the off periods that, in severe cases, may
mon in PD. Factors that disrupt sleep include nighttime
mimic panic attacks.
reemergence of bradykinesia and rigidity, with difculty
Mild or moderate cognitive abnormalities affect many
turning in bed, as well as tremor and involuntary move-
Diseases of the Central Nervous System

patients with PD.These occur in the later stages of the ill-

ments (e.g., myoclonic jerks or periodic leg movements). ness and present as frontal lobe dysfunction. Difculties
Restless legs and rapid eye movement behavioral disorder with complex tasks, long-term planning, and memorizing
often precede the onset of motor signs of PD.Vivid dreams or retrieving new information are common. Although
and hallucinations related to dopaminomimetic therapy some of these symptoms represent bradyphrenia (the cog-
may also contribute to sleep disruption. Finally, sleep apnea nitive equivalent of bradykinesia), it is now clear that the
and other sleep disturbances can also occur. Correction of dysfunction also includes working memory, executive
these sleep disorders may improve daytime functioning, but function, attention, mental exibility, visuospatial func-
often alertness remains impaired, pointing to a separate dis- tion, and word uency. In contrast, language and simple
order of arousal or to drug-induced sedation. mathematical skills are relatively spared, unlike in patients
Autonomic dysfunction can produce diverse manifes- with AD. Iatrogenic contributors to cognitive decline in
tations, including orthostatic hypotension, constipation, vulnerable patients include the use of anticholinergics,
urinary urgency and frequency, excessive sweating, and amantadine, psychotropics, and even dopaminomimetic
seborrhea. Orthostatic hypotension is present in many medications. Depression and intercurrent medical ill-
patients resulting from impaired vasomotor reexes, sym- nesses, especially infections (of the urinary tract or else-
pathetic denervation of the heart, or as a side effect of where) and dehydration, are important reversible causes
dopaminomimetic therapy. This rarely leads to syncope of an acute change in cognitive function in PD.
unless the patient has developed true autonomic failure or The incidence of signicant dementia in PD may be
has an unrelated cardiac problem. Paroxysms of drenching as high as six times that in age-matched controls and, in
sweats may occur in advanced PD, often related to the subspecialty clinics, can be as high as 70% or greater
wearing off of antiparkinsonian medications. with long-term observation (8 years). In late stages the
presence of substantial cognitive impairment may limit
therapeutic options and contribute more to overall dis-
NEUROPSYCHIATRIC SYMPTOMS
ability than the motor symptoms in PD. Predictors of
Changes in mood, cognition, and behavior are common dementia include late age of onset, akinetic-rigid phe-
accompaniments of PD, especially in its later stages, and notype, presence of severe depression, persistent halluci-
may be the direct result of PD or its comorbid patholo- nations, and advanced stages of disease. In most instances,
gies [e.g., Alzheimers disease (AD), cortical dementia accumulating amyloid and -synuclein pathologies in
with Lewy bodies (DLB)] or may occur as a side effect the frontal lobes, basal forebrain, hippocampus, and
of antiparkinsonian or concomitant therapy. amygdala account for the progression of these symptoms
Depression affects approximately one-half of patients (see Pathology, below).
with PD and can occur at any phase of the illness. It is Psychotic symptoms affect up to 40% of patients with
often difcult to diagnose due to the overlap between the PD, depending on the age, disease duration, and prevalence
of dementia in the population surveyed. Early symptoms Pathology 323
include visual illusions (e.g., shadows of the edge of the Brainstem and cortex Hippocampus & basal forebrain
Lewy
visual eld) and formed visual hallucinations (usually Protofibrils, fibers bodies Cholinergic pathology
people and animals), both with retained insight.Although
depression and dementia are the most important risk Clinical course
factors for psychotic symptoms in PD, the symptoms are Non-motor symptoms

often triggered by drug therapy. Dopaminomimetics

Early motor symptoms
(especially dopamine agonists), anticholinergics, amanta-
dine, and psychotropics are the chief drug offenders. Fluctuations, dyskinesias, and falls
Delusions are more disturbing than hallucinations Clinical Dx
Decreasing motor response,
because they place an even heavier burden on the family dementia &
psychotic symptoms
and caregivers. The prodrome to these psychotic symp-
toms includes sleep disturbances and subtle erratic
behaviors with temperamental and sometimes unreason- 60 75
Age
able outbursts.
FIGURE 24-2
In recent years there has been increased recognition of
Proposed stages of Parkinsons disease (PD) based on
insidious behavioral disturbances in a subset of patients

CHAPTER 24
extrapolations from pathologic, clinical and brain imaging
with PD, referred to collectively as impulse control disorders studies. Broken black lines indicate that, by itself, Lewy (-
(ICDs); these include pathologic gambling, hypersexuality, synuclein) protobril or ber pathology is not sufcient to
compulsive shopping, and compulsive eating and are asso- make the pathologic diagnosis of PD. Broken blue lines rep-
ciated primarily with the use of dopaminergic agents. A resent non-motor signs that usually precede clinical recogni-
related disorder, termed punding, consists of stereotypical tion of PD, including impaired olfaction, sleep and mood dis-
motor behavior in which there is an intense fascination turbances, and constipation. Broken yellow lines indicate that

Parkinsons Disease and Other Extrapyramidal Movement Disorders

with repetitive handling and examining of mechanical uctuations may be less apparent in the late stages of PD.
objects, such as picking at oneself, taking apart watches
and radios, or sorting and arranging common objects.
Current therapeutic approaches to these disorders include
reduction or discontinuation of dopamine agonist ther- play a role in the non-motor (e.g., autonomic, sleep, emo-
apy, psychosocial interventions, and in some cases consid- tional, and cognitive) and levodopa unresponsive motor
eration of deep brain stimulation with a goal of reducing aspects (e.g., postural instability, gait, and bulbar distur-
the requirement for drugs. bances) of PD.
The biochemical consequence of dopaminergic cell
loss in the SNpc is gradual denervation of the striatum,
PATHOLOGY
the main target projection for the SNpc neurons. Other
Gross examination of the brain in PD reveals mild target regions of these neurons include the intralaminar
frontal atrophy with loss of the normal dark melanin and parafascicular nuclei of the thalamus, the globus pal-
pigment of the midbrain. Microscopically there is lidus, and the subthalamic nucleus (STN). Dopamine
degeneration of the dopaminergic cells with the pres- denervation of the putamen, the motor portion of the
ence of Lewy bodies (LBs) in the remaining neurons striatum, leads to many of the motor symptoms of PD.
and processes of the substantia nigra pars compacta Symptoms develop when striatal dopamine depletion
(SNpc); other brainstem nuclei; and regions such as the reaches 5070% of normal. Pharmacologic restoration
medial temporal, limbic, and frontal cortices. LBs have a of dopamine transmission is the basis for symptomatic
high concentration of -synuclein and are the patho- drug treatment of PD.
logic hallmark of the disorder. Mutations in the -
synuclein gene can cause familial PD by promoting the GENETIC CONSIDERATIONS
formation of -synuclein-positive laments that aggre-
gate into LBs and Lewy neurites (Fig. 24-2). It is now Although the vast majority of cases of PD appear
generally accepted that this pathology appears rst in to be sporadic, increasing evidence indicates that
the anterior olfactory nuclei and lower brainstem (glos- genetic factors play an important role in many
sopharyngeal and vagal nerve nuclei), with ascending forms of PD. Much of this evidence comes from studies
brainstem involvement of the locus coeruleus, n. gigan- of the concordance rates for PD among monozygotic
tocellularis, and the raphe, before extending to the mag- and dizygotic twins. These studies suggest that heredity
nocellular nuclei of the basal forebrain, the central plays an important role in cases with age of onset <45
nucleus of the amygdala, and the SNpc. Further progres- years and a less important role in older patients. Eight
sion extends to the thalamus and cerebral cortex. genes have been clearly linked to familial forms of PD
Involvement of these extranigral areas is postulated to (Table 24-1), and a number of other candidate genes or
 324 genetic loci have been identied as possibly causative of carboxy-terminal hydroxylase L1 (UCH-L1), another
PD. Among the former, PARK1, PARK4, and PARK5 component of the ubiquitin proteasomal system.
lead to an autosomal dominant form of PD with atypi- Because ubiquitination of proteins targets them for
cal features such as early age of onset and rapid progres- degradation in the proteasome system, these ndings
sion of symptoms. PARK1 is due to a mutation in the suggest that abnormal proteasomal processing is impor-
gene for -synuclein leading to abnormal aggregation tant in the pathogenesis of at least some forms of PD.
of this protein (Fig. 24-3). PARK2 and PARK7 lead to The most recently identied mutation is the gene for
autosomal recessive disorders also with atypical features, LRRK2. Most cases are slowly progressive and begin in
including juvenile forms of parkinsonism. PARK2 late adulthood, closely resembling sporadic PD. The
encodes parkin, an E3 ubiquitin protein ligase. Mutations prevalence of causative LRRK2 mutations is highly
in parkin appear to be the major cause of autosomal dependent on the population under study, ranging from
recessive PD. Remarkably, PARK5 codes for the ubiquitin 1 to 2% of all PD cases, except in isolated pockets where

PINK-1 mutation
MPTP, rotenone, LRRK2 mutation
Mitochondrial
DJ-1 mutation, PINK-1 mutation, iv
SECTION III

dysfunction
mitochondrial DNA deletions
vi
Substrates
UCH-L1
mutation Abnormal Inappropriate
ubiquitination phosphorylation
Reactive oxygen species, v
Ubiquitin apoptosis, energy failure
Pa unc
dy
sf
rk tio
Diseases of the Central Nervous System

in n

Protease Neuronal Cellular protection,

vii
inhibitors cell death cellular replacement

Proteasome Misfolded
Substrate protein
accumulation iii

DJ-1 mutation,
proteasome inhibition,
abnormal phosphorylation,
oxidative stress
i ii
-Synuclein

Gene mutations/
multiplications
Abnormal
processing

Monomers Protofibrils Fibrils Lewy body

FIGURE 24-3
Pathogenesis of dopamine cell death in Parkinsons dis- (ii); interventions to down-regulate toxic substrates or up-
ease (PD) and possible sites for therapeutic intervention regulate parkin or proteasomal function (iii); interventions
in PD. Studies on inherited forms of PD (see text) have led to to enhance mitochondrial function with factors such as
the identication of genes that, when mutated, lead to CoQ10, DJ-1, or PINK-1 (iv); free radical scavengers and
dopaminergic cell loss. These genes are involved in cellular antioxidants (v); kinase inhibitors to block LRRK2 activity or
processes that include protein ubiquitination and degrada- interventions to increase PINK-1 function (vi); and other ther-
tion via the proteasomal system, response to oxidative apies using tropic factors such as GDNF (see text), survival
stress, mitochondrial function, protein phosphorylation, and genes, or fetal/stem cell replacement that would protect or
protein folding. Potential points for therapeutic intervention replace susceptible cells (vii). MPTP, 1-methyl-1,2,4,6
are highlighted: gene silencing therapies, to reduce synuclein tetrahydropyridine. (Reprinted from JM Savitt et al, with
levels (i); inhibition of synuclein aggregation and/or processing permission.)
the prevalence can be higher. Although the mechanism younger than 40 years, it is important to rule out Wilson 325
of action of the LRRK2 mutation is not certain, evi- disease. In younger individuals, Huntingtons disease
dence suggests that abnormal kinase activity may medi- (HD) sometimes presents with prominent parkinsonian
ate dopamine cell death; a similar mechanism may be features (Chap. 25). Although parkinsonian features are
operative in PARK6, resulting from mutations in PINK1 often present in AD, they occur late in the course and
(Fig. 24-3). Other mutations with yet-to-be-identied are greatly outweighed by cognitive and behavioral dis-
genes include PARK10, a late-onset PD susceptibility turbances (Chap. 23). In DLB the parkinsonian features
gene.The identication of these and other mutations are are compounded by the early appearance of hallucina-
proving invaluable in rening the correlation between tions and disturbances in arousal and behavior (Chap. 23).
genotypes and phenotypes, in generating animal models Parkinsonism may also develop following exposure to
to study pathogenesis, and in identifying target pathways certain neurotoxins such as carbon monoxide or
for possible therapeutic intervention. manganese. MRI is useful in selected cases to rule out
disorders such as normal pressure hydrocephalus, vascular
disease, or mass lesions. Positron emission tomography
PATHOGENESIS (PET) is helpful in conrming the diagnosis but cannot
In PD, nigral dopamine neurons and other cells die reliably separate PD from the most common atypical
forms. As yet, genetic screening has little place in general

CHAPTER 24
from a combination of factors, including: (1) genetic
vulnerability (e.g., abnormal processing or folding of - practice.
synuclein; Fig. 24-3, steps i, ii); (2) oxidative stress (steps In evaluating individuals with PD, it is also important
iv, v); (3) proteasomal dysfunction (step iii); (4) abnormal to rule out treatable conditions that may contribute to
kinase activity (step vi); and (5) environmental factors, the disability, such as B12 deciency, hypothyroidism,
most of which have yet to be identied. testosterone deciency, and vitamin D deciency.
Oxidative stress appears to play an important role in At present the frequency of misdiagnosis is still

Parkinsons Disease and Other Extrapyramidal Movement Disorders

the sporadic forms of PD. Endogenous sources of oxida- 1025% even in the best of hands.The differentiation of
tive stress include the free radicals produced by the sporadic (idiopathic) PD from atypical parkinsonism (see
metabolism of dopamine and melanin. Additional stress later) is often difcult, since early in their course these
may come from defects in mitochondrial complex I of atypical forms may meet diagnostic criteria for PD
the oxidative phosphorylation chain.This defect has been (Table 24-3). Accordingly, it is important to watch for
detected in platelets and muscle and in postmortem tis- the development of early imbalance, falls, and character-
sue from the substantia nigra. Several agents have been istic abnormalities of vertical gaze that suggest progressive
shown to cause oxidative toxicity and dopamine cell supranuclear palsy (PSP); and early urinary incontinence,
death in animal models of PD, further strengthening the orthostatic hypotension, and dysarthria suggestive of
above hypothesis. The most important of these are multiple system atrophy (MSA).The early appearance of
MPTP, a meperidine derivative, and rotenone, a com- drug-induced hallucinations strongly favors the diagno-
monly used insecticide. Both cause oxidative damage by sis of DLB. As a rule, the different forms of atypical PD
inhibiting complex I. In vitro, oxidative stress can lead to can be reliably differentiated from sporadic PD within
aggregation of -synuclein and proteasomal dysfunction. the rst 34 years of the illness.
Proteasomal system abnormalities have also been
described in the substantia nigra from sporadic cases of
PD. Other contributors to the selective dopamine neu-
ron degeneration in PD are abnormal phosphorylation Treatment:
of proteins, microglial activation, low-grade inamma- PARKINSONS DISEASE
tion, and apoptosis; each represents a potential target for
therapeutic intervention. GENERAL CONSIDERATIONS The goals of
therapy in PD are to maintain function and quality of life
and to avoid drug-induced complications. Bradykinesia,
DIFFERENTIAL DIAGNOSIS AND tremor, rigidity, and abnormal posture respond well to
SCREENING EVALUATION symptomatic therapy early in the course of the illness. In
contrast, cognitive symptoms, hypophonia, autonomic
Primary and secondary causes must be considered in the
dysfunction, and imbalance tend to respond poorly.
differential diagnosis of parkinsonism (Table 24-2).
Primary motor disability in PD is often aggravated by
Essential tremor (ET) is sometimes confused with rest
secondary disability resulting from physical deconditioning
tremor in PD, but the absence of other signs of parkin-
following a sedentary lifestyle. Prevention of secondary
sonism, the bilaterality, higher frequency (810 Hz), and
disability requires a consistent program of physical
postural dependency of ET help differentiate this
exercise. Multiple open-label studies of exercise in PD
from the rest tremor of PD (Chap. 25). In individuals
 326 TABLE 24-2
DIFFERENTIAL DIAGNOSIS OF PARKINSONISM

Primary Parkinsonism
Genetically based PD (see Table 24-1)
Idiopathic (sporadic) PD (most common form)
Phenotype may be inuenced by vulnerability genes and environmental factors
Other neurodegenerative disorders
Disorders associated with -synuclein pathology
Multiple system atrophies (glial and neuronal inclusions)
Striatonigral degeneration
Olivopontocerebellar atrophy
Shy-Drager syndrome
Motor neuron disease with PD features
Dementia with Lewy bodies (cortical and brainstem neuronal inclusions)
Disorders associated with primary tau pathology (tauopathies)
Progressive supranuclear palsy
Corticobasal degeneration
Frontotemporal dementia
SECTION III

Disorders associated with primary amyloid pathology (amyloidopathies)

Alzheimers disease with parkinsonism
Genetically mediated disorders with occasional parkinsonian features
Wilsons disease
Hallervorden-Spatz disease
Chdiak-Hagashi syndrome
SCA-3 spinocerebellar ataxia
Diseases of the Central Nervous System

X-linked dystonia-parkinsonism (DYT3)

Fragile X premutation associated ataxia-tremor-parkinsonism syndrome
Huntingtons disease (Westphalt variant)
Prion disease
Miscellaneous acquired conditions
Vascular parkinsonism
Normal pressure hydrocephalus
Catatonia
Cerebral palsy
Secondary Parkinsonism
Repeated head trauma (Dementia pugilistica with parkinsonian features)
Infectious and postinfectious diseases
Postencephalitic PD
Neurosyphillis
Metabolic conditions
Hypoparathyroidism or pseudohypoparathyroidism with basal ganglia calcications
Non-Wilsonian hepatolenticular degeneration
Drugs
Neuroleptics (typical antipsychotics)
Selected atypical antipsychotics (see text)
Antiemetics (e.g., compazine, metoclopramide)
Dopamine-depleting agents (reserpine, tetrabenazine)
-Methyldopa
Lithium carbonate
Valproic acid
Fluoxetine
Toxins
1-Methyl-1,2,4,6 tetrahydropyridine (MPTP)
Manganese
Cyanide
Methanol
Carbon monoxide
Carbon disulde
Hexane
TABLE 24-3 327
As a general principle, patients should be treated as
HISTORY AND EXAMINATION FEATURES SUGGESTING soon as symptoms begin to interfere with function in
DIAGNOSES OTHER THAN PARKINSONS DISEASE
any way. Most specialists now have a low threshold for
ALTERNATIVE DIAGNOSIS initiating symptomatic therapy. The concern that symp-
SYMPTOMS/SIGNS TO CONSIDER tomatic therapy should be delayed as long as possible
History
since the available compounds are effective for only a
limited number of years is unfounded. Early initiation of
Falls as the rst symptom PSP therapy is often necessary to maintain an adequate level
Exposure to neuroleptics Drug-induced parkinsonism
of physical and mental activity. Another common con-
Onset prior to 40 years If PD, think genetic causes
Associated unexplained Wilsons disease
cern, that dyskinesias will develop sooner if levodopa is
liver disease introduced too early, is also unfounded. Recent studies
Early hallucinations Lewy body dementia (see later) have shown that the risk of troublesome
Sudden onset of Vascular parkinsonism dyskinesias in patients receiving levodopa therapy (up
parkinsonian symptoms to 300 mg/d) appears to be considerably lower than
Physical Exam previously reported.
Dementia as rst symptom Dementia with Lewy bodies A current priority is to move beyond symptom control

CHAPTER 24
Prominent orthostasis MSA-p to neuroprotective therapies. Unfortunately, no such
Early dysarthria MSA-c therapy is yet available. High doses of coenzyme Q10, oral
Lack of tremor Various Parkinsons-plus creatine supplementation, intrastriatal infusion (or deliv-
syndromes ery via viral vectors) of neurotrophic factors, and possibly
High frequency (810 Hz) Essential tremor the use of newer monoamine oxidase B (MAO-B)
symmetric tremor
inhibitors may hold promise in this regard and are under
investigation. In animal models of PD, forced exercise

Parkinsons Disease and Other Extrapyramidal Movement Disorders

(e.g., treadmill running) at moderate intensities appears
to promote neuroprotection in dopamine neurons.
support the importance of regular activity; one controlled
epidemiologic study revealed a hazard ratio of observed/ INITIATION OF THERAPY (Fig. 24-4) From a
expected deaths during the 4-year observation period of practical standpoint, dopaminomimetic therapy
1.8 in patients who did not exercise compared to those (Table 24-4) should be initiated as soon as the patients
who did. Remaining mentally active is probably equally symptoms begin to interfere with quality of life. The
important for preservation of cognition in general. ideal rst-line agent depends on the age and cognitive

Dopamine Agonist or Levodopa/Carbidopa

Inadequate
control

Inadequate
Add levodopa/carbidopa control and
wearing off
Inadequate
control and
wearing off

Levodopa/carbidopa Adjunct Therapy

dosed more frequently For tremor: add anticholinergic
or with higher dose For drug-induced dyskinesias: add amantadine
For freezing (off) episodes: add apomorphine
Inadequate
control and Failed
wearing off maximal
medical
Add COMT inhibitor or therapy
add MAO-B inhibitor
Consider surgical
Failed options including DBS
maximal
medical
therapy

FIGURE 24-4
Treatment approaches to newly diagnosed idiopathic PD.
 328 TABLE 24-4
LEVODOPA FORMULATIONS AND DOPAMINE AGONISTS USED IN PARKINSONS DISEASE

LD DOSE AVAILABLE
AGENTS EQUIVALENCY STRENGTHS (MG) INITIAL DOSING COMMENTS

Carbidopa/Levodopa (Typical Initial Strength)

Carbidopa/levodopa 100 mg (levodopa 10/100 25/100; Usual range = 300800 mg/d with
IR 25/100 anchor dose) 25/100 0.51 tab tid typical schedules being q8h
25/250 to q3h.
Carbidopa/levodopa 150 mg 25/100 50/200; 1 tab Increased bioavailability with food.
CR 50/200 50/200 bid to tid Splitting the tablet negates the
CR properties. Usual schedule is
q8h to q4h.
Carbidopa/levodopa/ 120 mg 12.5/50/200 25/100/200; Do not split tablets. May combine
entacapone 25/100/200 1 tab bid to tid with Sinemet IR. Usual schedule
25/100/200 37.5/150/200 is q8h to q4h.
Parcopa 25/100 100 mg 25/100 25/250 25/100; 1 tab tid Can be used as regular or
supplemental rescue doses in
SECTION III

cases of regular dose failure.

Orally dissolved without water.
Dopamine Agonists Approximate Target Doses

DA EQUIVALENT AVAILABLE AS
TO ABOVE LD STRENGTHS INITIAL ADJUNCTS OTHER
ANCHOR DOSE (MG) DOSING MONOTHERAPY TO LD CONSIDERATIONS
Diseases of the Central Nervous System

Non-ergot alkaloids
Pramipexole 1 mg 0.125, 0.25, 0.125 mg 1.54.5 mg/d 0.3753.0 Renal metabolism; dose
1, 1.5 tid mg/d adjustments needed in
renal insufciency.
Occasionally associated
with sleep attacks.
Ropinirole 5 mg 0.25, 0.5, 0.25 mg 1224 mg/d 616 mg/d Hepatic metabolism;
1, 2, 3, 4, 5 tid potential drug-drug
interactions. Occasionally
associated with sleep
attacks.
Ropinirole ex- Availability
tended release pending.
Rotigotine 2, 4, 6 2 mg/24 h 6 mg/d 26 mg/d Available as transdermal
patch.
Ergot alkaloids
Bromocriptine 2 mg 2.5, 5.0 1.25 mg 7.515 mg/d 3.757.5 Rare reports of
bid to mg/d pulmonary and
tid retroperitoneal brosis.
Relative incidence of
sleep attacks not well
studied.
Pergolide Removed from U.S. market in 2007. See text.
Cabergoline Used in select cases of PD in Europe. Not approved for the treatment of PD in the U.S.

Note: Equivalency doses are approximations based on clinical experience, may not be accurate in individual patients, and are not intended to
correlate with the in vitro binding afnities of these compounds.
DA, dopamine agonist; IR, immediate release; CR, controlled release; LD, levodopa (with carbidopa).
Carbidopa/levodopa/entacapone = Stalevo.

status of the patient and, to a lesser extent, the patients agonists is well tolerated and signicantly improves
clinical type and nances. The choices consist of either, a motor function and disability. Using this approach,
dopamine agonist, a levodopa preparation, or one of the patients experience ~50% lower risk of dyskinesias and
MAO-B inhibitors. Controlled studies support the view 25% lower risk of motor uctuations compared to
that, in early PD, monotherapy with any of the dopamine levodopa-treated patients. This difference lasts as long
as the patient remains on monotherapy. Once a Dopamine Agonists Dopamine agonists readily 329
levodopa preparation is added, dyskinesias and motor cross the blood-brain barrier and act directly on
uctuations begin to emerge, suggesting that dopamine postsynaptic dopamine receptors (primarily D2 type).
agonists delay the onset but do not prevent the Compared to levodopa, they are longer-acting and thus
development of these problems. In fact, about two-thirds provide a more uniform stimulation of dopamine
of patients on agonist monotherapy require levodopa receptors. They are effective as monotherapeutic agents
therapy by year 5 in order to maintain motor function. and as adjuncts to carbidopa/levodopa therapy. They
Motor uctuations, also known as on-off phenom- can also be used in combination with anticholinergics
ena, are the exaggerated ebb and ow of parkinsonian and amantadine. Table 24-4 provides a guide to the
signs experienced by many patients between doses of doses and uses of these agents.
antiparkinsonian medications. Dyskinesias refer to chor- Available agents for PD include three non-ergot
eiform and dystonic movements that can occur as a alkaloidspramipexole, ropinirole, and, more recently,
peak dose effect or at the beginning or end of the dose rotigotineplus the ergot alkaloids bromocriptine,
(diphasic dyskinesias). More than 50% of patients with cabergoline, and lisuride (the latter two only in Europe).
PD treated over 5 years with levodopa will develop Pergolide is a dopamine agonist recently removed from
these complications. the U.S. market due to its association with asympto-

CHAPTER 24
Successful dopamine agonist monotherapy requires matic valvular heart disease in 28% of patients treated
a higher dose of the agonist than is typically needed chronically. The incidence of symptomatic valvular dis-
when the agonist is used to supplement levodopa ease is far lower, perhaps as low as <1%. Nonetheless,
(Table 24-4). In both cases, titration has to be slow and patients currently on pergolide need to be transferred
cautious to avoid unnecessary side effects. Patients to alternative therapy, perhaps equivalent doses of non-
benet greatly from education and support during this ergot dopamine agonists (Table 24-4). The dose equiva-
titration. Most patients will require the addition of lency of pergolide is ~1:1 with pramipexole.

Parkinsons Disease and Other Extrapyramidal Movement Disorders

levodopa or another agent within 13 years of initiating Subcutaneous injectable apomorphine is approved
dopamine agonist monotherapy. Preclinical studies in the United States as a rescue therapy for dose failure
suggest that the advantages of dopamine agonist (usually due to erratic gastric emptying), motor uctua-
monotherapy can be maintained with agonist- tions, and especially for the debilitating off spells that
dominant therapy. In this case, dopamine agonists con- affect many patients with moderate to advanced dis-
tinue to provide the bulk of dopaminomimetic therapy, ease. Finally, sumanirole is another potent experimental
with levodopa playing a supplementary role. dopamine agonist that in a recent controlled study
Although dopamine agonist monotherapy is consid- proved to be comparable in efcacy to ropinirole and
ered the initial treatment of choice for most patients better tolerated.
with PD, the long-term benets noted above must be A long-acting formulation of ropinirole and a trans-
balanced against a higher incidence of non-motor side dermal patch delivery system of rotigotine will soon be
effects and a slightly higher level of motor disability approved for use in PD. Based on pharmacokinetic data,
than with levodopa. These recommendations may need these formulations can achieve levels of continuous
to be modied in patients with psychotic symptoms, dopaminergic stimulation that are closer to those
behavioral disturbances, or severe daytime sleep distur- achieved with subcutaneous infusions of apomorphine
bances. Older patients and those with akinetic rigid (not available in the United States). In comparison with
forms of PD have a lower risk of motor complications oral dopaminomimetics, infusion therapy has proved
and dyskinesias compared to the average PD patient superior at controlling motor uctuations and reducing
and may be satisfactorily treated with levodopa. dyskinesias over time. The convenience of these new
formulations should overcome the major limitation of
PHARMACOTHERAPY OF MOTOR SYMPTOMS infusions: cost and site reactions. Experience with the
The above practices in the initiation of therapy patch delivery system thus far indicates that it is safe
notwithstanding, levodopa remains the most effective and well tolerated except for occasional skin reactions
treatment for PD. It signicantly improves motor symptoms to the adhesive.
and increases quality of life and independence.The aim of Dopamine agonists have been approved for the
all dopaminomimetic strategies is to restore dopamine treatment of PD at every stage of disease and in combi-
transmission in the striatum. This is accomplished by nation with other antiparkinsonian agents; however, the
stimulating postsynaptic receptors (directly with dopamine use of two dopamine agonists simultaneously cannot
agonists), increasing dopamine precursor availability be recommended. Agonists are particularly effective in
(levodopa), blocking the metabolism of levodopa in the treating bradykinesia, loss of ne motor dexterity,
periphery and in the brain, and blocking the catabolism tremor, and gait disturbances. When used as monother-
of dopamine at the synapse. apy, they are less effective than levodopa-based
 330 formulations. Accordingly, it is imperative to titrate the controlled study oral administration of etilevodopa
dose as needed to control motor function; the maxi- (with carbidopa) proved no different from oral car-
mum dose provided in titration packs may be insuf- bidopa/levodopa with respect to mean dose require-
cient in some patients. As the dose is escalated it is ments, treatment failures, and hours of daily off time.
equally important to remain vigilant to potential dose-
dependent side effects, particularly when combining Levodopa Augmentation Strategies A number
these drugs with carbidopa/levodopa and psychotropics. of drugs can augment dopamine transmission by
Side effects of dopamine agonists include nausea, blocking the breakdown of dopamine at the level of the
postural hypotension, psychiatric symptoms, daytime synapse.
sedation, and occasional sleep attacks. These can be
managed by decreasing the dose; by decreasing con- MAO-B Inhibitors These are selective and irreversible
comitant medication with similar side effects; or, in the inhibitors of the catabolic breakdown of dopamine;
case of nausea, by the introduction of peripheral they work by inhibiting MAO-B at the synapse. These
dopamine blockers such as domperidone (not available compounds offer a modest symptomatic motor benet
in the United States) or a short course of trimethobenza- when used as monotherapy and enhance the efcacy of
mide or dronabinol until the patient develops tolerance carbidopa/levodopa formulations when used as adjuncts.
to these symptoms. Patients should be cautioned about Their potential additional role as neuroprotective agents
SECTION III

the potential for sleep attacks associated with remains unproven. Unlike patients taking unselective or
dopamine agonists (and to a lesser extent with car- MAO-A inhibitors who are subject to hypertensive crises
bidopa/levodopa). These can occur without warning from consumption of large doses of tyramine (the amino
and have resulted in trafc accidents. When used as acid precursor of norepinephrine), patients taking MAO-B
adjuncts to levodopa therapy, dopamine agonists can inhibitors do not require dietary tyramine restrictions.
aggravate dyskinesias if the doses of carbidopa/ At the approved doses, rasagiline and oral zydis selegiline
Diseases of the Central Nervous System

levodopa are not adjusted accordingly. Furthermore, (i.e., orally disintegrating) carry little risk of a hypertensive
dopamine agonists are more expensive than carbidopa/ complication.
levodopa, which is now available in generic form. Selegiline, a selective MAO-B inhibitor, was approved
Dopamine agonistinduced impulse control disorders in 1989 for the treatment of PD. As monotherapy, it has a
(pathologic gambling, etc.) are discussed earlier under small symptomatic effect. As an adjunct to levodopa
Neuropsychiatric Symptoms. therapy, it increases on time while reducing motor uc-
tuations; the dose is 5 mg with breakfast and lunch. A
Carbidopa/Levodopa Formulations Carbidopa/ signicant side effect of selegiline is insomnia, probably
levodopa is available in regular, immediate release (IR) due to an amphetamine-like metabolite.
formulations (Sinemet, Atamet, and others; 10/100 mg, In 2006, two additional, more potent MAO-B inhibitors
25/100 mg, and 25/250 mg), controlled release (CR) with once-daily dosing were introduced for the treat-
formulations (Sinemet CR 25/100 mg, 50/200 mg), or ment of PD. Rasagiline was approved for use as initial
more recently as Stalevo (Table 24-4).The latter combines monotherapy and as adjunctive therapy. It is metabo-
variable doses of IR-carbidopa/levodopa (12.5/50, 25/100, lized to an aminoindan metabolite that lacks the
37.5/150) with 200 mg of entacapone (see later). In most amphetamine-like properties of selegiline. As monother-
individuals, at least 75 mg/d of carbidopa is necessary to apy in treatment-nave patients it improves motor func-
block the peripheral decarboxylation of levodopa to tion compared to placebo, and as an adjunct it increases
dopamine, and to limit the symptoms of nausea and daily on time by about 1.8 h. The usual dose is 0.51
orthostasis associated with initiation of therapy. Initial mg/d. A recent trial suggested that rasagiline may alter
target doses of these medications are summarized in the course of the disease (i.e. provide benet other than
Table 24-4. Individualized dosing and gradual dose symptomatic treatment), but this will need to be con-
escalation is recommended.Initiation of dosing at mealtimes rmed as the trial demonstrated this effect for only one
will reduce the incidence and severity of nausea. As of two doses tested.
patients develop tolerance to nausea and other side Zydis selegiline is an orally disintegrating, freeze-
effects, these medications can be administered on an dried tablet that is absorbed through the oral mucosa;
empty stomach, which generally leads to a more brisk and this results in higher levels of selegiline and lower levels
predictable absorption. of the plasma amphetamine-like metabolites compared
Etilevodopa, the ethyl-ester pro-drug of levodopa, with the usual oral route. Its usual dose is 1.252.5 mg/d
has greater solubility than levodopa in the stomach and in the morning. In a 2004 controlled study, Zydis selegi-
a more rapid transit time to the duodenum, where it line in patients with PD and motor uctuations
is quickly absorbed after being hydrolyzed to levodopa. increased dyskinesias-free on time by 11.5 h/d in
In spite of these pharmacokinetic advantages, in a comparison with placebo.
 Although these compounds are generally well toler- a mechanism thought responsible for reducing drug- 331
ated, side effects include dose-dependent nausea, dys- induced dyskinesias. The side effects of amantadine are
pepsia, dizziness, insomnia, dyskinesias, orthostatic nausea, headaches, edema, erythema, and livedo reticularis.
hypotension, confusion, and hallucinations. They should In older patients, it may aggravate confusion and psychosis.
not be used with meperidine, tramadol, methadone, or Doses need to be decreased in patients with renal
propoxyphene. Rarely, a hyperserotonergic syndrome insufciency.
may result from use in combination with tricyclic antide-
pressants (TCAs) and selective serotonin reuptake THERAPY OF NON-MOTOR SYMPTOMS
inhibitors (SSRIs). This syndrome is characterized by anx- Patients with frequent nighttime awakenings due to
iety, tremulousness, myoclonus, and alterations in men- nocturnal akinesia or tremor can be treated with
tal status. Although the risk of this complication in PD supplemental doses of carbidopa/levodopa at night.
appears to be small at the approved doses, it is judicious A bedtime dose of a dopamine agonist helps restless
to remain vigilant to these possible side effects until leg symptoms and urinary urgency.Treatment of bladder
more Phase IV safety information is available. In the symptoms will improve sleep in many elderly patients
interim, the lower dose of these compounds should be with PD. Depression typically responds to antidepressants
considered in older individuals with active cardiac dis- (either TCAs or SSRIs). As discussed earlier, the combination

CHAPTER 24
ease, or in those who are prescribed concomitant anti- of SSRIs and selegiline carries an exceedingly low
depressant drugs. risk of a hyperserotonergic syndrome (delirium with
myoclonus and hyperpyrexia). Electroconvulsive therapy
COMT Inhibitors The catechol-O-methyltransferase
(ECT) is highly effective in drug-refractory cases or in
(COMT) inhibitors entacapone and tolcapone offer yet
patients intolerant of oral antidepressants. There are
another strategy to augment the effects of levodopa by
several reports indicating that ECT also has short-term
blocking the enzymatic degradation of levodopa and
benet for parkinsonian motor symptoms.

Parkinsons Disease and Other Extrapyramidal Movement Disorders

dopamine. Entacapone is preferred to tolcapone
In patients with psychotic symptoms or confusion,
because of the low but potentially serious incidence of
anticholinergics and amantadine should be eliminated
hepatic and hematologic side effects of the latter. When
rst. Following this, MAO-B inhibitors and dopamine
used in conjunction with carbidopa/levodopa, these
agonists should be reduced or discontinued as needed
agents increase the plasma levodopa levels by >30%
to control symptoms. This should be followed by grad-
and alleviate wearing-off symptoms. Entacaprone (200
ual reductions as needed in nocturnal and then daytime
mg with each dose of carbidopa/levodopa) increases
doses of Sinemet CR, and nally carbidopa/levodopa. If
on time by <1 h/d, whereas tolcapone (100200 mg
the patient improves after only a modest reduction of
tid) increases on time by about 1.8 h/d.
antiparkinsonian therapy, the overall impact on the
The more common side effects are gastrointestinal
parkinsonian motor symptoms may be negligible. If in
and hyperdopaminergic, including sleep disturbances
the process parkinsonian symptoms worsen, most spe-
and increased dyskinesias that may require reductions
cialists initiate treatment with an atypical antipsychotic
in the dose of carbidopa/levodopa. Hyperdopaminergic
that has a low incidence of extrapyramidal side effects
symptoms can be managed with appropriate decreases
rather than continuing to lower dopaminomimetic ther-
in the dose of other dopaminomimetics. Tolcapone can
apy. Clozapine (12.5100 mg/d) is the best established
be associated with a dose-dependent increase in
agent for treatment of psychotic symptoms in PD. Queti-
hepatic aminotransferase levels in 13% of cases and
apine (12.5100 mg) is sometimes used rst because it
rare instances of acute fulminant liver failure. ALT/AST
lacks the small risk of agranulocytosis associated with
levels should be monitored every 24 weeks for the rst
clozapine. Both are dosed at night to promote sleep and
6 months and periodically thereafter. Tolcapone should
minimize daytime sedation and orthostasis. Their use
not be used in patients with preexisting liver disease
and that of all antipsychotics in PD are limited by dose-
and should be discontinued if the ALT/AST levels exceed
dependent sedation, orthostatic hypotension, dizziness,
two times the upper limit of normal.
and confusion. Other atypical antipsychotics such as
Other Well-Established Agents Anticholinergics risperidone, olanzapine, and, more recently, aripiprazole
and amantadine are appropriate adjuncts to dopamino- are not well tolerated by most patients with PD due to a
mimetic therapy. Anticholinergics are particularly useful higher incidence of drug-induced parkinsonism (DIP)
for controlling rest tremor and dystonia, and amantadine and akathisia.
can reduce drug-induced dyskinesias by up to 70%. The Centrally acting acetylcholinesterase inhibitors can
mechanisms of action of amantadine are unknown, improve dementia symptoms in PD, providing the
although there is evidence it has both anticholinergic and same stabilization of cognitive decline noted in AD.
dopaminomimetic properties. Recently amantadine has Rivastigmine is approved by the Food and Drug Admin-
been shown to have weak glutamate antagonist properties, istration for the treatment of dementia in PD, and
 332 donepezil also appears to be effective. Both appear to proapoptotic cell signaling. Other promising agents
be well tolerated by most patients with PD and may also include nitric oxide synthetase inhibitors and antiapop-
be useful for treatment of psychotic symptoms such as totic agents such as Jun N-terminal kinase inhibitors and
hallucinations and delusions. desmethylselegiline. The latter, a metabolite of selegi-
Given the complexity of the above polypharmacy, the line, has been shown experimentally to have neuropro-
management of non-motor symptoms is best carried tective effects on dopamine neurons, possibly through
out in an interdisciplinary setting, coordinated by a neu- modulation of cellular antiapoptotic mechanisms, includ-
rologist who specializes in PD together with a psychia- ing Bcl-2, glyceraldehyde-3-phosphate dehydrogenase
trist and the patients primary care physician. (GAPDH); activation of the proteasome-ubiquitin com-
plex; and the prevention of caspase 3 activation. Clinical
NEUROPROTECTIVE THERAPY Slowing the trials to test the putative new effects of dopamine ago-
progression of PD through neuroprotective or restorative nists are now under way.
therapy is a major focus of research. Epidemiologic
studies suggest that the chronic use of nonsteroidal SURGICAL TREATMENTS Over the past decade
anti-inammatory agents or the use of estrogen there has been a renaissance in the surgical treatment
replacement in postmenopausal women may delay or of PD and other movement disorders. Although both
prevent the onset of PD through yet-unclear mechanisms. pallidotomy and thalamotomy were performed widely
SECTION III

Similarly, in large populations, the long-term use of in the 1950s, the introduction of levodopa in the 1960s
nicotine and caffeine has been associated with a lower led to the virtual abandonment of surgery.The resurgence
risk of PD. in the use of surgery has been motivated by the fact
From a pharmacologic standpoint, current strategies that after 5 or more years of treatment, many patients
involve interrupting the cascade of biochemical events develop signicant drug-induced motor uctuations
that leads to death of dopaminergic cells (Fig. 24-3). The and dyskinesias. Advances in understanding the
Diseases of the Central Nervous System

rst such clinical trial in PD was the large multicenter functional organization of the basal ganglia and the
DATATOP study in which selegiline monotherapy delayed pathophysiologic basis of parkinsonism have provided a
the need for levodopa therapy by 912 months in newly clearer rationale for the effectiveness of these procedures
diagnosed patients. Most evidence indicates that this and guidance for targeting specic structures (Fig. 24-5).
delay was due to a mild symptomatic effect of selegi- The most common indications for surgery in PD are
line. The antioxidant vitamin E had no effect. Long-term intractable tremor and drug-induced motor uctuations
follow-up of the DATATOP cohort revealed that patients or dyskinesias. The best candidates are patients with
who remained on selegiline for 7 years experienced clear levodopa-responsive parkinsonism who are free of
slower motor decline compared to those who were signicant dementia or psychiatric comorbidities. In
changed to placebo after 5 years. The 7-year patient general, patients with atypical parkinsonism or dementia
group was more likely to develop dyskinesias but less benet little, or not at all. Currently the subthalamic
likely to develop freezing gait. nucleus is the preferred target, but controlled clinical
Coenzyme Q10, an antioxidant and a cofactor of trials comparing the pallidal and subthalamic targets
complex I of the mitochondrial oxidative chain, has are nearing completion. Deep brain stimulation (DBS) is
been shown to have neuroprotective effects against most often performed bilaterally and simultaneously,
multiple toxic agents in vitro and in animal models of but unilateral DBS can be highly effective for asymmetric
PD. In a large controlled phase 2 trial, a dose of 1200 cases. DBS in these areas alleviates parkinsonian
mg/d appeared to delay progression of disability in motor signs, particularly during off periods, and
untreated patients with PD. Coenzyme Q10 was well reduces troublesome dyskinesias, dystonia, and motor
tolerated and devoid of toxicity. A phase 3 trial will uctuations that result from drug administration. Both
examine the disease-modifying effect of this com- procedures have been shown to strongly improve the
pound in untreated patients receiving up to 2400 patients quality of life, and both are more effective than
mg/d. Other potential neuroprotective agents under medical management in the target population of
investigation are creatine monohydrate and acetyl- patients with advanced PD. Signs and symptoms not
levo-carnitine. A phase 2 trial of creatine in early PD responding to levodopa, such as postural instability and
demonstrated promising results, and a phase 3 trial is falling, hypophonia, micrographia, drooling, and autonomic
now under way. dysfunction, are unlikely to benefit from surgery.
Dopamine agonists are also under investigation as As a rule of thumb, the benets from surgery are
putative agents to slow disease progression in PD, based unlikely to exceed the best results from antiparkinsonian
on their possible antioxidant properties resulting in medications but provide relief from motor uctuations,
part from their in vitro ability to decrease dopamine dyskinesias, and dystonia. In general, the decision for
turnover, scavenge free radicals, and interfere with surgery should be made by a movement-disorder neurologist
 CORTEX CORTEX
333

Striatum Striatum
CM VA/VL CM VA/VL
I D I D
SNc SNc
GPe GPe

STN GPi/SNr STN GPi/SNr

Brainstem/ PPN Brainstem/ PPN

spinal cord spinal cord
A B
FIGURE 24-5
Schematic diagram of the basal gangliathalamocortical thalamus to activate the frontal cortex leading to signs of
circuitry under normal conditions (A) and in Parkinsons parkinsonism. As discussed, changes in discharge pattern

CHAPTER 24
disease (PD) (B). Inhibitory connections are shown as black are also a major factor. D, direct pathway; I, indirect pathway;
arrows and excitatory connections as red arrows. Note that GPe, external segment of the globus pallidus; GPi, internal
in PD, striatal dopamine denervation results in increased traf- segment of the globus pallidus; SNr, substantia nigra, pars
c in the indirect pathway and decreased trafc in the direct reticulata; SNc, substantia nigra, pars compacta; STN, sub-
pathway. The downstream consequence of this is increased thalamic nucleus; VA/VL, ventral anterior/ventrolateral thala-
activity in striatal outow stemming from the increased activ- mus; CM, centromedian nucleus; PPN, pedunculopontine

Parkinsons Disease and Other Extrapyramidal Movement Disorders

ity of STN and ultimately GPi/SNr neurons. Because striatal nucleus. (Courtesy of T Wichmann, MD, Emory University
outow is inhibitory to the thalamus (main neurotransmitter = School of Medicine; with permission.)
-aminobutyric acid), there is a decrease in the ability of the

who is part of a team, including the neurosurgeon, apparent successful grafting observed by PET and at
neuropsychologist, and programmer. autopsy. Because of these disappointing results, the
The mechanism of action of DBS remains controver- considerable obstacles to obtaining sufcient fetal
sial. Because clinically it appears that ablation and stim- tissue, and opposition to the use of fetal tissue on
ulation of a given target have a similar effect, it has been ethical grounds, this approach is now viewed as purely
assumed that stimulation causes a functional blockade. investigational. It is hoped that these issues can be
It is likely, however, that multiple factors are involved. addressed with the development of other strategies to
The basis for improvement appears to be the replace- enhance dopaminergic cell function (e.g., carotid body
ment of abnormal neural activity by a more tolerable cells; stem cells; encapsulated and genetically engineered
pattern of activity. Whatever the mechanism, it is clear cells capable of producing levodopa, dopamine,
that these approaches can offer impressive and endur- and/or trophic factors). One approach uses genetically
ing results in properly selected patients. engineered retinal epithelial cells in gelatin capsules to
ensure their survival following implantation, typically
Neurotransplantation and Other Surgical into the putamen. The cells produce levodopa, which
Approaches Despite highly encouraging open- then diffuses into the cerebral microenvironment,
label pilot studies of fetal cell transplantation, this providing dopamine reinnervation to surrounding tissue.
approach has produced considerable disappointment A controlled clinical trial is under way to examine the
with the recent publication of the results from two large, potential benet of this approach in PD following
well-controlled clinical trials. The rst, using sham positive results in a small open-label study.
surgery, showed only modest benet in patients <60 The favorable response from direct infusion of glial
years and no benet in those >60 years. An unexpected cellderived neurotrophic factor (GDNF) to the putamen
complication in a number of patients was the in two small open-label trials in patients with PD raised
development of symptomatic dyskinesias, occurring off hopes that this approach may offer neuroprotection.
medication. The second study has shown similar However, a well-controlled trial using bilateral GDNF infu-
ndings with regard to benet and the development of sion to the putamen failed to demonstrate signicant
dyskinesias. A puzzling feature of these studies is the improvement. There is currently a moratorium on further
 334 trials with GDNF due to the development of GDNF- OTHER PARKINSONIAN DISORDERS
neutralizing antibodies in four patients and to a toxico-
logic study revealing cerebellar degeneration in an PARKINSONIAN DISORDERS ASSOCIATED
exposed primate. However, trials are currently under WITH ABNORMAL METABOLISM OF -
way using alternative vehicles for these and other neu- SYNUCLEIN (-SYNUCLEINOPATHIES)
rotrophins with actions similar to GDNF. These vehicles Multiple System Atrophy
include recombinant adeno-associated virus, lentivirus,
and pseudorabies virus. Stem cell transplantation in PD MSA comprises a group of sporadic disorders character-
will need to await successful application of this technol- ized by varying degrees of parkinsonism and cerebellar,
ogy in other areas of medicine. corticospinal, and autonomic dysfunction. The average
age of onset is 50 years (earlier than in PD) and the
median survival 69 years. The clinical presentation is
highly varied and may begin with any of the above clin-
DEMENTIA IN PARKINSONS DISEASE ical manifestations. The unifying pathologic hallmark is
the presence of -synuclein-positive inclusions located
The incidence of dementia in PD may be as high as six in various brain regions.
times that in the general non-PD population. Approxi-
SECTION III

mately a quarter of patients will develop dementia of the Clinical Phenotypes

Alzheimer type due to overlap of these two age-related With disease progression, 90% of patients exhibit
pathologies. Pathologically, the incidence of AD-type parkinsonian signs and 80% signs of autonomic failure; a
ndings in postmortem tissue from patients dying with similarly high percentage exhibit upper motor neuron
PD is as high as 40%. Conversely, 25% of AD patients signs. Tremor is common, but unlike in PD, this and
have at least mild clinical parkinsonian features such as other parkinsonian signs are more likely to present sym-
rigidity and bradykinesia, and 60% have coexistent -
Diseases of the Central Nervous System

metrically. Parkinsonian symptoms are typically poorly

synuclein pathology in the cortex. Patients with PD responsive to dopaminergic therapy, although some
dementia (PDD) are more likely to have the akinetic/rigid patients may respond favorably for years. Drug-induced
PD phenotype rather than the tremor-predominant dyskinesias typically involve the face and neck rather
phenotype. In this population the presence of dementia than the trunk and limbs, as is the case in PD. Corti-
makes management of the motor symptoms of PD more cospinal signs consist of spasticity, involving the legs
difcult due to the high incidence of cognitive side more than the arms, and pseudobulbar palsy. This aspect
effects from antiparkinsonian therapy, particularly anti- of the illness may mimic primary lateral sclerosis with
cholinergics and amantadine. Central dopaminomimetic lower motor neurons being occasionally involved. A few
toxicity can present in many ways, ranging from sleep dis- patients develop myoclonus.
ruption with daytime sleepiness, personality changes, Signs of autonomic failure include orthostatic hypoten-
depression, and executive dysfunction (e.g., organization, sion, leg swelling not due to drug therapy, changes in
planning, multitasking) to episodic confusion, hallucina- sweating patterns, and autonomic storms with diaphoresis
tions, and disruptive behaviors. and ushing. Orthostatic hypotension can present with
DLB is an increasingly recognized form of dementia dizziness, faintness, or syncope. Once patients are success-
with prominent parkinsonian features.The dementia may fully treated for syncope, they often develop fatigue and
precede or follow the parkinsonian syndrome. In patients lassitude. This is due in part to chronic tissue hypoperfu-
presenting with parkinsonian features, the dementia is sion caused by marginal blood pressures while sitting or
often heralded by levodopa-induced sedation, myoclonus, standing. More aggressive management of the blood pres-
and hallucinations. Early on, the phenotype can be sure is warranted but not always successful. Urinary symp-
indistinguishable from PD. Features that help differenti- toms include urgency, retention, and incontinence. In
ate this entity from PD include the presence of an action men, impotence is one of the earliest and most prominent
rather than a rest tremor; a rapidly fading response to lev- signs. The autonomic dysfunction can precede or follow
odopa; and rapidly uctuating, spontaneous, and drug- the development of other neurologic signs by several
induced problems with arousal. Another feature of DLB years. Dementia may not be as frequent as in PD.
is the higher incidence of neuropsychiatric symptoms The clinical phenotype of MSA can fall into one of
than in idiopathic PD. These symptoms include apathy, two broad categories, termed MSA-p (prominent parkin-
personality changes, depression, xed delusions, and hal- sonism at onset) and MSA-c (prominent cerebellar
lucinations. Finally, patients with DLB exhibit a height- involvement at onset). Disorders that have now been
ened sensitivity to DIP when exposed to any dopamine reclassied as part of this new naming scheme include
blocker. The progression of symptoms in DLB is inter- striatonigral degeneration (SND), olivopontocerebellar atrophy
mediate between the PD and PD/AD overlap. DLB is (OPCA), and progressive autonomic failure (PAF), either
discussed in detail in Chap. 23. without parkinsonism or with parkinsonism (Shy-Drager
syndrome). Patients presenting with a relatively pure PARKINSONIAN DISORDERS ASSOCIATED 335
form of akinetic rigid parkinsonism and a limited WITH ABNORMALITIES OF TAU
response to levodopa are designated as having MSA-p. METABOLISM (TAUOPATHIES)
Distinguishing these conditions from PD and each other
As in the synucleopathies, the discovery of a group of
can be difcult, particularly in the early stages of illness.
familial and sporadic disorders with pathology involving
Individuals with other signs such as ataxia, upper motor
the microtubule-associated protein tau has helped clas-
neuron and corticobulbar involvement, myoclonus, ocu-
sify a group of disorders characterized by atypical
lomotor abnormalities, peripheral neuropathy, and deaf-
parkinsonism and dementia. In the familial forms of
ness t into the category of MSA-c. This phenotype is
these disorders, mutations in the tau gene have been
notably heterogeneous, with both sporadic and heredi-
linked to rare forms of parkinsonism and to frontotem-
tary forms. The sporadic forms tend to form part of the
poral dementia (Chap. 23). The two entities discussed
spectrum discussed in this section, while the hereditary
below typically present as movement disorders.The rst,
forms usually represent one of the spinocerebellar atax-
progressive supranuclear palsy (PSP), has not been linked
ias (Chap. 26). Although MSA categories are clinically
to mutations in the tau gene but is associated with over-
useful, as disease progresses there tends to be more clini-
representation of the H1 tau gene haplotype. These and
cal and pathologic overlap than separation between the
other ndings support the view that abnormal process-
different entities.

CHAPTER 24
ing of tau may be directly linked to the pathogenesis of
The spectrum of disease in MSA is determined by
sporadic and familial tauopathies.
the location and density of the LB pathology. For
instance, the LBs are conned to neurons in the brain-
stem in PD and to the brainstem, cortex, and hippocam- Progressive Supranuclear Palsy
pus in DLB. In MSA these deposits take the form of
glial -synuclein-positive intracytoplasmic inclusions in This is a sporadic neurodegenerative disorder of unknown

Parkinsons Disease and Other Extrapyramidal Movement Disorders

the substantia nigra, putamen, inferior olives, pontine etiology associated with tau pathology. It presents in the
nuclei, pigmented nuclei of the brainstem, intermedio- sixth to seventh decades and progresses more rapidly
lateral nucleus of the spinal cord, and the cerebellum. In than PD, with death in 510 years. Risk factors include
addition, in MSA there is myelin degeneration and head trauma, vascular disease, dietary exposure to benzyl-
oligodendroglia containing argyrophilic glial cytoplas- tetrahydroisoquinolines (TIQ, reticuline), and beta-
mic inclusions that are immunoreactive for ubiquitin carbolines (reports from the West Indies).
and -synuclein. Similar inclusions can be found in PSP is characterized by akinetic rigid parkinsonism,
neuronal cell bodies and processes. dizziness, unsteadiness, slowness, falls, and pseudobulbar
Several diagnostic tests help differentiate MSA from dysarthria.Tremor is distinctly uncommon. Supranuclear
PD and other parkinsonian syndromes. In MSA-c, brain eye movement abnormalities affecting downgaze occur
MRI reveals prominent atrophy of the cerebellum, pons, rst, followed by variable limitations of upward and hor-
and olivary eminence of the medulla. In MSA-p, promi- izontal eye movement. Because the vestibular ocular
nent volume loss and T2-weighted image hyperintensity reex (dolls eyes maneuver) and the Bells reex (ele-
in the putamen, globus pallidus, and white matter may vation and abduction of eyes on attempted lid closure)
be present. Electrodiagnostic studies may reveal rectal are intact, these abnormalities are termed supranuclear.
sphincter abnormalities with signs of degeneration with Neurologic examination often reveals prominent stare
reinnervation due to anterior horn cell loss. Commer- and furrowed brow, axial (especially nuchal) and proxi-
cially available genetic tests are available for many of the mal limb rigidity and dystonia, as well as upper motor
spinocerebellar ataxias (Chap. 26) that present with fea- neuron and occasional cerebellar signs. Virtually all
tures that overlap OPCA. patients develop frontal-type cognitive dysfunction
(Chaps. 15, 23), and a signicant number may develop
dementia with distinct subcortical features (e.g., abulia,
mental inexibility, and defects in memory retrieval).
Treatment: Brain MRI reveals midbrain atrophy (superior collicu-
PARKINSONIAN DISORDERS OF - lus), and PET studies show symmetric frontal and striatal
SYNUCLEIN ABNORMAL METABOLISM hypometabolism. The diagnosis is made on clinical
Early in the course of the illness, parkinsonian features grounds. Although some response may occur to levodopa
may respond to dopaminomimetic agents. These have and other antiparkinson medications, especially early in
to be used with caution due to their tendency to pro- the course, treatment is generally not highly effective.
voke orthostatic hypotension. Treatment of orthostatic Pathologically, PSP is characterized by deposition of neu-
hypotension and other autonomic symptoms is dis- robrillary tangles histochemically positive for tau (mostly
cussed in Chap. 28. 4-repeat tau) and negative for amyloid or -synuclein.
The deposits are associated with varying degrees of
 336 degeneration in the brainstem, basal ganglia, and cerebel- such as reserpine and -methyldopa. Exposure to man-
lum. There is loss of dopamine and dopamine receptors ganese, carbon monoxide or disuldes, cyanide, and
due to intrinsic striatal damage.This is thought to account methanol can also lead to a parkinsonian state.The sever-
for the poor response to therapy. ity of the parkinsonian symptoms usually correlates with
the dose or exposure to a medication or toxin. If due to
Corticobasal Degeneration (CBD) medication, the symptoms tend to disappear within days
to weeks after stopping the offending agent but may be
CBD, another sporadic tauopathy, is less common but permanent. Patients with permanent symptoms may
has a broader range of clinical presentations than PSP. As have been in the process of developing parkinsonism.
with most atypical forms of parkinsonism, it begins DIP may respond to anticholinergic agents, amantadine,
insidiously in the sixth to seventh decades with varying and levodopa.
degrees of asymmetric progressive apraxia, rigidity, dys-
tonia, bradykinesia, and myoclonic jerks, with or with-
out cortical sensory loss.The alien limb phenomenon, Vascular Parkinsonism
consisting of involuntary purposeful movements of a The concept of vascular or atherosclerotic parkinsonism
hand or limb, is a characteristic sign. The disorder pro- remains a topic of controversy. Generally, patients with
gresses to become bilateral over 25 years, leading to vascular parkinsonism exhibit an akinetic-rigid syndrome
SECTION III

total incapacity with, ultimately, paraplegia in exion. A with short mincing steps without tremor. Most have neu-
signicant number of cases present with frontotemporal rologic signs distinguishable from those associated with
dementia or progressive aphasia, followed by asymmetric PD, including upper motor neuron signs, pseudobulbar
cortical sensory signs, including abnormalities of graph- palsy, or dementia. A poor response to levodopa therapy
esthesia and astereognosis (Chaps. 15, 23). Brain MRI is characteristic. Imaging studies are heterogeneous and
reveals focal cortical loss in the contralateral superior may reveal basal ganglia lacunes or multiple infarcts. The
Diseases of the Central Nervous System

frontal and parietal lobes with corresponding hypometa- hypertensive and diabetic microangiopathy and diffuse
bolic changes on PET scan as well as hyperintense signal white matter disease (Chap. 21) typically present with
abnormalities in white matter and sometimes atrophy of patchy, conuent, or diffuse white matter in the centrum
the corpus callosum.Treatment is largely ineffective. semiovale. Other causes of microangiopathy can also rarely
Grossly, CBD is a focal cortical degenerative process be responsible. The premortem diagnosis of these disor-
with asymmetric pathology and volume loss in the pari- ders is difcult to make with certainty, given the absence
etal and frontal regions. Most of the damage is in the dor- of disease markers.
sal peri-Rolandic, superior frontal, and superior parietal
cortices, whereas cases with aphasia show abnormalities in
the peri-Sylvian regions. Histologically, gliosis and swollen FURTHER READINGS
(ballooned) achromatic neurons and neuronal loss are pre- BENABID AL et al: Deep brain stimulation of the subthalamic nucleus
sent in these cortical regions as well as in the nigra, cau- for the treatment of Parkinsons disease. Lancet Neurol 8:67,
date, putamen, and thalamus. Recent clinicopathologic 2009
evidence indicates that the syndrome can occur in the DEUSCHL G et al: A randomized trial of deep-brain stimulation for
absence of basal ganglia or nigral degeneration. Parkinsons disease. N Engl J Med 355:896, 2006
FACTOR S,WEINER W (eds): Parkinsons Disease: Diagnosis and Clinical
Management, 2d ed. New York, Demos Medical Publishing, 2007
SECONDARY PARKINSONISM HARDY J et al: Genetics of Parkinsons disease and parkinsonism. Ann
Neurol 60:389, 2006
Drug-Induced Parkinsonism
LEES AJ et al: Parkinsons disease. Lancet 373:2055, 2009
DIP typically presents bilaterally with bradykinesia or LIPPA CF et al: DLB and PDD boundary issues: Diagnosis, treatment,
tremor. Asymmetry is far less prominent than in PD. It is molecular pathology, and biomarkers. Neurology 68:812, 2007
OLANOW CW et al: A double-blind, delayed-start trial of rasagiline in
commonly due to neuroleptics, some atypical antipsy-
Parkinsons disease. N Engl J Med 361:1268, 2009
chotics, lithium carbonate, or antiemetic agents (espe- SCHADE R et al: Dopamine agonists and the risk of cardiac-valve
cially metoclopramide). Less common causes include regurgitation. N Engl J Med 356:29, 2007
valproic acid and uoxetine. DIP can also be induced by WILLIAMS-GRAY CH et al: Evolution of cognitive dysfunction in an
the chronic administration of antihypertensive agents incident Parkinsons disease cohort. Brain 130:1787, 2007
 CHAPTER 25

HYPERKINETIC MOVEMENT DISORDERS

C. Warren Olanow

Hyperkinetic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Essential Tremor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
Choreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Tics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Myoclonus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Drug-Induced Movement Disorders . . . . . . . . . . . . . . . . . . . 344
Psychogenic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

neurologic examination is otherwise normal. ET can be

HYPERKINETIC DISORDERS differentiated from Parkinsons disease (PD) by the
Hyperkinetic movement disorders are characterized by absence of resting tremor, bradykinesia, rigidity, micro-
the presence of a variety of different involuntary move- graphia, and other parkinsonian features.Tremor can also
ments (Table 25-1).The major hyperkinetic movement be observed with a variety of drugs, multiple sclerosis,
disorders and the diseases with which they are associated degenerative disorders, and metabolic alterations.
are considered in this chapter.
Etiology and Pathophysiology
ESSENTIAL TREMOR The specic etiology and pathophysiology of ET are not
known. Approximately 50% of cases have a positive fam-
Clinical Features ily history with an autosomal dominant pattern of inher-
Essential tremor (ET) is the most common involuntary itance. Linkage studies have detected loci at chromosome
movement disorder, affecting ~510 million individuals 3q13 (ETM-1) and 2p22-25 (ETM-2), and it is likely
in the United States alone. It is a progressive disorder that there are many other undiscovered loci.The cerebel-
which can present in childhood but dramatically lum and inferior olives have been implicated as possible
increases in prevalence over the age of 70. ET is charac- sites of a tremor pacemaker based on the presence of
terized by a high-frequency tremor (up to 11Hz) that cerebellar signs in some patients and ndings of increased
predominantly affects the upper extremities. The tremor metabolic activity and blood ow in these regions.
is most prominent when trying to maintain a posture
(postural tremor) or perform an action such as touching
the nger to an object (kinetic tremor). It is typically Treatment:
bilateral and symmetric, but one side can be predomi- ESSENTIAL TREMOR
nantly affected. Tremor may also affect the head (hori-
Many cases are mild and require no treatment other
zontal or vertical), and speech may be tremulous. The
than reassurance. Occasionally, tremor can be severe
tremor characteristically improves with alcohol and may
and interfere with eating, writing, and activities of daily
worsen with stress. Occasionally, subtle impairment of
living. Primidone (251000 mg/d) and propranolol
coordination or tandem walking may be present, but the
337
 338 TABLE 25-1 later become sustained and extend to other body regions.
HYPERKINETIC MOVEMENT DISORDERS It can be aggravated by stress and fatigue and attenuated
by relaxation and sensory tricks such as touching the
DISORDERS MOVEMENT CHARACTERISTICS
affected body part. Dystonia can be classied based on
Athetosis Slow, distal, writhing, involuntary age of onset (childhood vs. adult), distribution (focal,
movements with a propensity to affect multifocal, segmental, or generalized), or etiology (primary
the arms and hands. or secondary).
Chorea Rapid, semipurposeful, graceful,
dancelike, nonpatterned involuntary
movements involving distal or proximal Primary Dystonias
muscle groups.
Dystonia Involuntary patterned sustained or Idiopathic torsion dystonia (ITD), or Oppenheims dysto-
repeated muscle contractions, often nia, is predominantly a childhood-onset form of dystonia
leading to twisting movements and with an autosomal dominant pattern of inheritance that
abnormal posture. primarily affects Ashkenazi Jewish families.The majority
Myoclonus Sudden, brief (<100 ms), shocklike, of patients have an age of onset younger than 26 years
arrhythmic muscle twitches. (mean 14 years). In young-onset patients, dystonia typi-
Tics Brief, repeated, stereotyped muscle
cally begins in a foot or arm and can progress to involve
contractions that are often suppressible.
SECTION III

Can be simple and involve a single

the other limbs as well as the head and neck. In severe
muscle group or complex and affect a cases, patients can suffer disabling postural deformities.
range of motor activities. Severity can vary even within a family, with some
Tremor Rhythmic oscillation of a body part due to affected relatives having mild dystonia that may not even
intermittent muscle contractions. have been appreciated. Several gene mutations are asso-
ciated with ITD. Most cases are linked to a mutation in
Diseases of the Central Nervous System

the DYT1 gene located on chromosome 9q34, which

results in a trinucleotide GAG deletion with loss of one
of a pair of glutamic acid residues in the protein torsin
(2080 mg/d) are the standard drug therapies and can
A. DYT1 mutations are found in 90% of Ashkenazi
be administered alone or in combination. Primidone fre-
Jewish patients with ITD and are probably related to a
quently causes sedation and should be started at low
founder effect that occurred about 350 years ago.
doses (12.5 mg) and gradually titrated to an effective
There is variable penetrance, with only about 30% of
dose. Propranolol and other beta blockers are con-
DYT1 gene carriers expressing a clinical phenotype.The
traindicated in patients with cardiac arrhythmias or
function of torsin A is not known, but it is a member of
asthma. Benets with these drugs are attained in ~50%
the AAA+ (ATPase) family of proteins that resemble
of patients but may not be sustained. Alprazolam,
heat shock proteins and may thus be related to protein
gabapentin, topiramate, clonazepam, clozapine, and
regulation. Indeed, postmortem studies have shown pro-
nimodipine have been reported to improve tremor in
tein aggregates and inclusions in the region of the
some patients. Botulinum toxin injections may be help-
pedunculopontine nucleus (PPN). Transgenic mice that
ful for limb or voice tremor, but treatment can be associ-
carry the DYT1 dystonia mutation express a hyperki-
ated with muscle weakness. Surgical therapies targeting
netic and dystonic phenotype and a similar pathology to
the VIM nucleus of the thalamus can be very effective in
human DYT1.
severe and drug-resistant cases.
Dopa responsive dystonia (DRD) or the Segawa variant
(DYT5) is a dominantly inherited form of childhood-
onset dystonia due to a mutation in the gene that
DYSTONIA encodes for guanosine triphosphate (GTP) cyclohydro-
lase I, the rate-limiting enzyme for the synthesis of
Clinical Features
tetrahydrobiopterin. This mutation leads to a defect in
Dystonia consists of sustained or repetitive involuntary the biochemical synthesis of tyrosine hydroxylase and
muscle contractions, frequently causing twisting move- dopamine. DRD typically presents in early childhood
ments with abnormal postures. Dystonia can range from (112 years) and is characterized by foot dystonia that
minor contractions in an individual muscle group to interferes with walking. Patients often experience diur-
severe and disabling involvement of multiple muscle nal uctuations, with worsening of gait as the day pro-
groups. The frequency is estimated at 300,000 cases in gresses and improvement with sleep. DRD is typied by
the United States but is likely greater since many cases an excellent and sustained response to small doses of
are not recognized. Dystonia is often initially brought levodopa. Some patients may present with parkinsonian
out by voluntary movements (action dystonia) and can features but can be differentiated from juvenile PD by
normal striatal uorodopa uptake on positron emission such as manganese, or carbon monoxide. In these cases, 339
tomography and the absence of levodopa-induced dysk- dystonia often assumes a segmental distribution. More
inesias. DRD patients may occasionally present with rarely, dystonia can develop following peripheral nerve
spasticity, increased reexes, and Babinski responses and injury.
be misdiagnosed as cerebral palsy. A mutation has also
been identied in the epsilon-sarcoglycan gene on chro-
mosome 7q21. These patients typically suffer from Dystonia-Plus Syndromes
myoclonic dystonia frequently accompanied by psychi- Dystonia may occur as a part of neurodegenerative con-
atric disturbances. ditions such as Huntingtons disease (HD), PD, Wilsons
disease, corticobasal degeneration, progressive supranu-
Focal Dystonias clear palsy, the Lubag form of dystonia-parkinsonism
(DYT3), and mitochondrial encephalopathies. In con-
These are the most common forms of dystonia. They
trast to the primary dystonias, dystonia is usually not the
typically present in the fourth to sixth decades and affect
dominant neurologic feature in these conditions.
women more than men.The major types are:
1. Blepharospasm: dystonic contractions of the eyelids
Pathophysiology of Dystonia

CHAPTER 25
with increased blinking that can interfere with read-
ing, watching TV, and driving. The pathophysiologic basis of dystonia is not known.The
2. Oromandibular dystonia (OMD): contractions of mus- phenomenon is characterized by cocontracting bursts in
cles of the lower face, lips, tongue, and jaw (opening agonist and antagonist muscle groups. This is associated
or closing). Meiges syndrome is a combination of with a loss of inhibition at multiple levels of the nervous
OMD and blepharospasm that predominantly affects system as well as increased cortical excitability and reorga-
women older than 60 years. nization. Attention has focused on the basal ganglia as the

Hyperkinetic Movement Disorders

3. Spasmodic dysphonia: dystonic contractions of the vocal site of origin of at least some types of dystonia as there are
cords during phonation, causing impaired speech. Most alterations in blood ow and metabolism in basal ganglia
cases affect the adductor muscles and cause speech to structures. Further, ablation or stimulation of the globus
have a choking or strained quality. Less commonly, the pallidus can both induce and ameliorate dystonia. The
abductors are affected, leading to speech with a breathy dopamine system has also been implicated in the patho-
or whispering quality. genesis of dystonia, as dopaminergic therapies can both
4. Cervical dystonia: dystonic contractions of neck mus- induce and treat some forms of dystonia. Recent studies
cles, causing the head to deviate to one side (torticol- have demonstrated pathologic changes in the PPN, and
lis), in a forward direction (anterocollis), or in a back- electrical stimulation in this region induces dystonic mus-
ward direction (retrocollis). Muscle contractions can cle contractures, suggesting that the PPN might also be
be painful and associated with dystonic tremor and a involved.
secondary cervical radiculopathy.
5. Limb dystonias: these can be present in either arms or
legs and are often brought out by task-specic activ-
ities such as handwriting (writers cramp), playing a Treatment:
musical instrument (musicians cramp), or putting in DYSTONIA
golf (the yips). Treatment is symptomatic for the most part, except in
Focal dystonias can extend to involve other body rare cases where treatment of a primary underlying con-
regions (~30% of cases) and are frequently misdiag- dition is available. Wilsons disease should be ruled out
nosed as psychiatric or orthopedic problems. Their in young patients with dystonia as well as in any young
cause is not known, but genetic factors, autoimmu- patient with a movement disorder. Levodopa should be
nity, and repeated trauma have been implicated. tried in all cases of childhood-onset dystonia. High-dose
anticholinergics (e.g., trihexyphenidyl 20120 mg/d)
Secondary Dystonias may be benecial in children but are less helpful in
adults who can rarely tolerate such high doses because
These occur as a consequence of drugs or other neuro-
of cognitive impairment with hallucinations. Oral
logic problems. Drug-induced dystonia is most commonly
baclofen (25120 mg) may be helpful, but benets are
seen with neuroleptic drugs or after chronic levodopa
usually modest, and side effects of sedation, weakness,
treatment in PD patients (see later). Secondary dystonia
and memory loss can be problematic. Intrathecal infu-
can also be observed following discrete lesions in the
sion of baclofen is more likely to be helpful, particularly
striatum, pallidum, thalamus, cortex, and brainstem due
with leg and trunk dystonia, but benets are frequently
to infarction, anoxia, trauma, tumor, infection, toxins
 340 not sustained and complications can be serious, CHOREAS
including infection, seizures, and coma. Tetrabenazine Huntingtons Disease
(12.5200 mg/d) may be helpful, but the drug is not
readily available in the United States. Neuroleptics typi-
HD is a progressive, fatal, autosomal dominant disorder
cally are not recommended because of the risk of
characterized by motor, behavioral, and cognitive dys-
extrapyramidal side effects. Clonazepam and diazepam
function. The disease is named for George Huntington,
are rarely effective. In general, dystonic patients are not
a family physician who described cases on Long Island,
satisfactorily controlled with drug therapies, particularly
New York, in the nineteenth century. Onset is typically
if they have a generalized dystonia.
between 25 and 45 years of age (range 370 years) with
On the other hand, botulinum toxin can be of great
a prevalence of two to eight cases per 100,000. HD is
benet for patients with focal dystonia, particularly if
characterized by rapid, nonpatterned, semipurposeful,
involvement is limited to small muscle groups such as in
involuntary choreiform movements. In the early stages
blepharospasm, torticollis, and spasmodic dysphonia.
the chorea tends to be focal or segmental, but it pro-
Botulinum toxin acts by blocking the release of acetyl-
gresses over time to involve multiple body regions.
choline at the neuromuscular junction, leading to mus-
Dysarthria, gait disturbance, and oculomotor abnormali-
cle weakness and reduced dystonia. Two serotypes of
ties are common features. With advancing disease, there
botulinum toxin are available (A and B). Both are effec-
is a reduction in the chorea and emergence of dystonia,
SECTION III

tive, and it is not clear if there are advantages of one

rigidity, bradykinesia, myoclonus, and spasticity. In
over the other. No systemic side effects are encountered
younger patients (about 10% of cases), HD can present
with the doses typically employed, but benets are tran-
as an akinetic-rigid or parkinsonian syndrome (West-
sient and repeat injections are required at 2- to 5-month
phall variant). HD patients eventually develop behavioral
intervals. Some patients fail to respond after having
and cognitive disturbances which can be a major source
experienced an initial benet. This has been attributed
of disability. Depression with suicidal tendencies, aggres-
Diseases of the Central Nervous System

to induction of antibodies, but improper muscle selec-

sive behavior, and psychosis can be prominent, and the
tion, injection technique, and inadequate dose should
majority of patients develop dementia. A clinical diag-
be excluded.
nosis of HD can be strongly suspected in cases of chorea
Surgical therapy is an alternative for patients with
with a positive family history. Neuropathologically, the
severe dystonia who are not responsive to other treat-
disease predominantly strikes the striatum. Atrophy of
ments. Peripheral procedures such as rhizotomy and
the caudate nuclei, which form the lateral margins of
myotomy were used in the past to treat cervical dysto-
the lateral ventricles, can be visualized on neuroimaging
nia but have been rarely employed since the introduc-
studies in the middle and late stages of the disease
tion of botulinum toxin therapy. Bilateral deep brain
(Fig. 25-1). More diffuse cortical atrophy can be seen
stimulation (DBS) of the pallidum can provide dramatic
late in the disease. Genetic testing can be used to con-
benets for patients with primary (DYT1) dystonia. This
rm the diagnosis and to detect affected individuals in
represents a major therapeutic advance as previously
the family, but this should be performed with caution
there was no consistently effective therapy for these
and in conjunction with trained counselors, as positive
patients. Patients with secondary dystonia are less likely
results can lead to depressive and suicidal reactions.
to benet from DBS. The value of DBS in patients with
Etiology
focal dystonia is currently being explored. Supportive
HD is caused by an increase in the number of polygluta-
treatments such as physical therapy and education are
mine (CAG) repeats (>40) in the coding sequence of the
important and should be a part of the treatment regi-
Huntington gene located on the short arm of chromo-
men for all dystonia patients.
some 4.The larger the number of repeats, the earlier the
Physicians should be aware of dystonic storm, a
disease is manifest. Anticipation occurs, particularly in
potentially fatal condition that typically occurs in
males, with subsequent generations having larger num-
response to a stress situation such as surgery in patients
bers of repeats and earlier age of disease onset. The gene
with a preexisting history of dystonia. It consists of the
encodes the highly conserved cytoplasmic protein hunt-
acute onset of generalized and persistent dystonic con-
ingtin, which is widely distributed in neurons through-
tractions that can involve the vocal cords or laryngeal
out the CNS, but whose function is not known. Models
muscles, leading to airway obstruction. Patients may
of HD with striatal pathology can be induced by excito-
experience rhabdomyolysis with renal failure. Patients
toxic agents such as kianic acid and 3-nitroproprionic
should be managed in an ICU and treated with one
acid, which promote calcium entry into the cell and
or a combination of anticholinergics, diphenhydramine,
cytotoxicity. Mitochondrial dysfunction has been observed
baclofen, benzodiazepines, or dopamine blockers. Spasms
in HD and has been theorized to promote weak excito-
may be difcult to control, and anesthesia with muscle
toxicity by reducing ATP formation necessary for main-
paralysis may be required.
taining the voltage-dependent magnesium blockade of
 341

FIGURE 25-1
Huntingtons disease. A. Coronal
FLAIR MRI shows enlargement of the
lateral ventricles reecting typical cau-
date atrophy (arrows). B. Axial FLAIR
image demonstrates abnormal high
signal in the caudate and putamen
(arrows).

CHAPTER 25
calcium channels. Recent evidence indicates that frag- Other Choreas
ments of the mutant huntingtin protein can be toxic,
Chorea can be seen in a number of disorders. Syden-
possibly by translocating into the nucleus and interfering
hams chorea (originally called Saint Vitus dance) is
with transcriptional regulatory proteins. Intraneuronal

Hyperkinetic Movement Disorders

more common in females and is typically seen in child-
inclusions containing aggregates of ubiquitin and the
hood (515 years). It often develops in association with
mutant protein huntingtin are found in nuclei of neurons
prior exposure to a group A streptococcal infection and
in the striatum and cerebral cortex. Neuronal inclusions
is thought to be the result of an autoimmune-mediated
found in affected regions in HD may represent a protec-
inammatory disorder. With the reduction in the inci-
tive mechanism aimed at segregating and facilitating the
dence of rheumatic fever, the incidence of Sydenhams
clearance of these toxic proteins.
chorea has fallen, but it can still be seen in developing
countries. It is characterized by the acute onset of chor-
eiform movements, behavioral disturbances, and occa-
Treatment: sionally other motor dysfunctions. Chorea generally
HUNTINGTONS DISEASE responds to dopamine-blocking agents, valproic acid, and
Treatment involves a multidisciplinary approach with carbamazepine but it tends to be self-limited, and treat-
medical, neuropsychiatric, social, and genetic counseling ment is generally restricted to those with severe chorea.
for patients and their families. Dopamine-blocking agents Chorea may recur in later life, particularly in association
may control the chorea but are generally not recom- with pregnancy (chorea gravidarum) or treatment with
mended because of their side-effect prole and potential sex hormones. Neuroacanthocytosis is a progressive and
to aggravate motor symptoms, and because the chorea typically fatal autosomal recessive disorder that is charac-
tends to be self-limited and is usually not disabling. terized by chorea coupled with red cell abnormalities on
Depression and anxiety can be greater problems, and peripheral blood smear (acanthocytes). The chorea can
patients should be treated with appropriate antidepres- be severe and associated with self-mutilating behavior,
sant and antianxiety drugs and monitored for mania and dystonia, tics, seizures, and a polyneuropathy.The cause is
suicidal ideations. Psychosis can be treated with atypical unknown, but linkage to chromosome 9q21 has been
neuroleptics such as clozapine (50600 mg/d), quetiapine described. A phenotypically similar X-linked form of the
(50600 mg/d), and risperidone (28 mg/d). There is no disorder has been described in older individuals who
adequate treatment for the cognitive or motor decline. have reactivity with Kell blood group antigens (McLeod
A neuroprotective therapy that slows or stops disease syndrome).
progression is the major unmet medical need in HD. Paroxysmal forms of chorea have been described in asso-
Antiglutamate agents, bioenergetics, caspase inhibitors, ciation with vascular diseases, hypo- and hyperglycemia,
inhibitors of protein aggregation, intracerebral delivery of and a variety of infections and degenerative disorders.
neurotrophic factors, and transplantation of fetal striatal Paroxysmal kinesigenic dyskinesia is rare and characterized
cells are all areas of active research, but none has as yet by brief episodes of chorea triggered by sudden voluntary
been demonstrated to have a disease-modifying effect. movements. A benign senile chorea in older individuals
and a benign inherited chorea of childhood have also
 342 been described. These conditions are somewhat contro- extreme cases, death.The most common cause is a partial
versial, and it is important to ensure that patients do not lesion (infarct or hemorrhage) in the STN, but cases can
have HD. also be seen with lesions in the putamen (Fig. 25-2).
Systemic lupus erythematosus is the most common Fortunately, hemiballismus is usually self-limiting and
systemic disorder that causes chorea; the chorea can last tends to resolve spontaneously after weeks or months.
for days to years. Choreas can also be seen in patients The condition is difcult to treat pharmacologically.The
with hyperthyroidism, various autoimmune disorders, drugs most consistently benecial are tetrabenazine (not
infections including HIV, metabolic alterations, poly- available in the United States), haloperidol, propranolol,
cythemia rubra vera, following open heart surgery in the phenytoin, clonazepam, and baclofen. In extreme cases,
pediatric population, and in association with a wide vari- pallidotomy can be very effective. Interestingly, surgically
ety of medications (especially anticonvulsants, cocaine, induced lesions of the STN in PD are usually not asso-
CNS stimulants, estrogens, and lithium). ciated with hemiballismus.

Treatment: CORTEX CORTEX

CHOREA
SECTION III

Diagnosis and treatment of the underlying condition, PUTAMEN PUTAMEN

where possible, is the rst priority. Tetrabenazine (not
available in the United States), neuroleptics, dopamine-
blocking agents, propranolol, clonazepam, and baclofen SNc SNc
may be helpful. Treatment is not indicated if the condi-
tion is mild and self-limited. GPe
GPe
Diseases of the Central Nervous System

VL
VL
STN
STN
STN
Levodopa-Induced Dyskinesia GPi
GPi
Chronic levodopa treatment in PD patients is frequently SNr
SNr
associated with choreiform dyskinesias that affect the A B PPN
PPN
head, neck, torso, and extremities. They are usually asso-
ciated with the peak plasma levodopa level and maximal FIGURE 25-2
clinical effect (peak dose dyskinesia) but may occur at the Schematic diagram of the basal gangliathalamocortical
onset and wearing off of the levodopa effect (diphasic circuitry in normal (A) and hemiballismus (B) conditions.
dyskinesia).The dyskinesias can be disabling and can also Inhibitory connections are shown as blue arrows and excita-
limit the ability to fully utilize levodopa to control PD tory connections as green arrows. A. In the normal condition,
features. Levodopa-induced dyskinesias are thought to the putamen connects to the GPi/SNr by direct and indirect
pathways. Output neurons from the globus pallidus provide
relate to plastic changes in basal ganglia neurons induced
an inhibitory input to the VL thalamus and modulate its exci-
by intermittent nonphysiologic activation of striatal
tatory effect on cortical motor neurons. B. In hemiballismus,
dopamine receptors due to the drugs short half-life.
the lesion of the STN results in reduced excitatory input to
Medical management with levodopa dose manipulations,
the GPi/SNr and, in turn, reduced inhibition of thalamocorti-
dopamine agonists, and amantadine may be helpful but cal neurons, leading to excessive activation of the cortex and
frequently do not provide satisfactory control. Surgical the emergence of choreiform movements. Dopamine ago-
therapies (ablation and stimulation) directed at the pal- nists may provide benet in hemiballismus or chorea by
lidum and subthalamic nucleus (STN) can be very effec- blocking excitation of inhibitory neurons in the direct path-
tive in severe cases (Chap. 24). Recent studies suggest way (e.g., putamen GPi/SNr) and preventing inhibition of
that dyskinesias can be prevented by more continuous remaining neurons in the excitatory indirect pathway (puta-
delivery of levodopa or other dopaminergic agents. Lev- men GPe STN GPi/SNr), thus increasing neuronal
odopa does not cause dyskinesias in normal individuals. activity in GPi and inhibiting thalamic excitation of the cortex.
Surgical lesions of the GPi are also benecial, suggesting
Hemiballismus that abnormal neuronal discharge patterns in basal ganglia
output neurons are an important contributing factor in the
Hemiballismus is a violent form of chorea that com- development of chorea. GPe, external segment of the globus
prises wild, inging, large-amplitude movements on one pallidus; GPi, internal segment of the globus pallidus; SNr,
side of the body. Proximal limb muscles tend to be pre- substantia nigra, pars reticulata; SNc, substantia nigra, pars
dominantly affected. The movements may be so severe compacta; STN, subthalamic nucleus; VL, ventrolateral thala-
as to cause exhaustion, dehydration, local injury, and, in mus; PPN, pedunculopontine nucleus.
TICS generally initiated with the agonist clonidine, starting 343
Tourette Syndrome (TS) at low doses and gradually increasing the dose and fre-
quency until satisfactory control is achieved. Guanfacine
TS is a neurobehavioral disorder named after the French (0.52 mg/d) is a new agonist that is preferred by
neurologist Georges Gilles de la Tourette. It predomi- many clinicians because it only requires once-a-day dos-
nantly affects males, and prevalence is estimated to be ing. If these agents are not effective, antipsychotics can
0.031.6%, but it is likely that many mild cases do not be employed. Atypical neuroleptics (risperidone 0.2516
come to medical attention.TS is characterized by multi- mg/d, olanzapine 2.515 mg/d, ziprasidone 20200
ple motor tics and vocalizations. A tic is a brief, rapid, mg/d) are preferred as they are associated with a
recurrent, and seemingly purposeless stereotyped motor reduced risk of extrapyramidal side effects. If they are
contraction. Motor tics can be simple, with movement not effective, classical neuroleptics such as haloperidol,
only affecting an individual muscle group (e.g., blinking, uphenazine, or pimozide can be tried. Botulinum toxin
twitching of the nose, jerking of the neck), or com- injections can be effective in controlling focal tics that
plex, with coordinated involvement of multiple muscle involve small muscle groups. Behavioral features, and
groups [e.g., jumping, snifng, head banging, and particularly anxiety and compulsions, can be a disabling
echopraxia (mimicking movements)].Vocal tics can also feature of TS and should be treated. The potential value
be simple (e.g., grunting) or complex [e.g., echolalia

CHAPTER 25
of DBS targeting the anterior portion of the internal cap-
(repeating other peoples words), palilalia (repeating your sule is currently being explored.
own words), and coprolalia (expression of obscene
words)]. Patients may also experience sensory tics, con-
sisting of unpleasant focal sensations in the face, head, or
neck. Patients may experience an irresistible urge to MYOCLONUS
express tics but characteristically can voluntarily suppress Myoclonus is a brief, rapid (<100 ms), shocklike, jerky

Hyperkinetic Movement Disorders

them for short periods of time.Tics vary in intensity and movement consisting of single or repetitive muscle dis-
may be absent for days or weeks only to recur, occasion- charges. Myoclonic jerks can be focal, multifocal, segmental,
ally in a different pattern. Tics tend to present between or generalized and can occur spontaneously, in association
ages 215 years (mean 7 years) and often lessen or even with voluntary movement (action myoclonus), or in
disappear in adulthood. Associated behavioral distur- response to an external stimulus (reex or startle myoclonus).
bances include anxiety, depression, attention-decit Negative myoclonus consists of a twitch due to a brief
hyperactivity disorder and obsessive compulsive disorder. loss of muscle activity (e.g., asterixis in hepatic failure).
Patients may experience personality disorders, self- Myoclonic jerks differ from tics in that they interfere with
destructive behaviors, difculties in school, and impaired normal movement and are not suppressible. They can be
interpersonal relationships. Tics may present in adult- seen in association with pathology in cortical, subcortical,
hood and can be seen in association with a variety of or spinal cord regions, associated with hypoxic damage
other disorders, including PD, HD, trauma, dystonia, (especially following cardiac arrest), encephalopathy, and
drugs (e.g., levodopa, neuroleptics), and toxins. neurodegenerative disorders. Reversible myoclonus can be
seen with metabolic disturbances (renal failure, electrolyte
Etiology and Pathophysiology imbalance, hypocalcemia), toxins, and many medications.
TS is thought to be a genetic disorder, but no specic gene Essential myoclonus is a relatively benign familial condi-
has been identied as yet. Current evidence supports a tion characterized by multifocal lightning-like movements.
complex inheritance pattern with one or more major Myoclonic jerks can be disabling when they interfere
genes, multiple loci, low penetrance, and environmental with normal movement. They can also be innocent and
inuences.The risk of a family with one affected child hav- are commonly observed in normal people when waking
ing a second is about 25%. The pathophysiology of TS is up or falling asleep.
not known, but alterations in dopamine neurotransmission,
opioids, and second messenger systems have been proposed.
Treatment:
MYOCLONUS
Treatment primarily consists of treating the underlying
Treatment: condition or removing an offending agent. Pharmaco-
TOURETTE SYNDROME
logic therapy involves one or a combination of GABAer-
Patients with mild disease often only require education gic agents such as valproic acid (12003000 mg/d),
and counseling (for themselves and family members). piracetam (820 g/d), clonazepam (215 mg/d), or primi-
Drug treatment is indicated only when the tics are done (5001000 mg/d). Recent studies suggest that lev-
disabling and interfere with quality of life. Therapy is etiracetam may be particularly effective.
 344 DRUG-INDUCED MOVEMENT DISORDERS are associated with a signicantly lower risk of TD in
comparison to traditional antipsychotics.Younger patients
This important group of movement disorders is primar-
have a lower risk of developing neuroleptic-induced TD,
ily associated with drugs that block dopamine receptors
while the elderly, the edentulous, and those with under-
(neuroleptics) or central dopaminergic transmission.
lying organic cerebral dysfunction are at greater risk.
These drugs are mostly used in psychiatry but are also
Since TD can be permanent and resistant to treatment,
important in the treatment of nausea or vomiting (e.g.,
antipsychotics should be used judiciously; atypical neu-
Compazine) or gastroesophageal disorders (e.g., meto-
roleptics should be employed whenever possible, and
clopramide). Hyperkinetic movement disorders sec-
the need for their continued use should be regularly
ondary to neuroleptic drugs can be divided into those
monitored.
which present acutely, subacutely, or after prolonged
Treatment primarily consists of stopping the antipsy-
exposure (tardive syndromes). Dopamine-blocking drugs
chotic. If the patient is receiving a traditional antipsy-
can also be associated with a reversible parkinsonian
chotic and withdrawal is not possible, replacement with
syndrome for which anticholinergics are often con-
an atypical antipsychotic should be tried.Abrupt cessation
comitantly prescribed, but there is concern that this may
of a neuroleptic should be avoided as acute withdrawal
increase the risk of developing a tardive syndrome.
can induce transient worsening.TD can persist after with-
drawal of antipsychotics and can be difcult to treat. Ben-
SECTION III

Acute ets may be achieved with valproic acid, anticholinergics,

Dystonia is the most common acute hyperkinetic drug or botulinum toxin injections. In refractory cases, cate-
reaction. It is typically generalized in children and focal cholamine depletors such as reserpine and tetrabenazine
(e.g., blepharospasm, torticollis, or oromandibular dystonia) may be helpful. Tetrabenazine can be associated with
in adults. The reaction can develop within minutes of dose-dependent sedation and orthostatic hypotension.
exposure and can be successfully treated in most cases with Reserpine is an alternative, but it is frequently associated
Diseases of the Central Nervous System

parenteral administration of anticholinergics (benztropine with depression and not often employed. Other approaches
or diphenhydramine) or benzodiazepines (lorazepam include baclofen (4080 mg/d), clonazepam (18 mg/d),
or diazepam). Choreas, stereotypic behaviors, and tics or valproic acid (7503000 mg/d).
may also be seen, particularly following acute exposure Chronic neuroleptic exposure can also be associated
to CNS stimulants such as methylphenidate, cocaine, or with tardive dystonia with preferential involvement of
amphetamines. axial muscles and characteristic rocking movements of
the trunk and pelvis. Tardive dystonia frequently persists
despite stopping medication, and patients are often
Subacute refractory to medical therapy.Valproic acid, anticholiner-
Akathisia is the commonest reaction in this category. It gics, and botulinum toxin may occasionally be bene-
consists of motor restlessness with a need to move that is cial.Tardive akathisia and tardive Tourette syndromes are
alleviated by movement. Therapy consists of removing rare but may also occur after neuroleptic exposure.
the offending agent(s). When this is not possible, symp- Neuroleptic medications can also be associated with a
toms may be ameliorated with benzodiazepines, anti- neuroleptic malignant syndrome (NMS). NMS is charac-
cholinergics, beta blockers, or dopamine agonists. terized by muscle rigidity, elevated temperature, altered
mental status, hyperthermia, tachycardia, labile blood
Tardive Syndromes pressure, and renal failure. Symptoms typically evolve
within days or weeks after initiating the drug. NMS can
These disorders develop months to years after initiation also be precipitated by the abrupt withdrawal of
of neuroleptic treatment. Tardive dyskinesia (TD) is the antiparkinsonian medications in PD patients. Treatment
commonest and typically comprises choreiform move- involves immediate cessation of the offending antipsy-
ments involving the mouth, lips, and tongue. In severe chotic drug and the introduction of a dopaminergic
cases the trunk, limbs, and respiratory muscles may be agent (e.g., dopamine agonists, levodopa), dantrolene, or
affected. Patients with affective disorders are more likely benzodiazepines. Treatment also includes supportive
to develop TD than are patients with schizophrenia. In measures such as control of body temperature (antipyret-
approximately one-third of patients, TD remits within ics and cooling blankets), hydration, electrolyte replace-
3 months of stopping the drug, and most patients gradu- ment, and control of renal function and blood pressure.
ally improve over the course of several years.The move- Drugs that have serotonin-like activity (tryptophan;
ments are often mild and more upsetting to the family MDMA, or ecstasy; meperidine) or that block sero-
than to the patient, but they can be severe and disabling, tonin reuptake can induce a rare, but potentially fatal,
particularly in the context of an underlying psychiatric serotonin syndrome that is characterized by confusion,
disorder. Atypical antipsychotics (e.g., clozapine, risperi- hyperthermia, tachycardia, and coma as well as rigidity,
done, olanzapine, quetiapine, ziprasidone, and aripiprazole) ataxia, and tremor. Myoclonus is often a prominent
feature, in contrast to NMS, which it resembles. Patients patient is distracted by being asked to perform a differ- 345
can be managed with propranolol, diazepam, diphenhy- ent task or is unaware that he or she is being observed.
dramine, chlorpromazine, or cyproheptadine as well as This is the opposite of what occurs with organic move-
supportive measures. ment disorders, which tend to worsen when the patient
A variety of other drugs can also be associated with is distracted and abate with attention. Other positive
hyperkinetic movement disorders. Some examples include features that suggest a psychogenic problem include a
phenytoin (chorea, dystonia, tremor, myoclonus); carba- tremor frequency that is variable or entrains with the
mazepine (tics and dystonia); tricyclic antidepressants (dyski- frequency of tapping in the contralateral limb and a pos-
nesias, tremor, myoclonus); uoxetine (myoclonus, chorea, itive response to placebo medication. Comorbid psychi-
dystonia); oral contraceptives (dyskinesia); adrenergics atric problems such as anxiety, depression, and emotional
(tremor); buspirone (akathisia, dyskinesias, myoclonus); and trauma may be present but are not necessary for the
digoxin, cimetidine, diazoxide, lithium, methadone, and diagnosis of a psychogenic movement disorder to be
fentanyl (dyskinesias). made. Psychogenic movement disorders can occur as an
isolated entity or in association with an underlying
organic problem.The diagnosis can often be made based
PSYCHOGENIC DISORDERS on clinical features alone, and unnecessary tests or med-
Virtually all movement disorders, including tremor, tics, ications should be avoided. Underlying psychiatric

CHAPTER 25
dystonia, myoclonus, chorea, ballismus, and parkinson- problems should be identied and treated. Psychother-
ism, can be psychogenic in origin. Tremor affecting the apy and hypnosis may be of value for patients with con-
upper limbs is the most common psychogenic move- version reaction, and cognitive behavioral therapy may
ment disorder. Psychogenic movements can result from be helpful for patients with somatoform disorders.
a somatoform or conversion disorder, malingering (e.g., Patients with hypochondriasis, factitious disorders, and
seeking nancial gain), or a factitious disorder (e.g., seek- malingering have a poor prognosis.

Hyperkinetic Movement Disorders

ing psychological gain). Psychogenic movement disor-
ders are common (estimated 23% of patients in a FURTHER READINGS
movement disorder clinic), more prominent in women,
CARDOSO F: Huntington disease and other choreas. Neurol Clin
disabling for the patient and family, and expensive for 27:719, 2009
society (estimated $20 billion annually). Clinical features GUSELLA JF, MACDONALD ME: Huntingtons disease: Seeing the
suggesting a psychogenic movement disorder include an pathogenic process through a genetic lens. Trends Biochem Sci
acute onset and a pattern of abnormal movement that is 31:533, 2006
inconsistent with a known movement disorder. Diagno- LOUIS ED: Essential tremors: a family of neurodegenerative disorders?
sis is based on the nonorganic quality of the movement, Arch neurol 66:1202, 2009
SCHWARZ CS, BRESSMAN SB: Genetics and treatment of dystonia.
the absence of ndings of an organic disease process, and
Neurol Clin 27:697, 2009
positive features that specically point to a psychogenic VIDAILHET M et al: Bilateral deep-brain stimulation of the globus
illness such as variability and distractibility. For example, pallidus in primary generalized dystonia. N Engl J Med 352:459,
the magnitude of a psychogenic tremor is increased with 2005
attention and diminishes or even disappears when the WALKER FO: Huntingtons disease. Lancet 369:218, 2007
 CHAPTER 26

ATAXIC DISORDERS

Roger N. Rosenberg

The Inherited Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

Autosomal Dominant Ataxias . . . . . . . . . . . . . . . . . . . . . . . . 348
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Autosomal Recessive Ataxias . . . . . . . . . . . . . . . . . . . . . . . . 355
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

immune, or toxic etiology. Conversely, focal, unilateral

Approach to the Patient:
symptoms with headache and impaired level of con-
ATAXIC DISORDERS
sciousness accompanied by ipsilateral cranial nerve
Symptoms and signs of ataxia consist of gait impair- palsies and contralateral weakness imply a space-
ment, unclear (scanning) speech, visual blurring due occupying cerebellar lesion.
to nystagmus, hand incoordination, and tremor with
movement. These result from the involvement of the SYMMETRIC ATAXIA Progressive and symmetric
cerebellum and its afferent and efferent pathways, ataxia can be classied with respect to onset as acute
including the spinocerebellar pathways, and the fronto- (over hours or days), subacute (weeks or months), or
pontocerebellar pathway originating in the rostral chronic (months to years). Acute and reversible ataxias
frontal lobe.True cerebellar ataxia must be distinguished include those caused by intoxication with alcohol,
from ataxia associated with vestibular nerve or labyrinthine phenytoin, lithium, barbiturates, and other drugs. Intoxi-
disease, as the latter results in a disorder of gait associ- cation caused by toluene exposure, gasoline snifng, glue
ated with a signicant degree of dizziness, light-head- snifng, spray painting, or exposure to methyl mercury or
edness, or the perception of movement (Chap. 9).True bismuth are additional causes of acute or subacute ataxia, as
cerebellar ataxia is devoid of these vertiginous com- is treatment with cytotoxic chemotherapeutic drugs such
plaints and is clearly an unsteady gait due to imbalance. as uorouracil and paclitaxel. Patients with a postinfec-
Sensory disturbances can also on occasion simulate the tious syndrome (especially after varicella) may develop gait
imbalance of cerebellar disease; with sensory ataxia, ataxia and mild dysarthria, both of which are reversible
imbalance dramatically worsens when visual input is (Chap. 34). Rare infectious causes of acquired ataxia
removed (Romberg sign). Rarely, weakness of proximal include poliovirus, coxsackievirus, echovirus, Epstein-Barr
leg muscles mimics cerebellar disease. In the patient virus, toxoplasmosis, Legionella, and Lyme disease.
who presents with ataxia, the rate and pattern of the The subacute development of ataxia of gait over
development of cerebellar symptoms help to narrow weeks to months (degeneration of the cerebellar ver-
the diagnostic possibilities (Table 26-1). A gradual and mis) may be due to the combined effects of alco-
progressive increase in symptoms with bilateral and sym- holism and malnutrition, particularly with deciencies
metric involvement suggests a biochemical, metabolic, of vitamins B1 and B12. Hyponatremia has also been
346
TABLE 26-1 347
ETIOLOGY OF CEREBELLAR ATAXIA

SYMMETRIC AND PROGRESSIVE SIGNS FOCAL AND IPSILATERAL CEREBELLAR SIGNS

ACUTE SUBACUTE CHRONIC ACUTE SUBACUTE CHRONIC

(HOURS (DAYS TO (MONTHS (HOURS (DAYS TO (MONTHS
TO DAYS) WEEKS) TO YEARS) TO DAYS) WEEKS) TO YEARS)

Intoxication: Intoxication: Paraneoplastic Vascular: Neoplastic: Stable gliosis

alcohol, lithium, mercury, solvents, syndrome cerebellar cerebellar secondary to
diphenylhydantoin, gasoline, glue; Anti-gliadin infarction, glioma or vascular lesion or
barbiturates cytotoxic antibody hemorrhage, metastatic tumor demyelinating
(positive history chemotherapeutic syndrome or subdural (positive for plaque (stable
and toxicology drugs Hypothyroidism hematoma neoplasm on lesion on MRI/CT
screen) Infectious: cerebellar MRI/CT) older than several
abscess (mass Demyelinating: months)
lesion on MRI/CT, multiple sclerosis
history in support (history, CSF,
of lesion) and MRI are

CHAPTER 26
consistent)
Acute viral Alcoholic-nutritional Inherited diseases AIDS-related
cerebellitis (CSF (vitamin B1 and Tabes dorsalis multifocal leuko- Congenital lesion:
supportive of B12 deciency) (tertiary syphilis) encephalopathy Chiari or Dandy-
acute viral (positive HIV test Walker malforma-
infection) and CD4+ cell tions (malformation
Postinfection Lyme disease Phenytoin toxicity count for AIDS) noted on MRI/CT)

Ataxic Disorders
syndrome

Note: CSF, cerebrospinal uid; CT, computed tomography; MRI, magnetic resonance imaging.

associated with ataxia. Paraneoplastic cerebellar ataxia considered as a readily treatable and reversible form of
is associated with a number of different tumors (and gait ataxia. Infectious diseases that can present with
autoantibodies) such as breast and ovarian cancers ataxia are meningovascular syphilis and tabes dorsalis
(anti-Yo), small-cell lung cancer (anti-PQ type voltage- due to degeneration of the posterior columns and
gated calcium channel), and Hodgkins disease spinocerebellar pathways in the spinal cord.
(anti-Tr) (Chap. 39). Another paraneoplastic syndrome
associated with myoclonus and opsoclonus occurs FOCAL ATAXIA Acute focal ataxia commonly results
with breast (anti-Ri) and lung cancers and neurob- from cerebrovascular disease, usually ischemic infarc-
lastoma. Elevated serum anti-glutamic acid decar- tion, or cerebellar hemorrhage. These lesions typically
boxylase (GAD) antibodies have been associated produce cerebellar symptoms ipsilateral to the injured
with a progressive ataxic syndrome affecting speech cerebellum and may be associated with an impaired
and gait. For all of these paraneoplastic ataxias, the level of consciousness due to brainstem compression
neurologic syndrome may be the presenting symp- and increased intracranial pressure; ipsilateral pontine
tom of the cancer. Another immune-mediated pro- signs, including sixth and seventh nerve palsies, may be
gressive ataxia is associated with anti-gliadin (and present. Focal and worsening signs of acute ataxia
anti-endomysium) antibodies and the HLA DQB1 should also prompt consideration of a posterior fossa
0201 haplotype; in some affected patients, biopsy of subdural hematoma, bacterial abscess, or primary or
the small intestine reveals villous atrophy consistent metastatic cerebellar tumor. CT or MRI studies will
with gluten-sensitive enteropathy. Finally, subacute reveal clinically signicant processes of this type. Many
progressive ataxia may be caused by a prion disorder, of these lesions represent true neurologic emergencies,
especially when an infectious etiology, such as trans- as sudden herniation, either rostrally through the ten-
mission from contaminated human growth hormone, torium or caudal herniation of cerebellar tonsils through
is responsible (Chap. 38). the foramen magnum, can occur and is usually devas-
Chronic symmetric gait ataxia suggests an inherited tating. Acute surgical decompression may be required
ataxia (discussed below), a metabolic disorder, or a (Chap. 22). Lymphoma or progressive multifocal
chronic infection. Hypothyroidism must always be leukoencephalopathy (PML) in a patient with AIDS
 348 may present with an acute or subacute focal cerebellar ataxins with more than ~40 glutamines are potentially
syndrome. Chronic etiologies of progressive ataxia toxic to neurons for a variety of reasons including the
include multiple sclerosis (Chap. 34) and congenital following: high levels of gene expression for the mutant
lesions such as a Chiari malformation (Chap. 30) or a polyglutamine ataxin in affected neurons; conforma-
congenital cyst of the posterior fossa (Dandy-Walker tional change of the aggregated protein to a -pleated
syndrome). structure; abnormal transport of the ataxin into the
nucleus (SCA1, MJD, SCA7); binding to other polyglut-
amine proteins, including the TATA-binding transcrip-
tion protein and the CREB-binding protein, impairing
their functions; altering the efciency of the ubiquitin-
THE INHERITED ATAXIAS proteosome system of protein turnover; and inducing
These may show autosomal dominant, autosomal reces- neuronal apoptosis. An earlier age of onset (anticipation)
sive, or maternal (mitochondrial) modes of inheritance. and more aggressive disease in subsequent generations
A genomic classication (Table 26-2) has now largely are due to further expansion of the CAG triplet repeat
superseded previous ones based on clinical expression and increased polyglutamine number in the mutant
alone. ataxin.The most common disorders are discussed below.
Although the clinical manifestations and neuropatho-
SECTION III

logic ndings of cerebellar disease dominate the clinical

picture, there may also be characteristic changes in the SCA1
basal ganglia, brainstem, spinal cord, optic nerves, retina,
SCA1 was previously referred to as olivopontocerebellar
and peripheral nerves. In large families with dominantly
atrophy, but genomic data have shown that entity repre-
inherited ataxias, many gradations are observed from
sents several different genotypes with overlapping clini-
purely cerebellar manifestations to mixed cerebellar and
Diseases of the Central Nervous System

cal features.
brainstem disorders, cerebellar and basal ganglia syn-
dromes, and spinal cord or peripheral nerve disease. Rarely,
dementia is present as well. The clinical picture may be
Symptoms and Signs
homogeneous within a family with dominantly inherited
ataxia, but sometimes most affected family members show SCA1 is characterized by the development in early or
one characteristic syndrome, while one or several mem- middle adult life of progressive cerebellar ataxia of the
bers have an entirely different phenotype. trunk and limbs, impairment of equilibrium and gait,
slowness of voluntary movements, scanning speech, nys-
tagmoid eye movements, and oscillatory tremor of the
head and trunk. Dysarthria, dysphagia, and oculomotor
AUTOSOMAL DOMINANT ATAXIAS
and facial palsies may also occur. Extrapyramidal symp-
The autosomal spinocerebellar ataxias (SCAs) include toms include rigidity, an immobile face, and parkinson-
SCA types 1 through SCA28, dentatorubropallidoluysian ian tremor.The reexes are usually normal, but knee and
atrophy (DRPLA), and episodic ataxia (EA) types 1 and ankle jerks may be lost, and extensor plantar responses
2 (Table 26-2). SCA1, SCA2, SCA3 [Machado-Joseph may occur. Dementia may be noted but is usually mild.
disease (MJD)], SCA6, SCA7, and SCA17 are caused by Impairment of sphincter function is common, with uri-
CAG triplet repeat expansions in different genes. SCA8 nary and sometimes fecal incontinence. Cerebellar and
is due to an untranslated CTG repeat expansion, SCA12 brainstem atrophy are evident on MRI (Fig. 26-1).
is linked to an untranslated CAG repeat, and SCA10 is Marked shrinkage of the ventral half of the pons, dis-
caused by an untranslated pentanucleotide repeat. The appearance of the olivary eminence on the ventral sur-
clinical phenotypes of these SCAs overlap.The genotype face of the medulla, and atrophy of the cerebellum are
has become the gold standard for diagnosis and classi- evident on gross postmortem inspection of the brain.
cation. CAG encodes glutamine, and these expanded Variable loss of Purkinje cells, reduced numbers of cells
CAG triplet repeat expansions result in expanded polyg- in the molecular and granular layer, demyelination of the
lutamine proteins, termed ataxins, that produce a toxic middle cerebellar peduncle and the cerebellar hemi-
gain of function with autosomal dominant inheritance. spheres, and severe loss of cells in the pontine nuclei and
Although the phenotype is variable for any given disease olives are found on histologic examination. Degenera-
gene, a pattern of neuronal loss with gliosis is produced tive changes in the striatum, especially the putamen, and
that is relatively unique for each ataxia. Immunohisto- loss of the pigmented cells of the substantia nigra may
chemical and biochemical studies have shown cytoplas- be found in cases with extrapyramidal features. More
mic (SCA2), neuronal (SCA1, MJD, SCA7), and nucleolar widespread degeneration in the central nervous system
(SCA7) accumulation of the specic mutant polyglutamine- (CNS), including involvement of the posterior columns
containing ataxin proteins. Expanded polyglutamine and the spinocerebellar bers, is often present.
TABLE 26-2 349
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS

NAME LOCUS PHENOTYPE

SCA1 (autosomal 6p22-p23 with CAG repeats (exonic); Ataxia with ophthalmoparesis, pyramidal and
dominant type 1) leucine-rich acidic nuclear protein extrapyramidal ndings
(LANP), region-specic interaction protein
Ataxin-1
SCA2 (autosomal 12q23-q24.1 with CAG repeats (exonic) Ataxia with slow saccades and minimal pyramidal
dominant type 2) Ataxin-2 and extrapyramidal ndings
Machado-Joseph 14q24.3-q32 with CAG repeats (exonic); Ataxia with ophthalmoparesis and variable pyramidal,
disease/SCA3 codes for ubiquitin protease (inactive with extrapyramidal, and amyotrophic signs
(autosomal polyglutamine expansion); altered turnover
dominant type 3) of cellular proteins due to proteosome
dysfunction
MJDataxin-3
SCA4 (autosomal 16q22.1-ter; pleckstrin homology domain- Ataxia with normal eye movements, sensory axonal
dominant type 4) containing protein, family G, member 4; neuropathy, and pyramidal signs

CHAPTER 26
(PLEKHG4; puratrophin-1: Purkinke cell
atrophy associated protein-1, including
spectrin repeat and the guanine-nucleotide
exchange factor, GEF for Rho GTPases)
SCA5 (autosomal 11p12-q12; -III spectrin mutations; (SPTBN2); Ataxia and dysarthria
dominant type 5) stabilizes glutamate transporter EAAT4;
descendants of President Abraham Lincoln
SCA6 (autosomal 19p13.2 with CAG repeats in 1A-voltage Ataxia and dysarthria, nystagmus, mild

Ataxic Disorders
dominant type 6) dependent calcium channel gene (exonic); proprioceptive sensory loss
CACNA1A protein, P/Q type calcium
channel subunit
SCA7 (autosomal 3p14.1-p21.1 with CAG repeats (exonic); Ophthalmoparesis, visual loss, ataxia, dysarthria,
dominant type 7) Ataxin-7; subunit of GCN5, histone extensor plantar response, pigmentary retinal
acetyltransferase-containing complexes; degeneration
ataxin 7 binding protein; Cbl-associated
protein (CAP; SH3D5)
SCA8 (autosomal 13q21 with CTG repeats; noncoding; Gait ataxia, dysarthria, nystagmus, leg spasticity, and
dominant type 8) 3 untranslated region of transcribed RNA reduced vibratory sensation
SCA10 (autosomal 22q13; pentanucleotide repeat ATTCT repeat; Gait ataxia, dysarthria, nystagmus; partial complex
dominant type 10) noncoding, intron 9 and generalized motor seizures; polyneuropathy
SCA11 (autosomal 15q14-q21.3 by linkage Slowly progressive gait and extremity ataxia,
dominant type 11) dysarthria, vertical nystagmus, hyperreexia
SCA12 (autosomal 5q31-q33 by linkage; CAG repeat; protein Tremor, decreased movement, increased reexes,
dominant type 12) phosphatase 2A, regulatory subunit B, dystonia, ataxia, dysautonomia, dementia,
(PPP2R2B); protein PP2A, serine/threonine dysarthria
phosphatase
SCA13 (autosomal 19q13.3-q14.4 Ataxia, legs>arms; dysarthria, horizontal nystagmus;
dominant type 13) delayed motor development; mental developmental
delay; tendon reexes increased; MRI: cerebellar
and pontine atrophy
SCA14 (autosomal 19q-13.4; protein kinase C (PRKCG), Gait ataxia; leg>arm ataxia; dysarthria; pure ataxia
dominant type 14) missense mutations including in-frame with later onset; myoclonus; tremor of head and
deletion and a splice site mutation among extremities; increased deep tendon reexes at
others; serine/threonine kinase ankles; occasional dystonia and sensory neuropathy
SCA15 (autosomal 3p24.2-3pter Gait and extremity ataxia, dysarthria; nystagmus;
dominant type 15) MRI: superior vermis atrophy; sparing of
hemispheres and tonsils
SCA16 (autosomal 8q22.1-24.1 Pure cerebellar ataxia and head tremor, gait ataxia,
dominant type 16) and dysarthria; horizontal gazeevoked nystagmus;
MRI, cerebellar atrophy; no brainstem changes
SCA17 (autosomal 6q27; CAG expansion in the TATA-binding Gait ataxia, dementia, parkinsonism, dystonia,
dominant type 17) protein (TBP) gene chorea, seizures; hyperreexia; dysarthria and
dysphagia; MRI shows cerebral & cerebellar atrophy

(Continued)
 350 TABLE 26-2 (CONTINUED)
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS

NAME LOCUS PHENOTYPE

SCA18 (autosomal 7q22-q32 Ataxia; motor/sensory neuropathy; head tremor;

dominant type 18) dysarthria; extensor plantar responses in some
patients; sensory axonal neuropathy; EMG
denervation; MRI: cerebellar atrophy
SCA19 (autosomal 1p21-q21 Ataxia, tremor, cognitive impairment, myoclonus;
dominant type 19) MRI: atrophy of cerebellum
SCA20 (assigned) Chromosome 11 Dysarthria; gait ataxia; ocular gaze evoked saccades;
palatal tremor; dentate calcication on CT; MRI:
cerebral atrophy
SCA21 (autosomal 7p21.3-p15.1 Ataxia, dysarthria, extrapyramidal features of
dominant type 21) akinesia, rigidity, tremor, cognitive defect; reduced
deep tendon reexes; MRI, cerebellar atrophy,
normal basal ganglia and brainstem
SCA22 (autosomal 1p21-q23 Pure cerebellar ataxia; dysarthria; dysphagia;
dominant) nystagmus; MRI: cerebellar atrophy
SECTION III

SCA23 (autosomal 20p13-12.3 Gait ataxia; dysarthria; extremity ataxia; ocular

dominant) nystagmus, dysmetria; leg vibration loss; extensor
plantar responses; MRI: cerebellar atrophy
SCA25 (autosomal 2p15-p21 Ataxia, nystagmus; vibratory loss in the feet; pain
dominant) loss in some; abdominal pain; nausea and vomiting
may be prominent; absent ankle reexes; sensory
nerve action potentials are absent; MRI: cerebellar
Diseases of the Central Nervous System

atrophy, normal brainstem

SCA26 (autosomal 19p13.3 Gait ataxia; extremity ataxia; dysarthria; nystagmus;
dominant) MRI: cerebellar atrophy
SCA27 (autosomal 13q34; broblast growth factor 14 protein; Tremor extremities and head and orofacial
dominant) mutation F145S; produces reduced dyskinesia; ataxia of arms>legs, gait ataxia;
protein stability dysarthria; nystagmus; psychiatric symptoms;
cognitive defect; MRI: cerebellar atrophy
SCA28 (autosomal 18p11.22-q11.2 Extremity and gait ataxia; dysarthria; nystagmus;
dominant) ophthalmoparesis; leg hyperreexia and extensor
plantar responses; MRI: cerebellar atrophy
Dentatorubropal- 12p13.31 with CAG repeats (exonic) Ataxia, choreoathetosis, dystonia, seizures,
lidoluysian atrophy Atrophin myoclonus, dementia
(autosomal
dominant)
Friedreichs ataxia 9q13-q21.1 with intronic GAA repeats, in Ataxia, areexia, extensor plantar responses, position
(autosomal intron at end of exon 1 sense decits, cardiomyopathy, diabetes mellitus,
recessive) Frataxin defective; abnormal regulation of scoliosis, foot deformities; optic atrophy; late onset
mitochondrial iron metabolism; iron form, as late as 50 years with preserved deep
accumulates in mitochondria in yeast mutants tendon reexes, slower progression, reduced
skeletal deformities, associated with an intermediate
number of GAA repeats and missense mutations in
one allele of frataxin
Friedreichs ataxia 8q13.1-q13.3 (-TTP deciency) Same as phenotype that maps to 9q but associated
(autosomal with vitamin E deciency
recessive)
Sensory ataxic 15q25; mutations in DNA polymerase-gamma Young-adult onset ataxia, sensory neuropathy,
neuropathy and (POLG) gene that leads to mtDNA deletions ophthalmoparesis, hearing loss, gastric symptoms;
ophthalmoparesis a variant of progressive external ophthalmoplegia;
(SANDO) with MRI: cerebellar and thalamic abnormalities; mildly
dysarthria (auto- increased lactate and creatine kinase
somal recessive)
Von Hippel-Lindau 3p26-p25 Cerebellar hemangioblastoma; pheochromocytoma
syndrome (auto-
somal dominant)
Baltic myoclonus 21q22.3; cystatin B; extra repeats of 12 base Myoclonus epilepsy; late onset ataxia; responds to
(Unverricht-Lund- pair tandem repeats valproic acid, Clonazepam; phenobarbital
borg recessive)
TABLE 26-2 (CONTINUED) 351
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS

NAME LOCUS PHENOTYPE

Marinesco-Sjogren 5q31; SIL 1 protein, nucleotide exchange factor Ataxia, dysarthria; nystagmus; retarded motor and
syndrome for the heat-shock protein 70 (HSP70); mental maturation; rhabdomyolysis after viral
(recessive) chaperone HSPA5; homozygous 4-nucleotide illness; weakness; hypotonia; areexia; cataracts
duplication in exon 6; also compound in childhood; short stature; kyphoscoliosis;
heterozygote contractures; hypogonadism
Autosomal recessive Chromosome 13q12; SACS gene; loss of Childhood onset of ataxia, spasticity, dysarthria,
spastic ataxia of Sacsin peptide activity distal muscle wasting, foot deformity, retinal
Charlevoix- striations, mitral valve prolapse
Saguenay(ARSACS)
Kearns-Sayre mtDNA deletion and duplication mutations Ptosis, ophthalmoplegia, pigmentary retinal
syndrome degeneration, cardiomyopathy, diabetes mellitus,
(sporadic) deafness, heart block, increased CSF protein, ataxia
Myoclonic epilepsy Mutation in mtDNA of the tRNAlys at 8344; Myoclonic epilepsy, ragged red ber myopathy,
and ragged red also mutation at 8356 ataxia

CHAPTER 26
ber syndrome
(MERRF) (maternal
inheritance)
Mitochondrial tRNAleu mutation at 3243; also at 3271 Headache, stroke, lactic acidosis, ataxia
encephalopathy, and 3252
lactic acidosis, and
stroke syndrome
(MELAS) (maternal

Ataxic Disorders
inheritance)
Neuropathy; ataxia; ATPase6 (Complex 5); mtDNA point Neuropathy; ataxia; retinitis pigmentosa; dementia;
retinitis mutation at 8993 seizures
pigmentosa
(NARP)
Episodic ataxia, 12p13; potassium voltage-gated channel Episodic ataxia for minutes; provoked by startle or
type 1 (EA-1) gene, KCNA1; Phe249Leu mutation; exercise; with facial and hand myokymia; cerebellar
(autosomal variable syndrome signs are not progressive; choreoathetotic
dominant) movements; responds to phenytoin
Episodic ataxia, 19p-13(CACNA1A) (allelic with SCA6) Episodic ataxia for days; provoked by stress, fatigue;
type 2 (EA-2) (1A-voltagedependent calcium channel with down-gaze nystagmus; nystagmus; vertigo;
(autosomal subunit); point mutations or small vomiting; headache; cerebellar atrophy results;
dominant) deletions; allelic with SCA6 and progressive cerebellar signs; responds to
familial hemiplegic migraine acetazolamide
Episodic ataxia, 1q42 Episodic ataxia; 1 min. to over 6 hrs.; induced by
type 3 (autosomal movement; vertigo and tinnitus; headache;
dominant) responds to acetazolamide
Episodic ataxia, Not mapped Episodic ataxia; vertigo; diplopia; ocular slow pursuit
type 4 (autosomal defect; no response to acetazolamide
dominant)
Episodic ataxia, 2q22-q23; CACNB44 protein Episodic ataxia; hours to weeks; seizures
type 5 (autosomal
dominant)
Episodic ataxia, 5p13; SLC1A3; glutamate transporter in Episodic ataxia; seizures; cognitive impairment;
type 6 astrocytes under 24 h
Episodic ataxia, 19q13 Episodic ataxia; vertigo, weakness; less than 24 h
type 7 (autosomal
dominant)
Episodic ataxia with SLC1A3; 5p13; EAAT1 protein; missense Ataxia, duration 24 days; episodic hypotonia;
seizures, migraine, mutations; glial glutamate transporter delayed motor milestones; seizures; migraine;
and alternating (GLAST); 1047 C to G; proline to arginine alternating hemiplegia; mild truncal ataxia; coma;
hemiplegia febrile illness as a trigger; MRI: cerebellar atrophy
(autosomal
dominant)

(Continued)
 352 TABLE 26-2 (CONTINUED)
CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS

NAME LOCUS PHENOTYPE

Fragile X tremor/ Xq27.3; CGG premutation expansion in FMR1 Late onset ataxia with tremor, cognitive impairment,
ataxia syndrome gene; expansions of 55200 repeats in occasional parkinsonism; males typically affected,
(FXTAS) X-linked 5 UTR of the FMR-1 mRNA; presumed although affected females also reported; syndrome
dominant dominant toxic RNA effect is of high concern if affected male has grandson
with mental retardation; MRI shows increased T2
signal in middle cerebellar peduncles, cerebellar
atrophy and occasional widespread brain atrophy
Ataxia telangiectasia 11q22-23; ATM gene for regulation of cell Telangiectasia, ataxia, dysarthria, pulmonary
(autosomal cycle; mitogenic signal transduction and infections, neoplasms of lymphatic system; IgA and
recessive) meiotic recombination IgG deciencies; diabetes mellitus, breast cancer
Early onset cerebellar 13q11-12 Ataxia; neuropathy; preserved deep tendon reexes;
ataxia with retained impaired cognitive and visuospatial functions; MRI:
deep tendon reexes cerebellar atrophy
(autosomal
recessive)
SECTION III

Ataxia with 9p13; protein is member of histidine triad Ataxia; dysarthria; limb dysmetria; dystonia;
oculomotor apraxia superfamily, role in DNA repair oculomotor apraxia; optic atrophy; motor
(AOA1) (autosomal neuropathy; late sensory loss (vibration)
recessive)
Ataxia with 9q34; senataxin protein, involved in RNA Gait ataxia; choreoathetosis; dystonia; oculomotor
oculomotor apraxia maturation and termination; apraxia; neuropathy, vibration loss, position sense
2 (AOA2) helicase superfamily 1 loss, and mild light touch loss; absent leg deep
Diseases of the Central Nervous System

(autosomal tendon reexes; extensor plantar response

recessive)
Cerebellar ataxia 9p13 Ataxia; hypotonia; seizures; mental retardation;
with muscle increased deep tendon reexes; extensor plantar
coenzyme Q10 responses; coenzyme Q10 levels reduced with
deciency about 25% of patients with a block in transfer of
(autosomal electrons to complex 3; may respond to
recessive) coenzyme 10
Joubert syndrome 9q34.3 Ataxia; ptosis; mental retardation; oculomotor
(autosomal apraxia; nystagmus; retinopathy; rhythmic tongue
recessive) protrusion; episodic hyperpnea or apnea; dimples
at wrists and elbows; telecanthus; micrognathia
Sideroblastic anemia Xq13; ATP-binding cassette 7 (ABCB7; ABC7) Ataxia; elevated free erythrocyte protoporphyrin
and spinocerebellar transporter; mitochondrial inner membrane; levels; ring sideroblasts in bone marrow;
ataxia (X-linked iron homeostasis; export from matrix to the heterozygous females may have mild anemia but
recessive) intermembrane space not ataxia
Infantile-onset 10q23.3-q24.1; twinkle protein (gene); Infantile ataxia, sensory neuropathy; athetosis,
spinocerebellar homozygous for Tyr508Cys missense hearing decit, reduced deep tendon reexes;
ataxia of Nikali mutations ophthalmoplegia, optic atrophy; seizures; primary
et al (autosomal hypogonadism in females
recessive)
Hypoceruloplas- Ceruloplasmin gene; 3q23-q25 (trp 858 ter) Gait ataxia and dysarthria; hyperreexia; cerebellar
minemia with ataxia atrophy by MRI; iron deposition in cerebellum, basal
and dysarthria ganglia, thalamus, and liver; onset in the 4th decade
(autosomal
recessive)
Spinocerebellar Tryosyl-DNA phosphodiesterase-1 Onset in 2nd decade; gait ataxia, dysarthria, seizures,
ataxia with (TDP-1) 14q31-q32 cerebellar vermis atrophy on MRI, dysmetria
neuropathy
(SCAN1)
(autosomal
recessive)

Note: MRI, magnetic resonance imaging; CSF, cerebrospinal uid.

 GENETIC CONSIDERATIONS 353
The gene in SCA2 families also contains CAG
repeat expansions coding for a polyglutamine-
containing protein, ataxin-2. Normal alleles con-
tain 1532 repeats; mutant alleles have 3577 repeats.

Machado-Joseph Disease/SCA3
MJD was rst described among the Portuguese and
their descendants in New England and California.
Subsequently, MJD has been found in families from
Portugal, Australia, Brazil, Canada, China, England,
France, India, Israel, Italy, Japan, Spain, Taiwan, and the
United States. In most populations, it is the most com-
mon autosomal dominant ataxia.

Symptoms and Signs

CHAPTER 26
MJD has been classied into three clinical types. In type I
FIGURE 26-1
MJD (amyotrophic lateral sclerosisparkinsonismdystonia
Sagittal MRI of the brain of a 60-year-old man with gait ataxia type), neurologic decits appear in the rst two decades
and dysarthria due to SCA1, illustrating cerebellar atrophy and involve weakness and spasticity of extremities, espe-
(arrows). cially the legs, often with dystonia of the face, neck,
trunk, and extremities. Patellar and ankle clonus are com-

Ataxic Disorders
mon, as are extensor plantar responses. The gait is slow
and stiff, with a slightly broadened base and lurching from
side to side; this gait results from spasticity, not true ataxia.
GENETIC CONSIDERATIONS
There is no truncal titubation. Pharyngeal weakness and
SCA1 encodes a gene product, called ataxin-1, spasticity cause difculty with speech and swallowing. Of
which is a novel protein of unknown function.The note is the prominence of horizontal and vertical nystag-
mutant allele has 40 CAG repeats located within mus, loss of fast saccadic eye movements, hypermetric and
the coding region, whereas alleles from unaffected indi- hypometric saccades, and impairment of upward vertical
viduals have 36 repeats. A few patients with 3840 gaze. Facial fasciculations, facial myokymia, lingual fascic-
CAG repeats have been described. There is a direct cor- ulations without atrophy, ophthalmoparesis, and ocular
relation between a larger number of repeats and a prominence are common early manifestations.
younger age of onset for SCA1. Juvenile patients have In type II MJD (ataxic type), true cerebellar decits
higher numbers of repeats, and anticipation is present in of dysarthria and gait and extremity ataxia begin in the
subsequent generations. Transgenic mice carrying SCA1 second to fourth decades along with corticospinal and
developed ataxia and Purkinje cell pathology. Nuclear extrapyramidal decits of spasticity, rigidity, and dysto-
localization, but not aggregation, of ataxin-1 appears to nia.Type II is the most common form of MJD. Ophthal-
be required for cell death initiated by the mutant protein. moparesis, upward vertical gaze decits, and facial and
lingual fasciculations are also present. Type II MJD can
be distinguished from the clinically similar disorders
SCA2 SCA1 and SCA2.
Symptoms and Signs Type III MJD (ataxic-amyotrophic type) presents in
Another clinical phenotype, SCA2, has been described the fth to the seventh decades with a pancerebellar dis-
in patients from Cuba and India. Cuban patients proba- order that includes dysarthria and gait and extremity
bly are descendants of a common ancestor, and the pop- ataxia. Distal sensory loss involving pain, touch, vibra-
ulation may be the largest homogeneous group of patients tion, and position senses and distal atrophy are promi-
with ataxia yet described.The age of onset ranges from 2 nent, indicating the presence of peripheral neuropathy.
to 65 years, and there is considerable clinical variability The deep tendon reexes are depressed to absent, and
within families. Although neuropathologic and clinical there are no corticospinal or extrapyramidal ndings.
ndings are compatible with a diagnosis of SCA1, includ- The mean age of onset of symptoms in MJD is 25 years.
ing slow saccadic eye movements, ataxia, dysarthria, Neurologic decits invariably progress and lead to death
parkinsonian rigidity, optic disk pallor, mild spasticity, from debilitation within 15 years of onset, especially in
and retinal degeneration, SCA2 is a unique form of patients with types I and II disease. Usually, patients
cerebellar degenerative disease. retain full intellectual function.
 354 The major pathologic ndings are variable loss of by various noncerebellar ndings, including ophthalmo-
neurons and glial replacement in the corpus striatum paresis and extensor plantar responses. The genetic
and severe loss of neurons in the pars compacta of the defect is an expanded CAG repeat in the SCA7 gene at
substantia nigra. A moderate loss of neurons occurs in 3p14-p21.1.The expanded repeat size in SCA7 is highly
the dentate nucleus of the cerebellum and in the red variable. Consistent with this, the severity of clinical
nucleus. Purkinje cell loss and granule cell loss occur in ndings varies from essentially asymptomatic to mild
the cerebellar cortex. Cell loss also occurs in the dentate late-onset symptoms to severe, aggressive disease in
nucleus and in the cranial nerve motor nuclei. Sparing childhood with rapid progression. Marked anticipation
of the inferior olives distinguishes MJD from other has been recorded, especially with paternal transmission.
dominantly inherited ataxias. The disease protein, ataxin-7, forms aggregates in nuclei
of affected neurons, as has also been described for SCA1
and SCA3/MJD.
GENETIC CONSIDERATIONS
The gene for MJD maps to 14q24.3-q32. Unstable SCA8
CAG repeat expansions are present in the MJD gene
coding for a polyglutamine-containing protein This form of ataxia is caused by a CTG repeat expansion
named ataxin-3, or MJD-ataxin. An earlier age of onset is in an untranslated region of a gene on chromosome 13q21.
SECTION III

associated with longer repeats. Alleles from normal indi- There is marked maternal bias in transmission, perhaps
viduals have between 12 and 37 CAG repeats, while MJD reecting contractions of the repeat during spermatogene-
alleles have 6084 CAG repeats. Polyglutamine-con- sis.The mutation is not fully penetrant. Symptoms include
taining aggregates of ataxin-3 (MJD-ataxin) have been slowly progressive dysarthria and gait ataxia beginning at
described in neuronal nuclei undergoing degeneration. ~40 years of age with a range between 20 and 65 years.
MJD ataxin codes for a ubiquitin protease, which is inac- Other features include nystagmus, leg spasticity, and
Diseases of the Central Nervous System

tive due to expanded polyglutamines. Proteosome function reduced vibratory sensation. Severely affected individuals
is impaired, resulting in altered clearance of proteins and are nonambulatory by the fourth to sixth decades. MRI
cerebellar neuronal loss. shows cerebellar atrophy. The mechanism of disease may
involve a dominant toxic effect occurring at the RNA
level, as occurs in myotonic dystrophy.
SCA6
Genomic screening for CAG repeats in other families Dentatorubropallidoluysian Atrophy
with autosomal dominant ataxia and vibratory and pro- DRPLA has a variable presentation that may include
prioceptive sensory loss have yielded another locus. Of
progressive ataxia, choreoathetosis, dystonia, seizures,
interest is that different mutations in the same gene for
myoclonus, and dementia. DRPLA is due to unstable
the 1A voltage-dependent calcium channel subunit
CAG triplet repeats in the open reading frame of a gene
(CACNLIA4; also referred to as the CACNA1A gene) at
named atrophin located on chromosome 12p12-ter.
19p13 result in different clinical disorders. CAG repeat
Larger expansions are found in patients with earlier onset.
expansions (2127 in patients; 416 triplets in normal
The number of repeats is 49 in patients with DRPLA
individuals) result in late-onset progressive ataxia with
and 26 in normal individuals. Anticipation occurs in
cerebellar degeneration. Missense mutations in this gene
successive generations, with earlier onset of disease in asso-
result in familial hemiplegic migraine. Nonsense muta-
ciation with an increasing CAG repeat number in children
tions resulting in termination of protein synthesis of the
who inherit the disease from their father. One well-char-
gene product yield hereditary paroxysmal cerebellar
acterized family in North Carolina has a phenotypic
ataxia or EA. Some patients with familial hemiplegic
variant known as the Haw River syndrome, now recog-
migraine develop progressive ataxia and also have cere-
nized to be due to the DRPLA mutation.
bellar atrophy.

Episodic Ataxia
SCA7
EA types 1 and 2 are two rare dominantly inherited
This disorder is distinguished from all other SCAs by disorders that have been mapped to chromosomes 12p
the presence of retinal pigmentary degeneration. The (a potassium channel gene) for type 1 and 19p for type 2.
visual abnormalities rst appear as blue-yellow color Patients with EA-1 have brief episodes of ataxia with
blindness and proceed to frank visual loss with macular myokymia and nystagmus that last only minutes. Startle,
degeneration. In almost all other respects, SCA7 resem- sudden change in posture, and exercise can induce episodes.
bles several other SCAs in which ataxia is accompanied Acetazolamide or anticonvulsants may be therapeutic.
Patients with EA-2 have episodes of ataxia with nystag- 355
mus that can last for hours or days. Stress, exercise, or
excessive fatigue may be precipitants. Acetazolamide may
be therapeutic and can reverse the relative intracellular
alkalosis detected by magnetic resonance spectroscopy.
Stop codon, nonsense mutations causing EA-2 have been
found in the CACNA1A gene, encoding the 1A voltage-
dependent calcium channel subunit (see SCA6, above).

AUTOSOMAL RECESSIVE ATAXIAS

Friedreichs Ataxia
This is the most common form of inherited ataxia,
comprising one-half of all hereditary ataxias. It can occur
in a classic form or in association with a genetically
determined vitamin E deciency syndrome; the two

CHAPTER 26
forms are clinically indistinguishable.

Symptoms and Signs FIGURE 26-2

Friedreichs ataxia presents before 25 years of age with Sagittal MRI of the brain and spinal cord of a patient with
progressive staggering gait, frequent falling, and tituba- Friedreichs ataxia, demonstrating spinal cord atrophy.
tion. The lower extremities are more severely involved
than the upper ones. Dysarthria occasionally is the pre-

Ataxic Disorders
senting symptom; rarely, progressive scoliosis, foot defor-
mity, nystagmus, or cardiopathy is the initial sign. large myelinated bers. Cardiac pathology consists of
The neurologic examination reveals nystagmus, loss of
myocytic hypertrophy and brosis, focal vascular bro-
fast saccadic eye movements, truncal titubation,
muscular dysplasia with subintimal or medial deposition
dysarthria, dysmetria, and ataxia of trunk and limb move-
of periodic acidSchiff (PAS)positive material, myocy-
ments. Extensor plantar responses (with normal tone in
topathy with unusual pleomorphic nuclei, and focal
trunk and extremities), absence of deep tendon reexes,
degeneration of nerves and cardiac ganglia.
and weakness (greater distally than proximally) are usu-
ally found. Loss of vibratory and proprioceptive sensation
occurs.The median age of death is 35 years.Women have
GENETIC CONSIDERATIONS
a signicantly better prognosis than men.
Cardiac involvement occurs in 90% of patients. Car- The classic form of Friedreichs ataxia has been
diomegaly, symmetric hypertrophy, murmurs, and con- mapped to 9q13-q21.1, and the mutant gene,
duction defects are reported. Moderate mental retardation frataxin, contains expanded GAA triplet repeats in
or psychiatric syndromes are present in a small percentage the rst intron. There is homozygosity for expanded
of patients. A high incidence of diabetes mellitus (20%) GAA repeats in >95% of patients. Normal persons have
is found and is associated with insulin resistance and 722 GAA repeats, and patients have 200900 GAA
pancreatic -cell dysfunction. Musculoskeletal deformi- repeats. A more varied clinical syndrome has been
ties are common and include pes cavus, pes equinovarus, described in compound heterozygotes who have one
and scoliosis. MRI of the spinal cord shows atrophy copy of the GAA expansion and the other copy a point
(Fig. 26-2). mutation in the frataxin gene. When the point mutation
The primary sites of pathology are the spinal cord, is located in the region of the gene that encodes the
dorsal root ganglion cells, and the peripheral nerves. amino-terminal half of frataxin, the phenotype is milder,
Slight atrophy of the cerebellum and cerebral gyri may often consisting of a spastic gait, retained or exaggerated
occur. Sclerosis and degeneration occur predominantly reexes, no dysarthria, and mild or absent ataxia.
in the spinocerebellar tracts, lateral corticospinal tracts, Patients with Friedreichs ataxia have undetectable or
and posterior columns. Degeneration of the glossopha- extremely low levels of frataxin mRNA, as compared with
ryngeal, vagus, hypoglossal, and deep cerebellar nuclei is carriers and unrelated individuals; thus, disease appears to
described. The cerebral cortex is histologically normal be caused by a loss of expression of the frataxin protein.
except for loss of Betz cells in the precentral gyri. The Frataxin is a mitochondrial protein involved in iron
peripheral nerves are extensively involved, with a loss of homeostasis. Mitochondrial iron accumulation due to loss
 356 of the iron transporter coded by the mutant frataxin gene with posterior column spinal cord demyelination. A
results in oxidized intramitochondrial iron. Excess oxi- poorly developed or absent thymus gland is the most
dized iron results in turn in the oxidation of cellular com- consistent defect of the lymphoid system.
ponents and irreversible cell injury.
Two forms of hereditary ataxia associated with abnor-
malities in the interactions of vitamin E (-tocopherol) GENETIC CONSIDERATIONS
with very low density lipoprotein (VLDL) have been delin- The gene for AT (the ATM gene) encodes a pro-
eated.These are abetalipoproteinemia (Bassen-Kornzweig tein that is similar to several yeast and mammalian
syndrome) and ataxia with vitamin E deciency (AVED). phosphatidylinositol-3-kinases involved in mito-
Abetalipoproteinemia is caused by mutations in the genic signal transduction, meiotic recombination, and
gene coding for the larger subunit of the microsomal cell cycle control. Defective DNA repair in AT brob-
triglyceride transfer protein (MTP). Defects in MTP lasts exposed to ultraviolet light has been demonstrated.
result in impairment of formation and secretion of The discovery of ATM will make possible the identica-
VLDL in liver. This defect results in a deciency of tion of heterozygotes who are at risk for cancer (e.g.,
delivery of vitamin E to tissues, including the central breast cancer) and permit early diagnosis.
and peripheral nervous system, as VLDL is the transport
molecule for vitamin E and other fat-soluble substitutes.
SECTION III

AVED is due to mutations in the gene for -toco- Mitochondrial Ataxias

pherol transfer protein (-TTP). These patients have an Spinocerebellar syndromes have been identied with
impaired ability to bind vitamin E into the VLDL pro- mutations in mitochondrial DNA (mtDNA). Thirty
duced and secreted by the liver, resulting in a deciency pathogenic mtDNA point mutations and 60 different
of vitamin E in peripheral tissues. Hence, either absence types of mtDNA deletions are known, several of which
of VLDL (abetalipoproteinemia) or impaired binding of cause or are associated with ataxia (Chap. 43).
Diseases of the Central Nervous System

vitamin E to VLDL (AVED) causes an ataxic syndrome.

Once again, a genotype classication has proved to be
essential in sorting out the various forms of the Friedre-
ichs disease syndrome, which may be clinically indistin-
guishable. Treatment:
ATAXIC DISORDERS
The most important goal in management of patients with
Ataxia Telangiectasia ataxia is to identify treatable disease entities. Mass lesions
must be recognized promptly and treated appropriately.
Symptoms and Signs
Paraneoplastic disorders can often be identied by the
Patients with ataxia telangiectasia (AT) present in the
clinical patterns of disease that they produce, measure-
rst decade of life with progressive telangiectatic lesions
ment of specic autoantibodies, and uncovering the
associated with decits in cerebellar function and nys-
primary cancer; these disorders are often refractory to
tagmus. The neurologic manifestations correspond to
therapy, but some patients improve following removal of
those in Friedreichs disease, which should be included
the tumor or immunotherapy (Chap. 39). Ataxia with anti-
in the differential diagnosis. Truncal and limb ataxia,
gliadin antibodies and gluten-sensitive enteropathy may
dysarthria, extensor plantar responses, myoclonic jerks,
improve with a gluten-free diet. Malabsorption syn-
areexia, and distal sensory decits may develop.There is
dromes leading to vitamin E deciency may lead to
a high incidence of recurrent pulmonary infections and
ataxia. The vitamin E deciency form of Friedreichs ataxia
neoplasms of the lymphatic and reticuloendothelial sys-
must be considered, and serum vitamin E levels mea-
tem in patients with AT.Thymic hypoplasia with cellular
sured. Vitamin E therapy is indicated for these rare
and humoral (IgA and IgG2) immunodeciencies, pre-
patients. Vitamin B1 and B12 levels in serum should be
mature aging, and endocrine disorders such as type 1
measured, and the vitamins administered to patients hav-
diabetes mellitus are described.There is an increased inci-
ing decient levels. Hypothyroidism is easily treated. The
dence of lymphomas, Hodgkins disease, acute leukemias
cerebrospinal uid should be tested for a syphilitic infec-
of the T cell type, and breast cancer.
tion in patients with progressive ataxia and other features
The most striking neuropathologic changes include
of tabes dorsalis. Similarly, antibody titers for Lyme disease
loss of Purkinje, granule, and basket cells in the cerebellar
and Legionella should be measured and appropriate antibi-
cortex as well as of neurons in the deep cerebellar nuclei.
otic therapy should be instituted in antibody-positive
The inferior olives of the medulla may also have neu-
patients. Aminoacidopathies, leukodystrophies, urea-cycle
ronal loss.There is a loss of anterior horn neurons in the
abnormalities, and mitochondrial encephalomyopathies
spinal cord and of dorsal root ganglion cells associated
may produce ataxia, and some dietary or metabolic thera- and genetic counseling, can reduce the incidence of 357
pies are available for these disorders. The deleterious these cerebellar syndromes in future generations.
effects of diphenylhydantoin and alcohol on the cerebel-
lum are well known and these exposures should be
avoided in patients with ataxia of any cause.
FURTHER READINGS
There is no proven therapy for any of the autosomal
dominant ataxias (SCA1 to -28). There is preliminary evi- BAUER PO, NUKINA N: The pathogenic mechanisms of polygluta-
mine diseases and current therapeutic strategies. J neurochem
dence that idebenone, a free-radical scavenger, can
110:1737, 2009
improve myocardial hypertrophy in patients with classic FOGEL BL, PERLMAN S: Clinical features and molecular genetics of
Friedreich ataxia; there is no current evidence, however, autosomal recessive cerebellar ataxias. Lancet Neurol 6:245,
that it improves neurologic function. Iron chelators and 2007
antioxidant drugs are potentially harmful in Friedreichs HADJIVASSILIOU M et al: Gluten ataxia. Cerebellum 7:494, 2008
patients as they may increase heart muscle injury. Aceta- ROSENBERG RN et al:The inherited ataxias, in The Molecular and Genetic
zolamide can reduce the duration of symptoms of Basis of Neurologic and Psychiatric Disease, 4th ed, RN Rosenberg et al
episodic ataxia. At present, identication of an at-risk (eds). Philadelphia, Lippincott Williams & Wilkins, Wolters Kluwer,
persons genotype, together with appropriate family 2008
http://www.neuro.wustl.edu/neuromuscular/ataxia, 2009

CHAPTER 26
Ataxic Disorders
 CHAPTER 27
AMYOTROPHIC LATERAL SCLEROSIS AND
OTHER MOTOR NEURON DISEASES
Robert H. Brown, Jr.

I Amyotrophic Lateral Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . 358

I Other Motor Neuron Diseases . . . . . . . . . . . . . . . . . . . . . . . . 363
Selected Lower Motor Neuron Disorders . . . . . . . . . . . . . . . 363
Selected Disorders of the Upper Motor Neuron . . . . . . . . . . . 364
Web Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365

primary lateral sclerosis (PLS), and familial spastic para-

AMYOTROPHIC LATERAL SCLEROSIS plegia (FSP) affect only upper motor neurons innervat-
Amyotrophic lateral sclerosis (ALS) is the most common ing the brainstem and spinal cord.
form of progressive motor neuron disease. It is a prime In each of these diseases, the affected motor neurons
example of a neurodegenerative disease and is arguably undergo shrinkage, often with accumulation of the pig-
the most devastating of the neurodegenerative disorders. mented lipid (lipofuscin) that normally develops in these
cells with advancing age. In ALS, the motor neuron
cytoskeleton is typically affected early in the illness.
Pathology Focal enlargements are frequent in proximal motor
axons; ultrastructurally, these spheroids are composed
The pathologic hallmark of motor neuron degenerative of accumulations of neurolaments and other proteins.
disorders is death of lower motor neurons (consisting of Also seen is proliferation of astroglia and microglia, the
anterior horn cells in the spinal cord and their brain- inevitable accompaniment of all degenerative processes
stem homologues innervating bulbar muscles) and in the central nervous system (CNS).
upper, or corticospinal, motor neurons (originating in The death of the peripheral motor neurons in the
layer ve of the motor cortex and descending via the brainstem and spinal cord leads to denervation and con-
pyramidal tract to synapse with lower motor neurons, sequent atrophy of the corresponding muscle bers.
either directly or indirectly via interneurons) (Chap. 10). Histochemical and electrophysiologic evidence indicates
Although at its onset ALS may involve selective loss of that in the early phases of the illness denervated muscle
function of only upper or lower motor neurons, it ulti- can be reinnervated by sprouting of nearby distal motor
mately causes progressive loss of both categories of nerve terminals, although reinnervation in this disease is
motor neurons. Indeed, in the absence of clear involve- considerably less extensive than in most other disorders
ment of both motor neuron types, the diagnosis of ALS affecting motor neurons (e.g., poliomyelitis, peripheral
is questionable. neuropathy). As denervation progresses, muscle atrophy
Other motor neuron diseases involve only particular is readily recognized in muscle biopsies and on clinical
subsets of motor neurons (Tables 27-1 and 27-2).Thus, examination. This is the basis for the term amyotrophy.
in bulbar palsy and spinal muscular atrophy (SMA; also The loss of cortical motor neurons results in thinning of
called progressive muscular atrophy), the lower motor the corticospinal tracts that travel via the internal cap-
neurons of brainstem and spinal cord, respectively, are sule (Fig. 27-1) and brainstem to the lateral and ante-
most severely involved. By contrast, pseudobulbar palsy, rior white matter columns of the spinal cord.The loss of
358
 TABLE 27-1 359
ETIOLOGY AND INVESTIGATION OF MOTOR NEURON DISORDERS

DIAGNOSTIC CATEGORY INVESTIGATIONS

Structural lesions MRI scan of head (including foramen

Parasagittal or foramen magnum tumors magnum), cervical spinea
Cervical spondylosis
Chiari malformation or syrinx
Spinal cord arteriovenous malformation
Infections CSF exam, culturea
Bacterialtetanus, Lyme Lyme antibody titera
Viralpoliomyelitis, herpes zoster Antiviral antibody titers
Retroviral myelopathy HTLV-I titers
Intoxications, physical agents
Toxinslead, aluminum, others 24-h urine for heavy metalsa
Drugsstrychnine, phenytoin Serum for lead levela
Electric shock, x-irradiation
Immunologic mechanisms Complete blood counta

CHAPTER 27
Plasma cell dyscrasias Sedimentation ratea
Autoimmune polyradiculoneuropathy Protein immunoelectrophoresisa
Motor neuropathy with conduction block Anti-GM1 antibodiesa
Paraneoplastic Anti-Hu antibody
Paracarcinomatous/lymphoma MRI scan, bone marrow biopsy
Metabolic
Hypoglycemia Fasting blood sugar (FBS), routine
chemistries including calciuma

Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

Hyperparathyroidism PTH, calcium, phosphate
Hyperthyroidism Thyroid functiona
Deciency of folate, vitamin B12, vitamin E Vitamin B12, vitamin E, folate levelsa
Malabsorption 24-h stool fat, carotene, prothrombin time
Mitochondrial dysfunction Fasting lactate, pyruvate, ammonia
Consider mtDNA analysis
Hereditary biochemical disorders
Superoxide dismutase 1 gene mutation White blood cell DNA analysis
Androgen receptor defect Abnormal CAG insert in androgen
(Kennedys disease) receptor gene
Hexosaminidase deciency Lysosomal enzyme screen
Infantile (-glucosidase deciency/ -glucosidase level
Pompes disease)
Hyperlipidemia Lipid electrophoresis
Hyperglycinuria Urine and serum amino acids
Methylcrotonylglycinuria CSF amino acids

a
Denotes studies that should be obtained in all cases.
Note: CSF, cerebrospinal uid; HTLV, human T cell lymphotropic virus; PTH, parathyroid hormone.

bers in the lateral columns and resulting brillary gliosis system, there is some selectivity of involvement. Thus,
impart a particular rmness (lateral sclerosis). A remarkable motor neurons required for ocular motility remain unaf-
feature of the disease is the selectivity of neuronal cell fected, as do the parasympathetic neurons in the sacral
death. By light microscopy, the entire sensory apparatus, spinal cord (the nucleus of Onufrowicz, or Onuf) that
the regulatory mechanisms for the control and coordina- innervate the sphincters of the bowel and bladder.
tion of movement, and the components of the brain that
are needed for cognitive processes, remain intact. How-
Clinical Manifestations
ever, immunostaining indicates that neurons bearing
ubiquitin, a marker for degeneration, are also detected in The manifestations of ALS are somewhat variable depend-
nonmotor systems. Moreover, studies of glucose metabo- ing on whether corticospinal neurons or lower motor
lism in the illness also indicate that there is neuronal dys- neurons in the brainstem and spinal cord are more promi-
function outside of the motor system. Within the motor nently involved. With lower motor neuron dysfunction
 360 TABLE 27-2 caused by denervation is associated with progressive wast-
SPORADIC MOTOR NEURON DISEASES ing and atrophy of muscles and, particularly early in the
illness, spontaneous twitching of motor units, or fascicula-
Chronic tions. In the hands, a preponderance of extensor over exor
Upper and lower motor neurons weakness is common. When the initial denervation
Amyotrophic lateral sclerosis involves bulbar rather than limb muscles, the problem at
Predominantly upper motor neurons onset is difculty with chewing, swallowing, and move-
Primary lateral sclerosis ments of the face and tongue. Early involvement of the
Predominantly lower motor neurons
Multifocal motor neuropathy with conduction block
muscles of respiration may lead to death before the disease
Motor neuropathy with paraproteinemia or cancer is far advanced elsewhere. With prominent corticospinal
Motor-predominant peripheral neuropathies involvement, there is hyperactivity of the muscle-stretch
Other reexes (tendon jerks) and, often, spastic resistance to pas-
Associated with other degenerative disorders sive movements of the affected limbs. Patients with signi-
Secondary motor neuron disorders (see Table 27-1) cant reex hyperactivity complain of muscle stiffness often
Acute out of proportion to weakness. Degeneration of the corti-
Poliomyelitis cobulbar projections innervating the brainstem results in
Herpes zoster dysarthria and exaggeration of the motor expressions of
SECTION III

Coxsackie virus emotion.The latter leads to involuntary excess in weeping

or laughing (so-called pseudobulbar affect).
Virtually any muscle group may be the rst to show
signs of disease, but, as time passes, more and more mus-
and early denervation, typically the rst evidence of the cles become involved until ultimately the disorder takes
disease is insidiously developing asymmetric weakness, on a symmetric distribution in all regions. It is charac-
Diseases of the Central Nervous System

usually rst evident distally in one of the limbs.A detailed teristic of ALS that, regardless of whether the initial dis-
history often discloses recent development of cramping ease involves upper or lower motor neurons, both will
with volitional movements, typically in the early hours of eventually be implicated. Even in the late stages of the
the morning (e.g., while stretching in bed). Weakness illness, sensory, bowel and bladder, and cognitive func-
tions are preserved. Even when there is severe brainstem
disease, ocular motility is spared until the very late stages
of the illness. Dementia is not a component of sporadic
ALS. In some families, ALS is co-inherited with fron-
totemporal dementia, characterized by early behavioral
abnormalities with prominent behavioral features indica-
tive of frontal lobe dysfunction.
A committee of the World Federation of Neurology
has established diagnostic guidelines for ALS. Essential for
the diagnosis is simultaneous upper and lower motor
neuron involvement with progressive weakness, and the
exclusion of all alternative diagnoses. The disorder is
ranked as denite ALS when three or four of the fol-
lowing are involved: bulbar, cervical, thoracic, and lum-
bosacral motor neurons.When two sites are involved, the
diagnosis is probable, and when only one site is impli-
cated, the diagnosis is possible. An exception is made
for those who have progressive upper and lower motor
neuron signs at only one site and a mutation in the gene
FIGURE 27-1 encoding superoxide dismutase (SOD1; later).
Amyotrophic lateral sclerosis. Axial T2-weighted MRI scan
through the lateral ventricles of the brain reveals abnormal Epidemiology
high signal intensity within the corticospinal tracts (arrows).
This MRI feature represents an increase in water content in The illness is relentlessly progressive, leading to death
myelin tracts undergoing Wallerian degeneration secondary from respiratory paralysis; the median survival is from
to cortical motor neuronal loss. This nding is commonly 35 years. There are very rare reports of stabilization or
present in ALS, but can also be seen in AIDS-related even regression of ALS. In most societies there is an
encephalopathy, infarction, or other disease processes that incidence of 13 per 100,000 and a prevalence of 35
produce corticospinal neuronal loss in a symmetric fashion. per 100,000. Several endemic foci of higher prevalence
exist in the western Pacic (e.g., in specic regions of gene encoding the cytosolic, copper- and zinc-binding 361
Guam or Papua New Guinea). In the United States and enzyme SOD1 as the cause of one form of FALS. How-
Europe, males are somewhat more frequently affected ever, this accounts for only 20% of inherited cases of ALS.
than females. Epidemiologic studies have incriminated Rare mutations in other genes are also clearly impli-
risk factors for this disease including exposure to pesti- cated in ALS-like diseases. Thus, a familial, dominantly
cides and insecticides, smoking and, in one report, service inherited motor disorder that in some individuals
in the military. While ALS is overwhelmingly a sporadic closely mimics the ALS phenotype arises from mutations
disorder, some 510% of cases are inherited as an auto- in a gene that encodes a vesicle-binding protein. A pre-
somal dominant trait. dominantly lower motor neuron disease with early
hoarseness due to laryngeal dysfunction has been
ascribed to mutations in the gene encoding the cellular
Familial ALS
motor protein dynactin. Mutations in senataxin, a heli-
Several forms of selective motor neuron disease are inher- case, cause an early adult-onset, slowly evolving ALS
itable (Table 27-3). Two involve both corticospinal and variant. Kennedys syndrome is an X-linked, adult-onset
lower motor neurons. The most common is familial ALS disorder that may mimic ALS, as described below.
(FALS). Apart from its inheritance as an autosomal domi- Genetic analyses are also beginning to illuminate the
nant trait, it is clinically indistinguishable from sporadic pathogenesis of some childhood-onset motor neuron

CHAPTER 27
ALS. Genetic studies have identied mutations in the diseases. For example, a slowly disabling degenerative,

TABLE 27-3
GENETIC MOTOR NEURON DISEASES

DISEASE LOCUS GENE

Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

I. Upper and lower motor neurons
(familial ALS)
A. Autosomal dominant 2p Dynactin
9q Senataxin
20q Vesicle-associated protein B
21q Superoxide dismutase
22q Neurolament heavy chain
B. Autosomal recessive 2q Alsin
C. Mitochondrial mtDNA Cytochrome c oxidase
mtDNA tRNA-isoleucine
II. Lower motor neurons
A. Spinal muscular atrophies 5q Survival motor neuron protein
B. X-linked spinobulbar muscular Xq Androgen receptor
atrophy
C. GM2 gangliosidosis
1. Sandhoff disease 5q Hexosaminidase B
2. AB variant 5q GM2 activator protein
3. Adult Tay-Sachs disease 15q Hexosaminidase A
III. Upper motor neuron (selected FSPs)
A. Autosomal dominant 2p Spastin
11q BSCL2
12q Kinesin heavy-chain KIF5A
14q Atlastin
15q NIPA1
B. Autosomal recessive 13q Spartin
15q Maspardin
16q Paraplegin
C. X-linked Xq Proteolipid protein
Xq L1-CAM
D. Adrenomyeloneuropathy Xq Adrenoleukodystrophy protein
IV. ALS-plus syndromes
Amyotrophy with behavioral 17q Tau protein
disorder and Parkinsonism

Note: ALS, amyotrophic lateral sclerosis; BSCL2, Bernadelli-Seip congenital lipodystrophy, 2B; FSP,
familial spastic paraplegia
 362 predominantly upper motor neuron disease that starts in is unknown, but it is thought to reect sublethal prior
the rst decade is caused by mutations in a gene that injury to motor neurons by poliovirus.
expresses a novel signaling molecule with properties of a Rarely, ALS develops concurrently with features
guanine-exchange factor, termed alsin. indicative of more widespread neurodegeneration. Thus,
one infrequently encounters otherwise typical ALS
Differential Diagnosis patients with a parkinsonian movement disorder or
dementia. It remains unclear whether this reects the
Because ALS is currently untreatable, it is imperative that unlikely simultaneous occurrence of two disorders or a
potentially remediable causes of motor neuron dysfunc- primary defect triggering two forms of neurodegenera-
tion be excluded (Table 27-1).This is particularly true in tion.The latter is suggested by the observation that mul-
cases that are atypical by virtue of (1) restriction to either tisystem neurodegenerative diseases may be inherited.
upper or lower motor neurons, (2) involvement of neu- For example, prominent amyotrophy has been described
rons other than motor neurons, and (3) evidence of as a dominantly inherited disorder in individuals with
motor neuronal conduction block on electrophysiologic bizarre behavior and a movement disorder suggestive of
testing. Compression of the cervical spinal cord or cervi- parkinsonism; many such cases have now been ascribed
comedullary junction from tumors in the cervical regions to mutations that alter the expression of tau protein in
or at the foramen magnum or from cervical spondylosis brain (Chap. 23). In other cases, ALS develops simultane-
SECTION III

with osteophytes projecting into the vertebral canal can ously with a striking frontotemporal dementia.These dis-
produce weakness, wasting, and fasciculations in the upper orders may be dominantly co-inherited; in some families,
limbs and spasticity in the legs, closely resembling ALS. this trait is linked to a locus on chromosome 9p,
The absence of cranial nerve involvement may be helpful although the underlying genetic defect is not established.
in differentiation, although some foramen magnum
lesions may compress the twelfth cranial (hypoglossal)
Pathogenesis
Diseases of the Central Nervous System

nerve, with resulting paralysis of the tongue. Absence of

pain or of sensory changes, normal bowel and bladder The cause of sporadic ALS is not well dened. Several
function, normal roentgenographic studies of the spine, mechanisms that impair motor neuron viability have
and normal cerebrospinal uid (CSF) all favor ALS. been elucidated in mice and rats induced to develop
Where doubt exists, MRI scans and contrast myelography motor neuron disease by SOD1 transgenes with ALS-
should be performed to visualize the cervical spinal cord. associated mutations. It is evident that excitotoxic neuro-
Another important entity in the differential diagnosis transmitters such as glutamate participate in the death of
of ALS is multifocal motor neuropathy with conduction block motor neurons in ALS. This may be a consequence of
(MMCB), discussed later. A diffuse, lower motor axonal diminished uptake of synaptic glutamate by an astroglial
neuropathy mimicking ALS sometimes evolves in associ- glutamate transporter, EAAT2. It is striking that one cel-
ation with hematopoietic disorders such as lymphoma lular defense against such excitotoxicity is the enzyme
or multiple myeloma. In this clinical setting, the pres- SOD1, which detoxies the free radical superoxide anion
ence of an M-component in serum should prompt con- (Chap. 19). Precisely why the SOD1 mutations are toxic
sideration of a bone marrow biopsy. Lyme disease may to motor nerves is not established, although it is clear the
also cause an axonal, lower motor neuropathy, although effect is not simply loss of normal scavenging of the
typically with intense proximal limb pain and a CSF superoxide anion. The mutant protein is conformation-
pleocytosis. ally unstable and prone to aberrant catalytic reactions. In
Other treatable disorders that occasionally mimic ALS turn, these features lead to aggregation of SOD1 protein,
are chronic lead poisoning and thyrotoxicosis. These dis- impairment of axonal transport, reduced production of
orders may be suggested by the patients social or occupa- ATP and other perturbations of mitochondrial function,
tional history or by unusual clinical features. When the activation of neuroinammatory cascades within the ALS
family history is positive, disorders involving the genes spinal cord, and ultimately induction of cell death via
encoding cytosolic SOD1, hexosaminidase A, or - pathways that are at least partially dependent on caspases.
glucosidase deciency must be excluded.These are readily Multiple recent studies have convincingly demonstrated
identied by appropriate laboratory tests. Benign fascicu- that nonneuronal cells importantly inuence the disease
lations are occasionally a source of concern because on course, at least in ALS transgenic mice.
inspection they resemble the fascicular twitching that
accompany motor neuron degeneration. The absence of
weakness, atrophy, or denervation phenomena on electro- Treatment:
physiologic examination usually excludes ALS or other AMYOTROPHIC LATERAL SCLEROSIS
serious neurologic disease. Patients who have recovered
No treatment arrests the underlying pathologic process
from poliomyelitis may experience a delayed deteriora-
in ALS. The drug riluzole (100 mg/d) was approved for
tion of motor neurons that presents clinically with
ALS because it produces a modest lengthening of
progressive weakness, atrophy, and fasciculations. Its cause
 survival. In one trial, the survival rate at 18 months with X-Linked Spinobulbar Muscular Atrophy 363
riluzole was similar to placebo at 15 months. The mech-
(Kennedys Disease)
anism of this effect is not known with certainty; rilu- This is an X-linked lower motor neuron disorder in which
zole may reduce excitotoxicity by diminishing gluta- progressive weakness and wasting of limb and bulbar
mate release. Riluzole is generally well tolerated; muscles begins in males in mid-adult life and is conjoined
nausea, dizziness, weight loss, and elevated liver with androgen insensitivity manifested by gynecomastia
enzymes occur occasionally. Pathophysiologic studies and reduced fertility. In addition to gynecomastia, which
of mutant SOD1related ALS in mice have disclosed may be subtle, two ndings distinguishing this disorder
diverse targets for therapy; consequently, multiple from ALS are the absence of signs of pyramidal tract dis-
therapies are presently in clinical trails in ALS. These ease (spasticity) and the presence of a subtle sensory neu-
include studies of insulin-like growth factor I (IGF-I), ropathy in some patients. The underlying molecular
which produced inconsistent results in ALS patients defect is an expanded trinucleotide repeat (-CAG-) in the
and is now undergoing further clinical trials and ceftri- rst exon of the androgen receptor gene on the X chro-
axone, which may augment astroglial glutamate trans- mosome. DNA testing is available. An inverse correlation
port and thereby be anti-excitotoxic. Interventions appears to exist between the number of -CAG- repeats
such as antisense oligonucleotides (ASO) or inhibitory and the age of onset of the disease.

CHAPTER 27
RNA that diminish expression of mutant SOD1 protein
prolong survival in transgenic ALS mice and rats. Based Adult Tay-Sachs Disease
on these data, a human trial of ASO is planned in
SOD1-mediated ALS. Several reports have described adult-onset, predomi-
In the absence of a primary therapy for ALS, a vari- nantly lower motor neuropathies arising from deciency
ety of rehabilitative aids may substantially assist ALS of the enzyme -hexosaminidase (hex A). These tend to
patients. Foot-drop splints facilitate ambulation by be distinguishable from ALS because they are very slowly

Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

obviating the need for excessive hip flexion and by progressive; dysarthria and radiographically evident cere-
preventing tripping on a floppy foot. Finger extension bellar atrophy may be prominent. In rare cases, spasticity
splints can potentiate grip. Respiratory support may be may also be present, although it is generally absent.
life-sustaining. For patients electing against long-term
ventilation by tracheostomy, positive-pressure ventila- Spinal Muscular Atrophy
tion by mouth or nose provides transient (several
weeks) relief from hypercarbia and hypoxia. Also
The SMAs are a family of selective lower motor neuron
extremely beneficial for some patients is a respiratory
diseases of early onset. Despite some phenotypic vari-
device (Cough Assist Device) that produces an artificial
ability (largely in age of onset), the defect in the major-
cough. This is highly effective in clearing airways and
ity of families with SMA maps to a locus on chromo-
preventing aspiration pneumonia. When bulbar dis-
some 5 encoding a putative motor neuron survival
ease prevents normal chewing and swallowing,
protein (SMN, for survival motor neuron) that is impor-
gastrostomy is uniformly helpful, restoring normal
tant in the formation and trafcking of RNA complexes
nutrition and hydration. Fortunately, an increasing vari-
across the nuclear membrane. Neuropathologically these
ety of speech synthesizers are now available to aug-
disorders are characterized by extensive loss of large
ment speech when there is advanced bulbar palsy.
motor neurons; muscle biopsy reveals evidence of den-
These facilitate oral communication and may be effec-
ervation atrophy. Several clinical forms exist.
tive for telephone use.
Infantile SMA (SMA I,Werdnig-Hoffmann disease) has
In contrast to ALS, several of the disorders (Tables 27-1
the earliest onset and most rapidly fatal course. In some
and 27-3) that bear some clinical resemblance to ALS
instances it is apparent even before birth, as indicated by
are treatable. For this reason, a careful search for causes
decreased fetal movements late in the third trimester.
of secondary motor neuron disease is warranted.
Although alert, aficted infants are weak and oppy
(hypotonic) and lack muscle stretch reexes. Death gen-
erally ensues within the rst year of life. Chronic childhood
SMA (SMA II) begins later in childhood and evolves
with a more slowly progressive course. Juvenile SMA
(SMA III, Kugelberg-Welander disease) manifests during
OTHER MOTOR NEURON DISEASES late childhood and runs a slow, indolent course. Unlike
most denervating diseases, in this chronic disorder weak-
SELECTED LOWER MOTOR NEURON
ness is greatest in the proximal muscles; indeed, the pat-
DISORDERS
tern of clinical weakness can suggest a primary myopathy
In these motor neuron diseases, the peripheral motor such as limb-girdle dystrophy. Electrophysiologic and
neurons are affected without evidence of involvement of muscle biopsy evidence of denervation distinguish SMA
the corticospinal motor system (Tables 27-1 to 27-3). III from the myopathic syndromes.
 364 Multifocal Motor Neuropathy with Familial Spastic Paraplegia
Conduction Block
In its pure form, FSP is usually transmitted as an autoso-
In this disorder lower motor neuron function is region- mal trait; most adult-onset cases are dominantly inher-
ally and chronically disrupted by remarkably focal blocks ited. Symptoms usually begin in the third or fourth
in conduction. Many cases have elevated serum titers of decade, presenting as progressive spastic weakness begin-
mono- and polyclonal antibodies to ganglioside GM1; it ning in the distal lower extremities; however, there are
is hypothesized that the antibodies produce selective, variants with onset so early that the differential diagnosis
focal, paranodal demyelination of motor neurons. MMCB includes cerebral palsy. FSP typically has a long survival,
is not typically associated with corticospinal signs. In presumably because respiratory function is spared. Late
contrast with ALS, MMCB may respond dramatically to in the illness there may be urinary urgency and inconti-
therapy such as IV immunoglobulin or chemotherapy; it nence and sometimes fecal incontinence; sexual function
is thus imperative that MMCB be excluded when con- tends to be preserved.
sidering a diagnosis of ALS. In pure forms of FSP, the spastic leg weakness is often
accompanied by posterior column sensory loss and dis-
turbance of bowel and bladder function. Some family
Other Forms of Lower Motor members may have spasticity without clinical symptoms.
Neuron Disease
SECTION III

By contrast, particularly when recessively inherited, FSP

In individual families, other syndromes characterized by may have complex or complicated forms in which altered
selective lower motor neuron dysfunction in an SMA- corticospinal and dorsal column function is accompanied
like pattern have been described.There are rare X-linked by signicant involvement of other regions of the nervous
and autosomal dominant forms of apparent SMA. There system, including amyotrophy, mental retardation, optic
is an ALS variant of juvenile onset, the Fazio-Londe syn- atrophy, and sensory neuropathy.
drome, that involves mainly the musculature innervated Neuropathologically, in FSP there is degeneration of
Diseases of the Central Nervous System

by the brainstem. A component of lower motor neuron the corticospinal tracts, which appear nearly normal in
dysfunction is also found in degenerative disorders such the brainstem but show increasing atrophy at more cau-
as Machado-Joseph disease and the related olivoponto- dal levels in the spinal cord; in effect, the pathologic pic-
cerebellar degenerations (Chap. 26). ture is of a dying-back or distal axonopathy of long
neuronal bers within the CNS.
Defects at numerous loci underlie both dominantly
SELECTED DISORDERS OF THE UPPER and recessively inherited forms of FSP (Table 27-3).
MOTOR NEURON Eleven FSP genes have now been identied. The gene
most commonly implicated in dominantly inherited
Primary Lateral Sclerosis
FSP is spastin, which encodes a microtubule interacting
This exceedingly rare disorder arises sporadically in protein. The most common childhood-onset dominant
adults in mid- to late life. Clinically PLS is characterized form arises from mutations in the atlastin gene. A kinesin
by progressive spastic weakness of the limbs, preceded or heavy-chain protein implicated in microtubule motor
followed by spastic dysarthria and dysphagia, indicating function was found to be defective in a family with
combined involvement of the corticospinal and corti- dominantly inherited FSP of variable onset age.
cobulbar tracts. Fasciculations, amyotrophy, and sensory An infantile-onset form of X-linked, recessive FSP
changes are absent; neither electromyography nor muscle arises from mutations in the gene for myelin proteolipid
biopsy shows denervation. On neuropathologic exami- protein (Chap. 19). This is an example of rather striking
nation there is selective loss of the large pyramidal cells allelic variation, as most other mutations in the same
in the precentral gyrus and degeneration of the corti- gene cause not FSP but Pelizaeus-Merzbacher disease, a
cospinal and corticobulbar projections. The peripheral widespread disorder of CNS myelin. Another recessive
motor neurons and other neuronal systems are spared. variant is caused by defects in the paraplegin gene. Para-
The course of PLS is variable; while long-term survival plegin has homology to metalloproteases that are impor-
is documented, the course may be as aggressive as in tant in mitochondrial function in yeast.
ALS, with ~3-year survival from onset to death. Early in
its course, PLS raises the question of multiple sclerosis or
WEB SITES
other demyelinating diseases such as adrenoleukodystro-
phy as diagnostic considerations (Chap. 34). A myelopa- Several web sites provide valuable information on ALS
thy suggestive of PLS is infrequently seen with infection including those offered by the Muscular Dystrophy
with the retrovirus human T cell lymphotropic virus Association (www.mdausa.org), the Amyotrophic Lateral
(HTLV-I) (Chap. 30).The clinical course and laboratory Sclerosis Association (www.alsa.org), and the World Fed-
testing will distinguish these possibilities. eration of Neurology and the Neuromuscular Unit at
Washington University in St. Louis (www.neuro.wustl. edu/ management, and cognitive/behavioral impairment (an evidence- 365
neuromuscular). based review): report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 73:1227, 2009
_________ et al: Practice parameter update: The care of the patient
FURTHER READINGS
with amyotrophic lateral sclerosis: drug, nutritional, and respira-
BOILLEE S et al: ALS: A disease of motor neurons and their nonneu- tory therapies (an evidence-based review): report of the Quality
ronal neighbors. Neuron 52:39, 2006 Standards Subcommittee of the American Academy of Neurol-
BROWN RH et al: Amyotrophic Lateral Sclerosis, 2d ed. London, ogy. Neurology 73:1218, 2009
Informa Healthcare, 2006 PASINELLI P, BROWN RH: Molecular biology of amyotrophic lateral
BRUIJN LI, CUDKOWICZ M: Therapeutic targets for amyotrophic lat- sclerosis: Insights from genetics. Nat Rev Neurosci 7:710, 2006
eral sclerosis: Current treatments and prospects for more effective PHUKAN J, HARDIMAN O: The management of amyotrophic lateral
therapies. Expert Rev Neurother 6:417, 2006 sclerosis. J Neurol 256:176, 2009
DIGIORGIO et al: Non-cell autonomous effect of glia on motor neu- RALPH GS et al: Silencing mutant SOD1 using RNAi protects
rons in an embryonic stem cell-based ALS model. Nat Neurosci against neurodegeneration and extends survival in an ALS
10:608, 2007 model. Nat Med 11:429, 2005
GALLO V et al: Smoking and risk for amyotrophic lateral sclerosis: SALINAS S et al: Hereditary spastic paraplegia: clinical features and
Analysis of the EPIC cohort.Ann Neurol 65:378, 2009 pathogenetic mechanisms. Lancet Neurol 7:1127, 2008
MILLER RG et al: Practice parameter update: The care of the patient VALDMANIS PN et al: Recent advances in the genetics of amy-
with amyotrophic lateral sclerosis: multidisciplinary care, symptom otrophic lateral sclerosis. Curr Neurol Neurosci Rep 9:198, 2009

CHAPTER 27
Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases
 CHAPTER 28
DISORDERS OF THE AUTONOMIC
NERVOUS SYSTEM
Phillip A. Low I John W. Engstrom

I Anatomic Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 Pure Autonomic Failure (PAF) . . . . . . . . . . . . . . . . . . . . . . . . 373

I Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 Postural Orthostatic Tachycardia Syndrome (POTS) . . . . . . . 373
Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 Inherited Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Symptoms of Autonomic Dysfunction . . . . . . . . . . . . . . . . . . 367 Primary Hyperhidrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
I Specic Syndromes of ANS Dysfunction . . . . . . . . . . . . . . . . 371 Acute Autonomic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . 374
Multiple System Atrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 Reex Sympathetic Dystrophy and Causalgia . . . . . . . . . . . . 375
Peripheral Nerve and Neuromuscular Junction Disorders . . . 372 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

The autonomic nervous system (ANS) innervates the postganglionic autonomic nerves that innervate organs
entire neuraxis and permeates all organ systems. It regu- and tissues throughout the body. Responses to sympathetic
lates blood pressure (BP), heart rate, sleep, and bladder and parasympathetic stimulation are frequently antagonistic
and bowel function. It operates automatically; its full (Table 28-1), reecting highly coordinated interactions
importance becomes recognized only when ANS func- within the CNS; the resultant changes in parasympathetic
tion is compromised, resulting in dysautonomia. Hypo- and sympathetic activity provide more precise control of
thalamic disorders that cause disturbances in homeostasis autonomic responses than could be achieved by the mod-
are discussed in Chap. 33. ulation of a single system.
Acetylcholine (ACh) is the preganglionic neurotrans-
mitter for both divisions of the ANS as well as the post-
ANATOMIC ORGANIZATION ganglionic neurotransmitter of the parasympathetic
neurons. Norepinephrine (NE) is the neurotransmitter of
The activity of the ANS is regulated by central neurons the postganglionic sympathetic neurons, except for cholin-
responsive to diverse afferent inputs. After central inte- ergic neurons innervating the eccrine sweat glands.
gration of afferent information, autonomic outow is
adjusted to permit the functioning of the major organ
systems in accordance with the needs of the organism as CLINICAL EVALUATION
a whole. Connections between the cerebral cortex and
CLASSIFICATION
the autonomic centers in the brainstem coordinate
autonomic outow with higher mental functions. Disorders of the ANS may result from pathology of
The preganglionic neurons of the parasympathetic either the CNS or the peripheral nervous system (PNS)
nervous system leave the central nervous system (CNS) in (Table 28-2). Signs and symptoms may result from
the third, seventh, ninth, and tenth cranial nerves as well interruption of the afferent limb, CNS processing cen-
as the second and third sacral nerves, while the pregan- ters, or efferent limb of reex arcs controlling auto-
glionic neurons of the sympathetic nervous system exit nomic responses. For example, a lesion of the medulla
the spinal cord between the rst thoracic and the second produced by a posterior fossa tumor can impair BP
lumbar segments (Fig. 28-1). The postganglionic neu- responses to postural changes and result in orthostatic
rons, located in ganglia outside the CNS, give rise to the hypotension (OH). OH can also be caused by lesions of
366
Parasympathetic Sympathetic TABLE 28-1 367
FUNCTIONAL CONSEQUENCES OF NORMAL ANS
ACTIVATION
A
III SYMPATHETIC PARASYMPATHETIC
VII
IX Heart rate Increased Decreased
B X
Blood pressure Increased Mildly decreased
Bladder Increased Voiding (decreased
C
sphincter tone tone)
D H Bowel motility Decreased Increased
motility
Lung Bronchodilation Bronchoconstriction
J
E Sweat glands Sweating
T1 Pupils Dilation Constriction
2
3
Adrenal glands Catecholamine
4 Arm release
Heart
F 5 Heart Sexual function Ejaculation, Erection
6
7
orgasm

CHAPTER 28
8 Viscera Lacrimal glands Tearing
9 Parotid glands Salivation
10
11 K
12
L1
Adrenal medulla
2
(preganglionic
Bowel supply)
polyneuropathy, medical illnesses, medication use, and

Disorders of the Autonomic Nervous System

S2
family history are often important considerations. Some
G 3 syndromes do not t easily into any classication scheme.
L

SYMPTOMS OF AUTONOMIC
Leg
DYSFUNCTION
Sympathetic Clinical manifestations result from a loss of function (e.g.,
Terminal ganglion
chain
(coccygeal) impaired baroreexes leading to OH), overactivity (e.g.,
hyperhidrosis, hypertension, tachycardia), or loss of regula-
Parasympathetic system Sympathetic system tion (e.g., autonomic storms, autonomic dysreexia) of
from cranial nerves III, VII, IX, X from T1-L2
and from sacral nerves 2 and 3 Preganglionic fibers autonomic circuits. Symptoms may be widespread or
Postganglionic fibers regional in distribution. An autonomic history focuses on
A Ciliary ganglion H Superior cervical ganglion systemic functions (BP, heart rate, sleep, thermoregulation)
B Sphenopalatine J Middle cervical ganglion and and involvement of individual organ systems (pupils,
(pterygopalatine) ganglion inferior cervical (stellate) bowel, bladder, sexual function). More formal assessment
C Submandibular ganglion ganglion including T1 is possible using a standardized instrument such as the
D Otic ganglion ganglion
E Vagal ganglion cells
autonomic symptom prole. It is also important to recog-
K Coeliac and other
in the heart wall abdominal ganglia nize the modulating effects of age and gender. For
F Vagal ganglion cells in
L Lower abdominal instance, OH commonly results in lightheadedness in the
bowel wall
G Pelvic ganglia
sympathetic ganglia young, whereas cognitive slowing is more common in the
elderly. Specic symptoms of orthostatic intolerance are
FIGURE 28-1
diverse (Table 28-3). Autonomic symptoms may vary
Schematic representation of the autonomic nervous sys-
dramatically, reecting the dynamic nature of autonomic
tem. (From M Moskowitz: Clin Endocrinol Metab 6:77, 1977.)
control over homeostatic function. For example, OH
might be manifest only in the early morning, following a
the spinal cord or peripheral vasomotor nerve bers meal, or with exercise, depending upon the regional vas-
(e.g., diabetic autonomic neuropathy). The site of reex cular bed affected by dysautonomia.
interruption is usually established by the clinical context Early symptoms may be overlooked. Impotence,
in which the dysautonomia arises, combined with judi- although not specic for autonomic failure, often heralds
cious use of ANS testing and neuroimaging studies. The autonomic failure in men and may precede other symp-
presence or absence of CNS signs (pathophysiology and toms by years. A decrease in the frequency of sponta-
prognosis differ), association with sensory or motor neous early morning erections may occur months before
 368 TABLE 28-2
CLASSIFICATION OF CLINICAL AUTONOMIC DISORDERS
I. Autonomic disorders with brain involvement
A. Associated with multisystem degeneration
1. Multisystem degeneration: autonomic failure clinically prominent
a. Multiple system atrophy (MSA)
b. Parkinsons disease with autonomic failure
c. Diffuse Lewy body disease (some cases)
2. Multisystem degeneration: autonomic failure clinically not usually prominent
a. Parkinsons disease
b. Other extrapyramidal disorders (inherited spinocerebellar atrophies, progressive
supranuclear palsy, corticobasal degeneration, Machado-Joseph disease)
B. Unassociated with multisystem degeneration
1. Disorders mainly due to cerebral cortex involvement
a. Frontal cortex lesions causing urinary/bowel incontinence
b. Partial complex seizures
2. Disorders of the limbic and paralimbic circuits
a. Shapiros syndrome (agenesis of corpus callosum, hyperhidrosis, hypothermia)
b. Autonomic seizures
3. Disorders of the hypothalamus
SECTION III

a. Wernicke-Korsakoff syndrome
b. Diencephalic syndrome
c. Neuroleptic malignant syndrome
d. Serotonin syndrome
e. Fatal familial insomnia
f. Antidiuretic hormone (ADH) syndromes (diabetes insipidus, inappropriate ADH)
g. Disturbances of temperature regulation (hyperthermia, hypothermia)
h. Disturbances of sexual function
Diseases of the Central Nervous System

i. Disturbances of appetite
j. Disturbances of BP/HR and gastric function
k. Horners syndrome
4. Disorders of the brainstem and cerebellum
a. Posterior fossa tumors
b. Syringobulbia and Arnold-Chiari malformation
c. Disorders of BP control (hypertension, hypotension)
d. Cardiac arrhythmias
e. Central sleep apnea
f. Baroreex failure
g. Horners syndrome
II. Autonomic disorders with spinal cord involvement
A. Traumatic quadriplegia
B. Syringomyelia
C. Subacute combined degeneration
D. Multiple sclerosis
E. Amyotrophic lateral sclerosis
F. Tetanus
G. Stiff-man syndrome
H. Spinal cord tumors
III. Autonomic neuropathies
A. Acute/subacute autonomic neuropathies
1. Subacute autoimmune autonomic neuropathy (panautonomic neuropathy,
pandysautonomia)
a. Subacute paraneoplastic autonomic neuropathy
b. Guillain-Barr syndrome
c. Botulism
d. Porphyria
e. Drug induced autonomic neuropathies
f. Toxic autonomic neuropathies
B. Chronic peripheral autonomic neuropathies
1. Distal small ber neuropathy
2. Combined sympathetic and parasympathetic failure
a. Amyloid
b. Diabetic autonomic neuropathy
c. Autoimmune autonomic neuropathy (paraneoplastic and idiopathic)
d. Sensory neuronopathy with autonomic failure
e. Familial dysautonomia (Riley-Day syndrome)

Note: BP, blood pressure; HR, heart rate.

TABLE 28-3 TABLE 28-4 369
SYMPTOMS OF ORTHOSTATIC INTOLERANCE PREVALENCE OF ORTHOSTATIC HYPOTENSION IN
DIFFERENT DISORDERS
Lightheadedness (dizziness) 88%
Weakness or tiredness 72% DISORDER PREVALENCE
Cognitive difculty (thinking/concentrating) 47%
Blurred vision 47% Aging 1420%
Tremulousness 38% Diabetic neuropathy 10%
Vertigo 37% Other autonomic neuropathies 1050 per 100,000
Pallor 31% Multiple system atrophy 515 per 100,000
Anxiety 29% Pure autonomic failure 1030 per 100,000
Palpitations 28%
Clammy feeling 19%
Nausea 18%
patients receiving antihypertensive treatment may indicate
Source: From PA Low et al: Mayo Clin Proc 70:617,1995.
overtreatment or the onset of an autonomic disorder. The
most common causes of OH are not neurologic in origin;
these must be distinguished from the neurogenic causes

CHAPTER 28
loss of nocturnal penile tumescence and development of (Table 28-5). Neurocardiogenic and cardiac syncope are
total impotence. Bladder dysfunction may appear early in considered in Chap. 8.
men and women, particularly in those with CNS involve-
ment. Brain and spinal cord disease above the level of the
lumbar spine results rst in urinary frequency and small Approach to the Patient:
bladder volumes and eventually in incontinence (upper ORTHOSTATIC HYPOTENSION AND

Disorders of the Autonomic Nervous System

motor neuron or spastic bladder). Disease of PNS auto- OTHER ANS DISORDERS
nomic nerve bers results in large bladder volumes, uri- The rst step in the evaluation of symptomatic OH is
nary frequency, and overow incontinence (lower motor the exclusion of treatable causes. The history should
neuron accid bladder). Measurement of bladder volume include a review of medications that may affect the
(post-void residual) is a useful bedside test for distin-
guishing between upper and lower motor neuron blad-
der dysfunction in the early stages of dysautonomia.
Gastrointestinal autonomic dysfunction typically presents TABLE 28-5
as severe constipation. Diarrhea occurs occasionally (as in
NONNEUROGENIC CAUSES OF ORTHOSTATIC
diabetes mellitus) due to rapid transit of contents or unco- HYPOTENSION
ordinated small-bowel motor activity, or on an osmotic basis
from bacterial overgrowth associated with small-bowel Cardiac pump failure Venous pooling
Myocardial infarction Alcohol
stasis. Impaired glandular secretory function may cause
Myocarditis Postprandial dilation of
difculty with food intake due to decreased salivation or Constrictive pericarditis splanchnic vessel beds
eye irritation due to decreased lacrimation. Occasionally, Aortic stenosis Vigorous exercise with
temperature elevation and vasodilation can result from Tachyarrhythmias dilation of skeletal
anhidrosis because sweating is normally important for Bradyarrhythmias vessel beds
heat dissipation. Salt-losing nephropathy Heat: hot environment,
OH (also called postural hypotension) is perhaps the most Adrenal insufciency hot showers and baths,
disabling feature of autonomic dysfunction.The prevalence Diabetes insipidus fever
Venous obstruction Prolonged recumbency
of OH is relatively high, especially when OH associated
Reduced intravascular or standing
with aging and diabetes mellitus is included (Table 28-4). volume Sepsis
OH can cause a variety of symptoms, including dimming Straining or heavy lifting, Medications
or loss of vision, lightheadedness, diaphoresis, diminished urination, defecation Antihypertensives
hearing, pallor, and weakness. Syncope results when the Dehydration Diuretics
drop in BP impairs cerebral perfusion. Other manifestations Diarrhea, emesis Vasodilators: nitrates,
of impaired baroreexes are supine hypertension, a heart Hemorrhage hydralazine
Burns Alpha- and beta-blocking
rate that is fixed regardless of posture, postprandial
Metabolic agents
hypotension, and an excessively high nocturnal BP. Many Adrenocortical insufciency CNS sedatives:
patients with OH have a preceding diagnosis of hyperten- Hypoaldosteronism barbiturates, opiates
sion or have concomitant supine hypertension, reecting Pheochromocytoma Tricyclic antidepressants
the great importance of baroreexes in maintaining pos- Severe potassium depletion Phenothiazines
tural and supine normotension.The appearance of OH in
 370 TABLE 28-6
sensation (polyneuropathies). In patients without a clear
SOME DRUGS THAT AFFECT AUTONOMIC FUNCTION diagnosis initially, follow-up clinical and laboratory
SPECIFIC evaluations may reveal the underlying cause.
SYMPTOM DRUG CLASS EXAMPLES Disorders of autonomic function should be consid-
Impotence Opioids Tylenol #3
ered in patients with symptoms of altered sweating
Anabolic steroids (hyperhidrosis or hypohidrosis), gastroparesis (bloating,
Some antiarrhythmics Prazosin nausea, vomiting of old food), constipation, impotence,
Some antihypertensives Clonidine or bladder dysfunction (urinary frequency, hesitancy,
Some diuretics Benazepril or incontinence).
Some SSRIs Venlafaxine
Urinary Opioids Fentanyl AUTONOMIC TESTING Autonomic function
retention Decongestants Brompheniramine
tests (Table 28-7) are helpful when the history and
Diphenhydramine
Diaphoresis Some antihypertensives Amlodipine examination ndings are inconclusive, to detect sub-
Some SSRIs Citalopram clinical involvement, or to follow the course of an
Opioids Morphine autonomic disorder.
Hypotension Tricyclics Amitriptyline
Beta blockers Propranolol Heart Rate Variation with Deep Breathing
SECTION III

Diuretics HCTZ This is a test of parasympathetic function on cardio-

CCBs Verapamil vascular reexes, via the vagus nerve. Results are
inuenced by the subjects posture, rate and depth of
Note: SSRIs, selective serotonin reuptake inhibitors; HCTZ, hydro-
respiration [6 breaths per minute and a forced vital
chlorothiazide; CCBs, calcium channel blockers.
capacity (FVC) >1.5 L are optimal], age, medications,
and degree of hypocapnia. Interpretation of results
Diseases of the Central Nervous System

requires comparison of test data with results from

normal individuals collected under the same test con-
autonomic system (Table 28-6). The main classes of ditions. For example, the lower limit of normal heart
drugs that may cause OH are diuretics, antihyperten- rate variation with deep breathing in persons <20
sives, antidepressants, phenothiazines, ethanol, narcotics, years is >1520 beats/min, but for persons >60 years
insulin, dopamine agonists, barbiturates, and calcium it is 58 beats/min. Heart rate variation with deep
channel blocking agents. However, the precipitation breathing (respiratory sinus arrhythmia) is abolished
of OH by medications may also be the rst sign of an by atropine but is unaffected by sympathetic blockade
underlying autonomic disorder.The history may reveal (e.g., propranolol).
an underlying cause for symptoms (e.g., diabetes,
Parkinsons disease) or specic underlying mechanisms
(e.g., cardiac pump failure, reduced intravascular
volume). The relationship of symptoms to meals TABLE 28-7
(splanchnic pooling), standing on awakening in the NEURAL PATHWAYS UNDERLYING SOME
morning (intravascular volume depletion), ambient STANDARDIZED AUTONOMIC TESTS
warming (vasodilatation), or exercise (muscle arterio- TEST AUTONOMIC
lar vasodilatation) should be sought. EVALUATED PROCEDURE FUNCTION
Physical examination includes measurement of supine HRBD 6 deep breaths/min Cardiovagal function
and standing pulse and BP. OH is dened as a sustained Valsalva Expiratory pressure, Cardiovagal function
drop in systolic (20 mmHg) or diastolic (10 mmHg) ratio 40 mm Hg for 1015 s
BP within 3 min of standing. In nonneurogenic causes QSART Axon-reex test Postganglionic
of OH (such as hypovolemia), the BP drop is accom- 4 limb sites sudomotor function
panied by a compensatory increase in heart rate of >15 BPBB to VM BPBB response to VM Adrenergic function:
baroreex
beats/min. An important clinical clue that the patient
adrenergic control
has neurogenic OH is the aggravation or precipitation of vagal and
of OH by autonomic stressors (such as a meal, hot tub/ vasomotor function
hot bath, and exercise). Neurologic evaluation should HUT BPBB and heart rate Adrenergic and
include mental status (to exclude neurodegenerative response to HUT cardiovagal
disorders), cranial nerves (impaired downgaze with pro- responses to HUT
gressive supranuclear palsy; abnormal pupils with
Horners or Adies syndrome), motor tone (Parkinsons Note: HRDB, heart rate response to deep breathing; BPBB, beat-to-
disease and parkinsonian syndromes), reexes, and beat blood pressure; QSART, quantitative sudomotor axon-reex
test; VM, Valsalva maneuver; HUT, head-up tilt.
Valsalva Response This response (Table 28-7) tilt-back positions are useful to quantitate orthostatic 371
assesses the integrity of the baroreex control of heart failure of BP control. It is important to allow a 20-min
rate (parasympathetic) and BP (adrenergic). The period of supine rest before assessing changes in BP
response is obtained with the subject supine. A con- during tilting. The BP change combined with heart
stant expiratory pressure of 40 mm Hg is maintained rate monitoring can be useful for the evaluation of
for 15 s while measuring changes in heart rate and patients with suspected OH, unexplained syncope, or
beat-to-beat BP. There are four phases of BP and to detect vagally mediated syncope.
heart rate response to the Valsalva maneuver. Phases I
Tilt Table Testing for Syncope The great
and III are mechanical and related to changes in
majority of patients with syncope do not have auto-
intrathoracic and intraabdominal pressure. In early
nomic failure. Tilt-table testing can be used to make
phase II, reduced venous return results in a fall in
the diagnosis of vasovagal syncope with sensitivity,
stroke volume and BP, counteracted by a combina-
specicity, and reproducibility. A standardized proto-
tion of reex tachycardia and increased total periph-
col is used that species the tilt apparatus, angle and
eral resistance. Increased total peripheral resistance
duration of tilt, and procedure for provocation of
arrests the BP drop ~58 s after the onset of the
vasodilation (e.g., sublingual or spray nitroglycerin).
maneuver. Late phase II begins with a progressive rise
A positive nitroglycerin-stimulated test predicts recur-

CHAPTER 28
in BP toward or above baseline. Venous return and
rence of syncope. Recommendations for the perfor-
cardiac output return to normal in phase IV. Persis-
mance of tilt study for syncope have been incorporated
tent peripheral arteriolar vasoconstriction and increased
in consensus guidelines.
cardiac adrenergic tone results in a temporary BP
overshoot and phase IV bradycardia (mediated by the Pharmacologic Tests Pharmacologic assess-
baroreceptor reex). ments can help localize an autonomic defect to the
Autonomic function during the Valsalva maneuver CNS or the PNS. A useful method to evaluate the

Disorders of the Autonomic Nervous System

can be measured using beat-to-beat blood pressure or systemic adrenergic response is the measurement of
heart rate changes. The Valsalva ratio is dened as the plasma NE, rst with the patient supine and then
maximum phase II tachycardia divided by the mini- after standing for at least 5 min. Supine values are
mum phase IV bradycardia. The ratio reects cardio- reduced in postganglionic disorders (such as auto-
vagal function. nomic neuropathy or pure autonomic failure) and
may fail to increase in preganglionic or postgan-
Sudomotor Function Sweating is induced by
glionic disorders (e.g., multiple system atrophy).
release of ACh from sympathetic postganglionic
Administration of tyramine (releases NE from post-
bers. The quantitative sudomotor axon reex test
ganglionic terminals) and phenylephrine (denervation
(QSART) is a measure of regional autonomic func-
supersensitivitydirectly acting 1 agonist) is used to
tion mediated by ACh-induced sweating. A reduced
evaluate postganglionic adrenergic function. In a post-
or absent response indicates a lesion of the postgan-
ganglionic lesion, the response to tyramine is reduced
glionic sudomotor axon. For example, sweating may
and there is an excessive response to subthreshold
be reduced in the legs as a result of peripheral neu-
doses of phenylephrine. Other strategies include gan-
ropathy (e.g., diabetes) before other signs of auto-
glionic blockade with trimethaphan (greater fall in
nomic dysfunction emerge. The thermoregulatory
resulting BP with a preganglionic lesion) or adminis-
sweat test (TST) is a qualitative measure of regional
tration of arginine vasopressin (to evaluate afferent
sweat production in response to an elevation of body
central pathways).
temperature. An indicator powder placed on the
anterior surface of the body changes color with sweat
production during temperature elevation.The pattern
of color changes is a measure of regional sweat secre-
tion. Combining TST and QSART results will deter- SPECIFIC SYNDROMES OF ANS
mine the site of the lesion. A postganglionic lesion is DYSFUNCTION
present if both QSART and TST show absent sweat-
MULTIPLE SYSTEM ATROPHY
ing. In a preganglionic lesion, QSART is intact but
TST shows anhidrosis. Measurement of galvanic skin Multiple system atrophy (MSA) is an uncommon entity
responses in the limbs after an induced electrical that comprises autonomic failure (OH and/or a neuro-
potential is a simple qualitative test for detecting the genic bladder are required for diagnosis) combined with
presence or absence of sweating. either striatonigral degeneration (Shy-Drager syndrome)
or sporadic olivopontocerebellar atrophy (Chap. 26).The
Orthostatic BP Recordings Beat-to-beat BP
Parkinsonism is usually unassociated with rest tremor
measurements determined in supine, 70 tilt, and
and is not responsive to levodopa. Levodopa-induced
 372 dyskinesia is also uncommon. Autonomic function tests by autonomic involvement include botulism and
can usually differentiate MSA from Parkinsons disease; Lambert-Eaton syndrome.
the severity and distribution of autonomic failure are more
severe and generalized in MSA. Cardiac postganglionic Diabetes Mellitus
adrenergic innervation, measured as labeled metaiodoben-
zylguanidine (MIBG) uptake on single photon emission Autonomic neuropathy typically begins ~10 years after
computed tomography or uorodopamine on positron the onset of diabetes and slowly progresses. The earliest
emission tomography, is markedly impaired in the dysau- autonomic abnormalities, typically asymptomatic, consist
tonomia of Parkinsons disease but is normal in MSA. of vagal disturbances, which can be detected as reduced
MSA generally progresses relentlessly to death 710 heart rate variation with deep breathing, and loss of dis-
years after onset. Neuropathologic changes include neu- tal sudomotor function, detected by QSART. Loss of
ronal loss and gliosis in many CNS regions, including small myelinated and unmyelinated nerve bers in the
the brainstem, cerebellum, striatum, and intermediolat- splanchnic distribution, carotid sinus, and vagus nerves is
eral cell column of the thoracolumbar spinal cord. characteristic. In advanced disease, widespread enteric
Autonomic dysfunction is a common feature in neuropathy can cause profound disturbances in gut motil-
dementia with Lewy bodies (Chap. 23); the severity is ity (gastroparesis), nausea and vomiting, malnutrition,
usually less than that found in MSA or Parkinsons achlorhydria, and bowel incontinence. Other symptoms
SECTION III

disease. can include impotence, urinary incontinence, pupillary

abnormalities, and OH. Typical symptoms and signs of
hypoglycemia may fail to appear because damage to the
SPINAL CORD sympathetic innervation of the adrenal gland can result
in a lack of epinephrine release. Insulin increases ow
Spinal cord lesions from any cause may result in focal
through arteriovenous shunts and may also aggravate
autonomic decits or autonomic hyperreexia. Spinal
Diseases of the Central Nervous System

OH. Autonomic dysfunction may lengthen the QT

cord transection or hemisection may be attended by
interval, increasing the risk of sudden death due to car-
autonomic hyperreexia affecting bowel, bladder, sexual,
diac arrhythmia. Hyperglycemia appears to be a direct
temperature-regulation, or cardiovascular functions. Dan-
risk factor for autonomic involvement in diabetes. Bio-
gerous increases or decreases in body temperature may
chemical and pharmacologic studies in diabetic neu-
result from an inability to experience the sensory
ropathy are compatible with autonomic failure localized
accompaniments of heat or cold exposure below the
to the PNS.
level of the injury. Quadriparetic patients exhibit both
supine hypertension and OH after upward tilting.
Markedly increased autonomic discharge can be elicited Amyloidosis
by stimulation of the bladder, skin, or muscles; suprapu-
Autonomic neuropathy occurs in both sporadic and
bic palpation of the bladder, a distended bladder,
familial forms of amyloidosis. The AL (immunoglobulin
catheter insertion, catheter obstruction, or urinary infec-
light chain) type is associated with primary amyloidosis
tion are common and correctable precipitants.This phe-
or amyloidosis secondary to multiple myeloma. The
nomenon, termed autonomic dysreexia, affects 85% of
ATTR type, with transthyretin as the primary protein
patients with a traumatic spinal cord lesion above the
component, is responsible for the most common form
C6 level. In patients with supine hypertension, BP can
of inherited amyloidosis. Although patients usually pre-
be lowered by tilting the head upward.Vasodilator drugs
sent with a distal painful neuropathy accompanied by
may be used to treat acute elevations in BP. Clonidine is
sensory loss, autonomic insufciency can precede the
used prophylactically to reduce the hypertension result-
development of the polyneuropathy or occur in isola-
ing from bladder stimulation. Sudden, dramatic increases
tion. Diagnosis can be made by protein electrophoresis
in BP can lead to intracranial hemorrhage and death. of blood and urine, tissue biopsy (abdominal fat pad,
rectal mucosa, or sural nerve) to search for amyloid
deposits, and genetic testing for transthyretin in familial
PERIPHERAL NERVE AND NEUROMUSCULAR
cases. Treatment of familial cases with liver transplanta-
JUNCTION DISORDERS
tion can be successful. The response of primary amyloi-
Peripheral neuropathies (Chap. 40) are the most com- dosis to melphalan and stem cell transplantation has
mon cause of chronic autonomic insufciency. Neu- been mixed. Death is usually due to cardiac or renal
ropathies that affect small myelinated and unmyelinated involvement. Postmortem studies reveal amyloid deposi-
bers of the sympathetic and parasympathetic nerves tion in many organs, including two sites that contribute
commonly occur in diabetes mellitus, amyloidosis, to autonomic failure: intraneural blood vessels and auto-
chronic alcoholism, porphyria, and Guillain-Barr syn- nomic ganglia. Pathologic examination reveals a loss of
drome. Neuromuscular junction disorders accompanied unmyelinated and myelinated nerve bers.
Alcoholic Neuropathy to respond to immunotherapy. The spectrum of autoim- 373
mune autonomic neuropathy (AAN) is now broader than
Abnormalities in parasympathetic vagal and efferent sym-
originally thought; some antibody-positive cases have an
pathetic function are usually mild in individuals with alco-
insidious onset and slow progression with a pure autonomic
holic polyneuropathy. Pathologic changes can be demon-
failure (see below) phenotype. A recent report describes a
strated in the parasympathetic (vagus) and sympathetic
dramatic clinical response to repeated plasma exchange com-
bers, and in ganglia. OH is usually due to brainstem
bined with immunosuppression in a patient with long-
involvement. Impotence is a major problem, but concur-
standing AAN.
rent gonadal hormone abnormalities may obscure the
AAN can have a paraneoplastic basis (Chap. 39). The
parasympathetic component. Clinical symptoms of auto-
clinical features of the autonomic neuropathy may be
nomic failure generally appear when the polyneuropathy
indistinguishable from the nonparaneoplastic form, or a
is severe, and there is usually coexisting Wernickes
coexisting paraneoplastic syndrome, such as cerebellar
encephalopathy (Chap. 22). Autonomic involvement may
involvement or dementia, may be present (see Tables 39-2
contribute to the high mortality rates associated with
and 39-3).The neoplasm may be truly occult and possi-
alcoholism (Chap. 50).
bly suppressed by the autoantibody.

Porphyria

CHAPTER 28
Botulism
Although each of the porphyrias can cause autonomic
Botulinum toxin binds presynaptically to cholinergic
dysfunction, the condition is most extensively docu-
nerve terminals and, after uptake into the cytosol, blocks
mented in the acute intermittent type. Autonomic
ACh release. Manifestations consist of motor paralysis
symptoms include tachycardia, sweating, urinary reten-
and autonomic disturbances that include blurred vision,
tion, hypertension, or (less commonly) hypotension.
dry mouth, nausea, unreactive or sluggishly reactive
Other prominent symptoms include anxiety, abdominal

Disorders of the Autonomic Nervous System

pupils, constipation, and urinary retention.
pain, nausea, and vomiting. Abnormal autonomic func-
tion can occur both during acute attacks and during
remissions. Elevated catecholamine levels during acute PURE AUTONOMIC FAILURE (PAF)
attacks correlate with the degree of tachycardia and
This sporadic syndrome consists of postural hypoten-
hypertension that is present.
sion, impotence, bladder dysfunction, and defective
sweating.The disorder begins in the middle decades and
Guillain-Barr Syndrome occurs in women more often than men. The symptoms
(Chap. 41) BP uctuations and arrhythmias can be severe. can be disabling, but the disease does not shorten life
It is estimated that between 2 and 10% of patients with span.The clinical and pharmacologic characteristics sug-
severe Guillain-Barr syndrome suffer fatal cardiovascular gest primary involvement of postganglionic sympathetic
collapse. Gastrointestinal autonomic involvement, sphinc- neurons. There is a severe reduction in the density of
ter disturbances, abnormal sweating, and pupillary dys- neurons within sympathetic ganglia that results in low
function also occur. Demyelination has been described in supine plasma NE levels and noradrenergic supersensi-
the vagus and glossopharyngeal nerves, the sympathetic tivity. Some studies have questioned the specicity of
chain, and the white rami communicantes. Interestingly, PAF as a distinct clinical entity. Some cases are gan-
the degree of autonomic involvement appears to be inde- glionic antibodypositive and thus represent a type of
pendent of the severity of motor or sensory neuropathy. AAN. Between 10 and 15% of cases evolve into MSA.

Autoimmune Autonomic Neuropathy POSTURAL ORTHOSTATIC TACHYCARDIA

SYNDROME (POTS)
This disorder presents with the subacute development of
autonomic failure with OH, enteric neuropathy (gastro- This syndrome is characterized by symptomatic orthosta-
paresis, ileus, constipation/diarrhea), and cholinergic fail- tic intolerance (not OH) and by either an increase in heart
ure; the latter consists of loss of sweating, sicca complex, rate to >120 beats/min or an increase of 30 beats/min
and a tonic pupil. Autoantibodies against the ganglionic with standing that subsides on sitting or lying down.
ACh receptor (A3 AChR) are present in the serum of Women are affected approximately ve times more
many patients and are now considered to be diagnostic often than men, and most develop the syndrome
of this syndrome. In general, the antibody titer correlates between the ages of 15 and 50. Approximately half of
with the severity of autonomic failure. Symptoms of affected patients report an antecedent viral infection.
cholinergic failure are also associated with a high anti- Syncopal symptoms (lightheadedness, weakness, blurred
body titer. Onset of the neuropathy follows a viral infec- vision) combined with symptoms of autonomic overac-
tion in approximately half of cases. Some patients appear tivity (palpitations, tremulousness, nausea) are common.
 374 Recurrent unexplained episodes of dysautonomia and palmar hyperhidrosis.The advent of endoscopic transax-
fatigue also occur. The pathogenesis is unclear in most illary T2 sympathectomy has lowered the complication
cases; hypovolemia, venous pooling, impaired brainstem rate of the procedure. The most common postoperative
regulation, or -receptor supersensitivity may play a complication is compensatory hyperhidrosis, which
role. In one affected individual, a mutation in the NE improves spontaneously over months; other potential
transporter, which resulted in impaired NE clearance complications include recurrent hyperhidrosis (16%),
from synapses, was responsible. Some cases are due to an Horners syndrome (<2%), gustatory sweating, wound
underlying limited autonomic neuropathy. Although infection, hemothorax, and intercostal neuralgia. Local
~80% of patients improve, only one-quarter eventually injection of botulinum toxin has also been used to block
resume their usual daily activities (including exercise and cholinergic, postganglionic sympathetic bers to sweat
sports). Expansion of uid volume and postural training glands in patients with palmar hyperhidrosis. This
(see Rx: Autonomic Failure) are initial approaches to approach is limited by the need for repetitive injections
treatment. If these approaches are inadequate, then (the effect usually lasts 4 months before waning), pain
midodrine, udrocortisone, phenobarbital, beta blockers, with injection, the high cost of botulinum toxin, and the
or clonidine may be used with some success. possibility of temporary intrinsic hand muscle weakness.

INHERITED DISORDERS ACUTE AUTONOMIC SYNDROMES

SECTION III

There are ve known hereditary sensory and autonomic The physician may be confronted occasionally with an
neuropathies (HSAN IV). The most important ones are acute autonomic syndrome, either acute autonomic fail-
HSAN I and HSAN III (Riley-Day syndrome; familial ure (acute AAN syndrome) or a state of sympathetic
dysautonomia). HSAN I is dominantly inherited and often overactivity. An autonomic storm is an acute state of sus-
presents as a distal small-ber neuropathy (burning feet tained sympathetic surge that results in variable combi-
Diseases of the Central Nervous System

syndrome). The responsible gene, on chromosome 9q, is nations of alterations in blood pressure and heart rate,
designated SPTLC1. SPTLC is an important enzyme in body temperature, respiration and sweating. Causes of
the regulation of ceramide. Cells from HSAN I patients autonomic storm are brain and spinal cord injury, toxins
affected by mutation of SPTLC1 produce higher-than- and drugs, autonomic neuropathy, and chemodectomas
normal levels of glucosyl ceramide, perhaps triggering (e.g., pheochromocytoma).
apoptosis. Brain injury is most commonly a cause of autonomic
HSAN III, an autosomal recessive disorder of infants storm following severe head trauma (with diffuse axonal
and children that occurs among Ashkenazi Jews, is much injury) and in postresuscitation encephalopathy follow-
less prevalent than HSAN I. Decreased tearing, hyper- ing anoxic-ischemic brain insult. Autonomic storm can
hidrosis, reduced sensitivity to pain, areexia, absent also occur with other acute intracranial lesions such as
fungiform papillae on the tongue, and labile BP may be hemorrhage, cerebral infarction, rapidly expanding tumors,
present. Episodic abdominal crises and fever are com- subarachnoid hemorrhage, hydrocephalus, or (less com-
mon. Pathologic examination of nerves reveals a loss of monly) an acute spinal cord lesion. Lesions involving the
small myelinated and unmyelinated nerve bers. The diencephalon may be more prone to present with
defective gene, named IKBKAP, is also located on the dysautonomia, but the most consistent setting is that of
long arm of chromosome 9. Pathogenic mutations may an acute intracranial catastrophe of sufcient size and
prevent normal transcription of important molecules in rapidity to produce a massive catecholaminergic surge.
neural development. The surge can cause seizures, neurogenic pulmonary
edema, and myocardial injury. Manifestations include
fever, tachycardia, hypertension, tachypnea, hyperhidro-
PRIMARY HYPERHIDROSIS
sis, pupillary dilatation, and ushing.
This syndrome presents with excess sweating of the Drugs and toxins may also be responsible, including
palms of the hands and soles of the feet. The disorder sympathomimetics such as phenylpropanolamine, cocaine,
affects 0.61.0% of the population; the etiology is amphetamines, and tricyclic antidepressants; tetanus; and,
unclear, but there may be a genetic component. While less often, botulinum. Phenylpropanolamine, now off the
not dangerous, the condition can be socially embarrass- market, was in the past a potent cause of this syndrome.
ing (e.g., shaking hands) or disabling (e.g., inability to Cocaine, including crack, can cause a hypertensive state
write without soiling the paper). Onset of symptoms is with CNS hyperstimulation. Tricyclic overdose, such as
usually in adolescence; the condition tends to improve amitriptyline, can cause ushing, hypertension, tachycar-
with age.Topical antiperspirants are occasionally helpful. dia, fever, mydriasis, anhidrosis, and a toxic psychosis.
More useful are potent anticholinergic drugs such as Neuroleptic malignant syndrome refers to a syndrome of mus-
glycopyrrolate (12 mg po tid). T2 ganglionectomy or cle rigidity, hyperthermia, and hypertension in psychotic
sympathectomy is successful in >90% of patients with patients treated with phenothiazines.
 The hyperadrenergic state with Guillain-Barr syndrome CRPS type I (RSD) has classically been divided into 375
can produce a moderate autonomic storm. Pheochromo- three clinical phases but is now considered to be more
cytoma presents with a paroxysmal or sustained hypera- variable. Phase I consists of pain and swelling in the dis-
drenergic state, headache, hyperhidrosis, palpitations, tal extremity occurring within weeks to 3 months after
anxiety, tremulousness, and hypertension. the precipitating event. The pain is diffuse, spontaneous,
Management of autonomic storm includes ruling out and either burning, throbbing, or aching in quality. The
other causes of autonomic instability, including malignant involved extremity is warm and edematous, and the
hyperthermia, porphyria, and epilepsy. Sepsis and encephali- joints are tender. Increased sweating and hair growth
tis need to be excluded with appropriate studies. EEG develop. In phase II (36 months after onset), thin, shiny,
should be done to detect epileptiform activity; MRI of cool skin appears. After an additional 36 months (phase
the brain and spine are often necessary.The patient should III), atrophy of the skin and subcutaneous tissue plus
be managed in an intensive care unit. Management with exion contractures complete the clinical picture.
morphine sulphate (10 mg every 4 h) and labetalol The natural history of typical CRPS may be more
(100200 mg twice daily) have worked relatively well. benign than reected in the literature. A variety of sur-
Treatment may need to be maintained for several weeks. gical and medical treatments have been developed, with
conicting reports of efcacy. Clinical trials suggest that
early mobilization with physical therapy or a brief

CHAPTER 28
MISCELLANEOUS
course of glucocorticoids may be helpful for CRPS type
Other conditions associated with autonomic failure I. Other medical treatments include the use of adrener-
include infections, poisoning (organophosphates), malig- gic blockers, nonsteroidal anti-inflammatory drugs,
nancy, and aging. Disorders of the hypothalamus can calcium channel blockers, phenytoin, opioids, and calci-
affect autonomic function and produce abnormalities in tonin. Stellate ganglion blockade is a commonly used
temperature control, satiety, sexual function, and circa- invasive therapeutic technique that often provides tem-

Disorders of the Autonomic Nervous System

dian rhythms. porary pain relief, but the efcacy of repetitive blocks is
uncertain.
REFLEX SYMPATHETIC DYSTROPHY AND
CAUSALGIA
The failure to identify a primary role of the ANS in the Treatment:
pathogenesis of these disorders has resulted in a change AUTONOMIC FAILURE
of nomenclature. Complex regional pain syndrome Management of autonomic failure is aimed at specic
(CRPS) types I and II are now used in place of reex treatment of the cause and alleviation of symptoms. Of
sympathetic dystrophy (RSD) and causalgia, respectively. particular importance is the removal of drugs or amelio-
CRPS type I is a regional pain syndrome that usually ration of underlying conditions that cause or aggravate
develops after tissue trauma. Examples of associated the autonomic symptoms, especially in the elderly. For
trauma include myocardial infarction, minor shoulder or instance, OH can be caused or aggravated by angiotensin-
limb injury, and stroke. Allodynia (the perception of a converting enzyme inhibitors, calcium channel blocking
nonpainful stimulus as painful), hyperpathia (an exagger- agents, tricyclic antidepressants, levodopa, alcohol, or
ated pain response to a painful stimulus), and sponta- insulin. A summary of drugs that can cause OH by class,
neous pain occur. The symptoms are unrelated to the putative mechanism, and magnitude of the BP drop, is
severity of the initial trauma and are not conned to the given in Table 28-6.
distribution of a single peripheral nerve. CRPS type II is
PATIENT EDUCATION OH can be asymptomatic
a regional pain syndrome that develops after injury to a
or symptomatic. Neurogenic OH requires treatment, but
peripheral nerve, usually a major nerve trunk. Sponta-
only a minority of patients require pharmacologic treat-
neous pain initially develops within the territory of the
ment. All patients should be taught the mechanisms of
affected nerve but eventually may spread outside the
postural normotension (volume status, resistance and
nerve distribution.
capacitance bed, autoregulation) and the nature of
Pain is the primary clinical feature of CRPS.Vasomo-
orthostatic stressors (time of day and the inuence of
tor dysfunction, sudomotor abnormalities, or focal edema
meals, heat, standing, and exercise). Patients should
may occur alone or in combination but must be present
learn to recognize orthostatic symptoms early in their
for diagnosis. Limb pain syndromes that do not meet
evolution (especially subtle cognitive symptoms, weak-
these criteria are best classied as limb painnot other-
ness, and fatigue) and to modify activities that provoke
wise specied. In CRPS, localized sweating (increased
episodes. Other helpful measures may include keeping a
resting sweat output) and changes in blood ow may
BP log, dietary education (salt/uids), and recognizing
produce temperature differences between affected and
medications and situations to avoid. Learning physical
unaffected limbs.
 376 TABLE 28-8
include pruritus, uncomfortable piloerection, and supine
INITIAL TREATMENT OF ORTHOSTATIC hypertension. Pyridostigmine appears to improve OH
HYPOTENSION (OH) without aggravating supine hypertension by enhancing
Patient education: mechanisms and stressors of OH ganglionic transmission (maximal when orthostatic,
High-salt diet (1020 g/d) minimal supine). Fludrocortisone will reduce OH, but it
High-uid intake (2 L/D) aggravates supine hypertension. At doses between
Elevate head of bed 10 cm (4 in.) 0.1 mg/d and 0.3 mg bid orally, it enhances renal
Maintain postural stimuli
sodium conservation and increases the sensitivity of
Learn physical countermaneuvers
Compression garments arterioles to NE. Susceptible patients may develop uid
Correct anemia overload, congestive heart failure, supine hypertension,
or hypokalemia. Potassium supplements are often nec-
essary with chronic administration of udrocortisone.
Sustained elevations of supine BP >180/110 mm Hg
should be avoided.
Postprandial OH may respond to several measures.
countermaneuvers that reduce standing OH, practicing
Frequent, small, low-carbohydrate meals may diminish
postural and resistance training, and learning to manage
splanchnic shunting of blood after meals and reduce
SECTION III

worsening OH in specic situations and at specic times

postprandial OH. Prostaglandin inhibitors (ibuprofen or
are helpful measures.
indomethacin) taken with meals or midodrine (10 mg
SYMPTOMATIC TREATMENT Nonpharmaco- with the meal) can be helpful.The somatostatin analogue
logic approaches are summarized in Table 28-8. Ade- octreotide can be useful in the treatment of postprandial
quate intake of salt and uids to produce a voiding vol- syncope by inhibiting the release of gastrointestinal
ume between 1.5 and 2.5 L of urine (containing >170 peptides that have vasodilator and hypotensive effects.
Diseases of the Central Nervous System

meq of Na+) each 24 h is essential. Sleeping with the The subcutaneous dose ranges from 25 g bid to
head of the bed elevated will minimize the effects of 100200 g tid.
supine nocturnal hypertension. Prolonged recumbency The patient should be taught to self-treat transient
should be avoided when possible. Patients are advised worsening of OH. Drinking two 250-mL (8-oz) glasses of
to sit with legs dangling over the edge of the bed for water can raise standing BP 2030 mm Hg for about 2 h,
several minutes before attempting to stand in the morn- beginning ~20 min after the uid load. The patient can
ing; other postural stresses should be similarly increase intake of salt and uids (bouillon treatment),
approached in a gradual manner. Physical counterma- increase use of physical countermaneuvers, temporarily
neuvers that can reduce OH include leg-crossing, with resort to a full-body stocking (compression pressure
maintained contraction of leg muscles for 30 s. Such 3040 mm Hg), or increase the dose of midodrine.
maneuvers compress leg veins and increase systemic Supine hypertension (>180/110 mm Hg) can be self-
resistance. Compressive garments, such as compression treated by avoiding the supine position and reducing
stockings and abdominal binders, are helpful on occa- udrocortisone. A daily glass of wine, if requested by the
sion but uncomfortable for some patients. Anemia should patient, can be taken shortly before bedtime. If these
be corrected with erythropoietin, administered subcuta- simple measures are not adequate, drugs to be consid-
neously at doses of 2575 U/kg three times per week.The ered include oral hydralazine (25 mg qhs), oral procardia
hematocrit increases after 26 weeks. A weekly mainte- (10 mg qhs), or a nitroglycerin patch.
nance dose is usually necessary. The increased intravas-
cular volume that accompanies the rise in hematocrit
can exacerbate supine hypertension. FURTHER READINGS
If these measures are not sufcient, drug treatment
may be necessary. Midodrine is effective, but at higher LOW PA et al: Postural tachycardia syndrome (POTS). J Cardiovasc
Electrophysiol 20:352, 2009
doses it can aggravate supine hypertension. The drug is
_______, SINGER W: Management of neurogenic orthostatic hypoten-
a directly acting 1-agonist that does not cross the sion: an update. Lancet Neurol 7:451, 2008
blood-brain barrier. It has a duration of action of 24 h. POEWE W: Dysautonomia and cognitive dysfunction in Parkinsons
The usual dose is 510 mg orally tid, but some patients disease. Mov Disord Suppl 17:S374, 2007
respond best to a decremental dose (e.g., 15 mg on SCHROEDER C et al: Plasma exchange for primary autoimmune
awakening, 10 mg at noon, and 5 mg in the afternoon). autonomic failure. N Engl J Med 353:1585, 2005
Midodrine should not be taken after 6 P.M. Side effects VINIK AI, ZIEGLER D: Diabetic cardiovascular autonomic neuropathy.
Circulation 115:387, 2007
 CHAPTER 29
TRIGEMINAL NEURALGIA, BELLS PALSY,
AND OTHER CRANIAL NERVE DISORDERS
M. Flint Beal Stephen L. Hauser

Facial Pain or Numbness . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Other Cranial Nerve Disorders . . . . . . . . . . . . . . . . . . . . . . . . 382

Anatomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 377 Glossopharyngeal Neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . 382
Trigeminal Neuralgia (Tic Douloureux) . . . . . . . . . . . . . . . . . . 377 Dysphagia and Dysphonia . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Trigeminal Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Neck Weakness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Facial Weakness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Tongue Paralysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
Anatomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 Multiple Cranial Nerve Palsies . . . . . . . . . . . . . . . . . . . . . . . . 383
Bells Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
Other Motor Disorders of the Face . . . . . . . . . . . . . . . . . . . . 381

Symptoms and signs of cranial nerve pathology are a few seconds or a minute or two but may be so intense
common in internal medicine. They often develop in that the patient winces, hence the term tic. The parox-
the context of a widespread neurologic disturbance, and ysms, experienced as single jabs or clusters, tend to recur
in such situations cranial nerve involvement may repre- frequently, both day and night, for several weeks at a
sent the initial manifestation of the illness. In other dis- time. They may occur spontaneously or with move-
orders, involvement is largely restricted to one or several ments of affected areas evoked by speaking, chewing, or
cranial nerves; these distinctive disorders are reviewed in smiling. Another characteristic feature is the presence of
this chapter. Disorders of ocular movement are discussed trigger zones, typically on the face, lips, or tongue, that
in Chap. 17, disorders of hearing in Chap. 18, and ver- provoke attacks; patients may report that tactile stimuli
tigo and disorders of vestibular function in Chap. 9. e.g. washing the face, brushing the teeth, or exposure to
a draft of airgenerate excruciating pain. An essential
feature of trigeminal neuralgia is that objective signs of sensory
FACIAL PAIN OR NUMBNESS
loss cannot be demonstrated on examination.
ANATOMIC CONSIDERATIONS Trigeminal neuralgia is relatively common, with an
estimated annual incidence of 4.5 per 100,000 individu-
The trigeminal (fifth cranial) nerve supplies sensation als. Middle-aged and elderly persons are affected primar-
to the skin of the face and anterior half of the head ily, and ~60% of cases occur in women. Onset is typically
(Fig. 29-1). Its motor part innervates the masseter and sudden, and bouts tend to persist for weeks or months
pterygoid masticatory muscles. before remitting spontaneously. Remissions may be
long-lasting, but in most patients the disorder ultimately
TRIGEMINAL NEURALGIA recurs.
(TIC DOULOUREUX)
Clinical Manifestations Pathophysiology
Trigeminal neuralgia is characterized by excruciating Symptoms result from ectopic generation of action
paroxysms of pain in the lips, gums, cheek, or chin and, potentials in pain-sensitive afferent bers of the fth
very rarely, in the distribution of the ophthalmic divi- cranial nerve root just before it enters the lateral surface
sion of the fth nerve. The pain seldom lasts more than of the pons. Compression or other pathology in the
377
 378 produce objective signs of sensory loss in the trigeminal
alm
ic (V1) nerve distribution (trigeminal neuropathy, see below).
hth
Op

Laboratory Evaluation
An ESR is indicated if temporal arteritis is suspected. In

2)
typical cases of trigeminal neuralgia, neuroimaging studies
(V C2
ry
are usually unnecessary but may be valuable if multiple
illa

3)
ax

sclerosis is a consideration or in assessing overlying vascu-

r (V
M
lar lesions in order to plan for decompression surgery.
ula

n dib
Ma
C3

C4 Treatment:
TRIGEMINAL NEURALGIA

FIGURE 29-1 Drug therapy with carbamazepine is effective in

~5075% of patients. Carbamazepine should be started
SECTION III

The three major sensory divisions of the trigeminal nerve

consist of the ophthalmic, maxillary, and mandibular nerves. as a single daily dose of 100 mg taken with food and
increased gradually (by 100 mg daily every 12 days)
until substantial (>50%) pain relief is achieved. Most
patients require a maintenance dose of 200 mg qid.
nerve leads to demyelination of large myelinated bers Doses >1200 mg daily provide no additional benet.
that do not themselves carry pain sensation but become Dizziness, imbalance, sedation, and rare cases of agranu-
Diseases of the Central Nervous System

hyperexcitable and electrically coupled with smaller locytosis are the most important side effects of carba-
unmyelinated or poorly myelinated pain bers in close mazepine. If treatment is effective, it is usually continued
proximity; this may explain why tactile stimuli, conveyed for 1 month and then tapered as tolerated. If carba-
via the large myelinated bers, can stimulate paroxysms mazepine is not well tolerated or is ineffective, phenytoin,
of pain. Compression of the trigeminal nerve root by a 300400 mg daily, can be tried; other anticonvulsants
blood vessel, most often the superior cerebellar artery or may also be effective. Baclofen may also be administered,
on occasion a tortuous vein, is the source of trigeminal either alone or in combination with carbamazepine or
neuralgia in a substantial proportion of patients. In cases phenytoin. The initial dose is 510 mg tid, gradually
of vascular compression, age-related brain sagging and increasing as needed to 20 mg qid.
increased vascular thickness and tortuosity may explain If drug treatment fails, surgical therapy should be
the prevalence of trigeminal neuralgia in later life. offered. The most widely applied procedure creates a
heat lesion of the trigeminal (gasserian) ganglion or
Differential Diagnosis nerve, a method termed radiofrequency thermal rhizo-
tomy. This procedure produces short-term relief in >95%
Trigeminal neuralgia must be discriminated from other
of patients; however, long-term studies indicate that
causes of face and head pain (Chap. 6) and from pain
pain recurs in up to one-third of treated patients. These
arising from diseases of the jaw, teeth, or sinuses. Pain
procedures result in partial numbness of the face,
from migraine or cluster headache tends to be deep-
sometimes with unpleasant dysesthesias. Masseter (jaw)
seated and steady, unlike the supercial stabbing quality
weakness is another potential complication, especially
of trigeminal neuralgia; rarely, cluster headache is associ-
following bilateral procedures. When used for first-
ated with trigeminal neuralgia, a syndrome known as
division trigeminal neuralgia, there is also a risk of
cluster-tic. In temporal arteritis, supercial facial pain is
corneal denervation with secondary keratitis.
present but is not typically shocklike, the patient fre-
Gamma knife radiosurgery is also utilized for treat-
quently complains of myalgias and other systemic symp-
ment and results in complete pain relief in more than
toms, and an elevated erythrocyte sedimentation rate
two-thirds of patients; the response is often long-lasting.
(ESR) is usually present. When trigeminal neuralgia
Compared with thermal rhizotomy, gamma knife
develops in a young adult or is bilateral, multiple sclero-
surgery appears to be somewhat less effective but has a
sis is a key consideration, and in such cases the cause is a
lower risk of serious complications.
demyelinating plaque at the root entry zone of the fth
A third surgical treatment, microvascular decompres-
nerve in the pons; often, evidence of facial sensory loss
sion to relieve pressure on the trigeminal nerve as it
can be found on careful examination. Cases that are sec-
exits the pons, requires a suboccipital craniotomy. This
ondary to mass lesionssuch as aneurysms, neurobro-
procedure has >70% efcacy rate and a low rate of pain
mas, acoustic schwannomas, or meningiomasusually
 recurrence in responders; in a small number of cases, Rarely, an idiopathic form of trigeminal neuropathy is 379
there is perioperative damage to the eighth or seventh observed. It is characterized by numbness and paresthe-
cranial nerves or to the cerebellum. High-resolution sias, sometimes bilaterally, with loss of sensation in the
magnetic resonance angiography is useful preopera- territory of the trigeminal nerve but without weakness
tively to visualize the relationships between the fth of the jaw. Gradual recovery is the rule. Tonic spasm of
cranial nerve root and nearby blood vessels. the masticatory muscles, known as trismus, is sympto-
matic of tetanus or may occur in patients treated with
phenothiazine drugs.

TRIGEMINAL NEUROPATHY
FACIAL WEAKNESS
A variety of diseases may affect the trigeminal nerve
(Table 29-1). Most present with sensory loss on the ANATOMIC CONSIDERATIONS
face or with weakness of the jaw muscles. Deviation of (Fig. 29-2) The seventh cranial nerve supplies all the
the jaw on opening indicates weakness of the pterygoids muscles concerned with facial expression. The sensory
on the side to which the jaw deviates. Some cases are component is small (the nervus intermedius); it conveys

CHAPTER 29
due to Sjgrens syndrome or a collagen-vascular disease taste sensation from the anterior two-thirds of the
such as systemic lupus erythematosus, scleroderma, or tongue and probably cutaneous impulses from the ante-
mixed connective tissue disease. Among infectious rior wall of the external auditory canal. The motor
causes, herpes zoster and leprosy should be considered. nucleus of the seventh nerve lies anterior and lateral to
Tumors of the middle cranial fossa (meningiomas), of the abducens nucleus. After leaving the pons, the seventh
the trigeminal nerve (schwannomas), or of the base of nerve enters the internal auditory meatus with the
the skull (metastatic tumors) may cause a combination acoustic nerve.The nerve continues its course in its own

Trigeminal Neuralgia, Bells Palsy, and Other Cranial Nerve Disorders

of motor and sensory signs. Lesions in the cavernous bony channel, the facial canal, and exits from the skull
sinus can affect the rst and second divisions of the via the stylomastoid foramen. It then passes through the
trigeminal nerve, and lesions of the superior orbital s- parotid gland and subdivides to supply the facial muscles.
sure can affect the rst (ophthalmic) division; the
accompanying corneal anesthesia increases the risk of
ulceration (neurokeratitis).
Loss of sensation over the chin (mental neuropathy)
can be the only manifestation of systemic malignancy.

Superior
salivatory
nucleus Geniculate Major superficial
Motor nucleus ganglion petrosal nerve Lacrimal gland
TABLE 29-1 VI n. Trigeminal
V n. ganglion
TRIGEMINAL NERVE DISORDERS Motor nucleus
VII n. 1
Nuclear (brainstem) lesions Peripheral nerve lesions 2
Nucleus 3
Multiple sclerosis Nasopharyngeal carcinoma C
fasciculus Pterygopalatine
solitarius VII n. B
Stroke Trauma ganglion

Syringobulbia Guillain-Barr syndrome To nasal and

A palatine glands
Glioma Sjgrens syndrome
Fasciculus Chorda
Lymphoma Collagen-vascular diseases solitarius tympani
Preganglionic lesions Sarcoidosis
Lingual
Acoustic neuroma Leprosy nerve
Meningioma Drugs (stilbamidine, Submandibular
Sublingual gland
Metastasis trichloroethylene) ganglion Submandibular gland
Chronic meningitis Idiopathic trigeminal
Cavernous carotid neuropathy
aneurysm
FIGURE 29-2
Gasserian ganglion lesions
Trigeminal neuroma The facial nerve. A, B, and C denote lesions of the facial
Herpes zoster nerve at the stylomastoid foramen, distal and proximal to the
Infection (spread from geniculate ganglion, respectively. Green lines indicate the
otitis media or parasympathetic bers, red line indicates motor bers, and
mastoiditis) purple lines indicate visceral afferent bers (taste). (Adapted
from Carpenter.)
 380 A complete interruption of the facial nerve at the sty- lymphocytosis. MRI may reveal swelling and uniform
lomastoid foramen paralyzes all muscles of facial expres- enhancement of the geniculate ganglion and facial nerve
sion. The corner of the mouth droops, the creases and and, in some cases, entrapment of the swollen nerve in
skinfolds are effaced, the forehead is unfurrowed, and the the temporal bone. Approximately 80% of patients
eyelids will not close. Upon attempted closure of the lids, recover within a few weeks or months. Electromyogra-
the eye on the paralyzed side rolls upward (Bells phenom- phy may be of some prognostic value; evidence of dener-
enon).The lower lid sags and falls away from the conjunc- vation after 10 days indicates there has been axonal
tiva, permitting tears to spill over the cheek. Food col- degeneration, that there will be a long delay (3 months as
lects between the teeth and lips, and saliva may dribble a rule) before regeneration occurs, and that it may be
from the corner of the mouth. The patient complains of incomplete. The presence of incomplete paralysis in the
a heaviness or numbness in the face, but sensory loss is rst week is the most favorable prognostic sign.
rarely demonstrable and taste is intact.
If the lesion is in the middle-ear portion, taste is lost
over the anterior two-thirds of the tongue on the same Pathophysiology
side. If the nerve to the stapedius is interrupted, there is Bells palsy is associated with the presence of herpes
hyperacusis (sensitivity to loud sounds). Lesions in the simplex virus (HSV) type 1 DNA in endoneurial uid
internal auditory meatus may affect the adjacent audi- and posterior auricular muscle, suggesting that a reacti-
SECTION III

tory and vestibular nerves, causing deafness, tinnitus, or vation of this virus in the geniculate ganglion may be
dizziness. Intrapontine lesions that paralyze the face usu- responsible. However, a causal role for HSV in Bells
ally affect the abducens nucleus as well, and often the palsy is unproven. An increased incidence of Bells palsy
corticospinal and sensory tracts. was also reported among recipients of inactivated
If the peripheral facial paralysis has existed for some intranasal inuenza vaccine, and it was hypothesized
time and recovery of motor function is incomplete, a that this could have resulted from the Escherichia coli
Diseases of the Central Nervous System

continuous diffuse contraction of facial muscles may enterotoxin used as adjuvant or to reactivation of latent
appear.The palpebral ssure becomes narrowed, and the virus.
nasolabial fold deepens. Attempts to move one group of
facial muscles may result in contraction of all (associated
movements, or synkinesis). Facial spasms, initiated by Differential Diagnosis
movements of the face, may develop (hemifacial spasm).
Anomalous regeneration of seventh nerve bers may There are many other causes of acute facial palsy that
result in other troublesome phenomena. If bers origi- must be considered in the differential diagnosis of Bells
nally connected with the orbicularis oculi come to palsy. Lyme disease can cause unilateral or bilateral facial
innervate the orbicularis oris, closure of the lids may palsies; in endemic areas, 10% or more of cases of facial
cause a retraction of the mouth, or if bers originally palsy are likely due to infection with Borrelia burgdorferi.
connected with muscles of the face later innervate the The Ramsay Hunt syndrome, caused by reactivation of
lacrimal gland, anomalous tearing (crocodile tears) herpes zoster in the geniculate ganglion, consists of a
may occur with any activity of the facial muscles, such as severe facial palsy associated with a vesicular eruption in
eating. Another facial synkinesia is triggered by jaw the external auditory canal and sometimes in the phar-
opening, causing closure of the eyelids on the side of the ynx and other parts of the cranial integument; often the
facial palsy (jaw-winking). eighth cranial nerve is affected as well. Facial palsy that is
often bilateral occurs in sarcoidosis and in Guillain-Barr
syndrome (Chap. 41). Leprosy frequently involves the
BELLS PALSY facial nerve, and facial neuropathy may also occur in
diabetes mellitus, connective tissue diseases including
The most common form of facial paralysis is Bells palsy. Sjgrens syndrome, and amyloidosis.The rare Melkersson-
The annual incidence of this idiopathic disorder is ~25 per Rosenthal syndrome consists of recurrent facial paralysis;
100,000 annually, or about 1 in 60 persons in a lifetime. recurrentand eventually permanentfacial (particu-
larly labial) edema; and, less constantly, plication of the
tongue. Its cause is unknown. Acoustic neuromas fre-
Clinical Manifestations quently involve the facial nerve by local compression.
The onset of Bells palsy is fairly abrupt, maximal weak- Infarcts, demyelinating lesions of multiple sclerosis, and
ness being attained by 48 h as a general rule. Pain behind tumors are the common pontine lesions that interrupt
the ear may precede the paralysis for a day or two. Taste the facial nerve bers; other signs of brainstem involve-
sensation may be lost unilaterally, and hyperacusis may be ment are usually present.Tumors that invade the tempo-
present. In some cases there is mild cerebrospinal uid ral bone (carotid body, cholesteatoma, dermoid) may
produce a facial palsy, but the onset is insidious and the 381
course progressive. Treatment:
All these forms of nuclear or peripheral facial palsy must BELLS PALSY
be discriminated from the supranuclear type. In the latter, Symptomatic measures include (1) the use of paper
the frontalis and orbicularis oculi muscles are involved less tape to depress the upper eyelid during sleep and pre-
than those of the lower part of the face, since the upper vent corneal drying, and (2) massage of the weakened
facial muscles are innervated by corticobulbar pathways muscles. A course of glucocorticoids, given as pred-
from both motor cortices, whereas the lower facial muscles nisone 6080 mg daily during the rst 5 days and then
are innervated only by the opposite hemisphere. In tapered over the next 5 days, appears to shorten the
supranuclear lesions there may be a dissociation of emo- recovery period and modestly improve the functional
tional and voluntary facial movements and often some outcome. A recently published randomized trial found
degree of paralysis of the arm and leg, or an aphasia (in no added benet of acyclovir (400 mg ve times daily
dominant hemisphere lesions) is present. for 10 days) in comparison with prednisolone alone for
treatment of acute Bells palsy; the value of valacyclovir
(usual dose 1000 mg daily for 57 days) either alone or
Laboratory Evaluation in combination with glucocorticoids is not known.

CHAPTER 29
The diagnosis of Bells palsy can usually be made clini-
cally in patients with (1) a typical presentation, (2) no risk
factors or preexisting symptoms for other causes of facial
OTHER MOTOR DISORDERS OF THE FACE
paralysis, (3) absence of cutaneous lesions of herpes zoster
in the external ear canal, and (4) a normal neurologic Hemifacial spasm consists of painless irregular involuntary
examination with the exception of the facial nerve. Par- contractions on one side of the face. Symptoms may
ticular attention to the eighth cranial nerve, which develop as a sequela to Bells palsy but may also be due

Trigeminal Neuralgia, Bells Palsy, and Other Cranial Nerve Disorders

courses near to the facial nerve in the pontomedullary to an irritative lesion of the facial nerve (e.g., an acoustic
junction and in the temporal bone, and to other cranial neuroma, an aberrant artery that compresses the nerve,
nerves is essential. In atypical or uncertain cases, an ESR, or a basilar artery aneurysm). However, in the most com-
testing for diabetes mellitus, a Lyme titer, angiotensin- mon form of hemifacial spasm, the cause and pathology
converting enzyme and chest imaging studies for possible are unknown. Mild cases can be treated with carba-
sarcoidosis, a lumbar puncture for possible Guillain-Barr mazepine, gabapentin, or, if these drugs fail, with baclofen.
syndrome, or MRI scanning may be indicated. MRI Local injections of botulinum toxin into affected muscles
often shows swelling and enhancement of the facial nerve can relieve spasms for 34 months, and the injections can
in idiopathic Bells palsy (Fig. 29-3). be repeated. Refractory cases due to vascular compression

FIGURE 29-3
Axial and coronal T1 weighted images post-Gadolinium with without evidence of mass lesion. Although highly suggestive
fat suppression demonstrate diffuse smooth linear enhance- of Bells palsy, similar ndings may be seen with other etiolo-
ment of the left facial nerve, involving the genu, tympanic, gies such as Lyme disease, sarcoidosis, and perineural
and mastoid segments within the temporal bone (arrows), malignant spread.
 382 usually respond to surgical decompression of the facial ear because of involvement of the tympanic branch of the
nerve. Blepharospasm is an involuntary recurrent spasm of glossopharyngeal nerve. Spasms of pain may be initiated
both eyelids that usually occurs in elderly persons as an by swallowing or coughing. There is no demonstrable
isolated phenomenon or with varying degrees of spasm motor or sensory decit; the glossopharyngeal nerve sup-
of other facial muscles. Severe, persistent cases of ble- plies taste sensation to the posterior third of the tongue
pharospasm can be treated by local injection of botu- and, together with the vagus nerve, sensation to the pos-
linum toxin into the orbicularis oculi. Facial myokymia terior pharynx. Cardiac symptomsbradycardia or asys-
refers to a ne rippling activity of the facial muscles; it tole, hypotension, and faintinghave been reported.
may be caused by multiple sclerosis or follow Guillain- Medical therapy is similar to that for trigeminal neuralgia,
Barr syndrome (Chap. 41). and carbamazepine is generally the rst choice. If drug
Facial hemiatrophy occurs mainly in women and is therapy is unsuccessful, surgical proceduresincluding
characterized by a disappearance of fat in the dermal microvascular decompression if vascular compression is
and subcutaneous tissues on one side of the face. It usu- evidentor rhizotomy of glossopharyngeal and vagal
ally begins in adolescence or early adult years and is bers in the jugular bulb is frequently successful.
slowly progressive. In its advanced form, the affected side Very rarely, herpes zoster involves the glossopharyn-
of the face is gaunt, and the skin is thin, wrinkled, and geal nerve. Glossopharyngeal neuropathy in conjunction
brown. The facial hair may turn white and fall out, and with vagus and accessory nerve palsies may also occur
SECTION III

the sebaceous glands become atrophic. Bilateral involve- with a tumor or aneurysm in the posterior fossa or in
ment may occur. A limited form of systemic sclerosis the jugular foramen. Hoarseness due to vocal cord paral-
(scleroderma) may be the cause of some cases.Treatment ysis, some difculty in swallowing, deviation of the soft
is cosmetic, consisting of transplantation of skin and sub- palate to the intact side, anesthesia of the posterior wall
cutaneous fat. of the pharynx, and weakness of the upper part of the
trapezius and sternocleidomastoid muscles make up the
Diseases of the Central Nervous System

jugular foramen syndrome (Table 29-2).

OTHER CRANIAL NERVE DISORDERS
GLOSSOPHARYNGEAL NEURALGIA DYSPHAGIA AND DYSPHONIA
This form of neuralgia involves the ninth (glossopharyn- When the intracranial portion of one vagus (tenth cra-
geal) and sometimes portions of the tenth (vagus) cranial nial) nerve is interrupted, the soft palate droops ipsilater-
nerves. It resembles trigeminal neuralgia in many respects ally and does not rise in phonation. There is loss of the
but is much less common.The pain is intense and parox- gag reex on the affected side, as well as of the curtain
ysmal; it originates on one side of the throat, approxi- movement of the lateral wall of the pharynx, whereby
mately in the tonsillar fossa. In some cases the pain is the faucial pillars move medially as the palate rises in say-
localized in the ear or may radiate from the throat to the ing ah. The voice is hoarse and slightly nasal, and the

TABLE 29-2
CRANIAL NERVE SYNDROMES

SITE CRANIAL NERVES USUAL CAUSE

Sphenoid ssure III, IV, rst division V, VI Invasive tumors of sphenoid bone; aneurysms
(superior orbital)
Lateral wall of cavernous sinus III, IV, rst division V, VI, Infection, thrombosis, aneurysm, or stula of
often with proptosis cavernous sinus; invasive tumors from sinuses and
sella turcica; benign granuloma responsive to
glucocorticoids
Retrosphenoid space II, III, IV, V, VI Large tumors of middle cranial fossa
Apex of petrous bone V, VI Petrositis; tumors of petrous bone
Internal auditory meatus VII, VIII Tumors of petrous bone (dermoids, etc.); infectious
processes; acoustic neuroma
Pontocerebellar angle V, VII, VIII, and sometimes IX Acoustic neuroma; meningioma
Jugular foramen IX, X, XI Tumors and aneurysms
Posterior laterocondylar space IX, X, XI, XII Tumors of parotid gland and carotid body and
metastatic tumors
Posterior retroparotid space IX, X, XI, XII and Horner Tumors of parotid gland, carotid body, lymph nodes;
syndrome metastatic tumor; tuberculous adenitis
vocal cord lies immobile midway between abduction and TONGUE PARALYSIS 383
adduction. Loss of sensation at the external auditory
The hypoglossal (twelfth cranial) nerve supplies the ipsi-
meatus and the posterior pinna may also be present.
lateral muscles of the tongue. The nucleus of the nerve
The pharyngeal branches of both vagal nerves may be
or its bers of exit may be involved by intramedullary
affected in diphtheria; the voice has a nasal quality, and
lesions such as tumor, poliomyelitis, or most often motor
regurgitation of liquids through the nose occurs during
neuron disease. Lesions of the basal meninges and the
the act of swallowing.
occipital bones (platybasia, invagination of occipital
The vagus nerve may be involved at the meningeal
condyles, Pagets disease) may compress the nerve in its
level by neoplastic and infectious processes and within
extramedullary course or in the hypoglossal canal. Iso-
the medulla by tumors, vascular lesions (e.g., the lateral
lated lesions of unknown cause can occur. Atrophy and
medullary syndrome), and motor neuron disease. This
fasciculation of the tongue develop weeks to months
nerve may be involved by infection with herpes zoster
after interruption of the nerve.
virus. Polymyositis and dermatomyositis, which cause
hoarseness and dysphagia by direct involvement of
laryngeal and pharyngeal muscles, may be confused with
diseases of the vagus nerves. Dysphagia is also a symp- MULTIPLE CRANIAL NERVE PALSIES
tom in some patients with myotonic dystrophy.

CHAPTER 29
The recurrent laryngeal nerves, especially the left, are Several cranial nerves may be affected by the same dis-
most often damaged as a result of intrathoracic disease. ease process. In this situation, the main clinical problem
Aneurysm of the aortic arch, an enlarged left atrium, is to determine whether the lesion lies within the brain-
and tumors of the mediastinum and bronchi are much stem or outside it. Lesions that lie on the surface of the
more frequent causes of an isolated vocal cord palsy brainstem are characterized by involvement of adjacent
than are intracranial disorders. However, a substantial cranial nerves (often occurring in succession) and late

Trigeminal Neuralgia, Bells Palsy, and Other Cranial Nerve Disorders

number of cases of recurrent laryngeal palsy remain and rather slight involvement of the long sensory and
idiopathic. motor pathways and segmental structures lying within
When confronted with a case of laryngeal palsy, the the brainstem. The opposite is true of primary lesions
physician must attempt to determine the site of the within the brainstem.The extramedullary lesion is more
lesion. If it is intramedullary, there are usually other likely to cause bone erosion or enlargement of the fora-
signs, such as ipsilateral cerebellar dysfunction, loss of mens of exit of cranial nerves.The intramedullary lesion
pain and temperature sensation over the ipsilateral face involving cranial nerves often produces a crossed sensory
and contralateral arm and leg, and an ipsilateral Horner or motor paralysis (cranial nerve signs on one side of the
syndrome. If the lesion is extramedullary, the glos- body and tract signs on the opposite side).
sopharyngeal and spinal accessory nerves are frequently Involvement of multiple cranial nerves outside the
involved (jugular foramen syndrome). If it is extracra- brainstem is frequently the result of diabetes or trauma,
nial in the posterior laterocondylar or retroparotid localized infections such as herpes zoster, infectious and
space, there may be a combination of ninth, tenth, noninfectious (especially carcinomatous) causes of menin-
eleventh, and twelfth cranial nerve palsies and a gitis (Chaps. 35 and 36), granulomatous diseases such as
Horner syndrome (Table 29-2). If there is no sensory Wegeners granulomatosis, Behets disease, enlarging sac-
loss over the palate and pharynx and no palatal weak- cular aneurysms, or tumors. Among the tumors, nasopha-
ness or dysphagia, the lesion is below the origin of the ryngeal cancers, lymphomas, neurobromas, meningiomas,
pharyngeal branches, which leave the vagus nerve high chordomas, cholesteatomas, carcinomas, and sarcomas have
in the cervical region; the usual site of disease is then all been observed to involve a succession of lower cranial
the mediastinum. nerves. Owing to their anatomic relationships, the multi-
ple cranial nerve palsies form a number of distinctive syn-
dromes, listed in Table 29-2. Sarcoidosis is the cause of
NECK WEAKNESS some cases of multiple cranial neuropathy, and chronic
Isolated involvement of the accessory (eleventh cranial) glandular tuberculosis the cause of a few others. Platybasia,
nerve can occur anywhere along its route, resulting in basilar invagination of the skull, and the adult Chiari mal-
partial or complete paralysis of the sternocleidomastoid formation are additional causes. A purely motor disorder
and trapezius muscles. More commonly, involvement without atrophy always raises the question of myasthenia
occurs in combination with decits of the ninth and gravis (Chap. 42). As noted above, Guillain-Barr syn-
tenth cranial nerves in the jugular foramen or after exit drome commonly affects the facial nerves bilaterally. In
from the skull (Table 29-2). An idiopathic form of acces- the Fisher variant of the Guillain-Barr syndrome, oculo-
sory neuropathy, akin to Bells palsy, has been described, motor paresis occurs with ataxia and areexia in the limbs
and it may be recurrent in some cases. Most but not all (Chap. 41). Wernicke encephalopathy can cause a severe
patients recover. ophthalmoplegia combined with other brainstem signs.
 384 Ant. cerebral a. In infectious cases, prompt administration of broad-
Int. carotid a. spectrum antibiotics, drainage of any abscess cavities, and
Ant. clinoid process identication of the offending organism are essential.
Subarachnoid Anticoagulant therapy may benet cases of primary
space
Optic thrombosis. Repair or occlusion of the carotid artery may
chiasma
Oculomotor (III) n.
be required for treatment of stulas or aneurysms. The
Trochlear (IV) n. Tolosa-Hunt syndrome generally responds to glucocorti-
Hypophysis coids. A dramatic improvement in pain is usually evident
Ophthalmic (VI) n.
within a few days; oral prednisone (60 mg daily) is usually
Maxillary (V2) n. continued for several weeks and then gradually tapered.
Sphenoid
sinus Pia An idiopathic form of multiple cranial nerve involve-
Arachnoid ment on one or both sides of the face is occasionally
Dura seen. The syndrome consists of a subacute onset of bor-
ing facial pain, followed by paralysis of motor cranial
Abducens (VI) n. nerves. The clinical features overlap those of the Tolosa-
FIGURE 29-4 Hunt syndrome and appear to be due to idiopathic
Anatomy of the cavernous sinus in coronal section, illus- inammation of the dura mater, which may be visual-
SECTION III

trating the location of the cranial nerves in relation to the vas- ized by MRI. The syndrome is frequently responsive to
cular sinus, internal carotid artery (which loops anteriorly to glucocorticoids.
the section), and surrounding structures.

ACKNOWLEDGMENT
The authors acknowledge the contributions of Dr. Joseph B.
The cavernous sinus syndrome (Fig. 29-4) is a distinctive
Diseases of the Central Nervous System

Martin to this chapter in previous editions of Harrisons Princi-

and frequently life-threatening disorder. It often presents
ples of Internal Medicine.
as orbital or facial pain; orbital swelling and chemosis due
to occlusion of the ophthalmic veins; fever; oculomotor
neuropathy affecting the third, fourth, and sixth cranial FURTHER READINGS
nerves; and trigeminal neuropathy affecting the ophthalmic ENGSTROM M et al: Prednisolone and valaciclovir in Bells palsy: a
(V1) and occasionally the maxillary (V2) divisions of the randomised, double-blind, placebo-controlled, multicentre trial.
trigeminal nerve. Cavernous sinus thrombosis, often sec- Lancet Neurol. 7:993, 2008
ondary to infection from orbital cellulitis (frequently GILDEN DH: Clinical practice. Bells Palsy. N Engl J Med 351:13,
Staphylococcus aureus), a cutaneous source on the face, or 2004
GRONSETH G et al: Practice parameter: the diagnostic evaluation and
sinusitis (especially with mucormycosis in diabetic patients), treatment of trigeminal neuralgia (an evidence-based review):
is the most frequent cause; other etiologies include report of the Quality Standards Subcommittee of the American
aneurysm of the carotid artery, a carotid-cavernous stula Academy of Neurology and the European Federation of Neuro-
(orbital bruit may be present), meningioma, nasopharyngeal logical Societies. Neurology 71:1183, 2008
carcinoma, other tumors, or an idiopathic granulomatous PEARCE JMS: Glossopharyngeal neuralgia. Eur Neurol 55:49, 2006
disorder (Tolosa-Hunt syndrome). The two cavernous QUANT EC et al: The benets of steroids versus steroids plus antivi-
sinuses directly communicate via intercavernous channels; rals for treatment of Bells palsy: a meta-analysis. BMJ 339:b3354,
2009
thus, involvement on one side may extend to become
SULLIVAN FM et al: Early treatment with prednisolone or acyclovir in
bilateral. Early diagnosis is essential, especially when due Bells palsy. N Engl J Med 357:1598, 2007
to infection, and treatment depends on the underlying SWEENEY CJ, GILDEN DH: Ramsay Hunt syndrome. J Neurol Neu-
etiology. rosurg Psychiatry 71:149, 2001
 CHAPTER 30

DISEASES OF THE SPINAL CORD

Stephen L. Hauser Allan H. Ropper

Acute and Subacute Spinal Cord Diseases . . . . . . . . . . . . . . 388 Subacute Combined Degeneration
Compressive Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 389 (Vitamin B12 Deciency) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Noncompressive Myelopathies . . . . . . . . . . . . . . . . . . . . . . . 392 Hypocupric Myelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Chronic Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Tabes Dorsalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Spondylitic Myelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Familial Spastic Paraplegia . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Vascular Malformations of the Cord and Dura . . . . . . . . . . . . 394 Adrenomyeloneuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Retrovirus-Associated Myelopathies . . . . . . . . . . . . . . . . . . . 395 Other Chronic Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . 397
Syringomyelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 Rehabilitation of Spinal Cord Disorders . . . . . . . . . . . . . . . . . 397
Chronic Myelopathy of Multiple Sclerosis . . . . . . . . . . . . . . . 396 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Diseases of the spinal cord are frequently devastating. neurons that innervate the upper and lower extremi-
They produce quadriplegia, paraplegia, and sensory ties, respectively, are located. The white matter tracts
decits far beyond the damage they would inict else- containing ascending sensory and descending motor
where in the nervous system because the spinal cord pathways are located peripherally, whereas nerve cell
contains, in a small cross-sectional area, almost the entire bodies are clustered in an inner region shaped like a
motor output and sensory input of the trunk and limbs. four-leaf clover that surrounds the central canal
Many spinal cord diseases are reversible if recognized (anatomically an extension of the fourth ventricle).
and treated at an early stage (Table 30-1); thus, they are The membranes that cover the spinal cordthe pia,
among the most critical of neurologic emergencies. The arachnoid, and duraare continuous with those of
efcient use of diagnostic procedures, guided by knowl- the brain.
edge of the anatomy and the clinical features of spinal The spinal cord has 31 segments, each dened by an
cord diseases, is required for a successful outcome. exiting ventral motor root and entering dorsal sensory
root. During embryologic development, growth of the
cord lags behind that of the vertebral column, and the
Approach to the Patient:
mature spinal cord ends at approximately the rst lum-
SPINAL CORD DISEASE bar vertebral body. The lower spinal nerves take an
increasingly downward course to exit via intervertebral
SPINAL CORD ANATOMY RELEVANT TO foramina.The rst seven pairs of cervical spinal nerves
CLINICAL SIGNS The spinal cord is a thin, tubular exit above the same-numbered vertebral bodies, whereas
extension of the central nervous system contained all the subsequent nerves exit below the same-num-
within the bony spinal canal. It originates at the bered vertebral bodies because of the presence of eight
medulla and continues caudally to the conus cervical spinal cord segments but only seven cervical
medullaris at the lumbar level; its brous extension, the vertebrae.The relationship between spinal cord segments
lum terminale, terminates at the coccyx. The adult and the corresponding vertebral bodies is shown in
spinal cord is ~46 cm (18 in.) long, oval in shape, and Table 30-2.These relationships assume particular impor-
enlarged in the cervical and lumbar regions, where tance for localization of lesions that cause spinal cord

385
 386 TABLE 30-1
Determining the Level of the Lesion The
TREATABLE SPINAL CORD DISORDERS presence of a horizontally dened level below which
Compressive sensory, motor, and autonomic function is impaired is
Epidural, intradural, or intramedullary neoplasm a hallmark of spinal cord disease. This sensory level is
Epidural abscess sought by asking the patient to identify a pinprick or
Epidural hemorrhage cold stimulus (e.g., a dry tuning fork after immersion
Cervical spondylosis
in cold water) applied to the proximal legs and lower
Herniated disc
Posttraumatic compression by fractured or displaced
trunk and sequentially moved up toward the neck on
vertebra or hemorrhage each side. The sensory level indicates damage to the
Vascular spinothalamic tract one to two segments above the
Arteriovenous malformation perceived level of a unilateral spinal cord lesion and at
Antiphospholipid syndrome and other hypercoagulable the level of a bilateral lesion. That is the result of the
states ascent of second-order sensory bers, which origi-
Inammatory nate in the dorsal horn, proceed to cross anterior to
Multiple sclerosis
Neuromyelitis optica
the central canal while ascending to join the opposite
Transverse myelitis spinothalamic tract. Lesions that transect the descend-
ing corticospinal and other motor tracts cause para-
SECTION III

Sarcoidosis
Vasculitis plegia or quadriplegia, with the evolution over time
Infectious of increased muscle tone, heightened deep tendon
Viral: VZV, HSV-1 and -2, CMV, HIV, HTLV-I, others reexes, and Babinski signs (the upper motor neuron
Bacterial and mycobacterial: Borrelia, Listeria, syphilis, syndrome). Such lesions also typically produce auto-
others
nomic disturbances consisting of absent sweating
Mycoplasma pneumoniae
below the implicated cord level and bladder, bowel,
Diseases of the Central Nervous System

Parasitic: schistosomiasis, toxoplasmosis

Developmental and sexual dysfunction.
Syringomyelia The uppermost level of a spinal cord lesion can
Meningomyelocoele also be localized by attention to the segmental signs
Tethered cord syndrome corresponding to disturbed motor or sensory inner-
Metabolic vation by an individual cord segment. A band of
Vitamin B12 deciency (subacute combined degeneration)
altered sensation (hyperalgesia or hyperpathia) at the
Copper deciency
upper end of the sensory disturbance, fasciculations
or atrophy in muscles innervated by one or several
Note: VZV, varicella-zoster virus; HSV, herpes simplex virus; CMV,
cytomegalovirus; HTLV, human T cell lymphotropic virus. segments, or a muted or absent deep tendon reex
may be noted at this level.These signs also occur with
focal root or peripheral nerve disorders; thus, seg-
mental signs are most useful when they occur
compression.A T10 spinal cord sensory level, for exam- together with signs of long tract damage. With severe
ple, indicates involvement of the cord adjacent to the and acute transverse lesions, the limbs initially may be
seventh or eighth thoracic vertebral body (Figs. 12-2 accid rather than spastic.This state of spinal shock
and 12-3). In addition, at every level the main ascend- lasts for several days, rarely for weeks, and should not
ing and descending tracts are somatotopically organized be mistaken for extensive damage to many segments
with a laminated distribution that reects the origin or of the cord or for an acute polyneuropathy.
destination of nerve bers. The main features of transverse damage at each
level of the spinal cord are summarized below.
Cervical Cord Upper cervical cord lesions pro-
TABLE 30-2
duce quadriplegia and weakness of the diaphragm.
SPINAL CORD LEVELS RELATIVE TO THE Lesions at C4-C5 produce quadriplegia; at C5-C6,
VERTEBRAL BODIES there is loss of power and reexes in the biceps; at C7
SPINAL CORD LEVEL CORRESPONDING VERTEBRAL BODY weakness is found only in nger and wrist extensors
and triceps; and at C8, nger and wrist exion are
Upper cervical Same as cord level
impaired. Horners syndrome (miosis, ptosis, and facial
Lower cervical 1 level higher
Upper thoracic 2 levels higher hypohidrosis) may accompany a cervical cord lesion
Lower thoracic 2 to 3 levels higher at any level.
Lumbar T10-T12
Thoracic Cord Lesions here are localized by the
Sacral T12-L1
sensory level on the trunk and by the site of midline
 back pain if it accompanies the syndrome. Useful impotence. The bulbocavernosus (S2-S4) and anal 387
markers for localization are the nipples (T4) and (S4-S5) reexes are absent (Chap. 1). Muscle strength
umbilicus (T10). Leg weakness and disturbances of is largely preserved. By contrast, lesions of the cauda
bladder and bowel function accompany the paralysis. equina, the cluster of nerve roots derived from the
Lesions at T9-T10 paralyze the lowerbut not the lower cord, are characterized by low back and radicu-
upperabdominal muscles, resulting in upward lar pain, asymmetric leg weakness and sensory loss,
movement of the umbilicus when the abdominal wall variable areexia in the lower extremities, and relative
contracts (Beevors sign). sparing of bowel and bladder function. Mass lesions
in the lower spinal canal often produce a mixed clini-
Lumbar Cord Lesions at the L2-L4 spinal cord
cal picture in which elements of both cauda equina
levels paralyze exion and adduction of the thigh,
and conus medullaris syndromes coexist. Cauda
weaken leg extension at the knee, and abolish the
equina syndromes are also discussed in Chap. 7.
patellar reex. Lesions at L5-S1 paralyze only move-
ments of the foot and ankle, exion at the knee, and
Special Patterns of Spinal Cord Disease
extension of the thigh, and abolish the ankle jerks (S1).
The location of the major ascending and descending
Sacral Cord/Conus Medullaris The conus pathways of the spinal cord are shown in Fig. 30-1.

CHAPTER 30
medullaris is the tapered caudal termination of the Most ber tractsincluding the posterior columns
spinal cord, comprising the lower sacral and single and the spinocerebellar and pyramidal tractsare sit-
coccygeal segments. The conus syndrome is distinc- uated on the side of the body they innervate. How-
tive, consisting of bilateral saddle anesthesia (S3-S5), ever, afferent bers mediating pain and temperature
prominent bladder and bowel dysfunction (urinary sensation ascend in the spinothalamic tract contralateral
retention and incontinence with lax anal tone), and to the side they supply.The anatomic congurations of

Diseases of the Spinal Cord

Posterior Columns
(Joint Position, Vibration, Pressure)

Fasciculus Fasciculus
cuneatus gracilis Anterior horn
Dorsal root
Dorsal (motor neurons)
spinocerebellar S
T L
tract C
Lateral
corticospinal
Ventral L/ Distal limb
(pyramidal tract)
spinocerebellar S
movements
tract S
L Rubrospinal
T
C tract
L/
S T C
L
S Lateral
F
P reticulospinal
D
Lateral E tract
spinothalamic
tract
S L T C Vestibulospinal
Pain, tract Axial and
temperature Ventral proximal
reticulospinal limb
Ventral tract movements
root Ventral Tectospinal
spinothalamic Ventral tract
tract (uncrossed)
corticospinal
Pressure, touch tract
(minor role)
Distal limb
movements
(minor role)
FIGURE 30-1
Transverse section through the spinal cord, composite spinothalamic tracts (blue) ascend contralateral to the side of
representation, illustrating the principal ascending (left) the body that is innervated. C, cervical; T, thoracic; L, lumbar;
and descending (right) pathways. The lateral and ventral S, sacral; P, proximal; D, distal; F, exors, E, extensors.
 388 these tracts produce characteristic syndromes that leg bers in the corticospinal tract. Intramedullary
provide clues to the underlying disease process. lesions tend to produce poorly localized burning pain
rather than radicular pain and spare sensation in the
Brown-Sequard Hemicord Syndrome This
perineal and sacral areas (sacral sparing), reecting
consists of ipsilateral weakness (corticospinal tract)
the laminated conguration of the spinothalamic
and loss of joint position and vibratory sense (poste-
tract with sacral bers outermost; corticospinal tract
rior column), with contralateral loss of pain and tem-
signs appear later. Regarding extramedullary lesions, a
perature sense (spinothalamic tract) one or two levels
further distinction is made between extradural and
below the lesion. Segmental signs, such as radicular
intradural masses, as the former are generally malig-
pain, muscle atrophy, or loss of a deep tendon reex,
nant and the latter benign (neurobroma being a
are unilateral. This classical pattern is rare, and partial
common cause). Consequently, a long duration of
forms are more commonly encountered.
symptoms favors an intradural origin.
Central Cord Syndrome The central cord syn-
drome results from damage to the gray matter nerve
cells and crossing spinothalamic tracts near the central
canal. In the cervical cord, the central cord syndrome
produces arm weakness out of proportion to leg weak-
ACUTE AND SUBACUTE SPINAL CORD
SECTION III

ness and a dissociated sensory loss, signifying a loss of DISEASES

pain and temperature sense in a cape distribution over The initial symptoms of disease that evolve over days or
the shoulders, lower neck, and upper trunk in contrast weeks are focal neck or back pain, followed by various
to preservation of light touch, joint position, and vibra- combinations of paresthesias, sensory loss, motor weak-
tion sense in these regions. Trauma, syringomyelia, ness, and sphincter disturbance evolving over hours to
tumors, and anterior spinal artery ischemia (including several days. There may be only mild sensory symptoms
Diseases of the Central Nervous System

from aortic dissection) are the main causes. or a devastating functional transection of the cord. Par-
Anterior Spinal Artery Syndrome Infarction tial lesions selectively involve the posterior columns or
of the cord is generally the result of occlusion or anterior spinothalamic tracts or are limited to one side
diminished ow in this artery. The result is extensive of the cord. Paresthesias or numbness typically begins in
bilateral tissue destruction that spares the posterior the feet and ascends symmetrically or asymmetrically.
columns. All spinal cord functionsmotor, sensory, These symptoms initially simulate Guillain-Barr syn-
and autonomicare lost below the level of the drome, but involvement of the trunk with a sharply
lesion, with the striking exception of retained vibra- demarcated spinal cord level indicates the myelopathic
tion and position sensation. nature of the process. In severe and abrupt cases, areexia
reecting spinal shock may be present, but hyperreexia
Foramen Magnum Syndrome Lesions in this supervenes over days or weeks; persistent areexic paral-
area interrupt decussating pyramidal tract bers des- ysis with a sensory level indicates necrosis over multiple
tined for the legs, which cross caudal to those of the segments of the spinal cord.
arms, resulting in weakness of the legs (crural paresis).
Compressive lesions near the foramen magnum may
produce weakness of the ipsilateral shoulder and arm
followed by weakness of the ipsilateral leg, then the Approach to the Patient:
contralateral leg, and nally the contralateral arm, an COMPRESSIVE AND NONCOMPRESSIVE
around the clock pattern that may begin in any of MYELOPATHY
the four limbs. There is typically suboccipital pain
spreading to the neck and shoulders. DISTINGUISHING COMPRESSIVE FROM
NONCOMPRESSIVE MYELOPATHY The rst
Intramedullary and Extramedullary Syn- priority is to exclude a treatable compression of the
dromes It is useful to differentiate intramedullary cord by a mass.The common causes are tumor, epidural
processes, arising within the substance of the cord, abscess or hematoma, herniated disc, or vertebral
from extramedullary ones that compress the spinal cord pathology. Epidural compression due to malignancy or
or its vascular supply. The differentiating features are abscess often causes warning signs of neck or back
only relative and serve as clinical guides. With pain, bladder disturbances, and sensory symptoms that
extramedullary lesions, radicular pain is often promi- precede the development of paralysis. Spinal subluxa-
nent, and there is early sacral sensory loss (lateral tion, hemorrhage, and noncompressive etiologies such
spinothalamic tract) and spastic weakness in the legs as infarction are more likely to produce myelopathy
(corticospinal tract) due to the supercial location of without antecedent symptoms. MRI with gadolinium
 infusion, centered on the clinically suspected level, is 389
the initial diagnostic procedure; in some cases it is
appropriate to image the entire spine (cervical through
sacral regions) to search for additional clinically silent
lesions. Once compressive lesions have been excluded,
noncompressive causes of acute myelopathy that are
intrinsic to the cord are considered, primarily vascular,
inammatory, and infectious etiologies.

COMPRESSIVE MYELOPATHIES
Neoplastic Spinal Cord Compression
In adults, most neoplasms are epidural in origin, result-
ing from metastases to the adjacent spinal bones. The A B
propensity of solid tumors to metastasize to the vertebral FIGURE 30-2

CHAPTER 30
column probably reects the high proportion of bone Epidural spinal cord compression due to breast carci-
marrow located in the axial skeleton. Almost any malig- noma. Sagittal T1-weighted (A) and T2-weighted (B) MRI
nant tumor can metastasize to the spinal column, with scans through the cervicothoracic junction reveal an inl-
breast, lung, prostate, kidney, lymphoma, and plasma cell trated and collapsed second thoracic vertebral body with
dyscrasia being particularly frequent. The thoracic cord posterior displacement and compression of the upper tho-
is most commonly involved; exceptions are metastases racic spinal cord. The low-intensity bone marrow signal in
A signies replacement by tumor.

Diseases of the Spinal Cord

from prostate and ovarian cancer, which occur dispro-
portionately in the sacral and lumbar vertebrae, probably
resulting from spread through Batsons plexus, a network
of veins along the anterior epidural space. Retroperi-
toneal neoplasms (especially lymphomas or sarcomas) tumor, they may cross the disk space to involve the adja-
enter the spinal canal through the intervertebral foram- cent vertebral body.
ina; they produce radicular pain and other signs of root If spinal cord compression is suspected, imaging should
involvement prior to cord compression. be obtained promptly. If there are radicular symptoms but
Pain is usually the initial symptom; it may be aching no evidence of myelopathy, it is usually safe, if necessary,
and localized or sharp and radiating in quality. This to defer imaging for 2448 h. With back or neck pain
spinal ache typically worsens with movement, coughing, only, imaging studies may be obtained within a few days.
or sneezing and characteristically awakens patients at Up to 40% of patients who present with cord compres-
night. A recent onset of persistent back pain, particularly sion at one level are found to have asymptomatic epidural
if in the thoracic spine (which is uncommonly involved disease elsewhere; thus, the length of the spine should be
by spondylosis), should prompt consideration of verte- imaged when epidural malignancy is in question.
bral metastasis. Rarely, pain is mild or absent. Plain radi-
ographs of the spine and radionuclide bone scans have
only a limited role in diagnosis because they do not
identify 1520% of metastatic vertebral lesions and fail Treatment:
to detect paravertebral masses that reach the epidural NEOPLASTIC SPINAL CORD
space through the intervertebral foramina. MRI pro- COMPRESSION
vides excellent anatomic resolution of the extent of Management of cord compression includes glucocorti-
spinal tumors (Fig. 30-2) and is able to distinguish coids to reduce cord edema, local radiotherapy (initiated
between malignant lesions and other massesepidural as early as possible) to the symptomatic lesion, and
abscess, tuberculoma, or epidural hemorrhage, among specic therapy for the underlying tumor type. Gluco-
othersthat present in a similar fashion. Vertebral corticoids (dexamethasone, up to 40 mg daily) can be
metastases are usually hypointense relative to a normal administered before the imaging study if the clinical
bone marrow signal on T1-weighted MRI scans; after suspicion is strong and continued at a lower dose until
the administration of gadolinium, contrast enhancement radiotherapy (generally 3000 cGy administered in 15
may deceptively normalize the appearance of the daily fractions) is completed. Radiotherapy appears to
tumor by increasing its intensity to that of normal bone be as effective as surgery, even for most classically
marrow. Infections of the spinal column (osteomyelitis radioresistant metastases. Biopsy of the epidural mass is
and related disorders) are distinctive in that, unlike
 390 unnecessary in patients with known preexisting cancer the foramen magnum, although they can arise from the
but is indicated if a history of underlying cancer is lack- meninges anywhere along the spinal canal. Neurobro-
ing. Surgery, either decompression by laminectomy or mas are benign tumors of the nerve sheath that typically
vertebral body resection, should be considered when arise near the posterior root; when multiple, neurobro-
signs of cord compression worsen despite radiotherapy, matosis is the likely etiology. Symptoms usually begin
when the maximum tolerated dose of radiotherapy has with radicular sensory symptoms followed by an asym-
been delivered previously to the site, or when a verte- metric, progressive spinal cord syndrome. Therapy is by
bral compression fracture or spinal instability contributes surgical resection.
to cord compression. A good response to radiotherapy Primary intramedullary tumors of the spinal cord are
can be expected in individuals who are ambulatory at uncommon.They present as central cord or hemicord syn-
presentation; new weakness is prevented, and some dromes, often in the cervical region; there may be poorly
recovery of motor function occurs in approximately half localized burning pain in the extremities and sparing of
of treated patients. Fixed motor decits (paraplegia or sacral sensation. In adults, these lesions are ependymomas,
quadriplegia), once established for >12 h, do not usually hemangioblastomas, or low-grade astrocytomas (Fig. 30-4).
improve, and beyond 48 h the prognosis for substantial Complete resection of an intramedullary ependymoma is
motor recovery is poor. often possible with microsurgical techniques. Debulking of
an intramedullary astrocytoma can also be helpful, as these
SECTION III

are often slowly growing lesions; the value of adjunctive

radiotherapy and chemotherapy is uncertain. Secondary
In contrast to tumors of the epidural space, most (metastatic) intramedullary tumors are also common, espe-
intradural mass lesions are slow-growing and benign. cially in patients with advanced metastatic disease (Chap. 32).
Meningiomas and neurobromas account for most of
these, with occasional cases caused by chordoma, Spinal Epidural Abscess
Diseases of the Central Nervous System

lipoma, dermoid, or sarcoma. Meningiomas (Fig. 30-3)

are often located posterior to the thoracic cord or near Spinal epidural abscess presents as a clinical triad of mid-
line dorsal pain, fever, and progressive limb weakness.
Prompt recognition of this distinctive process will in most
cases prevent permanent sequelae. Aching pain is almost
always present, either over the spine or in a radicular

FIGURE 30-4
FIGURE 30-3 MRI of an intramedullary astrocytoma. Sagittal T1-weighted
MRI of a thoracic meningioma. Coronal T1-weighted post- post-contrast image through the cervical spine demonstrates
contrast image through the thoracic spinal cord demonstrates expansion of the upper cervical spine by a mass lesion ema-
intense and uniform enhancement of a well-circumscribed nating from within the spinal cord at the cervicomedullary
extramedullary mass (arrows) which displaces the spinal cord junction. Irregular peripheral enhancement occurs within the
to the left. mass (arrows).
pattern. The duration of pain prior to presentation is question of associated meningitis, a feature that is found 391
generally 2 weeks but may on occasion be several in <25% of cases. The level of the puncture should be
months or longer. Fever is usual, accompanied by ele- planned to minimize the risk of meningitis due to passage
vated white blood cell count and sedimentation rate. As of the needle through infected tissue or herniation due to
the abscess expands, further spinal cord damage results decompression below an area of obstruction to the ow
from venous congestion and thrombosis. Once weakness of cerebrospinal uid (CSF). A high cervical tap is often
and other signs of myelopathy appear, progression may the safest approach. CSF abnormalities in subdural abscess
be rapid. A more chronic sterile granulomatous form of consist of pleocytosis with a preponderance of polymor-
abscess is also known, usually after treatment of an acute phonuclear cells, an elevated protein level, and a reduced
epidural infection. glucose level, but the responsible organism is not cultured
Risk factors include an impaired immune status (dia- unless there is associated meningitis. Blood cultures are
betes mellitus, renal failure, alcoholism, malignancy), positive in <25% of cases.
intravenous drug abuse, and infections of the skin or
other tissues. Two-thirds of epidural infections result
from hematogenous spread of bacteria from the skin
(furunculosis), soft tissue (pharyngeal or dental abscesses),
or deep viscera (bacterial endocarditis). The remainder Treatment:

CHAPTER 30
SPINAL EPIDURAL ABSCESS
arise from direct extension of a local infection to the
subdural space; examples of local predisposing condi- Treatment is by decompressive laminectomy with
tions are vertebral osteomyelitis, decubitus ulcers, lumbar debridement combined with long-term antibiotic treat-
puncture, epidural anesthesia, or spinal surgery. Most cases ment. Surgical evacuation prevents development of
are due to Staphylococcus aureus; gram-negative bacilli, paralysis and may improve or reverse paralysis in evolu-
Streptococcus, anaerobes, and fungi can also cause epidural tion, but it is unlikely to improve decits of more than

Diseases of the Spinal Cord

abscesses.Tuberculosis from an adjacent vertebral source, several days duration. Antibiotics should be started
Potts disease, remains an important cause in the under- empirically before surgery and then modied on the
developed world. basis of culture results; medication is continued for at
MRI scans (Fig. 30-5) localize the abscess and exclude least 4 weeks. If surgery is contraindicated or if there is a
other causes of myelopathy. Lumbar puncture is only xed paraplegia or quadriplegia that is unlikely to
required if encephalopathy or other clinical signs raise the improve following surgery, long-term administration of
systemic and oral antibiotics can be used; in such cases,
the choice of antibiotics may be guided by results of
blood cultures. However, paralysis may develop or
progress during antibiotic therapy; thus, initial surgical
management remains the treatment of choice unless
the abscess is limited in size and causes few or no neu-
rologic signs.

Spinal Epidural Hematoma

Hemorrhage into the epidural (or subdural) space causes
acute focal or radicular pain followed by variable signs of
a spinal cord or conus medullaris disorder. Therapeutic
anticoagulation, trauma, tumor, or blood dyscrasia are
predisposing conditions. Rare cases complicate lumbar
puncture or epidural anesthesia, sometimes in association
with use of low-molecular-weight heparin. MRI and
A B CT conrm the clinical suspicion and can delineate the
FIGURE 30-5 extent of the bleeding. Treatment consists of prompt
MRI of a spinal epidural abscess due to tuberculosis. reversal of any underlying clotting disorder and surgical
A. Sagittal T2-weighted free spin-echo MR sequence. decompression. Surgery may be followed by substantial
A hypointense mass replaces the posterior elements of C3 recovery, especially in patients with some preservation of
and extends epidurally to compress the spinal cord (arrows). motor function preoperatively. Because of the risk of
B. Sagittal T1-weighted image after contrast administration hemorrhage, lumbar puncture should be avoided when-
reveals a diffuse enhancement of the epidural process ever possible in patients with severe thrombocytopenia
(arrows) with extension into the epidural space. or other coagulopathies.
 392 Hematomyelia TABLE 30-3
EVALUATION OF ACUTE TRANSVERSE MYELOPATHY
Hemorrhage into the substance of the spinal cord is a
rare result of trauma, intraparenchymal vascular malfor- 1. MRI of spinal cord with and without contrast (exclude
mation (see later), vasculitis due to polyarteritis nodosa compressive causes).
or systemic lupus erythematosus (SLE), bleeding disor- 2. CSF studies: Cell count, protein, glucose, IgG
index/synthesis rate, oligoclonal bands, VDRL; Grams
ders, or a spinal cord neoplasm. Hematomyelia presents
stain, acid-fast bacilli, and India ink stains; PCR for
as an acute painful transverse myelopathy. With large VZV, HSV-2, HSV-1, EBV, CMV, HHV-6, enteroviruses,
lesions, extension into the subarachnoid space may HIV; antibody for HTLV-I, B. burgdorferi, M. pneumo-
occur, resulting in subarachnoid hemorrhage (Chap. 22). niae, and Chlamydia pneumoniae; viral, bacterial,
Diagnosis is by MRI or CT. Therapy is supportive, and mycobacterial, and fungal cultures.
surgical intervention is generally not useful. An excep- 3. Blood studies for infection: HIV; RPR; IgG and IgM
tion is hematomyelia due to an underlying vascular mal- enterovirus antibody; IgM mumps, measles, rubella,
formation, for which selective spinal angiography may group B arbovirus, Brucella melitensis, Chlamydia
psittaci, Bartonella henselae, schistosomal antibody;
be indicated, followed by surgery to evacuate the clot cultures for B. melitensis. Also consider nasal/pharyn-
and remove the underlying vascular lesion. geal/anal cultures for enteroviruses; stool O&P for
Schistosoma ova.
SECTION III

4. Immune-mediated disorders: ESR; ANA; ENA; dsDNA;

NONCOMPRESSIVE MYELOPATHIES rheumatoid factor; anti-SSA; anti-SSB, complement
levels; antiphospholipid and anticardiolipin antibodies;
The most frequent causes of noncompressive acute
p-ANCA; antimicrosomal and antithyroglobulin antibod-
transverse myelopathy (ATM) are spinal cord infarction; ies; if Sjgren syndrome suspected, Schirmer test, sali-
systemic inammatory disorders, including SLE and sar- vary gland scintography, and salivary/lacrimal gland
coidosis; demyelinating diseases, including multiple scle- biopsy.
rosis (MS) and neuromyelitis optica; postinfectious or
Diseases of the Central Nervous System

5. Sarcoidosis: Serum angiotensin-converting enzyme;

idiopathic transverse myelitis, which is presumed to be serum Ca; 24-h urine Ca; chest x-ray; chest CT; total
an immune condition related to acute disseminated body gallium scan; lymph node biopsy.
6. Demyelinating disease: Brain MRI scan, evoked poten-
encephalomyelitis (Chap. 34); and infectious (primarily
tials, CSF oligoclonal bands, neuromyelitis optica anti-
viral) causes. After spinal cord compression is excluded, body (aquaporin-4).
the evaluation generally requires a lumbar puncture and 7. Vascular causes: CT myelogram; spinal angiogram.
a search for underlying systemic disease (Table 30-3).
Note: VDRL, Venereal Disease Research Laboratory; PCR, polymerase
chain reaction; VZV, varicella-zoster virus; HHV, human herpes virus;
Spinal Cord Infarction RPR, rapid plasma reagin (test); O&P, ova and parasites; ESR, ery-
throcyte sedimentation rate; ANA, antinuclear antibodies; ENA,
The cord is supplied by three arteries that course verti- epithelial neutrophil-activating peptide.
cally over its surface: a single anterior spinal artery and
paired posterior spinal arteries. In addition to the verte-
bral arteries, the anterior spinal artery is fed by radicular
vessels that arise at C6, at an upper thoracic level, and, sparing vibration and position sense, and loss of sphinc-
most consistently, at T11-L2 (artery of Adamkiewicz). At ter control (anterior cord syndrome). Onset may be
each segment, paired penetrating vessels branch from the sudden and dramatic but more typically is progressive
anterior spinal artery to supply the anterior two-thirds over minutes or a few hours, quite unlike stroke in the
of the spinal cord; the posterior spinal arteries, which cerebral hemispheres. Sharp midline or radiating back
often become less distinct below the midthoracic level, pain localized to the area of ischemia is frequent. Are-
supply the posterior columns. exia due to spinal shock is often present initially; with
Spinal cord ischemia can occur at any level; however, time, hyperreexia and spasticity appear. Less common is
the presence of the artery of Adamkiewicz creates a infarction in the territory of the posterior spinal arteries,
watershed of marginal blood ow in the upper thoracic resulting in loss of posterior column function.
segments. With systemic hypotension, cord infarction Spinal cord infarction results from aortic atheroscle-
occurs at the level of greatest ischemic risk, usually T3- rosis, dissecting aortic aneurysm (manifest as chest or
T4, and also at boundary zones between the anterior back pain with diminished pulses in legs), vertebral
and posterior spinal artery territories. The latter may artery occlusion or dissection in the neck, or profound
result in a rapidly progressive syndrome over hours of hypotension from any cause. Cardiogenic emboli, vas-
weakness and spasticity with little sensory change. culitis related to collagen vascular disease [particularly
Acute infarction in the territory of the anterior spinal SLE and the antiphospholipid antibody syndrome (see
artery produces paraplegia or quadriplegia, dissociated later in this chapter)], and surgical interruption of aortic
sensory loss affecting pain and temperature sense but aneurysms are other causative conditions. Occasional cases
develop from embolism of nucleus pulposus material into mediastinal lymphadenopathy, serum angiotensin- 393
spinal vessels, usually from local spine trauma. In a sub- converting enzyme [(ACE); positive in only one-quarter
stantial number of cases no cause can be found, and of cases], serum calcium, and a gallium scan may assist in
thromboembolism in arterial feeders is suspected. The the diagnosis.The usefulness of spinal uid ACE is uncer-
MRI may fail to demonstrate limited infarctions of the tain. Initial treatment is with oral glucocorticoids;
cord, especially in the rst day, but as often it is abnor- immunosuppressant drugs are used for resistant cases.
mal at the affected level.
In cord infarction due to presumed thromboem- Demyelinating Myelopathies
bolism, acute anticoagulation is probably not indicated, Multiple sclerosis (MS) (Chap. 34) may present with
with the exception of the unusual transient ischemic myelitis, particularly in individuals of Asian or African
attack or incomplete infarction with a stuttering or pro- ancestry. In whites, MS rarely causes a complete trans-
gressive course. The antiphospholipid antibody syn- verse myelopathy (i.e., acute bilateral signs), but it is
drome is treated with anticoagulation. Drainage of spinal among the most common causes of a partial syndrome.
uid has reportedly been successful in some cases of Neuromyelitis optica (NMO) is a demyelinating syn-
cord infarction but has not been studied systematically. drome consisting of a severe myelopathy associated with
optic neuritis; the optic neuritis is often bilateral and
may precede or follow myelitis by weeks or months

CHAPTER 30
Inammatory and Immune Myelopathies
(Myelitis) (Chap. 34). A specic serum antibody test is available.
NMO is also associated with SLE and antiphospholipid
This broad category includes MS and postinfectious antibodies (see earlier) as well as with other connective
myelitis, both of which are demyelinating in nature (see tissue diseases.
later), as well as connective tissue disease. In approximately MRI ndings in MS-associated myelitis typically con-
one-quarter of cases of myelitis, no underlying cause can sist of mild swelling and edema of the cord and diffuse or
be identied. Some will later manifest additional symp-

Diseases of the Spinal Cord

multifocal areas of abnormal signal on T2-weighted
toms of a systemic immune-mediated disease such as SLE sequences. Contrast enhancement, indicating disruption
or, more often, MS. Recurrent episodes of myelitis are usually in the blood-brain barrier associated with inammation,
due to an immune-mediated disease such as a demyeli- is present in many acute cases. A brain MRI is most
nating disease, SLE, or sarcoid; or to infection with herpes helpful in gauging the likelihood that a case of myelitis
simplex virus (HSV) type 2 (see later). represents an initial attack of MS.A normal scan indicates
that the risk of evolution to MS is low, ~1015% over
Systemic Inammatory Disorders 5 years; in contrast, the nding of multiple periventricular
Myelitis occurs in a small number of patients with SLE, T2-bright lesions indicates a much higher risk, >50% over
many cases of which are associated with antiphospho- 5 years and >90% by 14 years.The CSF may be normal,
lipid antibodies. The CSF is usually normal or shows a but more often there is a mild pleocytosis, occasionally
mild lymphocytic pleocytosis; oligoclonal bands are a up to several hundred mononuclear cells per microliter,
variable nding. Responses to glucocorticoids and/or with normal or mildly elevated CSF protein levels; oligo-
cyclophosphamide have been reported, but there is no clonal bands are variable, but when bands are present, a
systematic evidence of their benet. Other immune- diagnosis of MS is more likely.These bands are generally
mediated myelitides include cases associated with Sjgrens absent in neuromyelitis optica.
syndrome, mixed connective tissue disease, Behets syn- There are no adequate trials of therapy for MS-
drome, and vasculitis with perinuclear antineutrophilic associated transverse myelitis. Intravenous methylpred-
cytoplasmic (p-ANCA) antibodies. nisolone (500 mg qd for 3 days) followed by oral
Another important consideration in this group is sar- prednisone (1 mg/kg per day for several weeks, then
coid myelopathy, in which an edematous swelling of the gradual taper) has been used as initial treatment. A
spinal cord may mimic tumor; there is almost always course of plasma exchange is indicated for severe cases if
gadolinium enhancement of the lesion and of the adja- glucocorticoids are ineffective. Preliminary data suggest
cent surface of the cord. The CSF prole consists of that treatment with anti-CD20 (anti-B cell) monoclonal
variable lymphocytic pleocytosis; oligoclonal bands are antibody may protect against relapses in patients with
present in one-third of cases. The diagnosis is particu- NMO.
larly difcult when systemic manifestations of sarcoid
are minor or absent (nearly 50% of cases) or when other Postinfectious Myelitis
classic neurologic manifestations of the diseasesuch Many cases of myelitis, termed postinfectious or postvaccinal,
as cranial neuropathy, hypothalamic involvement, or follow an infection or vaccination. Numerous organisms
meningeal enhancement visualized by MRIare lacking. have been implicated, including Epstein-Barr virus
A slit-lamp examination of the eye to search for uveitis, (EBV), cytomegalovirus (CMV), mycoplasma, inuenza,
chest x-ray and CT to assess pulmonary involvement and measles, varicella, rubeola, and mumps. As in the related
 394 disorder acute disseminated encephalomyelitis (Chap. 34), radicular arm pain, most often in a C5 or C6 distribu-
postinfectious myelitis often begins as the patient appears tion. Compression of the cervical cord, which occurs in
to be recovering from an acute febrile infection, or in the fewer than one-third of cases, produces a slowly progres-
subsequent days or weeks, but an infectious agent cannot sive spastic paraparesis, at times asymmetric and often
be isolated from the nervous system or spinal uid. The accompanied by paresthesias in the feet and hands.Vibra-
presumption is that the myelitis represents an autoim- tory sense is diminished in the legs, there is a Romberg
mune disorder triggered by infection and is not due to sign, and occasionally there is a sensory level for vibra-
direct infection of the spinal cord. Treatment is usually tion on the upper thorax. In some cases, coughing or
with glucocorticoids or, in fulminant cases, plasma exchange. straining produces leg weakness or radiating arm or
There are no trials by which to adequately judge these shoulder pain. Dermatomal sensory loss in the arms,
therapies. atrophy of intrinsic hand muscles, increased deep-tendon
reexes in the legs, and extensor plantar responses are
Acute Infectious Myelitis common. Urinary urgency or incontinence occurs in
Many viruses have been associated with an acute advanced cases, but there are many alternative causes of
myelitis that is infectious in nature rather than postinfec- these problems in older individuals. A tendon reex in
tious. Nonetheless, the two processes are often difcult the arms is often diminished at some level; the biceps is
to distinguish. Herpes zoster is the best characterized most often affected (C5-C6). In individual cases, radicu-
SECTION III

viral myelitis, but HSV types 1 and 2, EBV, CMV, and lar, myelopathic, or combined signs may predominate.
rabies virus are other well-described causes. HSV-2 (and The diagnosis should be considered in cases of progres-
less commonly HSV-1) produces a distinctive syndrome sive cervical myelopathy, paresthesias of the feet and
of recurrent sacral myelitis in association with outbreaks hands, or wasting of the hands.
of genital herpes mimicking MS. Poliomyelitis is the Diagnosis is made by MRI or myelography. Extrinsic
prototypic viral myelitis, but it is more or less restricted cord compression and deformation is appreciated on axial
Diseases of the Central Nervous System

to the gray matter of the cord. Chronic viral myelitic MRI views, and T2-weighted sequences may reveal
infections, such as that due to HIV, are discussed below. areas of high signal intensity within the cord adjacent to
Bacterial and mycobacterial myelitis (most are essen- the site of compression. A cervical collar may be helpful
tially abscesses) are far less common than viral causes. in milder cases, but denitive therapy consists of surgical
Almost any pathogenic species may be responsible, decompression. Posterior laminectomy or an anterior
including Listeria monocytogenes, Borrelia burgdorferi (Lyme approach with resection of the protruded disc and bony
disease), and Treponema pallidum (syphilis). Mycoplasma material may be required. Cervical spondylosis and
pneumoniae may be a cause of myelitis, but its status is related degenerative diseases of the spine are discussed in
uncertain since many cases are more properly classied Chap. 7.
as postinfectious.
Schistosomiasis is an important cause of parasitic
VASCULAR MALFORMATIONS OF THE
myelitis in endemic areas.The process is intensely inam-
CORD AND DURA
matory and granulomatous, caused by a local response to
tissue-digesting enzymes from the ova of the parasite. Although uncommon, vascular malformations of the cord
Toxoplasmosis can occasionally cause a focal myelopathy, and overlying dura are treatable causes of progressive
and this diagnosis should be considered, particularly in myelopathy. True arteriovenous malformations (AVMs)
patients with AIDS, Chap. 37). are located posteriorly along the surface of the cord or
In cases of suspected viral myelitis, it may be appro- within the dura, where they are more properly classied
priate to begin specic therapy pending laboratory con- as stulas. Most are at or below the midthoracic level.The
rmation. Herpes zoster, HSV, and EBV myelitis are typical presentation is a middle-aged man with a progres-
treated with intravenous acyclovir (10 mg/kg q8h) or sive myelopathy that worsens slowly or intermittently and
oral valacyclovir (2 gm tid) for 1014 days; CMV with may have periods of apparent remission resembling MS.
ganciclovir (5 mg/kg IV bid) plus foscarnet (60 mg/kg Acute deterioration due to hemorrhage into the spinal
IV tid), or cidofovir (5 mg/kg per week for 2 weeks). cord or subarachnoid space may also occur but is rare. A
saltatory progression is most common and is the result of
local ischemia and edema from venous congestion. Most
CHRONIC MYELOPATHIES patients have incomplete sensory, motor, and bladder dis-
turbances. The motor disorder may predominate and
SPONDYLITIC MYELOPATHY produce a mixture of upper and restricted lower motor
Spondylitic myelopathy is one of the most common neuron signs, simulating amyotrophic lateral sclerosis
causes of gait difculty in the elderly. Neck and shoulder (ALS). Pain over the dorsal spine, dysesthesias, or radicular
pain with stiffness are early symptoms; impingement of pain may be present. Other symptoms suggestive of AVM
bone and soft tissue overgrowth on nerve roots results in include intermittent claudication, symptoms that change
with posture, exertion such as singing, menses, or fever. with variable sensory and bladder disturbance. Approxi- 395
A rare AVM process presents as a progressive thoracic mately half of patients have mild back or leg pain. The
myelopathy with paraparesis developing over weeks or neurologic signs may be asymmetric, often lacking a
several months, characterized pathologically by abnormally well-dened sensory level; the only sign in the arms
thick, hyalinized vessels within the cord (Foix-Alajouanine may be hyperreexia after several years of illness. The
syndrome). onset is insidious, and the illness is slowly progressive at
Spinal bruits are infrequent but should be sought at a variable rate; most patients are unable to walk within
rest and after exercise in suspected cases. High-resolution 10 years of onset. This presentation may resemble pri-
MRI with contrast administration detects many but not mary progressive MS or a thoracic AVM. Diagnosis is
all AVMs (Fig. 30-6). A small number not detected by made by demonstration of HTLV-Ispecic antibody in
MRI may be visualized by CT myelography as enlarged serum by enzyme-linked immunosorbent assay (ELISA),
vessels along the surface of the cord. Denitive diagnosis conrmed by radioimmunoprecipitation or western blot
requires selective spinal angiography, which denes the analysis. There is no effective treatment, but sympto-
feeding vessels and the extent of the malformation. matic therapy for spasticity and bladder symptoms may
Endovascular embolization of the major feeding vessels be helpful.
may stabilize a progressive neurologic decit or allow A progressive myelopathy may also result from HIV
for gradual recovery. infection (Chap. 37). It is characterized by vacuolar

CHAPTER 30
degeneration of the posterior and lateral tracts, resem-
bling subacute combined degeneration (see later).
RETROVIRUS-ASSOCIATED MYELOPATHIES
The myelopathy associated with the human T cell lym- SYRINGOMYELIA
photropic virus type I (HTLV-I), formerly called tropical
spastic paraparesis, is a slowly progressive spastic syndrome Syringomyelia is a developmental cavitary expansion of

Diseases of the Spinal Cord

the cervical cord that is prone to enlarge and produce
progressive myelopathy. Symptoms begin insidiously in
adolescence or early adulthood, progress irregularly, and
may undergo spontaneous arrest for several years. Many
young patients acquire a cervical-thoracic scoliosis. More
than one-half of all cases are associated with Chiari type
1 malformations in which the cerebellar tonsils protrude
through the foramen magnum and into the cervical
spinal canal. The pathophysiology of syrinx expansion is
controversial, but some interference with the normal
ow of CSF seems likely, perhaps by the Chiari malfor-
mation. Acquired cavitations of the cord in areas of
necrosis are also termed syrinx cavities; these follow
trauma, myelitis, necrotic spinal cord tumors, and chronic
arachnoiditis due to tuberculosis and other etiologies.
The classic presentation is a central cord syndrome
consisting of a dissociated sensory loss and areexic
weakness in the upper limbs. The sensory decit is rec-
A B
ognizable by loss of pain and temperature sensation with
sparing of touch and vibration in a distribution that is
FIGURE 30-6
suspended over the nape of the neck, shoulders, and
Arteriovenous malformation. Sagittal MR scans of the tho-
upper arms (cape distribution) or in the hands. Most
racic spinal cord: T2 fast spin-echo technique (A) and T1
post-contrast image (B). On the T2-weighted image (left),
cases begin asymmetrically with unilateral sensory loss
abnormally high signal intensity is noted in the central aspect
in the hands that leads to injuries and burns that are not
of the spinal cord (arrowheads). Numerous punctate ow appreciated by the patient. Muscle wasting in the lower
voids indent the dorsal and ventral spinal cord (arrow). These neck, shoulders, arms, and hands with asymmetric or
represent the abnormally dilated venous plexus supplied by absent reexes in the arms reects expansion of the cav-
a dural arteriovenous stula. After contrast administration ity into the gray matter of the cord. As the cavity
(B), multiple, serpentine, enhancing veins (arrows) on the enlarges and further compresses the long tracts, spasticity
ventral and dorsal aspect of the thoracic spinal cord are visu- and weakness of the legs, bladder and bowel dysfunc-
alized, diagnostic of arteriovenous malformation. This patient tion, and a Horners syndrome appear. Some patients
was a 54-year-old man with a 4-year history of progressive develop facial numbness and sensory loss from damage
paraparesis. to the descending tract of the trigeminal nerve (C2 level
 396 of a number of methods, but the added benet of this
procedure is uncertain, and morbidity is common. With
Chiari malformations, shunting of hydrocephalus should
generally precede any attempt to correct the syrinx.
Surgery may stabilize the neurologic decit, and some
patients improve.
Syringomyelia secondary to trauma or infection is
treated with a decompression and drainage procedure
in which a small shunt is inserted between the syrinx
cavity and the subarachnoid space; alternatively, the
cavity can be fenestrated. Cases due to intramedullary
spinal cord tumor are generally managed by resection
of the tumor.

CHRONIC MYELOPATHY OF MULTIPLE

SECTION III

SCLEROSIS
FIGURE 30-7 A chronic progressive myelopathy is the most frequent
MRI of syringomyelia associated with a Chiari malforma- cause of disability in both primary progressive and sec-
tion. Sagittal T1-weighted image through the cervical and ondary progressive forms of MS. Involvement is typically
upper thoracic spine demonstrates descent of the cerebellar bilateral but asymmetric and produces motor, sensory,
Diseases of the Central Nervous System

tonsils and vermis below the level of the foramen magnum and bladder/bowel disturbances. Fixed motor disability
(black arrows). Within the substance of the cervical and tho- appears to result from extensive loss of axons in the cor-
racic spinal cord, a CSF collection dilates the central canal ticospinal tracts; thus, the symptoms are not simply due
(white arrows). to demyelination. Diagnosis is facilitated by identica-
tion of earlier attacks such as optic neuritis. MRI, CSF,
and evoked response testing are conrmatory. Therapy
or above). In cases with Chiari malformations, cough- with interferon , glatiramer acetate, or natalizumab is
induced headache and neck, arm, or facial pain are reported. indicated for patients with progressive myelopathy who
Extension of the syrinx into the medulla, syringobulbia, also have coexisting MS relapses. These therapies are
causes palatal or vocal cord paralysis, dysarthria, horizon- sometimes also offered to patients without relapses,
tal or vertical nystagmus, episodic dizziness, and tongue despite the lack of evidence supporting their value in
weakness. this setting. MS is discussed in Chap. 34.
MRI scans accurately identify developmental and
acquired syrinx cavities and their associated spinal cord
enlargement (Fig. 30-7). MRI scans of the brain and
SUBACUTE COMBINED DEGENERATION
the entire spinal cord should be obtained to delineate
(VITAMIN B12 DEFICIENCY)
the full longitudinal extent of the syrinx, assess posterior This treatable myelopathy presents with subacute paresthe-
fossa structures for the Chiari malformation, and deter- sias in the hands and feet, loss of vibration and position
mine whether hydrocephalus is present. sensation, and a progressive spastic and ataxic weakness.
Loss of reexes due to an associated peripheral neuropathy
in a patient who also has Babinski signs, is an important
diagnostic clue. Optic atrophy and irritability or other
Treatment: mental changes may be prominent in advanced cases and
SYRINGOMYELIA are rarely the presenting symptoms. The myelopathy of
Treatment of syringomyelia is generally unsatisfactory. subacute combined degeneration tends to be diffuse rather
The Chiari tonsillar herniation is usually decompressed, than focal; signs are generally symmetric and reect pre-
generally by suboccipital craniectomy, upper cervical dominant involvement of the posterior and lateral tracts,
laminectomy, and placement of a dural graft. Obstruc- including Rombergs sign. The diagnosis is conrmed by
tion of fourth ventricular outow is reestablished by this the nding of macrocytic red blood cells, a low serum B12
procedure. If the syrinx cavity is large, some surgeons concentration, elevated serum levels of homocysteine
recommend direct decompression or drainage by one and methylmalonic acid, and in uncertain cases a positive
Schilling test.Treatment is by replacement therapy, beginning
with 1000 g of intramuscular vitamin B12 repeated at insufciency beginning in childhood and then develop a 397
regular intervals or by subsequent oral treatment. progressive spastic (or ataxic) paraparesis beginning in
early adulthood; some patients also have a mild periph-
eral neuropathy. Female heterozygotes may develop a
HYPOCUPRIC MYELOPATHY
slower, insidiously progressive spastic myelopathy begin-
This recently described myelopathy is virtually identical ning later in adulthood and without adrenal insuf-
to subacute combined degeneration (described above) ciency. Diagnosis is usually made by demonstration of
and probably explains many cases previously described elevated levels of very long chain fatty acids in plasma
with normal serum levels of B12. Low levels of serum and in cultured broblasts.The responsible gene encodes
copper are found and often there is also a low level of ADLP, a peroxisomal membrane transporter that is a
serum ceruloplasmin. Some cases follow gastrointestinal member of the ATP-binding cassette (ABC) family.
procedures that result in impaired copper absorption, Steroid replacement is indicated if hypoadrenalism is
but many others are idiopathic. Improvement or at least present, and bone marrow transplantation and nutri-
stabilization may be expected with reconstitution of tional supplements have been attempted for this condi-
copper stores by oral supplementation. The pathophysi- tion without clear evidence of efcacy.
ology and pathology are not known.

CHAPTER 30
OTHER CHRONIC MYELOPATHIES
TABES DORSALIS
Primary lateral sclerosis (Chap. 27) is a degenerative dis-
The classic syndromes of tabes dorsalis and meningovascu- order characterized by progressive spasticity with weak-
lar syphilis of the spinal cord are now less frequent than in ness, eventually accompanied by dysarthria and dyspho-
the past but must be considered in the differential diagno- nia; bladder symptoms occur in approximately half of
sis of spinal cord disorders.The characteristic symptoms of patients. Sensory function is spared.The disorder resem-

Diseases of the Spinal Cord

tabes are eeting and repetitive lancinating pains, primarily bles ALS and is considered a variant of the motor neu-
in the legs or less often in the back, thorax, abdomen, ron degenerations, but without the characteristic lower
arms, and face. Ataxia of the legs and gait due to loss of motor neuron disturbance. Some cases may represent
position sense occurs in half of patients. Paresthesias, blad- familial spastic paraplegia, particularly autosomal reces-
der disturbances, and acute abdominal pain with vomiting sive or X-linked varieties in which a family history may
(visceral crisis) occur in 1530% of patients. The cardinal be absent.
signs of tabes are loss of reexes in the legs; impaired posi- There are a number of rare toxic causes of spastic
tion and vibratory sense; Rombergs sign; and, in almost all myelopathy, including lathyrism due to ingestion of chick
cases, bilateral Argyll Robertson pupils, which fail to con- peas containing the excitotoxin -N-oxalylaminoalanine
strict to light but accommodate. Diabetic polyradiculopa- (BOAA), seen primarily in the developing world, and
thy may simulate tabes. nitrous oxide inhalation producing a myelopathy identi-
cal to subacute combined degeneration. SLE, Sjgrens
FAMILIAL SPASTIC PARAPLEGIA syndrome, and sarcoidosis may each cause a myelopathy
without overt evidence of systemic disease. Cancer-related
Many cases of slowly progressive myelopathy are genetic causes of chronic myelopathy, besides the common neo-
in origin (Chap. 27). More than 20 different causative plastic compressive myelopathy discussed earlier, include
loci have been identied, including autosomal domi- a rare paraneoplastic myelopathy (Chap. 39) or radiation
nant, autosomal recessive, and X-linked forms. Most injury (Chap. 32). It is notable that metastases to the
patients present with almost imperceptibly progressive cord are probably more common than either of these. In
spasticity and weakness in the legs, usually but not obscure cases, a cause can often be identied through
always symmetrical. Sensory symptoms and signs are periodic reassessment.
absent or mild, but sphincter disturbances may be pre-
sent. In some families additional neurologic signs are
prominent, including nystagmus, ataxia, or optic atrophy. REHABILITATION OF SPINAL CORD
The onset may be as early as the rst year of life or as DISORDERS
late as middle adulthood. Only symptomatic therapies
for the spasticity are currently available. The prospects for recovery from an acute destructive
spinal cord lesion fade after ~6 months. There are cur-
ADRENOMYELONEUROPATHY rently no effective means to promote repair of injured
spinal cord tissue; promising experimental approaches
This X-linked disorder is a variant of adrenoleukodys- include the use of factors that inuence reinnervation
trophy. Affected males usually have a history of adrenal by axons of the corticospinal tract, nerve and neural
 398 TABLE 30-4
EXPECTED NEUROLOGIC FUNCTION FOLLOWING COMPLETE CORD LESIONS

LEVEL SELF-CARE TRANSFERS MAXIMUM MOBILITY

High quadriplegia (C1-C4) Dependent on others; Dependent on others Motorized wheelchair

requires respiratory support
Low quadriplegia (C5-C8) Partially independent with May be dependent or May use manual wheelchair, drive an
adaptive equipment independent automobile with adaptive equipment
Paraplegia (below T1) Independent Independent Ambulates short distances with aids

Source: Adapted from JF Ditunno, CS Formal: Chronic spinal cord injury. N Engl J Med 330:550, 1994; with permission.

sheath graft bridges, and the local introduction of stem Patients with acute cord injury are at risk for venous
cells. The disability associated with irreversible spinal thrombosis and pulmonary embolism. During the first
cord damage is determined primarily by the level of the 2 weeks, use of calf-compression devices and anticoagu-
lesion and by whether the disturbance in function is lation with heparin (5000 U subcutaneously every 12 h)
SECTION III

complete or incomplete (Table 30-4). Even a complete or warfarin (INR, 23) are recommended. In cases of
high cervical cord lesion may be compatible with a pro- persistent paralysis, anticoagulation should probably be
ductive life. The primary goals are development of a continued for 3 months.
rehabilitation plan framed by realistic expectations and Prophylaxis against decubitus ulcers should involve
attention to the neurologic, medical, and psychological frequent changes in position in a chair or bed, the use of
complications that commonly arise. special mattresses, and cushioning of areas where pres-
Diseases of the Central Nervous System

Many of the usual symptoms associated with medical sure sores often develop, such as the sacral prominence
illnesses, especially somatic and visceral pain, may be and heels. Early treatment of ulcers with careful cleans-
lacking because of the destruction of afferent pain path- ing, surgical or enzyme debridement of necrotic tissue,
ways. Unexplained fever, worsening of spasticity, or and appropriate dressing and drainage may prevent
deterioration in neurologic function should prompt a infection of adjacent soft tissue or bone.
search for infection, thrombophlebitis, or an intraab- Spasticity is aided by stretching exercises to maintain
dominal pathology.The loss of normal thermoregulation mobility of joints. Drug treatment is effective but may
and inability to maintain normal body temperature can result in reduced function, as some patients depend
produce recurrent fever (quadriplegic fever), although most upon spasticity as an aid to stand, transfer, or walk.
episodes of fever are due to infection of the urinary Baclofen (15240 mg/d in divided doses) is effective; it
tract, lung, skin, or bone. acts by facilitating GABA-mediated inhibition of motor
Bladder dysfunction generally results from loss of reex arcs. Diazepam acts by a similar mechanism and is
supraspinal innervation of the detrusor muscle of the useful for leg spasms that interrupt sleep (24 mg at
bladder wall and the sphincter musculature. Detrusor bedtime).Tizanidine (28 mg tid), an 2 adrenergic ago-
spasticity is treated with anticholinergic drugs (oxybu- nist that increases presynaptic inhibition of motor neu-
tinin, 2.55 mg qid) or tricyclic antidepressants with rons, is another option. For nonambulatory patients, the
anticholinergic properties (imipramine, 25200 mg/d). direct muscle inhibitor dantrolene (25100 mg qid) may
Failure of the sphincter muscle to relax during bladder be used, but it is potentially hepatotoxic. In refractory
emptying (urinary dyssynergia) may be managed with cases, intrathecal baclofen administered via an implanted
the -adrenergic blocking agent terazosin hydrochlo- pump, botulinum toxin injections, or dorsal rhizotomy
ride (12 mg tid or qid), with intermittent catheteriza- may be required to control spasticity.
tion, or, if that is not feasible, by use of a condom catheter A paroxysmal autonomic hyperreexia may occur fol-
in men or a permanent indwelling catheter. Surgical lowing lesions above the major splanchnic sympathetic
options include the creation of an articial bladder by iso- outow at T6. Headache, ushing, and diaphoresis above
lating a segment of intestine that can be catheterized the level of the lesion, as well as hypertension with brady-
intermittently (enterocystoplasty) or can drain continu- cardia or tachycardia, are the major symptoms.The trigger
ously to an external appliance (urinary conduit). Bladder is typically a noxious stimulusfor example, bladder or
areexia due to acute spinal shock or conus lesions is bowel distention, a urinary tract infection, or a decubitus
best treated by catheterization. Bowel regimens and dis- ulcerbelow the level of the cord lesion.Treatment con-
impaction are necessary in most patients to ensure at sists of removal of offending stimuli; ganglionic blocking
least biweekly evacuation and avoid colonic distention agents (mecamylamine, 2.55 mg) or other short-acting
or obstruction. antihypertensive drugs are useful in some patients.
 Attention to these details allows longevity and a KALB RG: Getting the spinal cord to think for itself. Arch Neurol 399
productive life for patients with complete transverse 60:805, 2003
myelopathies. KRINGS T, GEIBPRASERT S: Spinal dural arteriovenous stuals. AJNR:
Am J Neuroradiol. 30:639, 2009
KUMAR N: Copper deciency myelopathy (human swayback). Mayo
FURTHER READINGS Clin Proc 81:1371, 2006
TRANSVERSE MYELITIS CONSORTIUM WORKING GROUP: Proposed
COLE JS, PATCHELL RA: Metastatic epidural spinal cord compression.
diagnostic criteria and nosology of acute transverse myelitis.
Lancet Neurol. 7:459, 2008
Neurology 59:499, 2002
JACOB A, WEINSHENKER BG: An approach to the diagnosis of acute
TRAUL DE et al: Part I: Spinal-cord neoplasmsintradural neo-
transverse myelitis. Semin Neurol 28:95, 2008
plasms. Lancet Oncol 8:35, 2007

CHAPTER 30
Diseases of the Spinal Cord
 CHAPTER 31

CONCUSSION AND OTHER HEAD INJURIES

Allan H. Ropper

I Types of Head Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 I Clinical Syndromes and Treatment of

Concussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 Head Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Contusion, Brain Hemorrhage, and Axonal Minor Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Shearing Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Injury of Intermediate Severity . . . . . . . . . . . . . . . . . . . . . . . . 406
Skull Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Severe Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Cranial Nerve Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Grading and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Postconcussion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Subdural and Epidural Hematomas . . . . . . . . . . . . . . . . . . . 403 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Almost 10 million head injuries occur annually in the or report feeling star struck.The mechanics of concus-
United States, about 20% of which are serious enough sion involve a blunt forward impact that creates sudden
to cause brain damage. Among men <35 years, acci- deceleration of the head and an anterior-posterior
dents, usually motor vehicle collisions, are the chief movement of the brain within the skull. Severe concus-
cause of death, and >70% of these involve head injury. sion may precipitate a brief convulsion or autonomic
Furthermore, minor head injuries are so common that signs such as facial pallor, bradycardia, faintness with
almost all physicians will be called upon to provide mild hypotension, or sluggish pupillary reaction, but
immediate care or to see patients who are suffering from most patients are soon neurologically normal. The loss
various sequelae. of consciousness in concussion is believed to be a tran-
Medical personnel caring for head injury patients sient electrophysiologic dysfunction of the reticular acti-
should be aware that (1) spinal injury often accompanies vating system in the upper midbrain caused by rotation
head injury and care must be taken to prevent compres- of the cerebral hemispheres on the relatively xed brain-
sion of the spinal cord due to instability of the spinal stem (Chap. 14).
column; (2) intoxication is an important accompaniment Gross- and light-microscopic changes in the brain are
of traumatic brain injury and, when appropriate, testing usually absent following concussion, but biochemical
should be carried out for drugs and alcohol; and (3) and ultrastructural changes, such as mitochondrial ATP
accompanying systemic injuries, including rupture of depletion and local disruption of the blood-brain bar-
abdominal organs, may produce vascular collapse or res- rier, suggest that transient abnormalities occur. CT and
piratory compromise requiring immediate attention. MRI scans are usually normal; however, a small number
of patients will be found to have an intracranial hemor-
rhage or brain contusion.
TYPES OF HEAD INJURIES A brief period of both retrograde and anterograde
amnesia is typical of concussion and disappears rapidly
CONCUSSION
in alert patients. The memory loss spans the moments
This classically refers to an immediate but transient loss before impact but with severe injuries loss of memory
of consciousness that is associated with a short period of may encompass the previous days or weeks (rarely
amnesia. Some patients do not lose consciousness after a months). The extent of retrograde amnesia roughly cor-
minor head injury and instead may appear dazed, confused relates with the severity of injury. Memory is regained
400
in an orderly way from the most distant to recent mem- 401
ories, with islands of amnesia occasionally remaining.The
mechanism of amnesia is not known. Hysterical post-
traumatic amnesia is not uncommon after head injury
and should be suspected when inexplicable abnormalities
of behavior occur, such as recounting events that cannot
be recalled on later testing, a bizarre affect, forgetting
ones own name, or a persistent anterograde decit that
is excessive in comparison with the degree of injury. A
further discussion of amnesia is provided in Chap. 15.
A single, uncomplicated concussion only infrequently
produces permanent neurobehavioral changes in patients
who are free of preexisting psychiatric problems and sub-
stance abuse. Nonetheless, residual minor problems in
memory and concentration may have an anatomic corre-
late in microscopic cerebral lesions (see later).
FIGURE 31-1

CHAPTER 31
Traumatic cerebral contusion. Noncontrast CT scan demon-
strating a hyperdense hemorrhagic region in the anterior
CONTUSION, BRAIN HEMORRHAGE, AND temporal lobe.
AXONAL SHEARING LESIONS
A surface bruise of the brain, or contusion, consists of
varying degrees of petechial hemorrhage, edema, and
reactions result in scarred, hemosiderin-stained depres-
tissue destruction. Contusions and deeper hemorrhages

Concussion and Other Head Injuries

sions on the cortex (plaques jaunes) that are the main
result from mechanical forces that displace and compress
source of posttraumatic epilepsy.
the hemispheres forcefully and by deceleration of the
Torsion or shearing forces within the brain cause
brain against the inner skull, either under a point of
hemorrhages of the basal ganglia and other deep
impact (coup lesion) or, as the brain swings back, in the
regions. Large hemorrhages after minor trauma suggest
antipolar area (contrecoup lesion). Trauma sufcient to
that there is a bleeding diathesis or cerebrovascular amy-
cause prolonged unconsciousness usually produces some
loidosis. For unexplained reasons, deep cerebral hemor-
degree of contusion. Blunt deceleration impact, as from
rhages may not develop until several days after injury.
an automobile dashboard or from falling forward while
Sudden neurologic deterioration in a comatose patient
drunk, causes contusions on the orbital surfaces of the
or a sudden rise in intracranial pressure (ICP) should
frontal lobes and the anterior and basal portions of the
therefore prompt investigation with a CT scan.
temporal lobes.With lateral forces, as from impact on an
Another type of deep white matter lesion consists of
automobile door frame, the contusions are situated on
widespread acute disruption, or shearing, of axons at the
the lateral convexity of the hemisphere. The clinical
time of impact. Most characteristic are small areas of tis-
signs are determined by the location and size of the
sue injury in the corpus callosum and dorsolateral pons.
contusion; often, there are no focal neurologic abnor-
The presence of widespread axonal damage in both
malities. A hemiparesis or gaze preference is fairly typical
hemispheres, a state called diffuse axonal injury, is pro-
of moderately sized contusions. Large bilateral contu-
posed to explain persistent coma and the vegetative state
sions produce coma with extensor posturing, while
after closed head injury (Chap. 14), but small ischemic-
those limited to the frontal lobes cause a taciturn state.
hemorrhagic lesions in the midbrain and thalamus are as
Contusions in the temporal lobe may cause delirium or
often the cause of this clinical state. Only severe shearing
an aggressive, combative syndrome.
lesions that contain blood are visualized by CT, usually in
Contusions are easily visible on CT and MRI scans,
the corpus callosum and centrum semiovale (Fig. 31-2);
appearing as inhomogeneous hyperdensities on CT and
however, special imaging sequences of the MRI can
as hyperintensities on MRI; the signal changes reect
demonstrate such lesions throughout the white matter.
small scattered areas of cortical and subcortical blood
and localized brain edema (Fig. 31-1); there is usually
some subarachnoid bleeding detected by scans or lum-
SKULL FRACTURES
bar puncture. Blood in the cerebrospinal uid (CSF)
resulting from trauma may provoke a mild inammatory A blow to the skull causes fracture if the elastic tolerance
reaction. Over a few days, contusions acquire a sur- of the bone is exceeded. Intracranial lesions accompany
rounding contrast enhancement and edema that may be roughly two-thirds of skull fractures, and the presence of
mistaken for tumor or abscess. Glial and macrophage a skull fracture increases manyfold the chances of an
 402 Sellar fractures, even those associated with serious
neuroendocrine dysfunction, may be radiologically
occult or are evident by an air-uid level in the sphe-
noid sinus. Fractures of the dorsum sella cause sixth or
seventh nerve palsies or optic nerve damage.
Petrous bone fractures, especially those oriented along
the long axis of the bone, may be associated with facial
palsy, disruption of ear ossicles, and CSF otorrhea.Trans-
verse petrous fractures are less common; they almost
always damage the cochlea or labyrinths and often the
facial nerve as well. External bleeding from the ear is
usually from local abrasion of the external canal but can
also result from petrous fracture.
Fractures of the frontal bone are usually depressed,
involving the frontal and paranasal sinuses and the orbits;
FIGURE 31-2 permanent anosmia results if the olfactory laments in
Multiple small areas of hemorrhage and tissue disruption the cribriform plate are disrupted. Depressed skull frac-
SECTION III

in the white matter of the frontal lobes on noncontrast CT tures are typically compound, but they are often asymp-
scan. These appear to reect an extreme type of the diffuse tomatic because the impact energy is dissipated in
axonal shearing lesions that occur with closed head injury.
breaking the bone; however, a few have underlying brain
contusions. Debridement and exploration of compound
fractures are required in order to avoid infection; simple
underlying subdural or epidural hematoma. Conse- fractures do not require surgery.
Diseases of the Central Nervous System

quently, fractures are primarily markers of the site and

severity of injury. They also provide potential pathways
CRANIAL NERVE INJURIES
for entry of bacteria (meningitis) or air (pneumocephalus)
to the CSF and for leakage of CSF out through the The cranial nerves most often injured with head trauma
dura. are the olfactory, optic, oculomotor, and trochlear; the
Most fractures are linear and extend from the point of rst and second branches of the trigeminal nerve; and
impact toward the base of the skull. Basilar skull fractures the facial and auditory nerves. Anosmia and an apparent
are often extensions of adjacent linear fractures over the loss of taste (actually a loss of perception of aromatic a-
convexity of the skull but may occur independently vors, with elementary taste perception retained) occur in
owing to stresses on the oor of the middle cranial fossa ~10% of persons with serious head injuries, particularly
or occiput. Basilar fractures are usually parallel to the after falls on the back of the head. This is the result of
petrous bone or along the sphenoid bone and directed displacement of the brain and shearing of the olfactory
toward the sella turcica and ethmoidal groove. Although nerve laments and may occur in the absence of a frac-
most basilar fractures are uncomplicated, they can cause ture. At least partial recovery of olfactory and gustatory
CSF leakage, pneumocephalus, and cavernous-carotid s- function is the rule, but if bilateral anosmia persists for
tulas. Hemotympanum (blood behind the tympanic several months, the prognosis is poor. Partial optic nerve
membrane), delayed ecchymosis over the mastoid process injuries from closed trauma result in blurring of vision,
(Battle sign), or periorbital ecchymosis (raccoon sign) central or paracentral scotomas, or sector defects. Direct
are associated signs. Because routine x-ray examination orbital injury may cause short-lived blurred vision for
may fail to disclose basilar fractures, they should be sus- close objects due to reversible iridoplegia. Diplopia lim-
pected if these clinical signs are present. ited to downward gaze and corrected when the head is
CSF may leak through the cribriform plate or the tilted away from the side of the affected eye indicates
adjacent sinus and allow a watery discharge from the trochlear nerve damage. It occurs frequently as an iso-
nose (CSF rhinorrhea). Persistent rhinorrhea and recur- lated problem after minor head injury or may develop
rent meningitis are indications for surgical repair of torn after a delay of several days without pathophysiologic
dura underlying the fracture.The site of the leak is often explanation. Direct facial nerve injury caused by a basi-
difcult to determine, but useful diagnostic tests include lar fracture is present immediately in up to 3% of severe
the instillation of water-soluble contrast into the CSF injuries; it may also be delayed 57 days. Fractures
followed by CT with the patient in various positions, or through the petrous bone, particularly the less common
injection of radionuclide compounds or uorescein into transverse type, are liable to produce facial palsy. Delayed
the CSF and the insertion of absorptive nasal pledgets. palsy, the mechanism of which is unknown, has a good
The site of an intermittent leak is rarely delineated, and prognosis. Injury to the eighth cranial nerve from a frac-
many resolve spontaneously. ture of the petrous bone causes loss of hearing, vertigo,
and nystagmus immediately after injury. Deafness from 403
eighth nerve injury must be distinguished from that due
to rupture of the eardrum, blood in the middle ear, or
disruption of the ossicles from fracture through the mid-
dle ear. Dizziness and high-tone hearing loss occur with
direct cochlear concussion.

SEIZURES
Convulsions are surprisingly uncommon immediately
after a head injury, but a brief period of tonic extensor
posturing or a few clonic movements of the limbs just
after the moment of impact can occur. However, the
cortical scars that evolve from contusions are highly
epileptogenic and may later manifest as seizures, even
FIGURE 31-3
after many years (Chap. 20). The severity of injury Acute subdural hematoma. Noncontrast CT scan reveals a
roughly determines the risk of future seizures. It has

CHAPTER 31
hyperdense clot which has an irregular border with the brain
been estimated that 17% of individuals with brain con- and causes more horizontal displacement (mass effect) than
tusion, subdural hematoma, or prolonged loss of con- might be expected from its thickness. The disproportionate
sciousness will develop a seizure disorder and that this mass effect is the result of the large rostral-caudal extent of
risk extends for an indenite period of time, whereas these hematomas. Compare to Fig. 31-4.
the risk is 2% after mild injury. The majority of con-
vulsions in the latter group occurs within 5 years of

Concussion and Other Head Injuries

injury but may be delayed for decades. Penetrating hematomas may be asymptomatic and usually do not
injuries have a much higher rate of subsequent epilepsy. require evacuation.
A subacutely evolving syndrome due to subdural
hematoma occurs days or weeks after injury with
SUBDURAL AND EPIDURAL HEMATOMAS
drowsiness, headache, confusion, or mild hemiparesis; it
Hemorrhages beneath the dura (subdural) or between usually arises in alcoholics and in the elderly, often after
the dura and skull (epidural) each have characteristic only minor trauma.
clinical and radiologic features. They are associated with On imaging studies subdural hematomas appear as
underlying contusions and other injuries, often making crescentic collections over the convexity of one or both
it difcult to determine the relative contribution of each hemispheres, most commonly in the frontotemporal
component to the clinical state. The mass effect and region, and less often in the inferior middle fossa or over
raised ICP caused by these hematomas may be life the occipital poles (Fig. 31-3). Interhemispheric, poste-
threatening, making it imperative to identify them rior fossa, or bilateral convexity hematomas are less fre-
rapidly by CT or MRI scan and to remove them when quent and are difcult to diagnose clinically, although
appropriate. drowsiness and the signs expected for damage in each
region can usually be detected. The bleeding that causes
larger hematomas is primarily venous in origin, although
Acute Subdural Hematoma additional arterial bleeding sites are sometimes found at
(Fig. 31-3) Up to one-third of patients have a lucid operation and a few large hematomas have a purely arte-
interval lasting minutes to hours before coma super- rial origin.
venes, but most are drowsy or comatose from the
moment of injury. Direct cranial trauma may be minor
Epidural Hematoma
and is not required for acute subdural hemorrhage to
occur, especially in the elderly and those taking antico- (Fig. 31-4) These evolve more rapidly than subdural
agulant medications. Acceleration forces alone, as from hematomas and are correspondingly more treacherous.
whiplash, are sometimes sufcient to produce subdural They occur in up to 10% of cases of severe head injury
hemorrhage. A unilateral headache and slightly enlarged but are associated with underlying cortical damage less
pupil on the same side are frequently but not invariably often than are subdural hematomas. Most patients are
present. Stupor or coma, hemiparesis, and unilateral unconscious when rst seen. A lucid interval of several
pupillary enlargement are signs of larger hematomas. In minutes to hours before coma supervenes is most char-
an acutely deteriorating patient, burr (drainage) holes or acteristic of epidural hemorrhage, but it is still uncom-
an emergency craniotomy are required. Small subdural mon, and epidural hemorrhage is by no means the only
 404

FIGURE 31-4 FIGURE 31-5

Acute epidural hematoma. The tightly attached dura is CT scan of chronic bilateral subdural hematomas of dif-
stripped from the inner table of the skull, producing a charac- ferent ages. The collections began as acute hematomas and
SECTION III

teristic lenticular-shaped hemorrhage on noncontrast CT have become hypodense in comparison to the adjacent brain
scan. Epidural hematomas are usually caused by tearing of after a period during which they were isodense and difcult
the middle meningeal artery following fracture of the tempo- to appreciate. Some areas of resolving blood are contained
ral bone. on the more recently formed collection on the left (arrows).
Diseases of the Central Nervous System

cause of this temporal sequence. Rapid surgical evacua- Skull x-rays are usually normal except for a shift of the
tion and ligation or cautery of the damaged vessel that is calcied pineal body to one side or an occasional unex-
the source of bleeding, usually the middle meningeal pected fracture. In long-standing cases an irregular calci-
artery that has been lacerated by an overlying skull frac- cation of membranes that surround the hematoma may
ture, is indicated. be appreciated. CT without contrast infusion shows a
low-density mass over the convexity of the hemisphere
(Fig. 31-5), but between 2 and 6 weeks after the initial
Chronic Subdural Hematoma
bleeding the hemorrhage becomes isodense compared to
A history of trauma may or may not be elicited in rela- adjacent brain and is then inapparent. Many subdural
tion to chronic subdural hematoma.The causative injury hematomas that are a week or more in age contain areas
may have been trivial and forgotten; 2030% of patients of blood adjacent to intermixed serous uid. Bilateral
recall no head injury, particularly the elderly and those chronic hematomas may fail to be detected because of the
with clotting disorders. Headache is common but not absence of lateral tissue shifts; this circumstance is sug-
invariable. Additional features may include slowed think- gested by a hypernormal CT scan with fullness of the
ing, vague change in personality, seizure, or a mild cortical sulci and small ventricles in an older patient.The
hemiparesis.The headache may uctuate in severity, some- infusion of contrast material demonstrates enhancement
times with changes in head position. Bilateral chronic of the vascular brous capsule surrounding the collection.
subdural hematomas produce perplexing clinical syn- MRI reliably identies subacute and chronic hematomas.
dromes. Focal signs such as hemiparesis may be lacking, Clinical observation coupled with serial imaging is a
and the initial clinical impression may be of a stroke, reasonable approach to patients with few symptoms and
brain tumor, drug intoxication, depression, or a dement- small chronic subdural collections. Treatment with glu-
ing illness because drowsiness, inattentiveness, and inco- cocorticoids alone is sufcient for some hematomas, but
herence of thought are more prominent than focal signs surgical evacuation is more often successful. The brous
such as hemiparesis. Patients with undetected bilateral membranes that grow from the dura and encapsulate the
subdural hematomas have a low tolerance for surgery, collection require removal to prevent recurrent uid
anesthesia, and drugs that depress the nervous system, accumulation. Small hematomas are resorbed, leaving
remaining drowsy or confused for long periods. Chronic only the organizing membranes. On imaging studies
hematomas rarely cause brief episodes of hemiparesis or very chronic subdural hematomas may be difcult to
aphasia that are indistinguishable from transient ischemic distinguish from hygromas, which are collections of CSF
attacks; on occasion a chronic collection can expand from a rent in the arachnoid membrane. As noted, corti-
over a period of days or weeks and clinically resemble a cal damage underlying a chronic hematoma may serve
brain tumor. as the origin of seizures.
 TABLE 31-1 405
CLINICAL SYNDROMES AND
GUIDELINES FOR MANAGEMENT OF CONCUSSION
TREATMENT OF HEAD INJURY IN SPORTS
MINOR INJURY Severity of Concussion
The patient who is fully alert and attentive minutes after Grade 1: Transient confusion, no loss of consciousness
head injury but who has one or more symptoms of (LOC), all symptoms resolve within 15 min.
Grade 2: Transient confusion, no LOC, but concussive
headache, dizziness, faintness, nausea, a single episode of symptoms or mental status abnormalities persist longer
emesis, difculty with concentration, or slight blurring than 15 min.
of vision has a good prognosis with little risk of subse- Grade 3: Any LOC, either brief (seconds) or prolonged
quent deterioration. Such patients have usually sustained (minutes).
a concussion and are expected to have a brief amnestic On-site Evaluation
period. Children are particularly prone to drowsiness, 1. Mental status testing
vomiting, and irritability, which are sometimes delayed a. Orientationtime, place, person, circumstances of
for several hours after apparently minor injuries.Vasova- injury
gal syncope that follows injury may cause undue concern. b. Concentrationdigits backward, months of year in
reverse order
Constant generalized or frontal headache is common in c. Memorynames of teams, details of contest, recent

CHAPTER 31
the following days. It may be migrainous (throbbing and events, recall of three words and objects at 0 and 5 min
hemicranial) in nature or aching and bilateral. After 2. Finger-to-nose with eyes open and closed
several hours of observation, patients with minor injury 3. Pupillary symmetry and reaction
may be accompanied home and observed for a day by a 4. Romberg and tandem gait
5. Provocative testing40-yard sprint, 5 push ups, 5 sit ups,
family member or friend; written instructions to return 5 knee bends (development of dizziness, headaches, or
if symptoms worsen should be provided. other symptoms is abnormal)
Persistent severe headache and repeated vomiting in

Concussion and Other Head Injuries

Management Guidelines
the context of normal alertness and no focal neurologic
Grade 1: Remove from contest. Examine immediately and at
signs are usually benign, but radiologic studies should be 5 min intervals. May return to contest if exam clears within
obtained and a period of observation in the hospital is 15 min. A second grade 1 concussion eliminates player for
justied. The decision to perform imaging tests depends 1 week, with return contingent upon normal neurologic
largely on clinical signs that indicate the impact was assessment at rest and with exertion.
severe (e.g., prolonged concussion, periorbital or mas- Grade 2: Remove from contest, cannot return for at least
1 week. Examine at frequent intervals on sideline. Formal
toid hematoma, repeated vomiting, palpable skull frac- neurologic exam the next day. If headache or other symp-
ture), on the seriousness of other bodily injuries, and on toms persist for 1 week or longer, CT or MRI scan is indi-
the degree of surveillance that can be anticipated after cated. After 1 full asymptomatic week, repeat neurologic
discharge. Two prospective studies have suggested that assessment at rest and with exercise before cleared to
older age, two or more episodes of vomiting, >30 min resume play. A second grade 2 concussion eliminates player
for at least 2 weeks following complete resolution of
of retrograde or persistent anterograde amnesia, seizure,
symptoms at rest or with exertion. If imaging shows
and concurrent drug or alcohol intoxication are sensi- abnormality, player is removed from play for the season.
tive (but not specic) indicators of intracranial hemor- Grade 3: Transport by ambulance to emergency department if
rhage that justify CT scanning. It is appropriate to be still unconscious or worrisome signs are present; cervical
more liberal in obtaining CT scans in children since a spine stabilization may be indicated. Neurologic exam and,
when indicated, CT or MRI scan will guide subsequent
small number, even without loss of consciousness, will
management. Hospital admission indicated when signs of
display intracranial lesions. pathology are present or if mental status remains abnormal.
If ndings are normal at the time of the initial medical
evaluation, the athlete may be sent home, but daily exams as
Concussion in Sports an outpatient are indicated. A brief (LOC for seconds) grade 3
concussion eliminates player for 1 week, and a prolonged
In the current absence of adequate data, a common
(LOC for minutes) grade 3 concussion for 2 weeks, following
sense approach has been taken to returning an athlete complete resolution of symptoms. A second grade 3
who has suffered a concussion to physical activities. It is concussion should eliminate player from sports for at least
generally advisable to avoid contact sports for several 1 month following resolution of symptoms. Any abnormality
days at least, and for weeks after a severe concussion or on CT or MRI scans should result in termination of the season
for the athlete, and return to play at any future time should be
after more than one minor concussion or if there are
discouraged.
protracted neurologic symptoms (Table 31-1). These
guidelines are designed to avoid cognitive decline and Source: Modied from Quality Standards Subcommittee of the
an extremely rare complication of recurrent head injury, American Academy of Neurology: The American Academy of
termed the second impact syndrome, in which cerebral Neurology Practice Handbook. The American Academy of Neurol-
ogy, St. Paul, MN, 1997.
swelling follows a minor head injury. There is some
 406 evidence that repeated concussions in football and soc- complications that follow severe brain injury can be
cer players are associated with mild but cumulative cog- treated. Hypoxia should be reversed and normal saline
nitive decits, but this topic is controversial. used as the preferred resuscitation uid. The nding of
an epidural or subdural hematoma or large intracerebral
hemorrhage is an indication for prompt surgery and
INJURY OF INTERMEDIATE SEVERITY
intracranial decompression in an otherwise salvageable
Patients who have persistent confusion, behavioral patient.The use of prophylactic anticonvulsants has been
changes, subnormal alertness, extreme dizziness, or focal recommended by some neurosurgeons but there is little
neurologic signs such as hemiparesis should be admitted supportive data. Management of raised ICP, a frequent
to the hospital and soon thereafter have a CT scan. Usu- feature of severe head injury, is discussed in Chap. 22.
ally a cerebral contusion or hematoma is found. The
common clinical syndromes in this group include (1) GRADING AND PROGNOSIS
delirium with a disinclination to be examined or moved,
In severe head injury, the clinical features of eye open-
expletive speech, and resistance if disturbed (anterior
ing, motor responses of the limbs, and verbal output
temporal lobe contusions); (2) a quiet, disinterested, slowed
have been found to be generally predictive of outcome.
mental state (abulia) with dull facial expression alternat-
These three features are summarized in the Glasgow
ing with irascibility (inferior frontal and frontopolar
Coma Scale; a score between 3 and 15 is assigned based
SECTION III

contusions); (3) a focal decit such as aphasia or mild

on responses (Table 31-2). Over 85% of patients with
hemiparesis (due to subdural hematoma or convexity
aggregate scores of <5 die within 24 h. However, a num-
contusion, or, less often but frequently missed, carotid
ber of patients with slightly higher scores and a poor
artery dissection); (4) confusion and inattention, poor
initial prognosis, including a few without pupillary light
performance on simple mental tasks, and uctuating or
responses, survive, suggesting that an initially aggressive
slightly erroneous orientation (associated with several
approach is justied in most patients. Patients <20 years,
Diseases of the Central Nervous System

types of injuries, including those described above as well

particularly children, may make remarkable recoveries
as medial frontal contusions and interhemispheric sub-
after having grave early neurologic signs. In one large
dural hematoma); (5) repetitive vomiting, nystagmus,
study of severe head injury, 55% of children had a good
drowsiness, and unsteadiness (usually from labyrinthine
outcome at 1 year, compared with 21% of adults. Older
concussion, but occasionally due to a posterior fossa
age, increased ICP, early hypoxia or hypotension, and
subdural hematoma or vertebral artery dissection); and
evidence on imaging of compression of the cisterns sur-
(6) diabetes insipidus (damage to the median eminence
rounding the brainstem and shift of midline structures
or pituitary stalk). Injuries of this degree are often complicated
are all poor prognostic signs. A delay in the evacuation
by drug or alcohol intoxication, and clinically inapparent cervi-
of large intracerebral hemorrhages is also associated with
cal spine injury may be present.
a poorer prognosis.
Most patients in this category, after appropriate surgi-
cal removal of hematomas, improve over several days or
weeks. During the rst week the state of alertness,
memory, and other cognitive functions often uctuates, TABLE 31-2
and irascibility or agitation is common. Behavioral GLASGOW COMA SCALE FOR HEAD INJURY
changes are worse at night, as with many other Eye opening (E) Verbal response (V)
encephalopathies, and may be treated with small doses Spontaneous 4 Oriented 5
of antipsychotic medications. Subtle abnormalities of To loud voice 3 Confused, disoriented 4
attention, intellect, spontaneity, and memory tend to To pain 2 Inappropriate words 3
return to normal weeks or months after the injury, Nil 1 Incomprehensible sounds 2
sometimes surprisingly abruptly. Persistent problems in Best motor Nil 1
response (M)
cognition are discussed below.
Obeys 6
Localizes 5
SEVERE INJURY Withdraws (exion) 4
Abnormal exion 3
Patients who are comatose from the onset require posturing
immediate neurologic attention and resuscitation. After Extension posturing 2
intubation, with care taken to immobilize the cervical Nil 1
spine, the depth of coma, pupillary size and reactivity,
limb movements, and Babinski responses are assessed. As Note: Coma score = E + M + V. Patients scoring 3 or 4 have an 85%
chance of dying or remaining vegetative, whereas scores >11 indi-
soon as vital functions permit and cervical spine x-rays cate only a 510% likelihood of death or vegetative state and 85%
and a CT scan have been obtained, the patient should chance of moderate disability or good recovery. Intermediate scores
be transported to a critical care unit where systemic correlate with proportional chances of recovery.
POSTCONCUSSION SYNDROME prolonged use of drugs that produce dependence. 407
The postconcussion syndrome refers to a state of nervous Vestibular exercises (Chap. 9) and small doses of vestibu-
instability following mild or moderate head injury. The lar suppressants such as phenergan may be helpful
main features are fatigue, dizziness, headache, and dif- when dizziness is the main problem. Patients who after
culty in concentration.The syndrome is at times difcult minor or moderate injury report difculty with memory
to distinguish from asthenia and depression. Based largely or with complex cognitive tasks at work may also be
on experimental models, it has been proposed that subtle reassured that these problems usually improve over
axonal shearing lesions or as yet undened biochemical 612 months. It is helpful to obtain serial and quantied
alterations account for the cognitive symptoms. In mod- neuropsychological testing in order to adjust the work
erate and severe trauma, neuropsychological changes environment to the patients current abilities and to
such as difculty with attention, memory, and other document improvement over time. Whether cognitive
cognitive decits are undoubtedly present, sometimes exercises are useful is uncertain, but patients certainly
severe, but many decits identied by formal testing do report them to be so. Previously energetic individuals
not impact daily functioning.Test scores tend to improve usually have the best recoveries. In patients with persis-
rapidly during the rst 6 months after injury, then more tent symptoms, the possibility exists of malingering or
slowly for years. prolongation as a result of litigation.

CHAPTER 31
Treatment: FURTHER READINGS
CONCUSSION
DISCHINGER PC et al: Early predictors of postconcussive syndrome
Management of the various symptoms of the postcon-
in a population of trauma patients with mild traumatic brain
cussive syndrome requires the identication and treat- injury. J Trauma 66:289, 2009

Concussion and Other Head Injuries

ment of depression, sleeplessness, anxiety, persistent LOVELL M: The management of sports-related concussion: current
headache, and dizziness. A clear explanation of the status and future trends. Clin Sports Med 28:95, 2009
problems that may follow concussion has been shown ROPPER AH (ed): Neurological and Neurosurgical Intensive Care, 4th ed.
to reduce subsequent complaints. Care is taken to avoid Philadelphia, Lippincott Williams & Wilkins, 2004
GORSON KC: Concussion. N Engl J Med 356:166, 2007
 CHAPTER 32
PRIMARY AND METASTATIC TUMORS
OF THE NERVOUS SYSTEM
Stephen M. Sagar Mark A. Israel

Primary Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Tuberous Sclerosis (Bournevilles Disease) . . . . . . . . . . . . . . 417

Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Von HippelLindau Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 417
Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 Tumors Metastatic to Brain . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Oligodendrogliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Mechanisms of Brain Metastases . . . . . . . . . . . . . . . . . . . . . 418
Ependymomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Evaluation of Metastases from Known Cancer . . . . . . . . . . . 418
Medulloblastomas and Primitive Neuroectodermal Brain Metastases Without a Known Primary Tumor . . . . . . . . 418
Tumors (PNET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Leptomeningeal Metastases . . . . . . . . . . . . . . . . . . . . . . . . . 420
CNS Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Laboratory and Imaging Evaluation . . . . . . . . . . . . . . . . . . . . 420
Schwannomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Malignant Spinal Cord Compression . . . . . . . . . . . . . . . . . . . 421
Other Benign Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 416 Metastases to the Peripheral Nervous System . . . . . . . . . . . 421
Neurocutaneous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 417 Complications of Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
Neurobromatosis Type 1 Radiation Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421
(Von Recklinghausens Disease) . . . . . . . . . . . . . . . . . . . . . 417 Toxicities of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Neurobromatosis Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422

Malignant primary tumors of the central nervous system of a focal neurologic decit; (2) seizure; or (3) nonfocal
(CNS) occur in ~16,500 individuals and account for an esti- neurologic disorder such as headache, dementia, person-
mated 13,000 deaths in the United States annually, a mortal- ality change, or gait disorder. The presence of systemic
ity rate of 6 per 100,000.The age-adjusted incidence appears symptoms such as malaise, weight loss, anorexia, or fever
to be about the same worldwide. An approximately equal suggests a metastatic rather than a primary brain tumor.
number of benign tumors of the CNS are diagnosed, with a Progressive focal neurologic decits result from
much lower mortality rate. Glial tumors account for 5060% compression of neurons and white matter tracts by
of primary brain tumors, meningiomas for 25%, schwanno- expanding tumor and surrounding edema. Less com-
mas for 10%, and other CNS tumors for the remainder. monly, a brain tumor presents with a sudden stroke-
Brain and vertebral metastases from systemic cancer like onset of a focal neurologic decit. Although this
are far more prevalent than primary CNS tumors. About presentation may be caused by hemorrhage into the
15% of patients who die of cancer (80,000 individuals tumor, often no hemorrhage can be demonstrated and
each year in the United States) have symptomatic brain the mechanism is obscure. Tumors frequently associ-
metastases; an additional 5% suffer spinal cord involve- ated with hemorrhage include high-grade gliomas,
ment. Brain and spinal metastases therefore pose a major metastatic melanoma, and choriocarcinoma.
problem in the management of systemic cancer. Seizures may result from disruption of cortical circuits.
Tumors that invade or compress the cerebral cortex, even
small meningiomas, are more likely to be associated with
Approach to the Patient:
BRAIN TUMORS
seizures than subcortical neoplasms. Nonfocal neurologic
dysfunction usually reects increased intracranial pressure
CLINICAL FEATURES Brain tumors usually present (ICP), hydrocephalus, or diffuse tumor spread.Tumors in
with one of three syndromes: (1) subacute progression some areas of the brain may produce behavioral disorders;
408
 for example, frontal lobe tumors may present with per- pattern of edema, with accumulation of excess water 409
sonality change, dementia, or depression. in surrounding white matter. Contrast enhancement
Headache may result from focal irritation or dis- reects a breakdown of the blood-brain barrier within
placement of pain-sensitive structures (Chap. 6) or the tumor, permitting leakage of contrast agent.
from a generalized increase in ICP. A headache that Low-grade gliomas typically do not exhibit contrast
worsens rather than abates with recumbency is sug- enhancement.
gestive of a mass lesion. Headaches from increased Positron emission tomography (PET) and single-
ICP are usually holocephalic and episodic, occurring photon emission tomography (SPECT) have ancillary
more than once a day. They typically develop rapidly roles in the imaging of brain tumors, primarily in dis-
over several minutes, persist for 2040 min, and sub- tinguishing tumor recurrence from tissue necrosis that
side quickly. They may awaken the patient from a can occur after irradiation (see below). Functional
sound sleep, generally 6090 min after retiring.Vom- imaging with PET, MRI, or magnetoencephalography
iting may occur with severe headaches. As elevated may be of use in surgical or radiosurgical planning to
ICP becomes sustained, the headache becomes con- dene the anatomic relationship of the tumor to critical
tinuous but varying in intensity. Elevated ICP may brain regions such as the primary motor or language
cause papilledema (Chap. 17), although it is often not cortex.

CHAPTER 32
present in infants or patients >55 years.
LABORATORY EXAMINATION Primary brain
The Karnofsky performance scale is useful in assess-
tumors typically do not produce serologic abnormali-
ing patients with brain tumors (Table 32-1). A score
ties such as an elevated sedimentation rate or tumor-
70 indicates that the patient is ambulatory and inde-
specic antigens. In contrast, metastases to the nervous
pendent in self-care activities; it is often taken as a
system, depending on the type and extent of the pri-
level of function justifying aggressive therapy.
mary tumor, may be associated with systemic signs of

Primary and Metastatic Tumors of the Nervous System

NEUROIMAGING CT and MRI can reveal mass malignancy. Lumbar puncture is generally not useful in
effect and contrast enhancement. Mass effect reects the diagnosis of brain tumors. The cerebrospinal uid
the volume of neoplastic tissue as well as surrounding (CSF) rarely contains malignant cells, with the impor-
edema. Brain tumors typically produce a vasogenic tant exceptions of leptomeningeal metastases; primary
CNS lymphoma; and primitive neuroectodermal tumors,
including medulloblastoma.The primary use of lumbar
puncture in the evaluation of a brain tumor is to
TABLE 32-1 exclude other diagnoses, such as infection or demyeli-
KARNOFSKY PERFORMANCE INDEX nating disease. Moreover, lumbar puncture may precip-
itate brain herniation in patients with mass lesions and
PERFORMANCE FUNCTIONAL CAPABILITY OF
STATUS THE PATIENT should be performed only in patients in whom imag-
ing studies have demonstrated the basilar cisterns to be
100 Normal; no complaints; no evidence of
patent.
disease
90 Able to carry on normal activity; minor
signs or symptoms of disease
80 Normal activity with effort; some signs
or symptoms of disease
70 Cares for self; unable to carry on Treatment:
normal activity or do active work BRAIN TUMORS
60 Requires occasional assistance but is
able to care for most needs SYMPTOMATIC Glucocorticoids decrease the volume
50 Requires considerable assistance and of edema surrounding brain tumors and improve neuro-
frequent medical care logic function; dexamethasone (initially 1220 mg/d in
40 Disabled; requires special care and divided doses PO or IV) is used because it has relatively
assistance
little mineralocorticoid activity. Because of the toxicities
30 Severely disabled; hospitalization is
indicated although death is not of long-term glucocorticoid administration, the dexam-
imminent ethasone dose is rapidly tapered to the lowest dose that
20 Very sick; hospitalization necessary; relieves symptoms.
active supportive treatment is The treatment of epilepsy associated with brain
necessary tumors is identical to the treatment of other forms of
10 Moribund, fatal processes progressing partial epilepsy. The rst-line agents phenytoin, carba-
rapidly
mazepine, and valproic acid are equally effective; levirac-
0 Dead
tam and oxcarbazepine are also coming into wide use
 410 (Chap. 20). It is common practice to administer anti- patients with hereditary predisposition syndromes (Table
epileptic drugs prophylactically to all patients with supra- 32-2), most brain tumors do not occur in patients with
tentorial brain tumors, although there are no good data such recognizable syndromes. As is the case in all other
supporting this practice. tumor types, somatic mutations are almost invariably
Gliomas and primary CNS lymphomas are associated present in malignant brain tumor tissue. Amplication of
with an increased risk for deep vein thrombosis and pul- the EGFR gene occurs in approximately one-third of
monary embolism, probably because these tumors cases of glioblastoma multiforme (GBM), the highest
secrete procoagulant factors into the systemic circulation. grade astrocytoma. Moreover, cytogenetic analysis often
Even though hemorrhage within gliomas is a frequent reveals characteristic changes that can signal the alter-
histopathologic nding, patients are at no increased risk ation in cancer-related genes within these chromosomal
for symptomatic intracranial bleeding following treat- regions. In astrocytic tumors, DNA is commonly lost on
ment with an anticoagulant. Prophylaxis with low-dose chromosomes 10p, 17p, 13q, and 9. Oligodendrogliomas
SC heparin should be employed for patients with brain frequently have deletions of 1p and 19q, resulting from a
tumors who have lower limb immobility, which places centromeric translocation and loss of one of the translo-
them at risk for deep venous thrombosis. cated chromosomes. In meningiomas portions of 22q,
which contains the gene for neurobromatosis (NF)
type 2, are often lost.
SECTION III

The particular constellation of genetic alterations

varies among individual gliomas, even those that are
PRIMARY BRAIN TUMORS histologically indistinguishable. Moreover, gliomas are
genetically unstable. Genetic abnormalities tend to accu-
ETIOLOGY
mulate with time, and these changes correspond with an
Exposure to ionizing radiation is the only well- increasingly malignant phenotype.There are at least two
Diseases of the Central Nervous System

documented environmental risk factor for the develop- genetic routes for the development of GBM (Fig. 32-1).
ment of gliomas. A number of hereditary syndromes One route involves the progression, generally over years,
are associated with an increased risk of brain tumors from a low-grade astrocytoma with deletions of chro-
(Table 32-2). Genes that contribute to the development mosome 17 and inactivation of the p53 gene to a highly
of brain tumors, as well as other malignancies, fall into malignant glioma with additional chromosomal alter-
two general classes, tumor-suppressor genes and oncogenes. ations.The second route is characterized by the de novo
Whereas germ-line mutations of such genes do occur in appearance of a malignant glioma with amplication of

TABLE 32-2
HEREDITARY SYNDROMES ASSOCIATED WITH BRAIN TUMORS

SYNDROME GENE (LOCUS) GENE PRODUCT (FUNCTION) NERVOUS SYSTEM NEOPLASMS

Neurobromatosis type 1 NF1 (17q) Neurobromin (GTPase Neuroma, schwannoma,

(von Recklinghausens activating protein) meningioma, optic glioma
Disease)a
Neurobromatosis type 2a NF2 (22q) Merlin (cytoskeletal protein) Schwannoma, glioma,
ependymoma, meningioma
Tuberous sclerosis TSC1 (9q) Hamartin (unknown function) Astrocytoma
TSC2 (16p) Tuberin (GTPase activating protein) Hemangioblastoma of retina,
von Hippel-Lindaua VHL (3p) pVHL (modulator of cellular cerebellum and spinal cord;
hypoxic response) pheochromocytoma
Li-Fraumenia p53 (17p) TP53 (cell cycle and transcriptional Malignant glioma
regulator)
Retinoblastomaa RB1 (13q) RB (cell cycle regulator) Retinoblastoma, pineoblastoma,
malignant glioma
Turcot APC (5q) APC (cell adhesion) Medulloblastoma,
(adenomatous malignant glioma
polyposis coli)
Gorlin (basal cell nevus PTCH (9q) PTH (developmental regulator) Medulloblastoma
syndrome) (patched)
Multiple endocrine neoplasia MEN1 (11q13) Menin (cofactor for transcription) Pituitary adenoma, malignant
1 (Werner syndrome)a schwannoma

a
Genetic testing possible.
 411
Cell of origin Cell of origin

EGFR amplification LOH 17p (p53)

LOH 10 (PTEN) Astrocytoma

WHO Grade II

LOH 19q
CDK4 amplification LOH 9p (INK4a)

Astrocytoma
MDM2 amplification WHO Grade III

Other LOH (e.g., DCC) LOH 10q (PTEN)

Other LOH (eg.,DCC)

Other amplification
Other amplification (e.g., PDGFR)
(e.g., PDGFR)

CHAPTER 32
de novo: GBM, Secondary: GBM, FIGURE 32-2
WHO Grade IV WHO Grade IV Malignant astrocytoma (glioblastoma). Coronal proton
densityweighted MR scan through the temporal lobes
FIGURE 32-1 demonstrates a heterogeneous right temporal lobe mass
Model for the pathogenesis of human astrocytoma. (arrows) compressing the third and lateral ventricles. The
Glioblastoma multiforme (GBM) typically presents without area of hypointense signal (double arrows) indicates either

Primary and Metastatic Tumors of the Nervous System

evidence of a precursor lesion, referred to as de novo GBM, hemorrhage or calcication. Heterogeneous MR signal inten-
frequently associated with amplication of the epidermal sity is typical of glioblastoma.
growth factor receptor (EGFR) gene. Less commonly, GBM
arises in association with progressive genetic alterations
after the diagnosis of a lower grade astrocytoma. These
tumors are referred to as secondary GBM. The most widely cytoplasmic atypia, endothelial proliferation, mitotic activ-
described alterations are mutations of p53 and INK4a. Other ity, and necrosis. Endothelial proliferation and necrosis are
genes implicated in the development of these primary brain strong predictors of aggressive behavior.
tumors include CDK4, MDM2, DDC, and PDGFR. LOH, loss Quantitative measures of mitotic activity also corre-
of heterozygosity. late with prognosis.The proliferation index can be deter-
mined by immunohistochemical staining with antibodies
to the proliferating cell nuclear antigen (PCNA) or with
a monoclonal antibody termed Ki-67, which recognizes
the EGFR gene and an intact p53 gene in association a histone protein expressed in proliferating but not qui-
with other genetic abnormalities. escent cells.
The prognosis of brain tumor patients is closely asso-
ASTROCYTOMAS ciated with the histologic grade of the tumor. In a repre-
sentative Finnish population, the median survival was 93.5
Tumors with astrocytic cytologic features are the most months for patients with grade I or II astrocytomas, 12.4
common primary intracranial neoplasms (Fig. 32-2). months for patients with grade III (anaplastic astrocy-
The most widely used histologic grading system is the toma), and 5.1 months for patients with grade IV (GBM)
World Health Organization four-tiered grading system. tumors.Although these survival rates are somewhat lower
Grade I is reserved for special histologic variants of than are generally reported, they represent a population-
astrocytoma that occur mainly in childhood and can based experience and are not inuenced by selection
have an excellent prognosis after surgical excision.These bias. Clinical features correlating with poor prognosis
include juvenile pilocytic astrocytoma, subependymal giant cell include age >65 years and a poor functional status, as
astrocytoma (which most often occurs in patients with dened by the Karnofsky performance scale.
tuberous sclerosis), and pleiomorphic xanthoastrocytoma. At
the other extreme is grade IV GBM, a clinically aggres-
Low-Grade Astrocytoma
sive tumor. Astrocytoma (grade II) and anaplastic astrocy-
toma (grade III) are intermediate in their histologic and Low-grade astrocytomas are more common in children
clinical manifestations. The histologic features associated than adults. Pilocytic astrocytoma, named for its character-
with higher grade are hypercellularity, nuclear and istic spindle-shaped cells, is the most common childhood
 412 brain tumor and is typically benign. It frequently occurs primary glial tumors, radiation is generally administered
in the cerebellum and is well demarcated from adjacent to the tumor mass, as dened by contrast enhancement
brain. Complete surgical excision usually produces long- on a CT or MRI scan, plus a 2-cm margin. A total dose
term, disease-free survival. of 50007000 cGy is administered in 2535 equal frac-
The median overall survival of grade II astrocytoma is tions, 5 days per week.
56 years. The optimum timing of surgery and radiation The roles of stereotaxic radiosurgery and interstitial
therapy for these patients is unknown. Since astrocytomas brachytherapy in glioma treatment are uncertain. Stereo-
inltrate surrounding brain, total surgical excision is taxic radiosurgery is the administration of a focused high
impossible. Moreover, they are genetically unstable and dose of radiation to a precisely dened volume of tissue
accumulate mutations over time, leading to more aggres- in a single treatment. Stereotaxic radiosurgery can poten-
sive behavior. For patients who are symptomatic from mass tially achieve tumor ablation within the treated volume.
effect or poorly controlled epilepsy, surgical excision can A major limitation of stereotaxic radiosurgery is that
relieve symptoms. For patients who are asymptomatic or it can be used for only relatively small tumors, generally
minimally symptomatic at presentation, a diagnostic biopsy <4 cm in maximum diameter. Interstitial brachytherapy, the
should be performed and, when surgically feasible, the implantation of radioactive material into the tumor mass,
tumor may be resected. Whether radiation therapy is is generally reserved for tumor recurrence because of its
administered immediately postoperatively or at the time of associated toxicity, necrosis of adjacent brain tissue.
SECTION III

tumor progression is not thought to affect overall survival, Chemotherapy is marginally effective and is often
but immediate radiation therapy does delay tumor pro- used as an adjuvant therapy following surgery and radia-
gression. No role for chemotherapy in the management of tion therapy. Temozolomide, an orally administered
low-grade astrocytoma has been dened. alkylating agent, has replaced nitrosureas, including car-
mustine (BCNU) and lomustine (CCNU), as the most
High-Grade Astrocytoma widely used chemotherapeutic agent for high-grade
Diseases of the Central Nervous System

gliomas.Temozolomide is generally better tolerated than

The large majority of astrocytomas arising in adults are nitrosoureas, notably producing less fatigue and pulmonary
high grade, supratentorial, and do not have a clearly dened toxicity, and has the advantage of oral administration.
margin between normal and malignant tissue. Neoplastic Moreover, a randomized trial of radiation therapy plus
cells migrate away from the main tumor mass and inltrate temozolomide for the adjuvant treatment of GBM com-
adjacent brain, often tracking along white matter pathways. pared to radiation therapy alone was the rst clinical
Imaging studies do not indicate the full extent of the trial to demonstrate a clear-cut advantage of adjuvant
tumor.These tumors are almost all eventually fatal. Median chemotherapy for that disease. The patients who
survival of patients with grade III astrocytoma is <3 years received radiation therapy plus temozolomide had a
and for those with a grade IV tumor, <1 year. Longer sur- median survival 21/2 months longer than those who
vival correlates with younger age, better performance sta- received radiation therapy alone. The modest survival
tus, and greater extent of surgical resection. Late in their benet appears to be restricted to a subgroup of patients
course, astrocytomas, especially those located in the poste- with methylation and silencing of the promoter for the
rior fossa, can metastasize along CSF pathways to the spine. MGMT gene coding for O6-methylguanine-DNA
Metastases outside the CNS are rare. methyltransferase.
High-grade astrocytomas are managed with gluco- An alternative approach to the chemotherapy of
corticoids, surgery, radiation therapy, and chemotherapy. high-grade gliomas that has shown survival benet in
Dexamethasone is generally administered at the time of controlled trials is the surgical implantation directly into
diagnosis and continued for the duration of radiation the tumor resection cavity of polymer wafers that release
therapy. After completion of radiation therapy, dexam- BCNU locally into surrounding brain. The efcacy of
ethasone is tapered to the lowest possible dose. this approach is similar to but probably slightly less than
Because astrocytomas inltrate adjacent normal brain, that of temozolomide, although without the attendant
total surgical excision is not possible. Nevertheless, retro- systemic toxicity of chemotherapy.
spective studies indicate that the extent of tumor resection Experimental approaches to brain tumor chemother-
correlates with survival in younger patients. Therefore, apy include efforts to bypass the blood-brain barrier
accessible astrocytomas are generally resected aggressively. using local injection of chemotherapeutic agents into the
Surgery is indicated to obtain tissue for pathologic diag- tumor mass or the intraarterial injection of chemotherapy
nosis and to control mass effect. following osmotic disruption of the blood-brain barrier.
Postoperative radiation therapy prolongs survival and Molecularly targeted therapies are also being tested in
improves quality of life. Treated with dexamethasone patients with GBM. In particular, since mutation or
alone following surgery, the mean survival of patients overexpression of EGFR is common in GBM, EGFR
<65 years with glioblastoma is 79 months. Survival is antagonists or inhibitors of its signaling pathways are
prolonged to 1113 months with radiation therapy. For being evaluated in patients with GBM in clinical trials.
 Gliomatosis cerebri is a rare form of astrocytoma in Surgery, at minimum a stereotaxic biopsy, is necessary 413
which there is diffuse inltration of the brain by malig- to establish a diagnosis. Many oligodendrogliomas are
nant astrocytes without a focal enhancing mass. It gener- amenable to gross total surgical resection. In addition,
ally presents as a multifocal CNS syndrome or a more oligodendrogliomas may respond dramatically to systemic
generalized disorder including dementia, personality combination chemotherapy with procarbazine, lomustine,
change, or seizures. Neuroimaging studies are often non- and vincristine (PCV), or to temozolomide, which,
specic, and biopsy is required to establish the diagnosis. although not approved by the U.S. Food and Drug
Gliomatosis cerebri is treated with whole-brain radiation Administration (FDA) for this indication, is currently
therapy or temozolomide; in selected patients, radiation to much more widely used than PCV. Oligodendrogliomas
the entire neuroaxis is employed. with deletions of chromosome 1p always respond to
chemotherapy, but only ~25% of oligodendrogliomas
OLIGODENDROGLIOMAS lacking the 1p deletion respond. The simultaneous dele-
tion of 1p and 19q, which results from a centromeric
Oligodendrogliomas, which comprise about 15% of translocation of chromosomes 1 and 19, predicts a durable
gliomas in adults, have a more benign course and are response to chemotherapy (>31 months on average) and
more responsive to cytotoxic treatment than astrocy- a much longer survival. It appears that the chromosomal
tomas. For grade II oligodendrogliomas, the median sur- translocation identies a subgroup of anaplastic oligoden-

CHAPTER 32
vival is 78 years, and there are a substantial number of drogliomas with a less aggressive natural course, and
patients with prolonged survival (>10 years). For grade response to chemotherapy is another marker of that
III or anaplastic oligodendrogliomas, median survival is favorable phenotype.
~5 years. Oligodendrogliomas occur chiey in supraten-
torial locations; in adults, ~30% contain areas of calci-
EPENDYMOMAS
cation (Fig. 32-3).

Primary and Metastatic Tumors of the Nervous System

As a rule, oligodendrogliomas are less inltrative than In adults, the most frequent histologic type is myxopapil-
astrocytomas, permitting more complete surgical exci- lary ependymoma, which typically arises from the lum
sion. Histologic features of mitoses, necrosis, and nuclear terminale of the spinal cord and appears in the lum-
atypia are associated with a more aggressive clinical course. bosacral region. The term myxopapillary refers to the
If these features are prominent, the tumor is termed an papillary arrangement of tumor cells, which produce
anaplastic oligodendroglioma. Some gliomas contain mixtures mucin. Ependymomas in adults may also occur intracra-
of cells with astrocytic and oligodendroglial features. If nially or at higher levels of the spinal cord. On CT or
this mixed histology is prominent, the tumor is termed MRI, ependymomas typically appear as diffusely
a mixed glioma, or an oligoastrocytoma. The greater the enhancing masses relatively well demarcated from adja-
oligodendroglial component, the more benign the clini- cent neural tissue. Following gross total resection, the
cal course. prognosis is good, with >80% 5-year disease-free survival.

FIGURE 32-3
Oligodendroglioma. A. Noncontrast
CT scan reveals a calcied mass
involving the left temporal lobe
(arrows) associated with mild mass
effect but little edema. B. An MR T2-
weighted image demonstrates a het-
erogeneous mass with hypointense
signal (black arrows) surrounded by a
zone of higher signal intensity (white
arrows), consistent with a calcified
temporal lobe mass. The tumor
extends into the left medial temporal
A B lobe and compresses the midbrain.
 414 Ependymomas that cannot be totally resected are treated mainstay of denitive therapy is chemotherapy. A single
with stereotaxic radiosurgery or with a course of exter- dose of rituximab is generally administered prior to cyto-
nal beam radiation therapy. toxic chemotherapy as long as an enhancing mass lacking a
blood-tumor barrier is present. Chemotherapy includes
high-dose methotrexate, but multiagent chemotherapy,
MEDULLOBLASTOMAS AND PRIMITIVE
usually adding vincristine and procarbazine, appears to be
NEUROECTODERMAL TUMORS (PNET)
more effective than methotrexate alone. Chemotherapy is
These highly cellular malignant tumors are thought to followed in patients <60 years with whole-brain radiation
arise from neural precursor cells. Medulloblastomas occur therapy (WBRT). WBRT is postponed as long as possible
in the posterior fossa and, along with astrocytomas, are or administered at reduced doses in patients >60 years
the most frequent malignant brain tumors of children. because of the risk of dementia, gait disorder, and inconti-
PNET is a term applied to tumors histologically indis- nence as manifestations of late-delayed radiation toxicity.
tinguishable from medulloblastoma but occurring either Consolidation therapy is typically with high-dose cytara-
in adults or supratentorially in children. In adults, >50% bine. Intraarterial chemotherapy with or without blood-
present in the posterior fossa. These tumors frequently brain barrier disruption is an alternative. Intrathecal
disseminate along CSF pathways. chemotherapy with methotrexate can be added if lep-
If possible, these tumors should be surgically excised; tomeningeal disease is present, but it has not proven to offer
SECTION III

the less residual tumor left behind, the better the prog- added benet if high-dose methotrexate is used. Despite
nosis. In adults, surgical excision of a PNET should be aggressive therapy, >90% of patients develop recurrent
followed by irradiation of the entire neuraxis, with a CNS disease.The median survival of patients who tolerate
boost in radiation dose to the primary tumor. If the treatment with high-dose methotrexate is >3 years.
tumor is not disseminated at presentation, the prognosis In immunodecient patients, primary CNS lym-
is generally favorable. Aggressive treatment can result in phoma may be ring-enhancing rather than diffusely
Diseases of the Central Nervous System

prolonged survival, although half of adult patients enhancing on CT or MRI (Fig. 32-4). It may therefore
relapse within 5 years of treatment.Whereas chemother- be impossible by imaging criteria to distinguish primary
apy is widely used in medulloblastoma and PNET in CNS lymphoma from metastatic malignancies or infec-
children, its role in adults is not yet dened. tions, particularly toxoplasmosis. The standard approach
to this dilemma in a neurologically stable patient is to
CNS LYMPHOMA administer antibiotics to treat toxoplasmosis for 23 weeks
and then repeat neuroimaging. If the imaging shows
Primary CNS Lymphoma
clear improvement, antibiotic treatment is continued. If
Primary CNS lymphoma is typically a high-grade B cell not, a stereotaxic brain biopsy, which has substantially
malignancy that presents within the neuraxis without more risk in an immunodecient than an immunocom-
evidence of systemic lymphoma. These occur most fre- petent patient, is performed. Alternatively, when the
quently in immunocompromised individuals, specically clinical situation permits a safe lumbar puncture, a CSF
organ transplant recipients and patients with AIDS examination demonstrating Epstein-Barr virus DNA in
(Chap. 37). In immunocompromised patients, CNS lym- CSF in an immunodecient patient with neuroimaging
phomas are invariably associated with Epstein-Barr virus ndings consistent with lymphoma is diagnostic of pri-
infection of the tumor cells. mary CNS lymphoma. In organ transplant recipients,
In immunocompetent patients, neuroimaging studies reversal of the immunosuppressed state can improve
most often reveal a uniformly enhancing mass lesion. outcome. Survival with AIDS-related primary CNS
Stereotaxic needle biopsy can be used to establish the lymphoma is very poor, generally 3 months; pretreat-
diagnosis.There is no benet of surgical resection unless ment performance status, the degree of immunosuppres-
there is a need for immediate decompression of a life- sion, and the extent of CNS dissemination at diagnosis
threatening mass effect. Leptomeningeal involvement is all appear to inuence outcome.
present in ~15% of patients at presentation and in 50%
at some time during the course of the illness. Moreover,
Secondary CNS Lymphoma
the disease extends to the eyes in up to 15% of patients.
Therefore, a slit-lamp examination and, if indicated, Secondary CNS lymphoma is a manifestation of sys-
anterior chamber paracentesis or vitreous biopsy is nec- temic disease and almost always occurs in adults with
essary to dene radiation ports. progressive B cell lymphoma or B cell leukemia who
The prognosis of primary CNS lymphoma is poor have tumor involvement of bone, bone marrow, testes,
compared to histologically similar lymphoma occurring or the cranial sinuses. The leptomeninges are the most
outside the CNS. Many patients experience a dramatic common site of CNS metastasis. Leptomeningeal lym-
clinical and radiographic response to glucocorticoids; how- phoma is usually detectable with contrast-enhanced CT
ever, relapse almost invariably occurs within weeks. The or gadolinium-enhanced MRI of the brain and spine
 415

A B C

CHAPTER 32
FIGURE 32-4
CNS lymphoma. A. Proton densityweighted MR image lymphoma or toxoplasmosis; the presence of multiple lesions
through the temporal lobe demonstrates a low signal inten- favors toxoplasmosis. C. In a different patient with lymphoma-
sity nodule (small arrows) surrounded by a ring of high signal tous meningitis, an axial postcontrast T1-weighted MRI
intensity edema (larger arrows). B. T1-weighted contrast- through the midbrain demonstrates multiple areas of abnor-
enhanced axial MRI demonstrates ring enhancement sur- mal enhancement in periventricular and subependymal
rounded by a nonenhanced rim of edema. In this patient with regions (arrows). Lymphoma tends to spread subependy-

Primary and Metastatic Tumors of the Nervous System

AIDS, a solitary lesion of this type is consistent with either mally at interfaces of CSF and brain parenchyma.

or by CSF examination. Treatment consists of systemic Total surgical resection of benign meningiomas is
chemotherapy, intrathecal chemotherapy, and CNS irradi- curative. If a total resection cannot be achieved, local
ation. It is usually possible to suppress the leptomeningeal external beam radiotherapy or stereotaxic radiosurgery
disease effectively, although the overall prognosis is deter- reduces the recurrence rate to <10%. For meningiomas
mined by the course of the systemic lymphoma. Intra- that are not surgically accessible, radiosurgery is the
parenchymal lymphoma metastases may be treated with treatment of choice. Small asymptomatic meningiomas
radiation therapy or systemic chemotherapy. incidentally discovered in older patients can safely be
followed radiologically; these tumors grow at an average
rate of a few millimeters in diameter per year and only
MENINGIOMAS
rarely become symptomatic.
Meningiomas are derived from mesoderm, probably from Rare meningiomas invade the brain or have histologic
cells giving rise to the arachnoid granulations.These tumors evidence of malignancy such as nuclear pleomorphism
are usually benign and attached to the dura. They may and cellular atypia. A high mitotic index is also predictive
invade the skull but only infrequently invade the brain. of aggressive behavior. Hemangiopericytoma, although not
Meningiomas most often occur along the sagittal sinus, strictly a meningioma, is a meningeal tumor with an
over the cerebral convexities, in the cerebellar-pontine especially aggressive behavior. Meningiomas with fea-
angle, and along the dorsum of the spinal cord.They are tures of aggressiveness and hemangiopericytomas, even if
more frequent in women than men, with a peak inci- totally excised by gross inspection, frequently recur and
dence in middle age. should receive postoperative radiotherapy. Chemotherapy
Meningiomas may be found incidentally on a CT or has no proven benet.
MRI scan or may present with a focal seizure, a slowly
progressive neurologic decit, or symptoms of raised
SCHWANNOMAS
ICP. The radiologic image of a dural-based, extraaxial
mass with dense, uniform contrast enhancement is These tumors are also called neuromas, neurinomas, or neu-
essentially diagnostic, although a dural metastasis must rolemmomas.They arise from Schwann cells of nerve roots,
also be considered (Fig. 32-5). A meningioma may have most frequently in the eighth cranial nerve (vestibular
a dural tail, a streak of dural enhancement anking the schwannoma, formerly termed acoustic schwannoma or
main tumor mass; however, this nding may also be pre- acoustic neuroma).The fth cranial nerve is the second most
sent with other dural tumors. frequent site; however, schwannomas may arise from any
 416 vestibular system adapts to slow destruction of the eighth
nerve, patients with vestibular schwannomas characteris-
tically present with progressive unilateral hearing loss rather
than with dizziness or other vestibular symptoms. Unex-
plained unilateral hearing loss merits evaluation with
audiometry and an MRI scan (Chap. 18). As a vestibular
schwannoma grows, it can compress the cerebellum,
pons, or facial nerve.With rare exceptions schwannomas
are histologically and clinically benign.
Whenever possible, schwannomas should be surgi-
cally excised. When the tumors are small, it is usually
possible to preserve hearing in the involved ear. In the
case of large tumors, the patient is usually deaf at presen-
tation; nonetheless, surgery is indicated to prevent fur-
ther compression of posterior fossa structures. Stereotaxic
radiosurgery is also effective treatment for schwannoma
and has a complication rate equivalent to that of surgery.
SECTION III

FIGURE 32-5 OTHER BENIGN BRAIN TUMORS

Meningioma. Coronal postcontrast T1-weighted MR image Epidermoid tumors are cystic tumors with proliferative epi-
demonstrates an enhancing extraaxial mass arising from the dermal cells at the periphery and more mature epidermal
falx cerebri (arrows). There is a dural tail of contrast enhance- cells towards the center of the cyst. The mature cells
ment extending superiorly along the intrahemispheric septum.
Diseases of the Central Nervous System

desquamate into the liquid center of the cyst. Epider-

moid tumors are thought to arise from embryonic epi-
dermal rests within the cranium. They occur extraaxially
cranial or spinal root except the optic and olfactory near the midline, in the middle cranial fossa, the suprasel-
nerves, which are myelinated by oligodendroglia rather lar region, or the cerebellopontine angle. These well-
than Schwann cells. Neurobromatosis (NF) type 2 (see demarcated lesions are amenable to complete surgical
below) strongly predisposes to vestibular schwannoma. excision. Postoperative radiation therapy is unnecessary.
Schwannomas of spinal nerve roots also occur in patients Dermoid cysts are thought to arise from embryonic
with NF type 2 as well as patients with NF type 1. rests of skin tissue trapped within the CNS during clo-
Eighth cranial nerve schwannomas typically arise from sure of the neural tube. The most frequent locations are
the vestibular division of the nerve. On MRI they are in the midline supratentorially or at the cerebellopon-
densely and uniformly enhancing neoplasms (Fig. 32-6). tine angle. Histologically, they are composed of multiple
Vestibular schwannomas enlarge the internal auditory elements of the dermis including epidermis, hair folli-
canal, an imaging feature that helps distinguish them cles, and sweat glands; they frequently calcify. Treatment
from other cerebellopontine angle masses. Because the is surgical excision.

FIGURE 32-6
Vestibular schwannoma. A. Axial noncontrast MR
scan through the cerebellopontine angle demon-
strates an extraaxial mass that extends into a
widened internal auditory canal, displacing the
pons (arrows). B. Postcontrast T1-weighted image
demonstrates intense enhancement of the vestibu-
lar schwannoma (white arrow). Abnormal enhance-
ment of the left fth nerve (black arrow) most likely
represents another schwannoma in this patient
A B with neurobromatosis type 2.
 Craniopharyngiomas are thought to arise from remnants NEUROFIBROMATOSIS TYPE 2 417
of Rathkes pouch, the mesodermal structure from which
NF2 is characterized by the development of bilateral
the anterior pituitary gland is derived (Chap. 33). Cranio-
vestibular schwannomas in >90% of individuals who
pharyngiomas typically present as suprasellar masses.
inherit the gene. Patients with NF2 also have a predispo-
Because of their location, they may present as growth fail-
sition for the development of meningiomas, gliomas, and
ure in children, endocrine dysfunction in adults, or visual
schwannomas of cranial and spinal nerves. In addition, a
loss in either age group. Histologically, craniopharyn-
characteristic type of cataract, juvenile posterior subcap-
giomas resemble epidermoid tumors; they are usually
sular lenticular opacity, occurs in NF2. Multiple caf au
cystic, and in adults 80% are calcied. Treatment is surgi-
lait spots and peripheral neurobromas occur rarely.
cal excision; postoperative external beam radiation or
In patients with NF2, vestibular schwannomas are usu-
stereotaxic radiosurgery is added if total surgical removal
ally associated with progressive unilateral deafness early in
cannot be achieved.
the third decade of life. Bilateral vestibular schwannomas
Colloid cysts are benign tumors of unknown cellular
are generally detectable by MRI at that time (Fig. 32-6).
origin that occur within the third ventricle and can
Surgical management is designed to treat the underlying
obstruct CSF ow. Other rare benign primary brain tumors
tumor and preserve hearing as long as possible.
include neurocytomas, subependymomas, and pleomor-
This syndrome is caused by mutation of the NF2
phic xanthoastrocytomas. Surgical excision of these neo-

CHAPTER 32
gene on chromosome 22q. NF2 encodes a protein called
plasms is the primary treatment and can be curative.
neurobromin 2, schwannomin, or merlin, with homology to
Pituitary tumors are discussed in Chap. 33.
a family of cytoskeletal proteins that includes moesin,
ezrin, and radixin.
NEUROCUTANEOUS SYNDROMES
TUBEROUS SCLEROSIS (BOURNEVILLES
DISEASE)

Primary and Metastatic Tumors of the Nervous System

This group of genetic disorders, also known as the phako-
matoses, produces a variety of developmental abnormalities Tuberous sclerosis is characterized by cutaneous lesions,
of skin along with an increased risk of nervous system seizures, and mental retardation. The cutaneous lesions
tumors (Table 32-2). These disorders are inherited as include adenoma sebaceum (facial angiobromas), ash
autosomal dominant conditions with variable penetrance. leafshaped hypopigmented macules (best seen under
ultraviolet illumination with a Woods lamp), shagreen
NEUROFIBROMATOSIS TYPE 1 patches (yellowish thickenings of the skin over the lum-
(VON RECKLINGHAUSENS DISEASE) bosacral region of the back), and depigmented nevi.
Recognizable by neuroimaging studies, the presence of
NF1 is characterized by cutaneous neurobromas, pig- subependymal nodules, which may be calcied, is char-
mented lesions of the skin called caf au lait spots, freckling acteristic.Tuberous sclerosis patients are at increased risk
in non-sun-exposed areas such as the axilla, hamartomas of developing ependymomas and childhood astrocy-
of the iris termed Lisch nodules, and pseudoarthrosis of the tomas, of which >90% are subependymal giant cell astrocy-
tibia. Neurobromas are benign peripheral nerve tumors tomas. These are benign neoplasms that may develop in
composed of proliferating Schwann cells and broblasts. the retina or along the border of the lateral ventricles.
They present as multiple, palpable, rubbery, cutaneous They may obstruct the foramen of Monro and produce
tumors.They are generally asymptomatic; however, if they hydrocephalus. Rhabdomyomas of the myocardium and
grow in an enclosed space, e.g., the intervertebral fora- angiomyomas of the kidney, liver, adrenals, and pancreas
men, they may produce a compressive radiculopathy or may also occur.
neuropathy. Aqueductal stenosis with hydrocephalus, scol- Treatment is symptomatic.Anticonvulsants for seizures,
iosis, short stature, hypertension, epilepsy, and mental shunting for hydrocephalus, and behavioral and educa-
retardation may also occur. tional strategies for mental retardation are the mainstays
Patients with NF1 are at increased risk of developing of management. Severely affected individuals generally
nervous system neoplasms, including plexiform neurobro- die before 30 years of age.
mas, optic pathway gliomas, ependymomas, meningiomas, Mutations in either the TSC-1 gene at 9q or the
astrocytomas, and pheochromocytomas. Neurobromas may TSC-2 gene at 16p are associated with tuberous sclero-
undergo secondary malignant degeneration and become sis. These genes encode tuberins, proteins that modulate
sarcomatous. the GTPase activity of other cellular signaling proteins.
Mutation of the NF1 gene on chromosome 17 causes
von Recklinghausens disease.The NF1 gene is a tumor-
VON HIPPELLINDAU SYNDROME
suppressor gene; it encodes a protein, neurobromin, which
modulates signal transduction through the ras GTPase This syndrome consists of retinal, cerebellar, and spinal
pathway. hemangioblastomas, which are slowly growing cystic
 418 tumors. Hypernephroma, renal cell carcinoma, pheochro- surrounding a central mass of nonenhancing necrotic tis-
mocytoma, and benign cysts of the kidneys, pancreas, epi- sue that develops as the metastasis outgrows its blood sup-
didymis, or liver may also occur. Erythropoietin produced ply. Metastases are surrounded by variable amounts of
by hemangioblastomas may result in polycythemia. edema. Blood products may also be seen, reecting hem-
Mutation of the von HippelLindau (VHL) gene on orrhage of abnormal tumor vessels.
chromosome 3p, a tumor-suppressor gene, causes this dis- The radiologic appearance of a brain metastasis is not
order. VHL encodes a protein with multiple functions, specic. The differential diagnosis of ring-enhancing
including modulation of signal transduction in response lesions includes brain abscess, radiation necrosis, toxo-
to cellular hypoxia. plasmosis, granulomas, tuberculosis, sarcoidosis, demyeli-
nating lesions, primary brain tumors, primary CNS
lymphoma, stroke, hemorrhage, and trauma. Contrast-
TUMORS METASTATIC TO BRAIN enhanced CT scanning is less sensitive than MRI for the
detection of brain metastases. Cytologic examination of
MECHANISMS OF BRAIN METASTASES the CSF is not indicated, since intraparenchymal brain
Brain metastases arise from hematogenous spread. The metastases almost never shed cells into the CSF.
anatomic distribution of brain metastases generally
parallels regional cerebral blood flow, with a predilec- BRAIN METASTASES WITHOUT A KNOWN
SECTION III

tion for the gray matterwhite matter junction and for PRIMARY TUMOR
the border zone between middle cerebral and poste-
rior cerebral artery distributions. The lung is the most In general hospital populations, up to one-third of
common origin of brain metastases; both primary lung patients presenting with brain metastases do not have a
cancer and cancers metastatic to the lung frequently previously known underlying cancer.These patients gen-
metastasize to the brain. Breast cancer (especially ductal erally present with either a seizure or a progressive neu-
Diseases of the Central Nervous System

carcinoma) has a propensity to metastasize to the cere- rologic decit. Neuroimaging studies typically demonstrate
bellum and the posterior pituitary gland. Other common one or multiple ring-enhancing lesions. In individuals
origins of brain metastases are gastrointestinal malignan- who are not immunocompromised and not at risk for
cies and melanoma (Table 32-3). Certain less common brain abscesses, this radiologic pattern is most likely due
tumors have a special propensity to metastasize to brain, to brain metastasis.
including germ cell tumors and thyroid cancer. By con- Diagnostic evaluation begins with a search for the
trast, prostate cancer, ovarian cancer, and Hodgkins dis- primary tumor. Blood tests should include carcinoem-
ease rarely metastasize to the brain. bryonic antigen and liver function tests. Examination of
the skin for melanoma and the thyroid gland for masses
should be carried out. The search for a primary cancer
EVALUATION OF METASTASES FROM
most often discloses lung cancer (particularly small cell
KNOWN CANCER
lung cancer) or melanoma. In 30% of patients no pri-
On MRI scans brain metastases typically appear as well- mary tumor can be identied, even after extensive eval-
demarcated, approximately spherical lesions that are uation. A CT scan of the chest, abdomen, and pelvis
hypointense or isointense relative to brain on T1-weighted should be obtained. If these are all negative, further
images and bright on T2-weighted images.They invariably imaging studies, including bone scan, other radionuclide
enhance with gadolinium, reecting extravasation of scans, mammography, and upper and lower gastrointesti-
gadolinium through tumor vessels that lack a blood-tumor nal barium studies, are unlikely to be productive.
barrier (Fig. 32-7). Small metastases often enhance uni- A tissue diagnosis is essential. If a primary tumor is
formly. Larger metastases typically produce ring enhancement found, it will usually be more accessible to biopsy than a

TABLE 32-3
FREQUENCY OF NERVOUS SYSTEM METASTASES BY COMMON PRIMARY TUMORS

SITE OF PRIMARY BRAIN LEPTOMENINGEAL SPINAL CORD

TUMOR METASTASES, % METASTASES, % COMPRESSION, %

Lung 40 24 18
Breast 19 41 24
Melanoma 10 12 4
Gastrointestinal tract 7 13 6
Genitourinary tract 7 18
Other 17 10 30
 419

FIGURE 32-7
Brain metastasis. A. Axial T2-weighted MRI
through the lateral ventricles reveals two iso-
dense masses, one in the subependymal
region and one near the cortex (arrows).
B. T1-weighted postcontrast image at the
same level as A reveals enhancement of
the two masses seen on the T2-weighted
image as well as a third mass in the left
A B frontal lobe (arrows).

CHAPTER 32
brain lesion. If a single brain lesion is found in a surgically visualized by neuroimaging studies, WBRT is usually
accessible location, if a primary tumor is not found, or if used. Its benet has been established in controlled
the primary tumor is in a location difcult to biopsy, the studies, but no clear dose response has been shown.
brain metastasis should be biopsied or resected. Usually, 3037.5 Gy is administered in 1015 fractions; an

Primary and Metastatic Tumors of the Nervous System

additional dose (boost) of focal irradiation to a single or
large metastasis may also be administered. Stereotaxic
radiosurgery is of benet in patients with four or fewer
Treatment: metastases demonstrable by MRI. The addition of WBRT
TUMORS METASTATIC TO BRAIN to stereotaxic radiosurgery delays tumor recurrence in
Once a systemic cancer metastasizes to the brain it is, the brain but does not prolong survival.
with rare exception, incurable. Therapy is therefore pal-
liative, designed to prevent disability and suffering and, Surgery Up to 40% of patients with brain metastases
if possible, to prolong life. Published outcome studies have only a single tumor mass identied by CT. Accessible
have focused on survival as the primary endpoint, leaving single metastases may be surgically excised as a
questions regarding quality of life unanswered. There is, palliative measure. If the systemic disease is under
however, widespread agreement that glucocorticoids, control, total resection of a single brain lesion has been
anticonvulsants, radiation therapy, and surgery (see demonstrated to improve survival and minimize disability.
below) can contribute to the management of these Survival is further improved if surgery is followed by
patients. WBRT.

GENERAL MEASURES Glucocorticoids frequently Chemotherapy Brain metastases of certain tumors,

ameliorate symptoms of brain metastases. Improvement including breast cancer, small cell lung cancer, and
is often dramatic, occurring within 24 h, and is sustained germ cell tumors, are often responsive to systemic
with continued administration, although the toxicity chemotherapy. Although metastases frequently do not
of glucocorticoids is cumulative. Therefore, if possible, respond as well as the primary tumor, dramatic responses
a more denitive therapy for metastases should be to systemic chemotherapy or hormonal therapy may
instituted to permit withdrawal of glucocorticoid occur in some cases. In patients who are neurologically
therapy. One-third of patients with brain metastases asymptomatic, two to four cycles of systemic chemother-
have one or more seizures; anticonvulsants are used apy may be administered initially to reduce tumor mass
empirically for seizure prophylaxis. and render the residual tumor more amenable to
radiation therapy. Even if a complete radiologic remission
SPECIFIC MEASURES is achieved from chemotherapy, WBRT should then be
Radiation Therapy Radiation therapy is the administered. Gene therapy, immunotherapy, intraarterial
primary treatment for brain metastases. Since multiple chemotherapy, and chemotherapy administered following
microscopic deposits of tumor cells throughout the osmotic disruption of the blood-brain barrier are
brain are likely to be present in addition to metastases currently under investigation.
 420 LEPTOMENINGEAL METASTASES

Leptomeningeal metastases are also called carcinomatous

meningitis, meningeal carcinomatosis, and, in the case of spe-
cic tumors, leukemic meningitis or lymphomatous meningitis.
Clinical evidence of leptomeningeal metastases is present
in 8% of patients with metastatic solid tumors; at
necropsy, the prevalence is as high as 19%. Among solid
tumors, adenocarcinomas of the breast, lung, and gastroin-
testinal tract and melanoma are the most common cause
of leptomeningeal metastases (Table 32-3). In one-quarter
of patients the systemic cancer is under control, and
especially in these patients the effective control of lep-
tomeningeal disease can improve the quality and duration
of life.
Cancer usually metastasizes to the meninges via the
bloodstream. Alternatively, cells may invade the subarach-
SECTION III

noid space directly from a supercially located parenchy-

mal brain metastasis. Some tumors, including squamous
cell carcinoma of the skin and some non-Hodgkins lym-
phomas, have a propensity to grow along peripheral FIGURE 32-8
nerves and may seed the meninges by that route. Carcinomatous meningitis. Sagittal postcontrast MRI
through the lower thoracic region demonstrates diffuse pial
Diseases of the Central Nervous System

enhancement along the surface of the spinal cord (arrows),

typical of CSF spread of neoplasm.
CLINICAL FEATURES
Leptomeningeal metastases present with signs and
symptoms at multiple levels of the nervous system,
most often in a setting of known systemic malignancy.
Encephalopathy is frequent, and cranial neuropathy or
spinal radiculopathy from nodular nerve root compression Treatment:
is characteristic. Hydrocephalus can result from obstruc- LEPTOMENINGEAL METASTASES
tion of CSF outow. Focal neurologic decits reect Although the prognosis of patients with leptomeningeal
coexisting intraparenchymal metastases. metastases is poor, ~20% of patients treated aggressively
can expect a response of 6 months. Intrathecal therapy
exposes meningeal tumor implants to high concentra-
LABORATORY AND IMAGING tions of chemotherapy with minimal systemic toxicity.
EVALUATION Methotrexate can be safely administered intrathecally
and is effective against leptomeningeal metastases from
Leptomeningeal metastases are diagnosed by cytologic a variety of solid tumors including lymphoma; cytara-
demonstration of malignant cells in the CSF, by MRI bine and thiotepa are alternative agents. Liposomal
demonstration of nodular tumor deposits or diffuse cytarabine provides prolonged cytotoxic levels of
enhancement in the meninges (Fig. 32-8), and by cytarabine in the CSF, requiring administration only
meningeal biopsy. CSF ndings are usually those of an every 2 weeks, in contrast to weekly or twice weekly
inammatory meningitis consisting of lymphocytic administration of other agents. Intrathecal chemother-
pleocytosis, elevated protein levels, and normal or low apy may be administered either by repeated lumbar
CSF glucose. A positive CSF cytology is unequivocal puncture or through an indwelling Ommaya reservoir,
evidence of tumor spread to the subarachnoid space. which consists of a catheter in one lateral ventricle
CSF examination is more likely to be informative attached to a reservoir implanted under the scalp. If
when larger volumes of CSF are submitted for cytology there is a question of patency of CSF pathways, a
and when up to three CSF examinations are per- radionuclide ow study through the reservoir may be
formed. A complete MRI examination of the neuraxis performed.
is indicated in all cases of suspected leptomeningeal Large, nodular deposits of tumor on the meninges or
metastases; in addition to nodular meningeal lesions, along nerve roots are unlikely to respond to intrathecal
hydrocephalus due to obstruction of CSF pathways may chemotherapy, as the barrier to diffusion is too great.
be found.
 Therefore, external beam radiation is employed, and In patients with cancer who have brachial or lum- 421
these patients may also benet from systemic bosacral plexopathy, it may be difcult to distinguish
chemotherapy. Hydrocephalus is treated with a ven- tumor invasion from radiation injury. High radiation
triculoperitoneal shunt, although seeding of the peri- dose or the presence of myokymia (rippling contractions
toneum by tumor is a risk. of muscle) suggests radiation injury, whereas pain suggests
tumor. Radiographic imaging studies may be equivocal,
and surgical exploration is sometimes required.

MALIGNANT SPINAL CORD COMPLICATIONS OF THERAPY

COMPRESSION
RADIATION TOXICITY
Spinal cord compression from solid tumor metastases usu-
ally results from growth of a vertebral metastasis into the The nervous system is vulnerable to injury by therapeutic
epidural space. Primary tumors that frequently metastasize radiation. Histologically, there is demyelination, degener-
to bone include lung, breast, and prostate cancer. Back ation of small arterioles, and eventually brain infarction
pain is usually the rst symptom and is prominent at pre- and necrosis.

CHAPTER 32
sentation in 90% of patients. The pain is typically dull, Acute radiation injury to the brain occurs during or
aching, and may be associated with localized tenderness. If immediately after therapy. It is rarely seen with current
a nerve root is compressed, radicular pain is also present. protocols of external beam radiation but may occur after
The thoracic cord is most often affected. Weakness, sen- stereotaxic radiosurgery. Manifestations include headache,
sory loss, and autonomic dysfunction (urinary urgency sleepiness, and worsening of preexisting neurologic decits.
and incontinence, fecal incontinence, and sexual impo- Early delayed radiation injury occurs within 4 months
tence in men) are hallmarks of spinal cord compression. of therapy. It is associated with an increased white mat-

Primary and Metastatic Tumors of the Nervous System

Once signs of spinal cord compression appear, they tend ter T2 signal on MRI scans. In children, the somnolence
to progress rapidly. It is thus essential to recognize and syndrome is a common form of early delayed radiation
treat this serious complication of malignancy promptly to injury in which somnolence and ataxia develop after
prevent irreversible neurologic decits. Diagnosis and WBRT. Irradiation of the cervical spine may cause
management are discussed in Chap. 30. Lhermittes phenomenon, an electricity-like sensation
evoked by neck exion. Symptoms resulting from acute
and early delayed radiation injury often respond to glu-
METASTASES TO THE PERIPHERAL cocorticoid administration, are self-limited, and usually
NERVOUS SYSTEM resolve without residual decits. These injuries do not
increase the risk of late radiation injury.
Systemic cancer may compress or invade peripheral Late delayed radiation injury produces permanent dam-
nerves. Compression of the brachial plexus may occur age to the nervous system. It occurs >4 months (gener-
by direct extension of Pancoasts tumors (cancer of the ally 824 months) after completion of therapy; onset
apex of the lung), by lymphoma, or by extension of as late as 15 years after therapy has been described.
local lymph node metastases in breast or lung cancer. Following focal brain irradiation, radiation necrosis can
The lumbosacral plexus may be compressed by occur within the radiation eld, producing a contrast-
retroperitoneal tumor invasion such as occurs in cases of enhancing (frequently ring-enhancing) mass with sur-
prostate or ovarian cancer or lymphoma. Skull metas- rounding white matter signal abnormalities (Fig. 32-9).
tases may compress cranial nerve branches as they pass MRI or CT scans are often unable to distinguish radia-
through the skull, and pituitary metastases may extend tion necrosis from recurrent tumor, but PET or SPECT
into the cavernous sinus. scans may demonstrate the increased glucose metabolism
The epineurium generally provides an effective bar- typical of tumor tissue or the decreased metabolism of
rier to invasion of the peripheral nerves by solid tumors, necrotic tissue. Magnetic resonance spectroscopy may
but certain tumors characteristically invade and spread demonstrate a high lactate concentration with relatively
along peripheral nerves. Squamous cell carcinoma of the low choline concentration in areas of necrosis. Biopsy is
skin may spread along the trigeminal nerve and extend frequently required to establish the correct diagnosis.
intracranially. Non-Hodgkins lymphoma may be neu- Peripheral nerves, including the brachial and lum-
rotrophic and cause polyradiculopathy or a syndrome bosacral plexuses, may also develop late delayed radiation
resembling mononeuropathy multiplex (Chap. 40). Focal injury.
external beam radiation may reduce pain, prevent irre- If untreated, radiation necrosis of the CNS may act as
versible loss of peripheral nerve function, and possibly an expanding mass lesion. Symptoms may resolve spon-
restore function. taneously or respond to treatment with glucocorticoids.
 422

A B C

FIGURE 32-9
Radiation injury. A. Late delayed radiation injury 1 year after (B) demonstrates a mass in the right frontal lobe with sur-
whole-brain radiation (5500 cGy). T2-weighted MR image at rounding vasogenic edema. Abnormal signal changes are
SECTION III

the level of the temporal lobes reveals high signal intensity also present on the left. T1-weighted postcontrast MRI
abnormality in periventricular white matter (arrows). B and C. (C) reveals a heterogeneously enhancing mass in the right
Focal radiation necrosis 3 years after radiotherapy (7000 cGy) cingulate gyrus.
for carcinoma of the nasopharynx. Axial T2-weighted MRI
Diseases of the Central Nervous System

Progressive radiation necrosis is best treated with surgi- are associated with the development of altered mental
cal resection if the patient has a life expectancy of at states (e.g., confusion, depression), ataxia, and seizures.
least 6 months and a Karnofsky performance score >70. Chemotherapy for systemic malignancy is a more fre-
There are anecdotal reports that anticoagulation with quent cause of nervous system toxicity and is more
heparin or warfarin may be benecial. After WBRT, pro- often toxic to the peripheral than the central nervous
gressive dementia can occur, often accompanied by gait system. Cisplatin commonly produces tinnitus and high-
apraxia and urinary incontinence. Radiation injury of frequency bilateral hearing loss, especially in younger
large arteries also accelerates the development of athero- patients. At cumulative doses >450 mg/m2, cisplatin can
sclerosis, but an increase in the risk of stroke becomes produce a symmetric, large-ber axonal neuropathy that
signicant only years after radiation treatment. is predominantly sensory; paclitaxel (Taxol) produces a
Endocrine dysfunction resulting in hypopituitarism similar picture. Fluorouracil and high-dose cytarabine
frequently follows exposure of the hypothalamus or can cause cerebellar dysfunction that resolves after dis-
pituitary gland to therapeutic radiation. Growth hor- continuation of therapy.Vincristine, which is commonly
mone is the pituitary hormone most sensitive to radia- used to treat lymphoma, may cause an acute ileus and is
tion therapy, and thyroid-stimulating hormone is the frequently associated with development of a progressive
least sensitive; ACTH, prolactin, and the gonadotropins distal, symmetric sensory motor neuropathy with foot
have an intermediate sensitivity. drop and paresthesias.
Development of a second neoplasm is another risk of
therapeutic radiation that generally occurs many years
after radiation exposure. Depending on the irradiated FURTHER READINGS
eld, the risk of gliomas, meningiomas, sarcomas, and DEANGELIS L: Chemotherapy for brain tumorsa new beginning.
thyroid cancer is increased. N Engl J Med 352:1036, 2005
KEIME-GUIBERT F et al: Radiotherapy for glioblastoma in the elderly.
N Engl J Med 356:1527, 2007
TOXICITIES OF CHEMOTHERAPY MORRIS PG, ABREY LE: Therapeutic challenges in primary CNS
lymphoma. Lancet Neurol 8:581, 2009
Chemotherapy regimens used to treat primary brain PUROW B, SCHIFF D: Advances in the genetics of gliobastoma: are we
tumors generally include alkylating agents, either temo- reaching critical mass? Nat Rev Neurol 5:419, 2009
zolomide or nitrosoureas, and are relatively well toler- SANAI N et al: Functional outcome after language mapping for glioma
ated. Infrequently, drugs used to treat CNS neoplasms resection N Engl J Med 358:18, 2008
 CHAPTER 33
NEUROLOGIC DISORDERS OF THE PITUITARY
AND HYPOTHALAMUS
Shlomo Melmed I J. Larry Jameson I Gary L. Robertson

I Anatomy and Development . . . . . . . . . . . . . . . . . . . . . . . . . . 423

Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
I Hypothalamic and Anterior Pituitary Insufciency . . . . . . . . . . 424
I Developmental and Genetic Causes of Hypopituitarism . . . . 425
Acquired Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . 426
Laboratory Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
I Hypothalamic, Pituitary, and Other Sellar Masses . . . . . . . . . 428
Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
Other Sellar Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
I Metabolic Effects of Hypothalamic Lesions . . . . . . . . . . . . . . 431
I Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434

The anterior pituitary is often referred to as the master manifestations and performing the correct laboratory
gland because, together with the hypothalamus, it orches- diagnostic tests.
trates the complex regulatory functions of multiple other
endocrine glands.The anterior pituitary gland produces six
major hormones: (1) prolactin (PRL), (2) growth hor- ANATOMY AND DEVELOPMENT
mone (GH), (3) adrenocorticotropin hormone (ACTH),
ANATOMY
(4) luteinizing hormone (LH), (5) follicle-stimulating hor-
mone (FSH), and (6) thyroid-stimulating hormone (TSH). The pituitary gland weighs ~600 mg and is located within
Pituitary hormones are secreted in a pulsatile manner, the sella turcica ventral to the diaphragma sella; it com-
reecting stimulation by an array of specic hypothala- prises anatomically and functionally distinct anterior and
mic releasing factors. Each of these pituitary hormones posterior lobes. The sella is contiguous to vascular and
elicits specic responses in peripheral target tissues. The neurologic structures, including the cavernous sinuses, cra-
hormonal products of these peripheral glands, in turn, nial nerves, and optic chiasm. Thus, expanding intrasellar
exert feedback control at the level of the hypothalamus pathologic processes may have signicant central mass
and pituitary to modulate pituitary function (Fig. 33-1). effects in addition to their endocrinologic impact.
Pituitary tumors cause characteristic hormone excess Hypothalamic neural cells synthesize specic releas-
syndromes. Hormone deciency may be inherited or ing and inhibiting hormones that are secreted directly
acquired. Fortunately, efcacious treatments exist for the into the portal vessels of the pituitary stalk. Blood supply
various pituitary hormone excess and deciency syn- of the pituitary gland is derived from the superior and
dromes. Nonetheless, these diagnoses are often elusive, inferior hypophyseal arteries (Fig. 33-2). The hypothal-
emphasizing the importance of recognizing subtle clinical amic-pituitary portal plexus provides the major blood

423
 424 TRH GHRH
Hypothalamus Third ventricle
CRH GnRH Neuroendocrine
cell nuclei
Dopamine Hypothalamus

Superior
hypophyseal Stalk
artery
Inferior
Pituitary + + + + Long portal hypophyseal
vessels artery

ACTH Trophic
Target hormone
+ secreting
organs
TSH cells
GH Posterior
SECTION III

Cortisol LH PRL pituitary

Anterior
Cell homeostasis pituitary
and function Adrenal FSH
glands + Short portal
+ +
vessel
Hormone
secretion
T4/T3
Thermogenesis
FIGURE 33-2
Diseases of the Central Nervous System

metabolism Thyroid + Liver Diagram of hypothalamic-pituitary vasculature. The hypo-

glands
thalamic nuclei produce hormones that traverse the portal
Lactation
system and impinge on anterior pituitary cells to regulate
Testosterone
Inhibin
pituitary hormone secretion. Posterior pituitary hormones are
Spermatogenesis + derived from direct neural extensions.
Testes

Estradiol Chrondrocytes
Progesterone
Inhibin Ovaries Linear and
LH mlU/mL GnRH pg/mL

organ growth
Ovulation
IGF-1 GnRH pulses

FIGURE 33-1
Diagram of pituitary axes. Hypothalamic hormones regulate
anterior pituitary trophic hormones that, in turn, determine LH pulses
target gland secretion. Peripheral hormones feed back to
regulate hypothalamic and pituitary hormones. For abbrevia-
tions, see text.
FIGURE 33-3
Hypothalamic gonadotropin-releasing hormone (GnRH)
pulses induce secretory pulses of luteinizing hormone (LH).
source for the anterior pituitary, allowing reliable trans-
mission of hypothalamic peptide pulses without signi-
cant systemic dilution; consequently, pituitary cells are
exposed to releasing or inhibiting factors and in turn HYPOTHALAMIC AND ANTERIOR
release their hormones as discrete pulses (Fig. 33-3). PITUITARY INSUFFICIENCY
The posterior pituitary is supplied by the inferior
hypophyseal arteries. In contrast to the anterior pitu- Hypopituitarism results from impaired production of
itary, the posterior lobe is directly innervated by hypo- one or more of the anterior pituitary trophic hormones.
thalamic neurons (supraopticohypophyseal and tubero- Reduced pituitary function can result from inherited
hypophyseal nerve tracts) via the pituitary stalk. Thus, disorders; more commonly, it is acquired and reects the
posterior pituitary production of vasopressin [antidi- mass effects of tumors or the consequences of inamma-
uretic hormone (ADH)] and oxytocin is particularly tion or vascular damage.These processes may also impair
sensitive to neuronal damage by lesions that affect the synthesis or secretion of hypothalamic hormones, with
pituitary stalk or hypothalamus. resultant pituitary failure (Table 33-1).
TABLE 33-1 Increasing evidence suggests that patients with brain 425
ETIOLOGY OF HYPOPITUITARISM a injury including trauma, subarachnoid hemorrhage, and
irradiation have transient hypopituitarism and require
Development/structural intermittent long-term endocrine follow-up, as perma-
Transcription factor defect
Pituitary dysplasia/aplasia
nent hypothalamic or pituitary dysfunction will develop
Congenital CNS mass, encephalocele in 2540% of these patients.
Primary empty sella
Congenital hypothalamic disorders (septo-optic dysplasia, Hypothalamic Inltration Disorders
Prader-Willi syndrome, Laurence-Moon-Biedl
syndrome, Kallmann syndrome) These disordersincluding sarcoidosis, histiocytosis X,
Traumatic amyloidosis, and hemochromatosisfrequently involve
Surgical resection both hypothalamic and pituitary neuronal and neuro-
Radiation damage chemical tracts. Consequently, diabetes insipidus occurs
Head injuries in one-half of patients with these disorders. Growth
Neoplastic retardation is seen if attenuated GH secretion occurs
Pituitary adenoma before pubertal epiphyseal closure. Hypogonadotropic
Parasellar mass (meningioma, germinoma,
hypogonadism and hyperprolactinemia are also common.
ependymoma, glioma)

CHAPTER 33
Rathkes cyst
Craniopharyngioma Inammatory Lesions
Hypothalamic hamartoma, gangliocytoma
Pituitary metastases (breast, lung, colon carcinoma) Pituitary damage and subsequent dysfunction can be
Lymphoma and leukemia seen with chronic infections such as tuberculosis, with
Meningioma opportunistic fungal infections associated with AIDS,
Inltrative/inammatory and in tertiary syphilis. Other inammatory processes,

Neurologic Disorders of the Pituitary and Hypothalamus

Lymphocytic hypophysitis such as granulomas or sarcoidosis, may mimic the fea-
Hemochromatosis tures of a pituitary adenoma. These lesions may cause
Sarcoidosis extensive hypothalamic and pituitary damage, leading to
Histiocytosis X
trophic hormone deciencies.
Granulomatous hypophysitis
Vascular
Pituitary apoplexy Cranial Irradiation
Pregnancy-related (infarction with diabetes;
postpartum necrosis)
Cranial irradiation may result in long-term hypothalamic
Sickle cell disease and pituitary dysfunction, especially in children and adoles-
Arteritis cents, as they are more susceptible to damage following
Infections whole-brain or head and neck therapeutic irradiation.The
Fungal (histoplasmosis) development of hormonal abnormalities correlates strongly
Parasitic (toxoplasmosis) with irradiation dosage and the time interval after comple-
Tuberculosis tion of radiotherapy. Up to two-thirds of patients ultimately
Pneumocystis carinii develop hormone insufciency after a median dose of
50 Gy (5000 rad) directed at the skull base. The develop-
a
Trophic hormone failure associated with pituitary compression or ment of hypopituitarism occurs over 515 years and usu-
destruction usually occurs sequentially GH > FSH > LH > TSH >
ACTH. During childhood, growth retardation is often the presenting
ally reects hypothalamic damage rather than primary
feature, and in adults hypogonadism is the earliest symptom. destruction of pituitary cells. Although the pattern of hor-
mone loss is variable, GH deciency is most common,
followed by gonadotropin and ACTH deciency. When
deciency of one or more hormones is documented, the
DEVELOPMENTAL AND GENETIC
possibility of diminished reserve of other hormones is
CAUSES OF HYPOPITUITARISM likely. Accordingly, anterior pituitary function should be
ACQUIRED HYPOPITUITARISM evaluated over the long term in previously irradiated
patients, and replacement therapy instituted when appro-
Hypopituitarism may be caused by accidental or neuro- priate (see later).
surgical trauma; vascular events such as apoplexy; pituitary
or hypothalamic neoplasms such as pituitary adenomas,
Lymphocytic Hypophysitis
craniopharyngiomas, lymphoma, or metastatic tumors;
inammatory disease such as lymphocytic hypophysitis; This often occurs in postpartum women; it usually pre-
inltrative disorders such as sarcoidosis, hemochromatosis, sents with hyperprolactinemia and MRI evidence of a
and tuberculosis; or irradiation. prominent pituitary mass often resembling an adenoma,
 426 with mildly elevated PRL levels. Pituitary failure however, may develop insidiously. Pituitary masses may
caused by diffuse lymphocytic infiltration may be tran- undergo clinically silent infarction with development of
sient or permanent but requires immediate evaluation a partial or totally empty sella by cerebrospinal uid
and treatment. Rarely, isolated pituitary hormone defi- (CSF) lling the dural herniation. Rarely, small but
ciencies have been described, suggesting a selective functional pituitary adenomas may arise within the rim
autoimmune process targeted to specific cell types. of pituitary tissue, and these are not always visible on
Most patients manifest symptoms of progressive mass MRI.
effects with headache and visual disturbance. The ery-
throcyte sedimentation rate is often elevated. As the
MRI image may be indistinguishable from that of a PRESENTATION AND DIAGNOSIS
pituitary adenoma, hypophysitis should be considered The clinical manifestations of hypopituitarism depend
in a postpartum woman with a newly diagnosed pitu- on which hormones are lost and the extent of the hor-
itary mass before embarking on unnecessary surgical mone deciency. GH deciency causes growth disorders
intervention. The inflammatory process often resolves in children and leads to abnormal body composition in
after several months of glucocorticoid treatment, and adults (see below). Gonadotropin deciency causes
pituitary function may be restored, depending on the menstrual disorders and infertility in women and
extent of damage. decreased sexual function, infertility, and loss of sec-
SECTION III

ondary sexual characteristics in men. TSH and ACTH

deciency usually develop later in the course of pitu-
Pituitary Apoplexy
itary failure. TSH deciency causes growth retardation
Acute intrapituitary hemorrhagic vascular events can in children and features of hypothyroidism in children
cause substantial damage to the pituitary and surround- and in adults. The secondary form of adrenal insuf-
ing sellar structures. Pituitary apoplexy may occur ciency caused by ACTH deciency leads to hypocorti-
Diseases of the Central Nervous System

spontaneously in a preexisting adenoma; post-partum solism with relative preservation of mineralocorticoid

(Sheehans syndrome); or in association with diabetes, production. PRL deciency causes failure of lactation.
hypertension, sickle cell anemia, or acute shock. The When lesions involve the posterior pituitary, polyuria
hyperplastic enlargement of the pituitary during preg- and polydipsia reflect loss of vasopressin secretion.
nancy increases the risk for hemorrhage and infarction. Epidemiologic studies have documented an increased
Apoplexy is an endocrine emergency that may result in mortality rate in patients with longstanding pituitary
severe hypoglycemia, hypotension, central nervous sys- damage, primarily from increased cardiovascular and
tem (CNS) hemorrhage, and death. Acute symptoms cerebrovascular disease.
may include severe headache with signs of meningeal
irritation, bilateral visual changes, ophthalmoplegia,
and, in severe cases, cardiovascular collapse and loss of LABORATORY INVESTIGATION
consciousness. Pituitary computed tomography (CT) or
Biochemical diagnosis of pituitary insufficiency is
MRI may reveal signs of intratumoral or sellar hemor-
made by demonstrating low levels of trophic hor-
rhage, with deviation of the pituitary stalk and com-
mones in the setting of low target hormone levels. For
pression of pituitary tissue.
example, low free thyroxine in the setting of a low or
Patients with no evident visual loss or impaired con-
inappropriately normal TSH level suggests secondary
sciousness can be observed and managed conservatively
hypothyroidism. Similarly, a low testosterone level
with high-dose glucocorticoids. Those with signicant
without elevation of gonadotropins suggests hypogo-
or progressive visual loss or loss of consciousness require
nadotropic hypogonadism. Provocative tests may be
urgent surgical decompression. Visual recovery after
required to assess pituitary reserve (Table 33-2). GH
surgery is inversely correlated with the length of time
responses to insulin-induced hypoglycemia, arginine,
after the acute event. Therefore, severe ophthalmoplegia
l-dopa, growth hormonereleasing hormone (GHRH),
or visual decits are indications for early surgery.
or growth hormonereleasing peptides (GHRPs) can
Hypopituitarism is very common after apoplexy.
be used to assess GH reserve. Corticotropin-releasing
hormone (CRH) administration induces ACTH release,
and administration of synthetic ACTH (cortrosyn)
Empty Sella
evokes adrenal cortisol release as an indirect indicator of
A partial or apparently totally empty sella is often an pituitary ACTH reserve. ACTH reserve is most reliably
incidental MRI nding.These patients usually have nor- assessed during insulin-induced hypoglycemia. How-
mal pituitary function, implying that the surrounding ever, this test should be performed cautiously in
rim of pituitary tissue is fully functional. Hypopituitarism, patients with suspected adrenal insufficiency because
TABLE 33-2 427
TESTS OF PITUITARY SUFFICIENCY

HORMONE TEST BLOOD SAMPLES INTERPRETATION

Growth hormone Insulin tolerance test: 30, 0, 30, 60, 120 min for Glucose < 40 mg/dL;
Regular insulin glucose and GH GH should be >3 g/L
(0.050.15 U/kg IV)
GHRH test: 1 g/kg IV 0, 15, 30, 45, 60, 120 min for GH Normal response is GH >3 g/L
L-Arginine test: 30 g IV 0, 30, 60, 120 min for GH Normal response is GH >3 g/L
over 30 min
L-dopa test: 500 mg PO 0, 30, 60, 120 min for GH Normal response is GH >3 g/L
Prolactin TRH test: 200500 g IV 0, 20, and 60 min for TSH Normal prolactin is >2 g/L and
and PRL increase >200% of baseline
ACTH Insulin tolerance test: 30, 0, 30, 60, 90 min for Glucose <40 mg/dL
Regular insulin glucose and cortisol Cortisol should increase by
(0.050.15 U/kg IV) >7 g/dL or to >20 g/dL
CRH test: 1 g/kg ovine 0, 15, 30, 60, 90, 120 min Basal ACTH increases 2- to 4-fold
CRH IV at 0800 h for ACTH and cortisol and peaks at 20100 pg/mL

CHAPTER 33
Cortisol levels >2025 g/dL
Metyrapone test: Plasma 11-deoxycortisol and Plasma cortisol should be
Metyrapone (30 mg/kg) cortisol at 8 A.M.; ACTH can <4 g/dL to assure an
at midnight also be measured adequate response
Normal response is
11-deoxycortisol >7.5 g/dL
or ACTH >75 pg/mL

Neurologic Disorders of the Pituitary and Hypothalamus

Standard ACTH stimulation 0, 30, 60 min for cortisol Normal response is cortisol
test: ACTH 1-24 and aldosterone >21 g/dL and aldosterone
(Cosyntropin), 0.25 mg response of >4 ng/dL above
IM or IV baseline
Low-dose ACTH test: 0, 30, 60 min for cortisol Cortisol should be >21 g/dL
ACTH 1-24 (Cosyntropin),
1 g IV
3-day ACTH stimulation Cortisol >21 g/dL
test consists of 0.25 mg
ACTH 1-24 given IV over
8 h each day
TSH Basal thyroid function Basal tests Low free thyroid hormone levels
tests: T4, T3, TSH in the setting of TSH levels that
are not appropriately increased
TRH test: 200500 g IV 0, 20, 60 min for TSH and PRLa TSH should increase by
>5 mU/L unless thyroid
hormone levels are increased
LH, FSH LH, FSH, testosterone, Basal tests Basal LH and FSH should be
estrogen increased in postmenopausal
women
Low testosterone levels in the
setting of low LH and FSH
GnRH test: GnRH (100 g) IV 0, 30, 60 min for LH and FSH In most adults, LH should increase
by 10 IU/L and FSH by 2 IU/L
Normal responses are variable
Multiple Combined anterior pituitary 30, 0, 15, 30, 60, 90, 120 min Combined or individual releasing
hormones test: GHRH (1 g/kg), for GH, ACTH, cortisol, hormone responses must be
CRH (1 g/kg), LH, FSH, and TSH elevated in the context of
GnRH (100 g), basal target gland hormone
TRH (200 g) values and may not be uniformly
are given IV diagnostic (see text)

a
Evoked PRL response indicates lactotrope integrity.
Note: For abbreviations, see text.
 428 of enhanced susceptibility to hypoglycemia and hypoten- HYPOTHALAMIC, PITUITARY,
sion. Insulin-induced hypoglycemia is contraindicated in
patients with active coronary artery disease or seizure
AND OTHER SELLAR MASSES
disorders. PITUITARY TUMORS
Pituitary adenomas are the most common cause of
pituitary hormone hypersecretion and hyposecretion
Treatment: syndromes in adults. They account for ~15% of all
HYPOPITUITARISM intracranial neoplasms. At autopsy, up to one-quarter of
Hormone replacement therapy, including glucocorti- all pituitary glands harbor an unsuspected microade-
coids, thyroid hormone, sex steroids, growth hormone, noma (<10 mm diameter). Similarly, pituitary imaging
and vasopressin, is usually safe and free of complica- detects small clinically inapparent pituitary lesions in at
tions. Treatment regimens that mimic physiologic hor- least 10% of individuals.
mone production allow for maintenance of satisfactory
clinical homeostasis. Effective dosage schedules are out- Pathogenesis
lined in Table 33-3. Patients in need of glucocorticoid
replacement require careful dose adjustments during Pituitary adenomas are benign neoplasms that arise from
SECTION III

stressful events such as acute illness, dental procedures, one of the ve anterior pituitary cell types. The clinical
trauma, and acute hospitalization. and biochemical phenotype of pituitary adenomas
depend on the cell type from which they are derived.
Thus, tumors arising from lactotrope (PRL), somatotrope
TABLE 33-3
(GH), corticotrope (ACTH), thyrotrope (TSH), or
gonadotrope (LH, FSH) cells hypersecrete their respective
HORMONE REPLACEMENT THERAPY FOR ADULT
hormones (Table 33-4). Plurihormonal tumors that
Diseases of the Central Nervous System

HYPOPITUITARISMa
express combinations of GH, PRL,TSH, ACTH, and the
TROPHIC
HORMONE DEFICIT HORMONE REPLACEMENT

ACTH Hydrocortisone TABLE 33-4

(1020 mg A.M.; 510 mg P.M.) CLASSIFICATION OF PITUITARY ADENOMASa
Cortisone acetate
(25 mg A.M.; 12.5 mg P.M.) ADENOMA CELL HORMONE CLINICAL
Prednisone ORIGIN PRODUCT SYNDROME
(5 mg A.M.; 2.5 mg P.M.) Lactotrope PRL Hypogonadism,
TSH L-Thyroxine (0.0750.15 mg daily) galactorrhea
FSH/LH Males Gonadotrope FSH, LH, Silent or
Testosterone enanthate subunits hypogonadism
(200 mg IM every 2 weeks) Somatotrope GH Acromegaly/
Testosterone skin patch (5 mg/d) gigantism
Females Corticotrope ACTH Cushings disease
Conjugated estrogen Mixed growth GH, PRL Acromegaly,
(0.651.25 mg qd for 25 days) hormone and hypogonadism,
Progesterone prolactin cell galactorrhea
(510 mg qd) on days 1625 Other plurihormonal Any Mixed
Estradiol skin patch cell
(0.5 mg, every other day) Acidophil stem cell PRL, GH Hypogonadism,
For fertility: Menopausal galactorrhea,
gonadotropins, human acromegaly
chorionic gonadotropins Mammosomatotrope PRL, GH Hypogonadism,
GH Adults: Somatotropin galactorrhea,
(0.11.25 mg SC qd) acromegaly
Children: Somatotropin Thyrotrope TSH Thyrotoxicosis
[0.020.05 (mg/kg per day)] Null cell None Pituitary failure
Vasopressin Intranasal desmopressin Oncocytoma None Pituitary failure
(520 g twice daily)
Oral 300600 g qd a
Hormone-secreting tumors are listed in decreasing order of fre-
quency. All tumors may cause local pressure effects, including visual
a
All doses shown should be individualized for specic patients and disturbances, cranial nerve palsy, and headache.
should be reassessed during stress, surgery, or pregnancy. Male and Note: For abbreviations, see text.
female fertility requirements should be managed. Source: Adapted from S Melmed, in JL Jameson (ed): Principles of
Note: For abbreviations, see text. Molecular Medicine, Totowa, Humana Press, 1998.
glycoprotein hormone subunit may be diagnosed by PRL- and ACTH-producing adenomas and in some 429
careful immunocytochemistry or may manifest as clinical nonfunctioning tumors.
syndromes that combine features of these hormonal Compelling evidence also favors growth factor promo-
hypersecretory syndromes. Morphologically, these tumors tion of pituitary tumor proliferation. Basic broblast
may arise from a single polysecreting cell type or com- growth factor (bFGF) is abundant in the pituitary and has
prise cells with mixed function within the same tumor. been shown to stimulate pituitary cell mitogenesis. Other
Hormonally active tumors are characterized by factors involved in initiation and promotion of pituitary
autonomous hormone secretion with diminished respon- tumors include loss of negative-feedback inhibition (as
siveness to physiologic inhibitory pathways. Hormone seen with primary hypothyroidism or hypogonadism) and
production does not always correlate with tumor size. estrogen-mediated or paracrine angiogenesis. Growth
Small hormone-secreting adenomas may cause signicant characteristics and neoplastic behavior may also be inu-
clinical perturbations, whereas larger adenomas that pro- enced by several activated oncogenes, including RAS and
duce less hormone may be clinically silent and remain pituitary tumor transforming gene (PTTG).
undiagnosed (if no central compressive effects occur).
About one-third of all adenomas are clinically nonfunc- Genetic Syndromes Associated
tioning and produce no distinct clinical hypersecretory with Pituitary Tumors
syndrome. Most of these arise from gonadotrope cells

CHAPTER 33
and may secrete small amounts of - and -glycoprotein Several familial syndromes are associated with pituitary
hormone subunits or, very rarely, intact circulating tumors, and the genetic mechanisms for some of these
gonadotropins. True pituitary carcinomas with docu- have been unraveled.
mented extracranial metastases are exceedingly rare. Multiple endocrine neoplasia (MEN) 1 is an autosomal
Almost all pituitary adenomas are monoclonal in ori- dominant syndrome characterized primarily by a
gin, implying the acquisition of one or more somatic genetic predisposition to parathyroid, pancreatic islet,
and pituitary adenomas. MEN1 is caused by inactivating

Neurologic Disorders of the Pituitary and Hypothalamus

mutations that confer a selective growth advantage. In
addition to direct studies of oncogene mutations, this germline mutations in MENIN, a constitutively expressed
model is supported by X-chromosomal inactivation tumor-suppressor gene located on chromosome 11q13.
analyses of tumors in female patients heterozygous for Loss of heterozygosity, or a somatic mutation of the
X-linked genes. Consistent with their clonal origin, remaining normal MENIN allele, leads to tumorigene-
complete surgical resection of small pituitary adenomas sis. About half of affected patients develop prolactino-
usually cures hormone hypersecretion. Nevertheless, mas; acromegaly and Cushings syndrome are less com-
hypothalamic hormones, such as GHRH or CRH, also monly encountered.
enhance mitotic activity of their respective pituitary tar- Carney syndrome is characterized by spotty skin pig-
get cells, in addition to their role in pituitary hormone mentation, myxomas, and endocrine tumors including
regulation. Thus, patients harboring rare abdominal or testicular, adrenal, and pituitary adenomas. Acromegaly
chest tumors elaborating ectopic GHRH or CRH may occurs in about 20% of patients. A subset of patients
present with somatotrope or corticotrope hyperplasia. have mutations in the R1 regulatory subunit of pro-
Several etiologic genetic events have been implicated tein kinase A (PRKAR1A).
in the development of pituitary tumors.The pathogene- McCune-Albright syndrome consists of polyostotic brous
sis of sporadic forms of acromegaly has been particularly dysplasia, pigmented skin patches, and a variety of
informative as a model of tumorigenesis. GHRH, after endocrine disorders, including GH-secreting pituitary
binding to its G proteincoupled somatotrope receptor, tumors, adrenal adenomas, and autonomous ovarian func-
utilizes cyclic AMP as a second messenger to stimulate tion. Hormonal hypersecretion is the result of constitutive
GH secretion and somatotrope proliferation. A subset cyclic AMP production caused by inactivation of the
(~35%) of GH-secreting pituitary tumors contain spo- GTPase activity of Gs.The Gs mutations occur postzy-
radic mutations in Gs (Arg 201 Cys or His; Gln 227 gotically, leading to a mosaic pattern of mutant expression.
Arg). These mutations inhibit intrinsic GTPase activ- Familial acromegaly is a rare disorder in which family
ity, resulting in constitutive elevation of cyclic AMP, members may manifest either acromegaly or gigantism.
Pit-1 induction, and activation of cyclic AMP response The disorder is associated with LOH at a chromosome
element binding protein (CREB), thereby promoting 11q13 locus distinct from that of MENIN.
somatotrope cell proliferation and GH secretion.
Characteristic loss of heterozygosity (LOH) in vari-
ous chromosomes has been documented in large or OTHER SELLAR MASSES
invasive macroadenomas, suggesting the presence of Craniopharyngiomas are benign, suprasellar cystic masses
putative tumor suppressor genes at these loci. LOH of that present with headaches, visual eld decits, and
chromosome regions on 11q13, 13, and 9 is present in variable degrees of hypopituitarism. They are derived
up to 20% of sporadic pituitary tumors including GH-, from Rathkes pouch and arise near the pituitary stalk,
 430 commonly extending into the suprasellar cistern. show evidence of calcication or bony erosion. Menin-
Craniopharyngiomas are often large, cystic, and locally giomas may cause compressive symptoms.
invasive. Many are partially calcified, providing a char- Histiocytosis X comprises a variety of syndromes asso-
acteristic appearance on skull x-ray and CT images. ciated with foci of eosinophilic granulomas. Diabetes
More than one-half of all patients present before 20 insipidus, exophthalmos, and punched-out lytic bone
years of age, usually with signs of increased intracranial lesions (Hand-Schller-Christian disease) are associated
pressure, including headache, vomiting, papilledema, with granulomatous lesions visible on MRI, as well as a
and hydrocephalus. Associated symptoms include visual characteristic axillary skin rash. Rarely, the pituitary stalk
field abnormalities, personality changes and cognitive may be involved.
deterioration, cranial nerve damage, sleep difficulties, Pituitary metastases occur in ~3% of cancer patients.
and weight gain. Hypopituitarism can be documented Blood-borne metastatic deposits are found almost
in about 90% and diabetes insipidus occurs in about exclusively in the posterior pituitary. Accordingly, dia-
10%. About one-half of affected children present with betes insipidus can be a presenting feature of lung, gas-
growth retardation. MRI is generally superior to CT trointestinal, breast, and other pituitary metastases. About
to evaluate cystic structure and tissue components of one-half of pituitary metastases originate from breast
craniopharyngiomas. CT is useful to define calcifica- cancer; about 25% of patients with metastatic breast can-
tions and to evaluate invasion into surrounding bony cer have such deposits. Rarely, pituitary stalk involve-
SECTION III

structures and sinuses. ment results in anterior pituitary insufciency.The MRI

Treatment usually involves transcranial or transsphe- diagnosis of a metastatic lesion may be difcult to distin-
noidal surgical resection followed by postoperative guish from an aggressive pituitary adenoma; the diagno-
radiation of residual tumor. Surgery alone is curative in sis may require histologic examination of excised tumor
less than half of patients because of adherence to vital tissue. Primary or metastatic lymphoma, leukemias, and
structures or because of small tumor deposits in the plasmacytomas also occur within the sella.
Diseases of the Central Nervous System

hypothalamus or brain parenchyma. The goal of Hypothalamic hamartomas and gangliocytomas may arise
surgery is to remove as much tumor as possible with- from astrocytes, oligodendrocytes, and neurons with vary-
out risking complications associated with efforts to ing degrees of differentiation. These tumors may overex-
remove firmly adherent or inaccessible tissue. In the press hypothalamic neuropeptides including GnRH,
absence of radiotherapy, about 75% of tumors recur, GHRH, or CRH. In GnRH-producing tumors, chil-
and 10-year survival is less than 50%. In patients with dren present with precocious puberty, psychomotor
incomplete resection, radiotherapy improves 10-year delay, and laughing-associated seizures. Medical treatment
survival to 7090% but is associated with increased risk of GnRH-producing hamartomas with long-acting
of secondary malignancies. Most patients require life- GnRH analogues effectively suppresses gonadotropin
long pituitary hormone replacement. secretion and controls premature pubertal development.
Developmental failure of Rathkes pouch obliteration Rarely, hamartomas are also associated with craniofacial
may lead to Rathkes cysts, which are small (<5 mm) cysts abnormalities; imperforate anus; cardiac, renal, and lung
entrapped by squamous epithelium, and are found in disorders; and pituitary failure as features of Pallister-Hall
about 20% of individuals at autopsy. Although Rathkes syndrome, which is caused by mutations in the carboxyter-
cleft cysts do not usually grow and are often diagnosed minus of the GLI3 gene. Hypothalamic hamartomas are
incidentally, about a third present in adulthood with often contiguous with the pituitary, and preoperative MRI
compressive symptoms, diabetes insipidus, and hyperpro- diagnosis may not be possible. Histologic evidence of
lactinemia due to stalk compression. Rarely, internal hypothalamic neurons in tissue resected at transsphe-
hydrocephalus develops. The diagnosis is suggested pre- noidal surgery may be the rst indication of a primary
operatively by visualizing the cyst wall on MRI, which hypothalamic lesion.
distinguishes these lesions from craniopharyngiomas. Hypothalamic gliomas and optic gliomas occur mainly in
Cyst contents range from CSF-like uid to mucoid childhood and usually present with visual loss. Adults
material. Arachnoid cysts are rare and generate an MRI have more aggressive tumors; about a third are associated
image isointense with cerebrospinal uid. with neurobromatosis.
Sella chordomas usually present with bony clival ero- Brain germ-cell tumors may arise within the sellar
sion, local invasiveness, and, on occasion, calcication. region.These include dysgerminomas, which are frequently
Normal pituitary tissue may be visible on MRI, distin- associated with diabetes insipidus and visual loss. They
guishing chordomas from aggressive pituitary adenomas. rarely metastasize. Germinomas, embryonal carcinomas, ter-
Mucinous material may be obtained by ne-needle atomas, and choriocarcinomas may arise in the parasellar
aspiration. region and produce hCG. These germ-cell tumors pre-
Meningiomas arising in the sellar region may be dif- sent with precocious puberty, diabetes insipidus, visual
cult to distinguish from nonfunctioning pituitary adeno- field defects, and thirst disorders. Many patients are
mas. Meningiomas typically enhance on MRI and may GH-decient with short stature.
METABOLIC EFFECTS TABLE 33-5 431
OF HYPOTHALAMIC LESIONS FEATURES OF SELLAR MASS LESIONSa
Lesions involving the anterior and preoptic hypothalamic IMPACTED STRUCTURE CLINICAL IMPACT
regions cause paradoxical vasoconstriction, tachycardia,
Pituitary Hypogonadism
and hyperthermia. Acute hyperthermia is usually due to Hypothyroidism
a hemorrhagic insult, but poikilothermia may also occur. Growth failure and adult
Central disorders of thermoregulation result from poste- hyposomatotropism
rior hypothalamic damage. The periodic hypothermia syn- Hypoadrenalism
drome comprises episodic attacks of rectal temperatures Optic chiasm Loss of red perception
<30C, sweating, vasodilation, vomiting, and bradycardia. Bitemporal hemianopia
Superior or bitemporal
Damage to the ventromedial hypothalamic nuclei by
eld defect
craniopharyngiomas, hypothalamic trauma, or inamma- Scotoma
tory disorders may be associated with hyperphagia and Blindness
obesity. This region appears to contain an energy-satiety Hypothalamus Temperature dysregulation
center where melanocortin receptors are inuenced by Appetite and thirst disorders
leptin, insulin, POMC products, and gastrointestinal pep- Obesity

CHAPTER 33
tides. Polydipsia and hypodipsia are associated with dam- Diabetes insipidus
age to central osmoreceptors located in preoptic nuclei. Sleep disorders
Behavioral dysfunction
Slow-growing hypothalamic lesions can cause increased Autonomic dysfunction
somnolence and disturbed sleep cycles as well as obesity, Cavernous sinus Ophthalmoplegia with or
hypothermia, and emotional outbursts. Lesions of the without ptosis or diplopia
central hypothalamus may stimulate sympathetic neu- Facial numbness
rons, leading to elevated serum catecholamine and corti- Frontal lobe Personality disorder

Neurologic Disorders of the Pituitary and Hypothalamus

sol levels. These patients are predisposed to cardiac Anosmia
arrhythmias, hypertension, and gastric erosions. Brain Headache
Hydrocephalus
Psychosis
EVALUATION Dementia
Laughing seizures
Local Mass Effects
a
Clinical manifestations of sellar lesions vary, depending on As the intrasellar mass expands, it rst compresses intrasellar pituitary
the anatomic location of the mass and direction of its tissue, then usually invades dorsally through the dura to lift the optic
chiasm or laterally to the cavernous sinuses. Bony erosion is rare, as is
extension (Table 33-5). The dorsal sellar diaphragm pre- direct brain compression. Microadenomas may present with headache.
sents the least resistance to soft tissue expansion from the
sella; consequently, pituitary adenomas frequently extend
in a suprasellar direction. Bony invasion may occur as well. palsies as well as effects on the ophthalmic and maxillary
Headaches are common features of small intrasellar branches of the fth cranial nerve (Chap. 29). Patients may
tumors, even with no demonstrable suprasellar exten- present with diplopia, ptosis, ophthalmoplegia, and
sion. Because of the conned nature of the pituitary, decreased facial sensation, depending on the extent of
small changes in intrasellar pressure stretch the dural neural damage. Extension into the sphenoid sinus indicates
plate; however, headache severity correlates poorly with that the pituitary mass has eroded through the sellar oor.
adenoma size or extension. Aggressive tumors rarely invade the palate roof and cause
Suprasellar extension can lead to visual loss by several nasopharyngeal obstruction, infection, and CSF leakage.
mechanisms, the most common being compression of the Temporal and frontal lobe involvement may lead to unci-
optic chiasm, but direct invasion of the optic nerves or nate seizures, personality disorders, and anosmia. Direct
obstruction of CSF ow leading to secondary visual dis- hypothalamic encroachment by an invasive pituitary mass
turbances also occurs. Pituitary stalk compression by a may cause important metabolic sequelae, including preco-
hormonally active or inactive intrasellar mass may com- cious puberty or hypogonadism, diabetes insipidus, sleep
press the portal vessels, disrupting pituitary access to disturbances, dysthermia, and appetite disorders.
hypothalamic hormones and dopamine; this results in
hyperprolactinemia and concurrent loss of other pituitary
MRI
hormones. This stalk section phenomenon may also be
caused by trauma, whiplash injury with posterior clinoid Sagittal and coronal T1-weighted MRI imaging, before
stalk compression, or skull base fractures. Lateral mass inva- and after administration of gadolinium, allow precise
sion may impinge on the cavernous sinus and compress its visualization of the pituitary gland with clear delineation
neural contents, leading to cranial nerve III, IV, and VI of the hypothalamus, pituitary stalk, pituitary tissue and
 432 Ophthalmologic Evaluation
Because optic tracts may be contiguous to an expanding
pituitary mass, reproducible visual eld assessment that
uses perimetry techniques should be performed on all
patients with sellar mass lesions that abut the optic chi-
asm (Chap. 17). Bitemporal hemianopia or superior
bitemporal defects are classically observed, reecting the
location of these tracts within the inferior and posterior
part of the chiasm. Homonymous cuts reect postchias-
mal and monocular eld cuts prechiasmal lesions. Loss
of red perception is an early sign of optic tract pressure.
Early diagnosis reduces the risk of blindness, scotomas,
or other visual disturbances.

FIGURE 33-4
Laboratory Investigation
Pituitary adenoma. Coronal T1-weighted postcontrast MR The presenting clinical features of functional pituitary ade-
SECTION III

image shows a homogeneously enhancing mass (arrowheads) nomas (e.g., acromegaly, prolactinomas, or Cushings syn-
in the sella turcica and suprasellar region compatible with a drome) should guide the laboratory studies (Table 33-6).
pituitary adenoma; the small arrows outline the carotid arteries. However, for a sellar mass with no obvious clinical features

TABLE 33-6
Diseases of the Central Nervous System

surrounding suprasellar cisterns, cavernous sinuses, sphe-

noid sinus, and optic chiasm. Pituitary gland height SCREENING TESTS FOR FUNCTIONAL PITUITARY
ranges from 6 mm in children to 8 mm in adults; during ADENOMAS
pregnancy and puberty, the height may reach 1012 mm. TEST COMMENTS
The upper aspect of the adult pituitary is at or slightly
Acromegaly Serum IGF-I Interpret IGF-I relative
concave, but in adolescent and pregnant individuals, this to age- and
surface may be convex, reecting physiologic pituitary gender-matched
enlargement. The stalk should be midline and vertical. controls
CT scan is indicated to dene the extent of bony ero- Oral glucose Normal subjects
sion or the presence of calcication. tolerance test should suppress
Anterior pituitary gland soft tissue consistency is with GH obtained growth hormone
slightly heterogeneous on MRI, and signal intensity at 0, 30, and to <1 g/L
60 min
resembles that of brain matter on T1-weighted imaging
Prolactinoma Serum PRL Exclude medications
(Fig. 33-4). Adenoma density is usually lower than that MRI of the sella
of surrounding normal tissue on T1-weighted imaging, should be ordered
and the signal intensity increases with T2-weighted if prolactin is
images. The high phospholipid content of the posterior elevated
pituitary results in a pituitary bright spot. Cushings 24-h urinary Ensure urine
Sellar masses are commonly encountered as incidental disease free cortisol collection is total
and accurate
ndings on MRI, and most of these are pituitary adeno-
Dexamethasone Normal subjects
mas (incidentalomas). In the absence of hormone hyper- (1 mg) at 11 P.M. suppress to
secretion, these small lesions can be safely monitored by and fasting <5 g/dL
MRI, which is performed annually and then less often if plasma cortisol
there is no evidence of growth. Resection should be measured
considered for incidentally discovered macroadenomas, at 8 A.M.
as about one-third become invasive or cause local pres- ACTH assay Distinguishes
sure effects. If hormone hypersecretion is evident, spe- adrenal adenoma
(ACTH suppressed)
cic therapies are indicated.When larger masses (>1 cm) from ectopic ACTH
are encountered, they should also be distinguished from or Cushings
nonadenomatous lesions. Meningiomas are often associ- disease (ACTH
ated with bony hyperostosis; craniopharyngiomas may normal or elevated)
be calcied and are usually hypodense, whereas gliomas
are hyperdense on T2-weighted images. Note: For abbreviations, see text.
of hormone excess, laboratory studies are geared towards middle fossa, the optic nerves, or invading posteriorly 433
determining the nature of the tumor and assessing the behind the clivus. Intraoperative microscopy facilitates
possible presence of hypopituitarism. When a pituitary visual distinction between adenomatous and normal
adenoma is suspected based on MRI, initial hormonal pituitary tissue, as well as microdissection of small
evaluation usually includes (1) basal PRL; (2) insulin-like tumors that may not be visible by MRI (Fig. 33-5).
growth factor (IGF) I; (3) 24-h urinary free cortisol (UFC) Transsphenoidal surgery also avoids the cranial invasion
and/or overnight oral dexamethasone (1 mg) suppression and manipulation of brain tissue required by subfrontal
test; (4) subunit, FSH, and LH; and (5) thyroid function surgical approaches. Endoscopic techniques with three-
tests. Additional hormonal evaluation may be indicated dimensional intraoperative localization have improved
based on the results of these tests. Pending more detailed visualization and access to tumor tissue.
assessment of hypopituitarism, a menstrual history, testos- In addition to correction of hormonal hypersecretion,
terone and 8 A.M. cortisol levels, and thyroid function tests pituitary surgery is indicated for mass lesions that
usually identify patients with pituitary hormone decien- impinge on surrounding structures. Surgical decompres-
cies that require hormone replacement before further test- sion and resection are required for an expanding pituitary
ing or surgery. mass accompanied by persistent headache, progressive
visual eld defects, cranial nerve palsies, internal hydro-

CHAPTER 33
Histologic Evaluation cephalus, and, occasionally, intrapituitary hemorrhage and
apoplexy. Transsphenoidal surgery is sometimes used for
Immunohistochemical staining of pituitary tumor speci-
pituitary tissue biopsy to establish a histologic diagnosis.
mens obtained at transsphenoidal surgery conrms clin-
ical and laboratory studies and provides a histologic
diagnosis when hormone studies are equivocal and in
cases of clinically nonfunctioning tumors. Occasionally,

Neurologic Disorders of the Pituitary and Hypothalamus

ultrastructural assessment by electron microscopy is
required for diagnosis.

Treatment:
HYPOTHALAMIC, PITUITARY,
AND OTHER SELLAR MASSES
OVERVIEW Successful management of sellar
masses requires accurate diagnosis as well as selection
of optimal therapeutic modalities. Most pituitary tumors
are benign and slow-growing. Clinical features result
from local mass effects and hormonal hypo- or hyper-
secretion syndromes caused directly by the adenoma or
as a consequence of treatment. Thus, lifelong manage-
ment and follow-up are necessary for these patients.
MRI technology with gadolinium enhancement for
pituitary visualization, new advances in transsphenoidal
surgery and in stereotactic radiotherapy (including
gamma-knife radiotherapy), and novel therapeutic
agents have improved pituitary tumor management.
The goals of pituitary tumor treatment include normal-
ization of excess pituitary secretion, amelioration of
symptoms and signs of hormonal hypersecretion syn-
dromes, and shrinkage or ablation of large tumor
masses with relief of adjacent structure compression.
Residual anterior pituitary function should be preserved
and can sometimes be restored by removing the tumor
mass. Ideally, adenoma recurrence should be prevented.
TRANSSPHENOIDAL SURGERY Transsphe-
noidal rather than transfrontal resection is the desired FIGURE 33-5
surgical approach for pituitary tumors, except for the Transsphenoidal resection of pituitary mass via the
endonasal approach. (Adapted from Fahlbusch R: Endocrinol
rare invasive suprasellar mass surrounding the frontal or
Metab Clin 21:669, 1992.)
 434 Whenever possible, the pituitary mass lesion should be and in an attempt to prevent regrowth. Irradiation offers
selectively excised; normal tissue should be manipulated the only effective means for ablating signicant postop-
or resected only when critical for effective mass dissection. erative residual nonfunctioning tumor tissue. In con-
Nonselective hemihypophysectomy or total hypophysec- trast, PRL-, GH-, and sometimes ACTH-secreting tumor
tomy may be indicated if no mass lesion is clearly dis- tissues are amenable to medical therapy.
cernible, multifocal lesions are present, or the remaining Side Effects In the short term, radiation may cause
nontumorous pituitary tissue is obviously necrotic. This transient nausea and weakness. Alopecia and loss of
strategy, however, increases the likelihood of hypopitu- taste and smell may be more long-lasting. Failure of
itarism and the need for lifelong hormonal replacement. pituitary hormone synthesis is common in patients who
Preoperative mass effects, including visual eld have undergone head and neck or pituitary-directed
defects or compromised pituitary function, may be irradiation. More than 50% of patients develop loss of
reversed by surgery, particularly when these decits are GH, ACTH, TSH, and/or gonadotropin secretion within
not long-standing. For large and invasive tumors, it is 10 years, usually due to hypothalamic damage. Lifelong
necessary to determine the optimal balance between follow-up with testing of anterior pituitary hormone
maximal tumor resection and preservation of anterior reserve is therefore necessary after radiation treatment.
pituitary function, especially for preserving growth and Optic nerve damage with impaired vision due to optic
reproductive function in younger patients. Similarly,
SECTION III

neuritis is reported in about 2% of patients who

tumor invasion outside of the sella is rarely amenable to undergo pituitary irradiation. Cranial nerve damage is
surgical cure; the surgeon must judge the risk-benet uncommon now that radiation doses are 2 Gy (200 rad)
ratio of extensive tumor resection. at any one treatment session and the maximum dose is
Side Effects Tumor size, the degree of invasive- <50 Gy (5000 rad). The use of stereotactic radiotherapy
ness, and experience of the surgeon largely determine may reduce damage to adjacent structures. Radiother-
the incidence of surgical complications. Operative mor- apy of pituitary tumors has been associated with
Diseases of the Central Nervous System

tality is about 1%. Transient diabetes insipidus and adverse mortality, mainly from cerebrovascular disease.
hypopituitarism occur in up to 20% of patients. Perma- The cumulative risk of developing a secondary tumor
nent diabetes insipidus, cranial nerve damage, nasal after conventional radiation is 1.3% after 10 years and
septal perforation, or visual disturbances may be 1.9% after 20 years.
encountered in up to 10% of patients. CSF leaks occur in MEDICAL Medical therapy for pituitary tumors is
4% of patients. Less common complications include highly specic and depends on tumor type. For pro-
carotid artery injury, loss of vision, hypothalamic dam- lactinomas, dopamine agonists are the treatment of
age, and meningitis. Permanent side effects are rare choice. For acromegaly and TSH-secreting tumors,
after surgery for microadenomas. somatostatin analogues and, occasionally, dopamine
RADIATION Radiation is used either as a primary agonists are indicated. ACTH-secreting tumors and non-
therapy for pituitary or parasellar masses or, more com- functioning tumors are generally not responsive to
monly, as an adjunct to surgery or medical therapy. medications and require surgery and/or irradiation.
Focused megavoltage irradiation is achieved by precise
MRI localization, using a high-voltage linear accelerator
and accurate isocentric rotational arcing. A major deter-
minant of accurate irradiation is reproduction of the FURTHER READINGS
patients head position during multiple visits and main- AIMARETTI G et al: Residual pituitary function after brain injury-
tenance of absolute head immobility. A total of <50 Gy induced hypopituitarism: A prospective 12-month study. J Clin
(5000 rad) is given as 180-cGy (180-rad) fractions split Endocrinol Metab 90:6085, 2005
over about 6 weeks. Stereotactic radiosurgery delivers a CATUREGLI P et al: Autoimmune hypophysitis. Endocr Rev 26:599,
large single high-energy dose from a cobalt 60 source 2005
(gamma knife), linear accelerator, or cyclotron. Long-term MELMED S:Acromegaly. N Engl J Med 355(24):2558, 2006
MINNITI G et al: Risk of second brain tumor after conservative
effects of gamma-knife surgery are as yet unknown.
surgery and radiotherapy for pituitary adenomas: Update after an
The role of radiation therapy in pituitary tumor man- additional 10 years. J Clin Endocrinol Metab 90:800, 2005
agement depends on multiple factors including the MOLITCH ME: Evaluation and treatment of adult growth hormone
nature of the tumor, age of the patient, and the avail- deciency: An Endocrine Society Clinical Practice Guideline. J
ability of surgical and radiation expertise. Because of its Clin Endocrinol Metab 91:1621, 2006
relatively slow onset of action, radiation therapy is usu- PATIL CG et al: Non-surgical management of hormone-secreting
ally reserved for postsurgical management. As an adju- pituitary tumors. J Clin Neurosci 16:985, 2009
vant to surgery, radiation is used to treat residual tumor TABAEE A et al: Endoscopic pituitary surgery: a systematic review and
meta-analysis. J neurosurg 111:545, 2009
 CHAPTER 34
MULTIPLE SCLEROSIS AND OTHER
DEMYELINATING DISEASES
Stephen L. Hauser Douglas S. Goodin

Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Disease Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Clinical Variants of MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Acute Disseminated Encephalomyelitis (ADEM) . . . . . . . . . . . 449
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450

Demyelinating disorders are characterized by inamma- by perivenular cufng with inammatory mononuclear
tion and selective destruction of central nervous system cells, predominantly T cells and macrophages, which also
(CNS) myelin. The peripheral nervous system (PNS) is inltrate the surrounding white matter. At sites of inam-
spared, and most patients have no evidence of an associ- mation, the blood-brain barrier (BBB) is disrupted, but
ated systemic illness. unlike vasculitis, the vessel wall is preserved. In many
lesions, myelin-specic autoantibodies are present, pre-
sumably promoting demyelination directly as well as
MULTIPLE SCLEROSIS
stimulating macrophages and microglial cells (bone mar-
Multiple sclerosis (MS) is characterized by a triad of rowderived CNS phagocytes) that scavenge the myelin
inammation, demyelination, and gliosis (scarring); the debris. As lesions evolve, there is prominent astrocytic
course can be relapsing-remitting or progressive. Lesions of proliferation (gliosis). Surviving oligodendrocytes or
MS typically occur at different times and in different CNS those that differentiate from precursor cells may partially
locations (i.e., disseminated in time and space). MS affects remyelinate the surviving naked axons, producing so-
~350,000 individuals in the United States and 2.5 million called shadow plaques. In many lesions, oligodendrocyte
individuals worldwide. In Western societies, MS is second precursors are present in large numbers but fail to
only to trauma as a cause of neurologic disability begin- remyelinate. Ultrastructural studies of MS lesions suggest
ning in early to middle adulthood. Manifestations of MS that fundamentally different underlying pathologies may
vary from a benign illness to a rapidly evolving and inca- exist in different patients. Heterogeneity has been
pacitating disease requiring profound lifestyle adjustments. observed in terms of (1) whether the inammatory cell
inltrate is associated with antibody deposition and acti-
PATHOGENESIS vation of complement, and (2) whether the target of the
immunopathologic process is the myelin sheath itself or
Anatomy
the cell body of the oligodendrocyte. Although relative
The lesions of MS (plaques) vary in size from 1 or 2 mm to sparing of axons is typical of MS, partial or total axonal
several centimeters. Acute MS lesions are characterized destruction can also occur, especially within highly
435
 436 inammatory lesions. Evidence also suggests that axonal slowing occurs when the demyelinated segments support
loss is a major contributor to irreversible neurologic dis- only (slow) continuous nerve impulse propagation.
ability in MS (see Neurodegeneration, below).
Epidemiology
Physiology
MS is approximately threefold more common in women
Nerve conduction in myelinated axons occurs in a salta- than men. The age of onset is typically between 20 and
tory manner, with the nerve impulse jumping from one 40 years (slightly later in men than in women), but the
node of Ranvier to the next without depolarization of disease can present across the lifespan. Approximately
the axonal membrane underlying the myelin sheath 10% of cases begin before 18 years, and extremes with
between nodes (Fig. 34-1). This produces considerably onset as early as 12 years or as late as the eighth decade
faster conduction velocities (~70 m/s) than the slow have been described.
velocities (~1 m/s) produced by continuous propagation Geographical gradients have been repeatedly
in unmyelinated nerves. Conduction block occurs when observed in MS, with prevalence rates increasing
the nerve impulse is unable to traverse the demyelinated at higher latitudes.The highest known prevalence
segment. This can happen when the resting axon mem- for MS (250 per 100,000) occurs in the Orkney Islands,
brane becomes hyperpolarized due to the exposure of located north of Scotland, and similarly high rates are
SECTION III

voltage-dependent potassium channels that are normally found throughout northern Europe, the northern United
buried underneath the myelin sheath. A temporary con- States, and Canada. By contrast, the prevalence is low in
duction block often follows a demyelinating event before Japan (6 per 100,000), in other parts of Asia, in equatorial
sodium channels (originally concentrated at the nodes) Africa, and in the Middle East.
redistribute along the naked axon (Fig. 34-1).This redis- One proposed explanation for the latitude effect on
tribution ultimately allows continuous propagation of MS is that there is a protective effect of sun exposure.
Diseases of the Central Nervous System

nerve action potentials through the demyelinated seg- Ultraviolet radiation from sun is the most important
ment. On occasion, conduction block is incomplete, source of vitamin D in most individuals, and low levels
affecting, for example, high- but not low-frequency vol- of vitamin D are common at high latitudes where sun
leys of impulses. Variable conduction block can occur exposure may be low, particularly during winter
with raised body temperature or metabolic alterations months. Prospective studies have conrmed that vitamin
and may explain clinical uctuations that vary from hour D deciency is associated with an increase in MS risk.
to hour or appear with fever or exercise. Conduction Immunoregulatory effects of vitamin D could explain
this possible relationship.
Migration studies and identication of possible point
Saltatory nerve impulse
epidemics provide additional support for an environ-
Myelin sheath
mental effect on MS risk. Migration studies suggest that
Axon
some MS-related exposure occurs in childhood and
years before MS is clinically evident. In some studies,
migration early in life from a low- to high-risk area was
Na+ channels Node of Ranvier found to increase MS risk, and conversely, migration
A from a high- to a low-risk area decreased risk. With
respect to possible point epidemics, the most convincing
Continuous nerve impulse
example occurred in the Faeroe Islands north of Den-
Myelin sheath Myelin sheath
mark after the British occupation during World War II.
Axon
The prevalence of MS appears to have steadily
increased over the past century; furthermore, this increase
has occurred primarily in women. Interestingly, recent
Na+ channels
B epidemiologic data suggests that the latitude effect on
FIGURE 34-1
MS may currently be decreasing, for unknown reasons.
Nerve conduction in myelinated and demyelinated axons. MS risk also correlates with high socioeconomic status,
A. Saltatory nerve conduction in myelinated axons occurs which may reect improved sanitation and delayed initial
with the nerve impulse jumping from one node of Ranvier to exposures to infectious agents. By analogy, some viral
the next. Sodium channels (shown as breaks in the solid black infections (e.g., poliomyelitis and measles viruses) produce
line) are concentrated at the nodes where axonal depolariza- neurologic sequelae more frequently when the age of ini-
tion occurs. B. Following demyelination, additional sodium tial infection is delayed. Occasional reports seem to impli-
channels are redistributed along the axon itself, thereby allow- cate a specic infectious agent such as human herpes virus
ing continuous propagation of the nerve action potential type 6 (HHV-6) or Chlamydia pneumoniae, although, in
despite the absence of myelin. general, the available reports have been inconsistent.
 Most intriguingly, the evidence of a remote Epstein- Autoreactive T Lymphocytes 437
Barr virus (EBV) infection playing some role in MS is Myelin basic protein (MBP) is an important T cell anti-
supported by a number of epidemiologic and laboratory gen in EAE and probably also in human MS. Activated
studies. A higher risk of infectious mononucleosis MBP-reactive T cells have been identied in the blood,
(associated with relatively late EBV infection) and in cerebrospinal uid (CSF), and within MS lesions.
higher-antibody titers to latency-associated EBV nuclear Moreover, DR2 may inuence the autoimmune
antigen are associated with MS; conversely, individuals response because it binds with high afnity to a frag-
never infected with EBV are at low MS risk. At this ment of MBP (spanning amino acids 8996), stimulating
time, however, a causal role for EBV or for any specic T cell responses to this self-protein.
infectious agent in MS remains uncertain.
Humoral Autoimmunity
B cell activation and antibody responses also appear to
GENETIC CONSIDERATIONS be necessary for the full development of demyelinating
Evidence also supports an important genetic inu- lesions to occur, both in experimental models and in
ence on MS.Whites are inherently at higher risk for human MS. Increased numbers of clonally expanded B
MS than Africans or Asians, even when residing in a cells with properties of postgerminal center memory or
similar environment. MS also aggregates within some antibody-producing lymphocytes are present in MS

CHAPTER 34
families, and adoption, half-sibling, twin, and spousal stud- lesions and in CSF. Myelin-specic autoantibodies, some
ies indicate that familial aggregation is due to genetic, and directed against myelin oligodendrocyte glycoprotein
not environmental, factors (Table 34-1). (MOG), have been detected bound to vesiculated
Susceptibility to MS is polygenic, with each gene myelin debris in MS plaques. In the CSF, elevated levels
contributing a relatively small amount to the overall of locally synthesized immunoglobulins and oligoclonal
risk. The major histocompatibility complex (MHC) on antibodies derived from expansion of clonally restricted

Multiple Sclerosis and Other Demyelinating Diseases

chromosome 6 is the strongest MS susceptibility region plasma cells are also characteristic of MS.The pattern of
in the genome. Fine mapping studies implicate primarily oligoclonal banding is unique to each individual, and
the class II region of the MHC (encoding HLA mole- attempts to identify the targets of these antibodies have
cules involved in presenting peptide antigens to T cells) been largely unsuccessful, although one recent report
and specically the DR2 (molecular designation indicated that some bands recognized EBV antigens.
DRB1*1501) allele. Other recently identied MS sus-
ceptibility genes encode receptors for two proinamma- Cytokines
tory cytokines, the IL-7 receptor alpha chain (CD127) Cytokines and chemokines appear to regulate many of
and the IL-2 receptor alpha chain (CD25); the MS asso- the cellular interactions that operate in MS. Proinam-
ciated variant of the IL-7 receptor increases the amount matory TH1 cytokines including interleukin (IL) 2,
of soluble compared to membrane bound receptor. It is tumor necrosis factor (TNF) , and interferon (IFN)
also likely that genetic heterogeneity is present in MS, play key roles in activating and maintaining autoimmune
meaning that there are different causative genes in dif- responses, and TNF- and IFN- may directly injure
ferent individuals. oligodendrocytes or the myelin membrane.

Triggers
Immunology Studies reveal that in patients with early relapsing remit-
An autoimmune cause for MS is supported by the labo- ting MS, serial MRI has demonstrated bursts of focal
ratory model of experimental allergic encephalomyelitis inammatory disease activity occurring far more fre-
(EAE) and by studies of the immune system in MS quently than would have been predicted by the frequency
patients. of relapses. Thus, early in MS, most disease activity is
clinically silent. The triggers causing these bursts are
unknown, although the fact that patients may experience
TABLE 34-1 relapses after nonspecic upper respiratory infections sug-
RISK OF DEVELOPING MS gests that either molecular mimicry between viruses and
myelin antigens or viral superantigens activating patho-
1 in 3 If an identical twin has MS genic T cells may play a role in MS pathogenesis.
1 in 15 If a fraternal twin has MS
1 in 25 If a sibling has MS
1 in 50 If a parent or half-sibling has MS Neurodegeneration
1 in 100 If a rst cousin has MS
1 in 1000 If a spouse has MS Axonal damage occurs in every newly formed MS lesion,
1 in 1000 If no one in the family has MS and cumulative axonal loss is considered to be the major
cause of progressive and irreversible neurological disability
 438 in MS. As many as 70% of axons are lost from the lateral The weakness is of the upper motor neuron type
corticospinal tracts in patients with advanced paraparesis (Chap. 10) and is usually accompanied by other pyrami-
from MS, and longitudinal MRI studies suggest there is dal signs such as spasticity, hyperreexia and Babinski
progressive axonal loss over time within established, inac- signs. Occasionally a tendon reex may be lost (simulat-
tive, lesions. Knowledge of the mechanisms responsible ing a lower motor neuron lesion) if an MS lesion dis-
for axonal injury is incomplete, and it is even unclear rupts the afferent reex bers in the spinal cord.
whether demyelination is a prerequisite for axonal injury Spasticity (Chap. 10) is often associated with sponta-
in MS. Demyelination can result in reduced trophic neous and movement-induced muscle spasms. More than
support for axons, redistribution of ion channels, and 30% of MS patients have moderate to severe spasticity,
destabilization of action potential membrane potentials. especially in the legs. This is often accompanied by
Axons can initially adapt, but eventually distal and painful spasms, interfering with ambulation, work, or
retrograde degeneration occurs. Therefore the early pro- self-care. Occasionally spasticity provides support for the
motion of remyelination and preservation of oligoden- body weight during ambulation, and in these cases treat-
drocytes remain important therapeutic goals in MS. Some ment of spasticity may actually do more harm than good.
evidence suggests that axonal damage is mediated directly Optic neuritis (ON) presents as diminished visual acu-
by resident and invading inammatory cells and their ity, dimness, or decreased color perception (desaturation)
toxic products, in particular by microglia, macrophages, in the central eld of vision. These symptoms may be
SECTION III

and CD8 T lymphocytes. Activated microglia are particu- mild or may progress to severe visual loss. Rarely, there is
larly likely to cause axonal injury through the release of complete loss of light perception. Visual symptoms are
NO and oxygen radicals and via glutamate, which is toxic generally monocular but may be bilateral. Periorbital
to oligodendrocytes and neurons. pain (aggravated by eye movement) often precedes or
accompanies the visual loss. An afferent pupillary defect
(Chap. 17) is usually present. Funduscopic examination
CLINICAL MANIFESTATIONS
Diseases of the Central Nervous System

may be normal or reveal optic disc swelling (papillitis).

The onset of MS may be abrupt or insidious. Symptoms Pallor of the optic disc (optic atrophy) commonly fol-
may be severe or seem so trivial that a patient may not lows ON. Uveitis is rare and should raise the possibility
seek medical attention for months or years. Indeed, at of alternative diagnoses.
autopsy some individuals who were asymptomatic during Visual blurring in MS may result from ON or
life will be found, unexpectedly, to have MS. In others, an diplopia; if the symptom resolves when either eye is
MRI scan obtained for an unrelated reason may show covered, the cause is diplopia.
evidence of asymptomatic MS. Symptoms of MS are Diplopia may result from internuclear ophthalmople-
extremely varied and depend on the location and severity gia (INO) or from palsy of the sixth cranial nerve (rarely
of lesions within the CNS (Table 34-2). Examination the third or fourth). An INO consists of impaired
generally reveals evidence of neurologic dysfunction, adduction of one eye due to a lesion in the ipsilateral
often in asymptomatic locations. For example, a patient medial longitudinal fasciculus (Chap. 17). Prominent
may present with symptoms in one leg but signs in both. nystagmus is often observed in the abducting eye, along
Weakness of the limbs may manifest as loss of strength with a small skew deviation. A bilateral INO is particu-
or dexterity, fatigue, or a disturbance of gait. Exercise- larly suggestive of MS. Other common gaze disturbances
induced weakness is a characteristic symptom of MS. in MS include (1) a horizontal gaze palsy, (2) a one and
a half syndrome (horizontal gaze palsy plus an INO),
TABLE 34-2 and (3) acquired pendular nystagmus.
Sensory symptoms are varied and include both paresthe-
INITIAL SYMPTOMS OF MS
sias (e.g., tingling, prickling sensations, formications,pins
PERCENT PERCENT and needles, or painful burning) and hypesthesia (e.g.,
SYMPTOM OF CASES SYMPTOM OF CASES reduced sensation, numbness, or a dead feeling).
Sensory loss 37 Lhermitte 3 Unpleasant sensations (e.g., feelings that body parts are
Optic neuritis 36 Pain 3 swollen, wet, raw, or tightly wrapped) are also common.
Weakness 35 Dementia 2 Sensory impairment of the trunk and legs below a hori-
Paresthesias 24 Visual loss 2 zontal line on the torso (a sensory level) indicates that
Diplopia 15 Facial palsy 1
the spinal cord is the origin of the sensory disturbance. It
Ataxia 11 Impotence 1
Vertigo 6 Myokymia 1
is often accompanied by a bandlike sensation of tightness
Paroxysmal attacks 4 Epilepsy 1 around the torso. Pain is a common symptom of MS,
Bladder 4 Falling 1 experienced by >50% of patients. Pain can occur any-
where on the body and can change locations over time.
Source: After WB Matthews et al, McAlpines Multiple Sclerosis, Ataxia usually manifests as cerebellar tremors (Chap. 26).
New York, Churchill Livingstone, 1991. Ataxia may also involve the head and trunk or the voice,
producing a characteristic cerebellar dysarthria (scanning (see Acute Attacks or Initial Demyelinating Episodes, 439
speech). below). Such heat-related symptoms probably result
Bladder dysfunction is present in >90% of MS patients, from transient conduction block (see above).
and in a third of patients, dysfunction results in weekly Lhermittes symptom is an electric shocklike sensation
or more frequent episodes of incontinence. During nor- (typically induced by exion or other movements of the
mal reex voiding, relaxation of the bladder sphincter neck) that radiates down the back into the legs. Rarely,
(-adrenergic innervation) is coordinated with contrac- it radiates into the arms. It is generally self-limited but
tion of the detrusor muscle in the bladder wall (mus- may persist for years. Lhermittes symptom can also
carinic cholinergic innervation). Detrusor hyperreexia, occur with other disorders of the cervical spinal cord
due to impairment of suprasegmental inhibition, causes (e.g., cervical spondylosis).
urinary frequency, urgency, nocturia, and uncontrolled Paroxysmal symptoms are distinguished by their brief
bladder emptying. Detrusor sphincter dyssynergia, due to duration (10 s to 2 min), high frequency (540 episodes
loss of synchronization between detrusor and sphincter per day), lack of any alteration of consciousness or
muscles, causes difculty in initiating and/or stopping change in background electroencephalogram during
the urinary stream, producing hesitancy, urinary reten- episodes, and a self-limited course (generally lasting
tion, overow incontinence, and recurrent infection. weeks to months). They may be precipitated by hyper-
Constipation occurs in >30% of patients. Fecal ventilation or movement. These syndromes may include

CHAPTER 34
urgency or bowel incontinence is less common (15%) but Lhermittes symptom; tonic contractions of a limb, face,
can be socially debilitating. or trunk (tonic seizures); paroxysmal dysarthria and ataxia;
Cognitive dysfunction can include memory loss, impaired paroxysmal sensory disturbances; and several other less
attention, difculties in problem solving, slowed informa- well-characterized syndromes. Paroxysmal symptoms prob-
tion processing, and problems shifting between cognitive ably result from spontaneous discharges, arising at the
tasks. Euphoria (elevated mood) was once thought to be edges of demyelinated plaques and spreading to adjacent

Multiple Sclerosis and Other Demyelinating Diseases

characteristic of MS but is actually uncommon, occurring white matter tracts.
in <20% of patients. Cognitive dysfunction sufcient to Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal
impair activities of daily living is rare. neuralgia (Chap. 29) can occur when the demyelinating
Depression, experienced by approximately half of lesion involves the root entry (or exit) zone of the fth,
patients, can be reactive, endogenous, or part of the illness seventh, and ninth cranial nerve, respectively. Trigeminal
itself and can contribute to fatigue. Suicide in MS patients neuralgia (tic douloureux) is a very brief lancinating facial
is 7.5-fold more common than in age-matched controls. pain often triggered by an afferent input from the face or
Fatigue is experienced by 90% of patients; this symp- teeth. Most cases of trigeminal neuralgia are not MS-
tom is the most common reason for work-related dis- related; however, atypical features such as onset before age
ability in MS. Fatigue can be exacerbated by elevated 50 years, bilateral symptoms, objective sensory loss, or
temperatures, by depression, by expending exceptional nonparoxysmal pain should raise concerns that MS could
effort to accomplish basic activities of daily living, or by be responsible.
sleep disturbances (e.g., from frequent nocturnal awak- Facial myokymia consists of either persistent rapid
enings to urinate). ickering contractions of the facial musculature (espe-
Sexual dysfunction may manifest as decreased libido, cially the lower portion of the orbicularis oculus) or a
impaired genital sensation, impotence in men, and dimin- contraction that slowly spreads across the face. It results
ished vaginal lubrication or adductor spasms in women. from lesions of the corticobulbar tracts or brainstem
Facial weakness due to a lesion in the pons may resem- course of the facial nerve.
ble idiopathic Bells palsy (Chap. 29). Unlike Bells palsy,
facial weakness in MS is usually not associated with ipsi-
lateral loss of taste sensation or retroauricular pain. DISEASE COURSE
Vertigo may appear suddenly from a brainstem lesion, Four clinical types of MS have been described (Fig. 34-2):
supercially resembling acute labyrinthitis (Chap. 9).
Hearing loss may also occur in MS but is uncommon. 1. Relapsing/remitting MS (RRMS) accounts for 85% of
MS cases at onset and is characterized by discrete
attacks that generally evolve over days to weeks
Ancillary Symptoms
(rarely over hours).There is often complete recovery
Heat sensitivity refers to neurologic symptoms produced over the ensuing weeks to months (Fig. 34-2A).
by an elevation of the bodys core temperature. For However, when ambulation is severely impaired dur-
example, unilateral visual blurring may occur during a ing an attack, approximately half will fail to improve.
hot shower or with physical exercise (Uhthoffs symptom). Between attacks, patients are neurologically stable.
It is also common for MS symptoms to worsen tran- 2. Secondary progressive MS (SPMS) always begins as
siently, sometimes dramatically, during febrile illnesses RRMS (Fig. 34-2B). At some point, however, the
 440 RRMS PPMS majority of RRMS ultimately evolves into SPMS.
SPMS appears to represent a late stage of the same
underlying illness as RRMS.
Disability

Disability
3. Primary progressive MS (PPMS) accounts for ~15% of
cases. These patients do not experience attacks but
only a steady functional decline from disease onset
(Fig. 34-2C ). Compared to RRMS, the sex distrib-
Time Time
ution is more even, the disease begins later in life
(mean age ~40 years), and disability develops faster
SPMS PRMS (at least relative to the onset of the rst clinical
symptom). Whether PPMS is an uncommon form
of the same underlying illness as RRMS or whether
Disability

Disability

these are distinct illnesses is uncertain.

4. Progressive/relapsing MS (PRMS) overlaps PPMS and
SPMS and accounts for ~5% of MS patients. Like
patients with PPMS, these patients experience a
Time Time steady deterioration in their condition from disease
SECTION III

onset. However, like SPMS patients, they experience

FIGURE 34-2 occasional attacks superimposed upon their progres-
Clinical course of multiple sclerosis (MS). A. Relapsing/ sive course (Fig. 34-2D).
remitting MS. B. Secondary progressive MS. C. Primary pro-
gressive MS. D. Progressive/relapsing MS. DIAGNOSIS
There is no denitive diagnostic test for MS. Diagnostic
Diseases of the Central Nervous System

clinical course changes so that the patient experiences criteria for clinically denite MS require documentation
a steady deterioration in function unassociated with of two or more episodes of symptoms and two or more
acute attacks (which may continue or cease during signs that reect pathology in anatomically noncontigu-
the progressive phase). SPMS produces a greater ous white matter tracts of the CNS (Table 34-3). Symp-
amount of xed neurologic disability than RRMS. toms must last for >24 h and occur as distinct episodes
For a patient with RRMS, the risk of developing that are separated by a month or more. At least one of
SPMS is ~2.5% each year, meaning that the great the two required signs must be present on neurologic

TABLE 34-3
DIAGNOSTIC CRITERIA FOR MS
1. Examination must reveal objective abnormalities of the CNS.
2. Involvement must reect predominantly disease of white matter long tracts, usually including (a) pyramidal
pathways, (b) cerebellar pathways, (c) medial longitudinal fasciculus, (d) optic nerve, and (e) posterior columns.
3. Examination or history must implicate involvement of two or more areas of the CNS.
a. MRI may be used to document a second lesion when only one site of abnormality has been demonstrable
on examination. A conrmatory MRI must have either four lesions involving the white matter or three
lesions if one is periventricular in location. Acceptable lesions must be >3 mm in diameter. For patients
older than 50 years, two of the following criteria must also be met: (a) lesion size >5 mm, (b) lesions adja-
cent to the bodies of the lateral ventricles, and (c) lesion(s) present in the posterior fossa.
b. Evoked response testing may be used to document a second lesion not evident on clinical examination.
4. The clinical pattern must consist of (a) two or more separate episodes of worsening involving different sites of
the CNS, each lasting at least 24 h and occurring at least 1 month apart, or (b) gradual or stepwise progres-
sion over at least 6 months if accompanied by increased IgG synthesis or two or more oligoclonal bands. MRI
may be used to document dissemination in time if a new T2 lesion or a Gd-enhancing lesion is seen 3 or more
months after a clinically isolated syndrome.
5. The patients neurologic condition could not better be attributed to another disease.
DIAGNOSTIC CATEGORIES

1. Denite MS: All ve criteria fullled.

2. Probable MS: All ve criteria fullled except (a) only one objective abnormality despite two symptomatic
episodes or (b) only one symptomatic episode despite two or more objective abnormalities.
3. At risk for MS: Criteria 1, 2, 3, and 5 fullled; patient has only one symptomatic episode and one objective
abnormality.

Note: CNS, central nervous system; MRI, magnetic resonance imaging; Gd, gadolinium.
examination.The second may be documented by abnor- found in >95% of patients. An increase in vascular per- 441
mal paraclinical tests such as MRI or evoked potentials meability from a breakdown of the BBB is detected by
(EPs). Similarly, in the most recent diagnostic scheme, the leakage of intravenous gadolinium (Gd) into the
second clinical event (in time) may be supported solely parenchyma. Such leakage occurs early in the develop-
by paraclinical information, usually the development of ment of an MS lesion and serves as a useful marker of
new focal white matter lesions on MRI. In patients who inammation. Gd enhancement persists for approxi-
experience gradual progression of disability for 6 mately 1 month, and the residual MS plaque remains
months without superimposed relapses, documentation visible indefinitely as a focal area of hyperintensity
of intrathecal IgG may be used to support the diagnosis. (a lesion) on spin-echo (T2-weighted) and proton-density
images. Lesions are frequently oriented perpendicular to
DIAGNOSTIC TESTS the ventricular surface, corresponding to the pathologic
pattern of perivenous demyelination (Dawsons ngers).
Magnetic Resonance Imaging
Lesions are multifocal within the brain, brainstem, and
MRI has revolutionized the diagnosis and management spinal cord. Lesions larger than 6 mm located in the cor-
of MS (Fig. 34-3); characteristic abnormalities are pus callosum, periventricular white matter, brainstem,

CHAPTER 34
Multiple Sclerosis and Other Demyelinating Diseases

FIGURE 34-3
A. Axial rst-echo image from T2-weighted sequence demon- corpus callosum are frequent in MS and rare in vascular dis-
strates multiple bright signal abnormalities in white matter, ease. C. Sagittal T2-weighted fast spin echo image of the
typical for MS. B. Sagittal T2-weighted FLAIR (uid attenu- thoracic spine demonstrates a fusiform high-signal-intensity
ated inversion recovery) image in which the high signal of lesion in the mid thoracic spinal cord. D. Sagittal T1-weighted
CSF has been suppressed. CSF appears dark, while areas of image obtained after the intravenous administration of
brain edema or demyelination appear high in signal as shown gadolinium DTPA reveals focal areas of blood-brain barrier
here in the corpus callosum (arrows). Lesions in the anterior disruption, identied as high-signal-intensity regions (arrows).
 442 cerebellum, or spinal cord are particularly helpful diag- or more OCBs are found in 7590% of patients with
nostically. Different criteria for the use of MRI in the MS. OCBs may be absent at the onset of MS, and in
diagnosis of MS have been proposed (Table 34-3). individual patients the number of bands may increase
The total volume of T2-weighted signal abnormality with time. It is important that paired serum samples be
(the burden of disease) shows a signicant (albeit weak) studied to exclude a peripheral (i.e., non-CNS) origin
correlation with clinical disability, as do measures of brain of any OCBs detected in the CSF.
atrophy. Approximately one-third of T2-weighted lesions A mild CSF pleocytosis (>5 cells/L) is present in
appear as hypointense lesions (black holes) on T1-weighted ~25% of cases, usually in young patients with RRMS. A
imaging. Black holes may be a marker of irreversible pleocytosis of >75 cells/L, the presence of polymor-
demyelination and axonal loss, although even this measure phonuclear leukocytes, or a protein concentration of
depends on the timing of the image acquisition (e.g., most >1.0 g/L (>100 mg/dL) in CSF should raise concern
acute Gd-enhancing T2 lesions are T1 dark). that the patient may not have MS.
Newer MRI measures such as magnetization transfer
ratio (MTR) imaging and proton magnetic resonance
spectroscopic imaging (MRSI) may ultimately serve as DIFFERENTIAL DIAGNOSIS
surrogate markers of clinical disability. For example, No single clinical sign or test is diagnostic of MS. The
MRSI can quantitate molecules such as N-acetyl aspar- diagnosis is readily made in a young adult with relapsing
SECTION III

tate, which is a marker of axonal integrity, and MTR and remitting symptoms involving different areas of CNS
may be able to distinguish demyelination from edema. white matter. The possibility of an alternative diagnosis
should always be considered (Table 34-4), particularly
Evoked Potentials when (1) symptoms are localized exclusively to the pos-
terior fossa, craniocervical junction, or spinal cord; (2)
EP testing assesses function in afferent (visual, auditory, the patient is <15 or >60 years of age; (3) the clinical
Diseases of the Central Nervous System

and somatosensory) or efferent (motor) CNS pathways. course is progressive from onset; (4) the patient has never
EPs use computer averaging to measure CNS electric experienced visual, sensory, or bladder symptoms; or (5)
potentials evoked by repetitive stimulation of selected laboratory ndings (e.g., MRI, CSF, or EPs) are atypical.
peripheral nerves or of the brain.These tests provide the Similarly, uncommon or rare symptoms in MS (e.g.,
most information when the pathways studied are clini- aphasia, parkinsonism, chorea, isolated dementia, severe
cally uninvolved. For example, in a patient with a remit-
ting and relapsing spinal cord syndrome with sensory
decits in the legs, an abnormal somatosensory EP fol- TABLE 34-4
lowing posterior tibial nerve stimulation provides little
DISORDERS THAT CAN MIMIC MS
new information. By contrast, an abnormal visual EP in
this circumstance would permit a diagnosis of clinically Acute disseminated encephalomyelitis (ADEM)
denite MS (Table 34-3). Abnormalities on one or Antiphospholipid antibody syndrome
Behets disease
more EP modalities occur in 8090% of MS patients.
Cerebral autosomal dominant arteriopathy, subcortical
EP abnormalities are not specic to MS, although a infarcts, and leukoencephalopathy (CADASIL)
marked delay in the latency of a specic EP component Congenital leukodystrophies (e.g., adrenoleukodystrophy,
(as opposed to a reduced amplitude or distorted wave- metachromatic leukodystrophy)
shape) is suggestive of demyelination. Human immunodeciency virus (HIV) infection
Ischemic optic neuropathy (arteritic and nonarteritic)
Lyme disease
Cerebrospinal Fluid Mitochondrial encephalopathy with lactic acidosis and
stroke (MELAS)
CSF abnormalities found in MS include a mononuclear Neoplasms (e.g., lymphoma, glioma, meningioma)
cell pleocytosis and an increased level of intrathecally Sarcoid
synthesized IgG.The total CSF protein is usually normal Sjgrens syndrome
or slightly elevated.Various formulas distinguish intrathe- Stroke and ischemic cerebrovascular disease
cally synthesized IgG from IgG that may have entered Syphilis
the CNS passively from the serum. One formula, the Systemic lupus erythematosus and related collagen vas-
CSF IgG index, expresses the ratio of IgG to albumin in cular disorders
Tropical spastic paraparesis (HTLV I/II infection)
the CSF divided by the same ratio in the serum. The
Vascular malformations (especially spinal dural AV stulas)
IgG synthesis rate uses serum and CSF IgG and albumin Vasculitis (primary CNS or other)
measurements to calculate the rate of CNS IgG synthe- Vitamin B12 deciency
sis. The measurement of oligoclonal banding (OCB) in
the CSF also assesses intrathecal production of IgG. Note: HTLV, human T cell lymphotropic virus; AV, arteriovenous;
OCBs are detected by agarose gel electrophoresis. Two CNS, central nervous system.
muscular atrophy, peripheral neuropathy, episodic loss of Effect of Pregnancy 443
consciousness, fever, headache, seizures, or coma) should
Pregnant MS patients experience fewer attacks than
increase concern about an alternative diagnosis. Diagno-
expected during gestation (especially in the last trimester),
sis is also difcult in patients with a rapid or explosive
but more attacks than expected in the rst 3 months post-
(strokelike) onset or with mild symptoms and a normal
partum.When considering the pregnancy year as a whole
neurologic examination. Rarely, intense inammation
(i.e., 9 months pregnancy plus 3 months postpartum), the
and swelling may produce a mass lesion that mimics a
overall disease course is unaffected. Decisions about child-
primary or metastatic tumor. The specic tests required
bearing should thus be made based on (1) the mothers
to exclude alternative diagnoses will vary with each clin-
physical state, (2) her ability to care for the child, and
ical situation; however, an erythrocyte sedimentation rate,
(3) the availability of social support. Disease-modifying
serum B12 level, ANA, and treponemal antibody should
therapy is generally discontinued during pregnancy,
probably be obtained in all patients with suspected MS.
although the actual risk from the interferons and glati-
ramer acetate (see below) appears to be low.
PROGNOSIS
Most patients with MS ultimately experience progres-
sive neurologic disability. Fifteen years after onset, only

CHAPTER 34
Treatment:
20% of patients have no functional limitation; between MULTIPLE SCLEROSIS
one-third and one-half will have progressed to SPMS
Therapy for MS can be divided into several categories:
and will require assistance with ambulation. Twenty-ve
(1) treatment of acute attacks as they occur, (2) treat-
years after onset, ~80% of MS patients will have reached
ment with disease-modifying agents that reduce the
this level of disability. In 1998, it was estimated that the
biological activity of MS, and (3) symptomatic therapy.
total annual economic burden of MS in the United
Treatments that promote remyelination or neural

Multiple Sclerosis and Other Demyelinating Diseases

States exceeded $6.8 billion.
repair do not currently exist but would be highly
However, even if the prognosis for disability is grave
desirable.
for the average patient, the prognosis in an individual is
The Kurtzke Expanded Disability Status Score (EDSS)
difcult to establish. Certain clinical features suggest a
is a useful measure of neurologic impairment in MS
more favorable prognosis, including ON or sensory
(Table 34-5). Most patients with EDSS scores <3.5 have
symptoms at onset; fewer than two relapses in the rst
RRMS, walk normally, and are generally not disabled; by
year of illness; and minimal impairment after 5 years. By
contrast, patients with EDSS scores >5.5 have progres-
contrast, patients with truncal ataxia, action tremor,
sive MS (SPMS or PPMS), are gait-impaired and, typically,
pyramidal symptoms, or a progressive disease course are
are occupationally disabled.
more likely to become disabled.
Importantly, some MS patients have a benign variant
ACUTE ATTACKS OR INITIAL DEMYELINAT-
of MS and never develop neurologic disability.The like-
ING EPISODES When patients experience acute
lihood of having benign MS is thought to be <20%.
deterioration, it is important to consider whether this
Patients with benign MS 15 years after onset who have
change reects new disease activity or a pseudoexacer-
entirely normal neurologic examinations are likely to
bationresulting from an increase in ambient temperature,
maintain their benign course.
fever, or an infection. In such instances, glucocorticoid
In patients with their rst demyelinating event (i.e., a
treatment is inappropriate. Glucocorticoids are used to
clinically isolated syndrome), the brain MRI provides
manage either rst attacks or acute exacerbations. They
prognostic information. With three or more typical T2-
provide short-term clinical benet by reducing the
weighted lesions, the risk of developing MS after 10
severity and shortening the duration of attacks. Whether
years is 7080%. Conversely, with a normal brain MRI,
treatment provides any long-term benet on the course
the likelihood of developing MS is <20%. Similarly, two
of the illness is less clear. Therefore, mild attacks are
or more Gd-enhancing lesions at baseline is highly pre-
often not treated. Physical and occupational therapy can
dictive of future MS, as is the appearance of either new
help with mobility and manual dexterity.
T2-weighted lesions or new Gd enhancement 3 months
Glucocorticoid treatment is usually administered as
after the initial episode.
intravenous methylprednisolone, 5001000 mg/d for
Mortality as a direct consequence of MS is uncom-
35 days, either without a taper or followed by a course
mon, although it has been estimated that the 25-year
of oral prednisone beginning at a dose of 6080 mg/d
survival is only 85% of expected. Death can occur dur-
and gradually tapered over 2 weeks. Outpatient treat-
ing an acute MS attack, although this is distinctly rare.
ment is usually possible. If intravenous therapy is
More commonly, death occurs as a complication of MS
unavailable or inconvenient, oral glucocorticoids can be
(e.g., pneumonia in a debilitated individual). Death also
substituted.
results from suicide.
 444 TABLE 34-5
SCORING SYSTEMS FOR MS

KURTZKE EXPANDED DISABILITY STATUS SCORE (EDSS)

0.0 = Normal neurologic exam [all grade 0 in functional 6.0 = Unilateral assistance required to walk about 100 m with
status (FS)] or without resting
1.0 = No disability, minimal signs in one FS (i.e., grade 1) 6.5 = Constant bilateral assistance required to walk about 20 m
1.5 = No disability, minimal signs in more than one FS (more without resting
than one grade 1) 7.0 = Unable to walk beyond about 5 m even with aid;
2.0 = Minimal disability in one FS (one FS grade 2, others essentially restricted to wheelchair; wheels self and
0 or 1) transfers alone
2.5 = Minimal disability in two FS (two FS grade 2, others 7.5 = Unable to take more than a few steps; restricted to
0 or 1) wheelchair; may need aid to transfer
3.0 = Moderate disability in one FS (one FS grade 3, others 8.0 = Essentially restricted to bed or chair or perambulated in
0 or 1) or mild disability in three or four FS (three/four FS wheelchair, but out of bed most of day; retains many
grade 2, others 0 or 1) though fully ambulatory self-care functions; generally has
3.5 = Fully ambulatory but with moderate disability in one FS effective use of arms
(one grade 3) and one or two FS grade 2; or two FS grade 8.5 = Essentially restricted to bed much of the day; has some
3; or ve FS grade 2 (others 0 or 1) effective use of arm(s); retains some self-care functions
SECTION III

4.0 = Ambulatory without aid or rest for 500 m 9.0 = Helpless bed patient; can communicate and eat
4.5 = Ambulatory without aid or rest for 300 m 9.5 = Totally helpless bed patient; unable to communicate
5.0 = Ambulatory without aid or rest for 200 m or eat
5.5 = Ambulatory without aid or rest for 100 m 10.0 = Death due to MS
FUNCTIONAL STATUS (FS) SCORE

A. Pyramidal functions 5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate

0 = Normal decrease in touch or pain and/or loss of proprioception
Diseases of the Central Nervous System

1 = Abnormal signs without disability for most of the body below the head
2 = Minimal disability 6 = Sensation essentially lost below the head
3 = Mild or moderate paraparesis or hemiparesis, or severe E. Bowel and bladder functions
monoparesis 0 = Normal
4 = Marked paraparesis or hemiparesis, moderate 1 = Mild urinary hesitancy, urgency, or retention
quadriparesis, or monoplegia 2 = Moderate hesitancy, urgency, retention of bowel or
5 = Paraplegia, hemiplegia, or marked quadriparesis bladder, or rare urinary incontinence
6 = Quadriplegia 3 = Frequent urinary incontinence
B. Cerebellar functions 4 = In need of almost constant catheterization
0 = Normal 5 = Loss of bladder function
1 = Abnormal signs without disability 6 = Loss of bowel and bladder function
2 = Mild ataxia F. Visual (or optic) functions
3 = Moderate truncal or limb ataxia 0 = Normal
4 = Severe ataxia all limbs 1 = Scotoma with visual acuity (corrected) better than 20/30
5 = Unable to perform coordinated movements due to ataxia 2 = Worse eye with scotoma with maximal visual acuity
C. Brainstem functions (corrected) of 20/30 to 20/59
0 = Normal 3 = Worse eye with large scotoma, or moderate decrease in
1 = Signs only elds, but with maximal visual acuity (corrected) of 20/60
2 = Moderate nystagmus or other mild disability to 20/99
3 = Severe nystagmus, marked extraocular weakness, or 4 = Worse eye with marked decrease of fields and
moderate disability of other cranial nerves maximal acuity (corrected) of 20/100 to 20/200; grade 3
4 = Marked dysarthria or other marked disability plus maximal acuity of better eye of 20/60
5 = Inability to swallow or speak or less
D. Sensory functions 5 = Worse eye with maximal visual acuity (corrected) less
0 = Normal than 20/200; grade 4 plus maximal acuity of better eye
1 = Vibration or gure-writing decrease only, in 1 or 2 limbs of 20/60 or less
2 = Mild decrease in touch or pain or position sense, and/or 6 = Grade 5 plus maximal visual acuity of better eye of 20/60
moderate decrease in vibration in 1 or 2 limbs, or or less
vibratory decrease alone in 3 or 4 limbs G. Cerebral (or mental) functions
3 = Moderate decrease in touch or pain or position sense, 0 = Normal
and/or essentially lost vibration in 1 or 2 limbs, or mild 1 = Mood alteration only (does not affect EDSS score)
decrease in touch or pain, and/or moderate decrease in 2 = Mild decrease in mentation
all proprioceptive tests in 3 or 4 limbs 3 = Moderate decrease in mentation
4 = Marked decrease in touch or pain or loss of proprioception, 4 = Marked decrease in mentation
alone or combined, in 1 or 2 limbs or moderate decrease 5 = Chronic brain syndromesevere or incompetent
in touch or pain and/or severe proprioceptive decrease in
more than 2 limbs

Source: After JF Kurtzke: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33:1444, 1983.
 TABLE 34-6 445
TWO-YEAR OUTCOMES FOR FDA-APPROVED THERAPIES FOR MULTIPLE SCLEROSISa

OUTCOMESb MRI OUTCOMESc

DOSE, ROUTE, ATTACK CHANGE IN NEW T2 TOTAL BURDEN

AND SCHEDULE RATE, MEAN DISEASE SEVERITY LESIONSd OF DISEASE

IFN--1b, 250 g SC qod 34%e 29% (ns) 83%f 17%e

IFN--1a, 30 g IM qw 18%g 37%g 36%f 4% (ns)
IFN--1a, 44 g SC tiw 32%e 30%g 78%e 15%e
GA, 20 mg SC qd 29%f 12% (ns) 38%f 8%f
MTX, 12 mg/m2 IV q3mo 66%e 75%g 79%g nr
NTZ, 300 mg IV qmo 68%e 42%e 83%e 18%e

a
Percentage reductions (or increases) have been calculated by dividing the reported rates in the treated group by
the comparable rates in the placebo group, except for MRI disease burden, which was calculated as the differ-
ence in the median % change between the treated and placebo groups.
b
Severity = 1 point EDSS progression, sustained for 3 months (in the IFN--1a 30 g qw trial, this change was
sustained for 6 months; in the IFN--1b trial, this was over 3 years).

CHAPTER 34
c
Different studies measured these MRI measures differently, making comparisons difcult (numbers for new T2
represent the best case scenario for each trial).
d
New lesions seen on T2-weighted MRI.
e
p = .001.
f
p = .01.
g
p = .05.
Note: IFN-, interferon ; GA, glatiramer acetate; MTX, mitoxantrone; NTZ, natalizumab; IM, intramuscular; SC,
subcutaneous; IV, intravenous; qod, every other day; qw, once per week; tiw, three times per week; qd, daily;

Multiple Sclerosis and Other Demyelinating Diseases

q3mo, once every 3 months; qmo, once per month; ns, not signicant; nr, not reported.

Side effects of short-term glucocorticoid therapy lesions compared to placebo recipients (Table 34-6).
include fluid retention, potassium loss, weight gain, Mitoxantrone (Novantrone), an immune suppressant,
gastric disturbances, acne, and emotional lability. has also been approved in the United States, although it
Concurrent use of a low-salt, potassium-rich diet and is generally reserved for patients with progressive dis-
avoidance of potassium-wasting diuretics is advis- ability who have failed other treatments because of its
able. Lithium carbonate (300 mg orally bid) may help potential toxicity.
to manage emotional lability and insomnia associ-
Interferon , Glatiramer Acetate, and Natal-
ated with glucocorticoid therapy. Patients with a his-
izumab IFN- is a class I interferon originally identi-
tory of peptic ulcer disease may require cimetidine
ed by its antiviral properties. Efcacy in MS probably
(400 mg bid) or ranitidine (150 mg bid).
results from immunomodulatory properties including
Plasma exchange (seven exchanges: 4060 mL/kg per
(1) downregulating expression of MHC molecules on
exchange, every other day for 14 days) may benet
antigen-presenting cells, (2) inhibiting proinammatory
patients with fulminant attacks of demyelination (not
and increasing regulatory cytokine levels, (3) inhibition
only MS) that are unresponsive to glucocorticoids. How-
of T cell proliferation, and (4) limiting the trafcking of
ever, the cost is high, and the evidence of efcacy is only
inammatory cells in the CNS. Glatiramer acetate is a
preliminary.
synthetic, random polypeptide composed of four amino
DISEASE-MODIFYING THERAPIES FOR acids (l-glutamic acid, l-lysine, l-alanine, and l-tyrosine).
RELAPSING FORMS OF MS (RRMS, SPMS Its mechanism of action may include (1) induction of
WITH EXACERBATIONS) Five such agents are antigen-specic suppressor T cells; (2) binding to MHC
approved in the United States: (1) IFN--1a (Avonex), (2) molecules, thereby displacing bound MBP; or (3) altering
IFN--1a (Rebif ), (3) IFN--1b (Betaseron), (4) glatiramer the balance between proinammatory and regulatory
acetate (Copaxone), and (5) natalizumab (Tysabri). Each cytokines. Natalizumab is a humanized monoclonal anti-
of these treatments is also used in SPMS patients who body directed against the 4 subunit of 41 integrin, a
continue to experience attacks, because SPMS can be cellular adhesion molecule expressed on the surface of
difcult to distinguish from RRMS, and because clinical lymphocytes. It prevents lymphocytes from binding to
trials suggest that such patients also derive therapeutic endothelial cells, thereby preventing lymphocytes from
benet. In phase III clinical trials, recipients of IFN--1b, penetrating the BBB and entering the CNS.
IFN--1a, glatiramer acetate, and natalizumab experi- IFN- reduces the attack rate and improves dis-
enced fewer clinical exacerbations and fewer new MRI ease severity measures such as EDSS progression
 446 and MRI-documented disease burden. IFN- should be The long-term efcacy of these treatments remains
considered in patients with either RRMS or SPMS with uncertain, although several recent studies suggest that
superimposed relapses. In patients with SPMS but with- these agents can improve the long-term outcome of MS
out relapses, efcacy has not been established. Higher when administered in the RRMS stage of the illness. Bene-
IFN- doses appear to have slightly greater efcacy but cial effects seen in early MS include a reduction in the
are also more likely to induce neutralizing antibodies, relapse rate and a reduction in CNS inammation as mea-
which may reduce the clinical benet (see below). sured by MRI. Unfortunately, already established progres-
Glatiramer acetate also reduces the attack rate sive symptoms do not respond to treatment with these
(whether measured clinically or by MRI) in RRMS. Glati- disease-modifying therapies. Because progressive symp-
ramer acetate may also benet disease severity mea- toms are likely to result from delayed effects of earlier
sures, although this is less well-established than for the focal demyelinating episodes, many experts now believe
relapse rate. Therefore, glatiramer acetate should be that very early treatment with a disease-modifying drug is
considered in RRMS patients. Its usefulness in progres- appropriate for most MS patients. It is reasonable to delay
sive disease is entirely unknown. initiating treatment in patients with (1) normal neurologic
Natalizumab dramatically reduces the attack rate and exams, (2) a single attack or a low attack frequency, and (3)
signicantly improves all measures of disease severity in a low burden of disease as assessed by brain MRI.
MS. However, because of the development of progres- Untreated patients should be followed closely with peri-
SECTION III

sive multifocal leukoencephalopathy (PML) in nearly odic brain MRI scans; the need for therapy is reassessed if
two dozen patients treated with natalizumab, some in scans reveal evidence of ongoing, subclinical disease.
combination with other immunosuppressives, natal- Most treated patients with relapsing forms of MS
izumab is currently recommended only as monotherapy receive IFN- or glatiramer acetate as rst-line therapy.
for patients who have failed treatment with beta inter- Regardless of which agent is chosen rst, treatment
feron or glatiramer acetate, or who have particularly should probably be changed in patents who continue to
Diseases of the Central Nervous System

aggressive presentations. Its usefulness in the treatment have frequent attacks or progressive disability (Fig. 34-4).
of progressive disease has not been studied. The value of combination therapy is unknown.

Relapsing-Remitting MS Progressive MS

Secondary Primary
Acute neurologic change Stable progressive MS progressive MS

1. Low attack frequency or

Exacerbation Pseudoexacerbation single attack Symptomatic therapy
2. Normal neurologic exam
3. Low disease burden by MRI With relapses Without relapses

Functional No functional
impairment impairment
No Yes 1. IFN-1a, or No proven treatment
2. IFN-1b
Methylprednisolone/ Symptomatic
prednisone therapy Prophylaxis Repeat clinical exam Consider
1. IFN-1a, or and MRI in 6 months
Intolerant or
2. IFN-1b, or
poor response
3. Glatiramer acetate
Identify and treat any
underlying infection or trauma Clinical or No
MRI change change Consider Rx with one of the following:
Good Intolerant or 1. Mitoxantrone 4. Pulse cyclophosphamide
response poor response 2. Azathioprine 5. IVIg
Continue periodic 3. Methotrexate 6. Pulse methylprednisolone
clinical/ MRI
Continue Successive trials assessments
therapy of alternatives B

Intolerant or poor response

Natalizumab

A
FIGURE 34-4
Therapeutic decision-making for MS.
 IFN--1a (Avonex), 30 g, is administered by intra- trial in Europe, in addition to an even smaller phase II 447
muscular injection once every week. IFN--1a (Rebif ), study completed earlier. Mitoxantrone received (from
44 g, is administered by subcutaneous injection three the FDA) the broadest indication of any current treat-
times per week. IFN--1b (Betaseron), 250 g, is adminis- ment for MS. Thus, mitoxantrone is indicated for use in
tered by subcutaneous injection every other day. Glati- SPMS, in PRMS, and in patients with worsening RRMS
ramer acetate, 20 mg, is administered by subcutaneous (dened as patients whose neurologic status remains
injection every day. Natalizumab, 300 g, is adminis- signicantly abnormal between MS attacks). Despite this
tered by IV infusion each month. Common side effects broad indication, however, the data supporting its ef-
of IFN- therapy include ulike symptoms (e.g., fevers, cacy are weaker than for other approved therapies.
chills, and myalgias) and mild abnormalities on routine Mitoxantrone can be cardiotoxic (e.g., cardiomyopa-
laboratory evaluation (e.g., elevated liver function tests thy, reduced left ventricular ejection fraction, and irre-
or lymphopenia). Rarely, more severe hepatotoxicity versible congestive heart failure). As a result, a cumula-
may occur. Subcutaneous IFN- also causes reactions at tive dose >140 mg/m2 is not recommended. At currently
the injection site (e.g., pain, redness, induration, or, approved doses (12 mg/m2 every 3 months), the maxi-
rarely, skin necrosis). Side effects can usually be man- mum duration of therapy can be only 23 years. Further-
aged with concomitant nonsteroidal anti-inammatory more, >40% of women will experience amenorrhea,

CHAPTER 34
medications and with the use of an autoinjector. which may be permanent. Finally, there is risk of acute
Depression, increased spasticity, and cognitive changes leukemia, and this complication has already been
have been reported, although these symptoms can also reported in several mitoxantrone-treated MS patients.
be due to the underlying disease. In any event, side Given these risks, mitoxantrone should not be used
effects to IFN- therapy usually subside with time. as a rst-line agent in either RRMS or relapsing SPMS. It
Approximately 210% of IFN--1a (Avonex) recipi- is reasonable to consider mitoxantrone in selected
ents, 1525% of IFN--1a (Rebif ) recipients, and 3040% patients with a progressive course who have failed

Multiple Sclerosis and Other Demyelinating Diseases

of IFN--1b (Betaseron) recipients develop neutralizing other approved therapies.
antibodies to IFN-, which may disappear over time.
Some evidence suggests that neutralizing antibodies DISEASE-MODIFYING THERAPIES FOR SPMS
reduce efcacy, especially for MRI outcomes. The current High-dose IFN- probably has a benecial effect in
clinical data, however, are quite conicted. Moreover, patients with SPMS who are still experiencing acute
there are few situations where measurement of anti- relapses. IFN- is probably ineffective in patients with
bodies is necessary. Thus, for a patient doing well on SPMS who are not having acute attacks. Glatiramer
therapy, the presence of antibodies should not affect acetate and natalizumab have not been studied in this
treatment. Conversely, for a patient doing poorly on patient population.
therapy, alternative treatment should be considered, Although mitoxantrone has been approved for
even if there are no detectable antibodies. patients with progressive MS, this is not the population
Injection-site reactions also occur with glatiramer studied in the pivotal trial. Therefore no evidence-based
acetate but are less severe than with IFN--1b. Approxi- recommendation can be made with regard to its use in
mately 15% of patients experience one or more episodes this setting.
of ushing, chest tightness, dyspnea, palpitations, and
anxiety after injection. This systemic reaction is unpre- PPMS No currently available therapies have shown
dictable, brief (duration <1 h), and tends not to recur. any promise for treating PPMS at this time. A phase III
Treatment with natalizumab is, in general, well toler- clinical trial of glatiramer acetate in PPMS was recently
ated. A small percentage (<10%) of patients experience stopped because of lack of efcacy. Trials of mitox-
hypersensitivity reactions (including anaphylaxis) and antrone and rituximab in PPMS are currently underway.
~6% develop neutralizing antibodies to the molecule.
As noted above, of greater potential concern is the risk OFF-LABEL TREATMENT OPTIONS FOR RRMS
of PML. AND SPMS Azathioprine (23 mg/kg per day)
has been used primarily in SPMS. Meta-analysis of pub-
Mitoxantrone Hydrochloride Mitoxantrone lished trials suggests that azathioprine is marginally
(Novantrone), an anthracenedione, exerts its antineo- effective at lowering relapse rates, although a benet on
plastic action by (1) intercalating into DNA and produc- disability progression has not been demonstrated.
ing both strand breaks and interstrand cross-links, (2) Methotrexate (7.520 mg/wk) was shown in one
interfering with RNA synthesis, and (3) inhibiting topoi- study to slow the progression of upper-extremity dys-
somerase II (involved in DNA repair). The U.S. Food and function in SPMS. Because of the possibility of develop-
Drug Administration (FDA) approved mitoxantrone on ing irreversible liver damage, some experts recommend
the basis of a single (relatively small) phase III clinical a blind liver biopsy after 2 years of therapy.
 448 Cyclophosphamide (700 mg/m2, every other month) lioresal pump (delivering medication directly into the
may be helpful for treatment-refractory patients who CSF) can provide substantial relief.
are (1) otherwise in good health, (2) ambulatory, and Pain is treated with anticonvulsants (carbamazepine,
(3) <40 years of age. Because cyclophosphamide can be 1001000 mg/d; phenytoin, 300600 mg/d; gabapentin,
used for periods in excess of 3 years, it may be prefer- 3003600 mg/d; or pregabalin, 50300 mg/d ), antide-
able to mitoxantrone in these circumstances. pressants (amitriptyline, 25150 mg/d; nortriptyline,
Intravenous immunoglobulin (IVIg), administered in 25150 mg/d; desipramine, 100300 mg/d; or ven-
monthly pulses (up to 1 g/kg) for up to 2 years, appears lafaxine, 75225 mg/d), or antiarrhythmics (mexiletine,
to reduce annual exacerbation rates. However, its use is 300900 mg/d). If these approaches fail, patients
limited because of its high cost, questions about opti- should be referred to a comprehensive pain manage-
mal dose, and uncertainty about its effect on long-term ment program.
disability outcome. Bladder dysfunction management is best guided by
Methylprednisolone administered in one study as urodynamic testing. Evening uid restriction or frequent
monthly high-dose intravenous pulses, reduced disabil- voluntary voiding may help detrusor hyperreexia. If these
ity progression (see above). methods fail, propantheline bromide (1015 mg/d), oxy-
butynin (515 mg/d), hyoscyamine sulfate (0.50.75 mg/d),
OTHER THERAPEUTIC CLAIMS Many pur- tolterodine tartrate (24 mg/d), or solifenacin (510 mg/d)
SECTION III

ported treatments for MS have never been subjected to may help. Coadministration of pseudoephedrine (3060
scientific scrutiny. These include dietary therapies mg) is sometimes benecial.
(e.g., the Swank diet in addition to others), megadose Detrusor/sphincter dyssynergia may respond to phe-
vitamins, low-dose naltrexone, calcium orotate, bee noxybenzamine (1020 mg/d) or terazosin hydrochlo-
stings, cow colostrum, hyperbaric oxygen, procarin (a ride (120 mg/d). Loss of reex bladder wall contraction
combination of histamine and caffeine), chelation, may respond to bethanechol (30150 mg/d). However,
Diseases of the Central Nervous System

acupuncture, acupressure, various Chinese herbal reme- both conditions often require catheterization.
dies, and removal of mercury-amalgam tooth llings, Urinary tract infections should be treated promptly.
among many others. Patients should avoid costly or Patients with large post-void residual urine volumes are
potentially hazardous unproven treatments. Many such predisposed to infections. Prevention by urine acidica-
treatments lack biologic plausibility. For example, no reli- tion (with cranberry juice or vitamin C) inhibits some
able case of mercury poisoning resembling typical MS bacteria. Prophylactic administration of antibiotics is
has ever been described. sometimes necessary but may lead to colonization by
Although potential roles for EBV, HHV-6, or chlamydia resistant organisms. Intermittent catheterization may
have been suggested for MS, these reports are uncon- help to prevent recurrent infections.
rmed, and treatment with antiviral agents or antibi- Treatment of constipation includes high-ber diets
otics is not currently appropriate. and uids. Natural or other laxatives may help. Fecal
incontinence may respond to a reduction in dietary ber.
SYMPTOMATIC THERAPY Potassium channel Depression should be treated. Useful drugs include
blockers (e.g., 4-aminopyridine, 1040 mg/d; and 3,4- the selective serotonin reuptake inhibitors (uoxetine,
di-aminopyridine, 4080 mg/d) may be helpful for 2080 mg/d, or sertraline, 50200 mg/d); the tricyclic anti-
weakness, especially for heat-sensitive symptoms. At depressants (amitriptyline, 25150 mg/d, nortriptyline,
high doses they may cause seizures. These agents are 25150 mg/d, or desipramine, 100300 mg/d); and the
not FDA-approved but can be obtained from com- nontricyclic antidepressants (venlafaxine, 75225 mg/d).
pounding pharmacies around the United States. Fatigue may improve with assistive devices, help in the
Ataxia/tremor is often intractable. Clonazepam, home, or successful management of spasticity. Patients
1.520 mg/d; mysoline, 50250 mg/d; propranolol, with frequent nocturia may benet from anticholinergic
40200 mg/d; or ondansetron, 816 mg/d may help. medication at bedtime. Primary MS fatigue may respond
Wrist weights occasionally reduce tremor in the arm or to amantadine (200 mg/d), methylphenidate (525 mg/d),
hand. Thalamotomy or deep-brain stimulation has been or modanil (100400 mg/d).
tried with mixed success. Cognitive problems may respond to the cholinesterase
Spasticity and spasms may improve with physical inhibitor donepezil hydrochloride (10 mg/d).
therapy, regular exercise, and stretching. Avoidance of Paroxysmal symptoms respond dramatically to low-
triggers (e.g., infections, fecal impactions, bed sores) is dose anticonvulsants (acetazolamide, 200600 mg/d;
extremely important. Effective medications include liore- carbamazepine, 50400 mg/d; phenytoin, 50300 mg/d;
sal (20120 mg/d), diazepam (240 mg/d), tizanidine or gabapentin, 6001800 mg/d).
(832 mg/d), dantrolene (25400 mg/d), and cyclobenza- Heat sensitivity may respond to heat avoidance, air-
prine hydrochloride (1060 mg/d). For severe spasticity, a conditioning, or cooling garments.
 Sexual dysfunction may be helped by lubricants to aid Disease-modifying therapies for MS have not been 449
in genital stimulation and sexual arousal. Management rigorously studied in NMO. Acute attacks are usually
of pain, spasticity, fatigue, and bladder/bowel dysfunc- treated with high-dose glucocorticoids as for MS exacer-
tion may also help. Sildenal (50100 mg) taken 12 h bations (see above). Because of the possibility that NMO
before sex, is now the standard treatment for maintain- is antibody-mediated, plasma exchange has also been
ing erections. used empirically for acute episodes that fail to respond to
glucocorticoids. Immunosuppressants (cyclophosphamide
PROMISING EXPERIMENTAL THERAPIES or azathioprine with glucocorticoids) are sometimes used
Numerous clinical trials are currently underway. These in the hope that further relapses will be prevented. More
include: (1) oral sphingosine-1-phosphate receptor recently, in a small open-case series, B cell depletion with
modulators to sequester lymphocytes in the secondary anti-CD20 monoclonal antibody (rituxan) appeared to
lymphoid organs; (2) oral cladribine, a purine nucleo- show promise in preventing relapses of NMO.
side agonist; (3) monoclonal antibodies against CD20 to Acute MS (Marburgs variant) is a fulminant demyeli-
deplete B cells, against the IL-2 receptor on activated nating process that in some cases progresses inexorably
T- cells, or against CD52 to induce global lymphocyte to death within 12 years. Typically, there are no remis-
depletion; (4) use of MBP, or an altered peptide ligand sions.When acute MS presents as a solitary, usually cavi-
tary, lesion, a brain tumor is often suspected. In such

CHAPTER 34
resembling MBP, to induce antigen-specic tolerance;
(5) use of statins as immunomodulators; (6) estriol to cases a brain biopsy is usually required to establish the
induce a pregnancy-like state; and (7) bone marrow diagnosis. An antibody-mediated process appears to be
transplantation. responsible for most cases. Marburgs variant does not
seem to follow infection or vaccination, and it is unclear
whether this syndrome represents an extreme form of
CLINICAL VARIANTS OF MS MS or another disease altogether. No controlled trials of

Multiple Sclerosis and Other Demyelinating Diseases

therapy exist; high-dose glucocorticoids, plasma
Neuromyelitis optica (NMO), or Devics syndrome, consists exchange, and cyclophosphamide have been tried, with
of separate attacks of acute ON and myelitis. ON may be uncertain benet.
unilateral or bilateral and precede or follow an attack of
myelitis by days, months, or years. In contrast to MS,
patients with NMO do not experience brainstem, cerebel- ACUTE DISSEMINATED
lar, and cognitive involvement, and the brain MRI is typi- ENCEPHALOMYELITIS (ADEM)
cally normal.A focal enhancing region of swelling and cav-
itation, extending over three or more spinal cord segments, ADEM has a monophasic course and is frequently
is typically seen on MRI. Histopathology of these lesions associated with antecedent immunization (postvacci-
may reveal thickening of blood-vessel walls and deposition nal encephalomyelitis) or infection (postinfectious
of antibody and complement. Occasional patients with encephalomyelitis).The hallmark of ADEM is the pres-
apparent NMO also have brain MRI changes indicating ence of widely scattered small foci of perivenular
involvement of the cerebral hemispheres. inflammation and demyelination. In its most explosive
NMO, which is uncommon in whites compared with form, acute hemorrhagic leukoencephalitis, the lesions
Asians and Africans, is best understood as a syndrome are vasculitic and hemorrhagic, and the clinical course
with diverse causes. Some patients have a systemic is devastating.
autoimmune disorder, often systemic lupus erythemato- Postvaccinal encephalomyelitis may follow the
sus, Sjgrens syndrome, p-ANCA (perinuclear antineu- administration of smallpox and certain rabies vaccines.
trophil cytoplasmic antibody) associated vasculitis, or Postinfectious encephalomyelitis is most frequently asso-
mixed connective tissue disease. In others, onset may be ciated with the viral exanthems of childhood. Infection
associated with acute infection with varicella-zoster with measles virus is the most common antecedent
virus, EBV, HIV, or tuberculosis. More frequently, how- (1 in 1000 cases). Worldwide, measles encephalomyelitis
ever, NMO is idiopathic and probably represents an MS is still common, although use of the live measles vaccine
variant; in such cases the course can be monophasic but has dramatically reduced its incidence in developed
is more often recurrent. countries. An ADEM-like illness rarely follows vaccina-
A highly specic autoantibody directed against the tion with live measles vaccine (12 in 106 immunizations).
water channel protein aquaporin-4 is present in the sera ADEM is now most frequently associated with vari-
of more than one-half of patients who have a clinical cella (chickenpox) infections (1 in 400010,000 cases). It
diagnosis of NMO. Aquaporin-4 is localized to the foot may also follow infection with rubella, mumps, inuenza,
processes of astrocytes in close apposition to endothelial parainuenza, infectious mononucleosis viruses, and
surfaces. The role of aquaporin-4 antibodies in the Mycoplasma. Some patients may have a nonspecic upper
pathogenesis of NMO, however, is unknown. respiratory infection or no known antecedent illness.
 450 All forms of ADEM presumably result from a cross-
reactive immune response to the infectious agent or vac- Treatment:
cine that then triggers an inammatory demyelinating ACUTE DISSEMINATED
response. Autoantibodies to MBP and to other myelin ENCEPHALOMYELITIS
antigens have been detected in the CSF from many Initial treatment is with high-dose glucocorticoids as for
patients with ADEM. Attempts to demonstrate direct exacerbations of MS (see above); depending on the
viral invasion of the CNS have been unsuccessful. response, treatment may need to be continued for
48 weeks. Patients who fail to respond within a few
days may benet from a course of plasma exchange or
CLINICAL MANIFESTATIONS
intravenous immunoglobulin. The prognosis reects the
In severe cases, onset is abrupt and progression rapid severity of the underlying acute illness. Measles
(hours to days). In postinfectious ADEM, the neurologic encephalomyelitis is associated with a mortality rate of
syndrome generally begins late in the course of the viral 520%, and most survivors have permanent neurologic
illness as the exanthem is fading. Fever reappears, and sequelae. Children who recover may have persistent
headache, meningismus, and lethargy progressing to coma seizures and behavioral and learning disorders.
may develop. Seizures are common. Signs of disseminated
neurologic disease are consistently present (e.g., hemi-
SECTION III

paresis or quadriparesis, extensor plantar responses, lost or FURTHER READINGS

hyperactive tendon reexes, sensory loss and brainstem
GOLAN D et al: Impact of exposure to war stress on exacerbations of
involvement). In ADEM due to chickenpox, cerebellar multiple sclerosis.Ann Neurol 64:143, 2008
involvement is often conspicuous. CSF protein is mod- GOODIN DS et al: Disease modifying therapies in multiple sclerosis:
estly elevated [0.51.5 g/L (50150 mg/dL)]. Lympho- Report of the Therapeutics and Technology Assessment Sub-
cytic pleocytosis, generally 200 cells/l, occurs in 80% of committee of the American Academy of Neurology. Neurology
Diseases of the Central Nervous System

patients. Occasional patients have higher counts or a 58:169, 2002

mixed polymorphonuclear-lymphocytic pattern during HAWKER K et al: Rituximab in patients with primary progressive
the initial days of the illness. Transient CSF oligoclonal multiple sclerosis: Results of a randomized double-blind placebo-
controlled multicenter trial.Ann Neurol 66:460, 2009
banding has been reported. MRI may reveal extensive
JACOB A et al: Treatment of neuromyelitis optica with rituximab:
gadolinium enhancement of white matter in brain and retrospective analysis of 25 patients. Arch Neurol 65:1443, 2008
spinal cord. KAPPOS L et al: Effect of early vs delayed interferon beta-1b treat-
ment on disability after a rst clinical event suggestive of multi-
ple sclerosis: A 3-year follow-up analysis of the BENEFIT study.
DIAGNOSIS Lancet 370:389, 2007
The diagnosis is easily established when there is a history LENNON VA et al: A serum autoantibody marker of neuromyelitis
of recent vaccination or exanthematous illness. In severe optica: Distinction from multiple sclerosis. Lancet 364:2106, 2004
MILLER DH, Leary SM: Primary-progressive multiple sclerosis.
cases with predominantly cerebral involvement, acute
Lancet Neurol 6:903, 2007
encephalitis due to infection with herpes simplex or OKSENBERG JR et al: The genetics of multiple sclerosis: SNPs to
other viruses may be difcult to exclude.The simultane- pathways to pathogenesis. Nat Rev Genet 9:516, 2008
ous onset of disseminated symptoms and signs is com- RANSOHOFF RM: Natalizumab for multiple sclerosis. N Engl J Med
mon in ADEM and rare in MS. Similarly, meningismus, 356:2622, 2007
drowsiness, coma, or seizures suggest ADEM rather than THE CAMMS223 TRIAL INVESTIGATORS: Alemtuzumab versus inter-
MS. Unlike in MS, in ADEM optic nerve involvement is feron beta-1a in early multiple sclerosis. N Engl J Med 359:1786,
2008
generally bilateral and transverse myelopathy complete.
THE INTERNATIONAL MULTIPLE SCLEROSIS GENETICS CONSORTIUM:
MRI ndings that may support a diagnosis of ADEM Risk alleles for multiple sclerosis identied by a genomewide
include extensive and relatively symmetric white matter study. N Engl J Med 357:851, 2007
abnormalities and Gd enhancement of all abnormal TROJANO M et al: Real-life impact of early interferonbeta therapy in
areas, indicating active disease and a monophasic course. relapsing multiple sclerosis.Ann Neurol 66:513, 2009
 CHAPTER 35
MENINGITIS, ENCEPHALITIS, BRAIN
ABSCESS, AND EMPYEMA
Karen L. Roos I Kenneth L. Tyler

I Acute Bacterial Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 I Brain Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475

Denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Pathogenesis and Histopathology . . . . . . . . . . . . . . . . . . . . . 476
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
I Acute Viral Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 I Nonbacterial Causes of Infectious Focal CNS Lesions . . . . . 478
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 I Subdural Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Specic Viral Etiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
I Viral Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 I Epidural Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . 481
Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
I Subacute Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 I Suppurative Thrombophlebitis . . . . . . . . . . . . . . . . . . . . . . . 482
Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Denition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
I Chronic Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Anatomy and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . 482
Progressive Multifocal Leukoencephalopathy . . . . . . . . . . . . 473 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
Subacute Sclerosing Panencephalitis (SSPE) . . . . . . . . . . . . 474 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
Progressive Rubella Panencephalitis . . . . . . . . . . . . . . . . . . . 475 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Acute infections of the nervous system are among the prodrome of fever and headache, which in a previously
most important problems in medicine because early healthy individual may initially be thought to be
recognition, efcient decision-making, and rapid insti- benign, until (with the exception of viral meningitis)
tution of therapy can be lifesaving. These distinct clini- altered consciousness, focal neurologic signs, or seizures
cal syndromes include acute bacterial meningitis, appear. Key goals of early management are to emer-
viral meningitis, encephalitis, focal infections such as gently distinguish between these conditions, identify
brain abscess and subdural empyema, and infectious the responsible pathogen, and initiate appropriate
thrombophlebitis. Each may present with a nonspecic antimicrobial therapy.

451
 452 space (meningitis) or whether there is evidence of
Approach to the Patient:
CNS INFECTION
either generalized or focal involvement of brain tissue
in the cerebral hemispheres, cerebellum, or brainstem.
(Fig. 35-1) The rst task is to identify whether an When brain tissue is directly injured by a viral infec-
infection predominantly involves the subarachnoid tion the disease is referred to as encephalitis, whereas

Headache, Fever, Nuchal Rigidity

Altered mental status?

Yes No

Meningoencephalitis, ADEM, Meningitis

encephalopathy, or mass lesion
SECTION III

Papilledema and/or focal neurologic deficit?

Immunocompromised?
Yes History of recent head trauma, known
cancer, sinusitis?

Obtain blood culture and start

empirical antimicrobial therapy No
Diseases of the Central Nervous System

Imaging: Head CT or MRI (preferred)

Mass lesion No mass lesion

Abscess Focal or White matter

or tumor generalized abnormalities
gray matter
abnormalities
Appropriate medical or normal
ADEM
and/or surgical
interventions Immediate blood culture
Encephalitis and lumbar puncture

Pleocytosis with PMNs Pleocytosis with MNCs

Elevated protein Normal or increased protein
Decreased glucose Normal or decreased glucose
Grams stain positive Grams stain negative

Tier 1 Eval (no unusual historic points or exposures):

Bacterial process
Viral: CSF PCR for enterovirus, HSV, VZV
CSF IgM for WNV
Viral culture: CSF, throat, stool
If skin lesions DFA for HSV, VZV
HIV serology
Serology for enteroviruses and arthropod-borne
viruses
Fungal: CSF cryptococcal Ag, fungal cultures
Bacterial: VDRL and bacterial culture
Mycobacterial: CSF AFB stain and TB PCR, TB
culture, CXR, PPD
A

FIGURE 35-1
The management of patients with suspected CNS WNV, West Nile virus; DFA, direct uorescent antibody; Ag,
infection. ADEM, acute disseminated encephalomyelitis; CT, antigen; VDRL, Venereal Disease Research Laboratory; AFB,
computed tomography; MRI, magnetic resonance imaging; acid-fast bacillus; TB, tuberculosis; CXR, chest x-ray; PPD,
PMNs, polymorphonuclear leukocytes; MNCs, mononuclear puried protein derivative; EBV, Epstein-Barr virus; CTFV,
cells; CSF, cerebrospinal uid; PCR, polymerase chain reac- Colorado tick fever virus; HHV, human herpesvirus; LCMV,
tion; HSV, herpes simplex virus; VZV, varicella-zoster virus; lymphocytic choriomeningitis virus.
 453
Tier 2 Evaluation (if above negative):
EBV: Serum serology, CSF PCR
Mycoplasma: Serum serology, CSF PCR
Influenza A, B: Serology, respiratory culture, CSF PCR
Adenovirus: Serology, throat swab. CSF PCR
Fungal: CSF & serum coccidioidal antibody, Histoplasma
antigen & antibody

Tier 3 Evaluation
(based on epidemiology)

Mosquito or Recent Diarrhea Hepatitis

tick exposure exanthemal (infant/child)
illness
Hepatitis C
CTFV Rotavirus
Arbovirus Measles
Rickettsial Rubella
Borrelia HHV-6
Ehrilichia

CHAPTER 35
Raccoon Wild rodent Cat Swimming in
exposure or or hamster exposure lakes or ponds
Hx of pica exposure or nonchlorinated
water
Bartonella spp.

Meningitis, Encephalitis, Brain Abscess, and Empyema

Baylisascaris LCMV (cat scratch fever)
procyonis Acanthamoeba or
Naegleria fowleri
(amebic
Bat exposure Pet bird Exposure to meningoencephalitis)
Animal bite (Psittacine) cattle or
exposure unpasteurized
dairy products
Rabies
Chlamydia psittaci
(Psittacosis) Brucella spp. (Brucellosis)
Coxiella burnetii (Q fever)
B

FIGURE 35-1
(Continued.)

focal bacterial, fungal, or parasitic infections involving patients, immunocompromised individuals, or patients
brain tissue are classied as either cerebritis or abscess, with a severely depressed mental status. The high
depending on the presence or absence of a capsule. prevalence of cervical spine disease in older individu-
Nuchal rigidity (stiff neck) is the pathogno- als may result in false-positive tests for nuchal rigidity.
monic sign of meningeal irritation and is present Initial management can be guided by several con-
when the neck resists passive exion. Kernigs and siderations: (1) Empirical therapy should be initiated
Brudzinskis signs are also classic signs of meningeal promptly whenever bacterial meningitis is a signi-
irritation. Kernigs sign is elicited with the patient in cant diagnostic consideration. (2) All patients who
the supine position. The thigh is exed on the have had recent head trauma, are immunocompro-
abdomen, with the knee exed; attempts to passively mised, have known malignant lesions or central nervous
extend the knee elicit pain when meningeal irritation system (CNS) neoplasms, or have focal neurologic
is present. Brudzinskis sign is elicited with the patient ndings that include papilledema or a depressed level
in the supine position and is positive when passive of consciousness should undergo CT or MRI of the
exion of the neck results in spontaneous exion of brain prior to lumbar puncture (LP). In these cases
the hips and knees. Although commonly tested on empirical antibiotic therapy should not be delayed
physical examinations, the sensitivity and specicity pending test results but should be administered prior
of Kernigs and Brudzinskis signs are uncertain. Both to neuroimaging and LP. (3) A signicantly depressed
may be absent or reduced in very young or elderly level of consciousness (e.g., somnolence, coma),
 454 seizures, or focal neurologic decits do not occur in factors include coexisting acute or chronic pneumococ-
viral (aseptic) meningitis; patients with these symp- cal sinusitis or otitis media, alcoholism, diabetes, splenec-
toms should be hospitalized for further evaluation tomy, hypogammaglobulinemia, complement deciency,
and treated empirically for bacterial and viral menin- and head trauma with basilar skull fracture and CSF rhi-
goencephalitis. (4) Immunocompetent patients with a norrhea. Mortality remains ~20% despite antibiotic
normal level of consciousness, no prior antimicrobial therapy. Recently, pneumococcal vaccination has been
treatment, and a cerebrospinal uid (CSF) prole shown to decrease rates of meningitis.
consistent with viral meningitis (lymphocytic pleocy- N. meningitidis accounts for 25% of all cases of bacterial
tosis and a normal glucose concentration) can often meningitis (0.6 cases per 100,000 persons per year) and for
be treated as outpatients if appropriate contact and up to 60% of cases in children and young adults between 2
monitoring can be ensured. Failure of a patient with and 20 years of age.The presence of petechial or purpuric
suspected viral meningitis to improve within 48 h skin lesions can provide an important clue to the diagnosis
should prompt a reevaluation including follow-up of meningococcal infection. In some patients the disease is
neurologic and general medical examination and fulminant, progressing to death within hours of symptom
repeat imaging and laboratory studies, often including onset. Infection may be initiated by nasopharyngeal colo-
a second LP. nization, which can result in either an asymptomatic carrier
state or invasive meningococcal disease.The risk of invasive
SECTION III

disease following nasopharyngeal colonization depends on

both bacterial virulence factors and host immune defense
ACUTE BACTERIAL MENINGITIS mechanisms, including the hosts capacity to produce anti-
meningococcal antibodies and to lyse meningococci by
DEFINITION both classic and alternative complement pathways. Individ-
Bacterial meningitis is an acute purulent infection within uals with deciencies of any of the complement components,
Diseases of the Central Nervous System

the subarachnoid space. It is associated with a CNS including properdin, are highly susceptible to meningococcal
inammatory reaction that may result in decreased con- infections.
sciousness, seizures, raised intracranial pressure (ICP), Enteric gram-negative bacilli are an increasingly
and stroke. The meninges, the subarachnoid space, and common cause of meningitis in individuals with chronic
the brain parenchyma are all frequently involved in the and debilitating diseases such as diabetes, cirrhosis, or
inammatory reaction (meningoencephalitis). alcoholism and in those with chronic urinary tract
infections. Gram-negative meningitis can also compli-
cate neurosurgical procedures, particularly craniotomy.
EPIDEMIOLOGY Group B streptococcus, or S. agalactiae, was previously
Bacterial meningitis is the most common form of sup- responsible for meningitis predominantly in neonates, but
purative CNS infection, with an annual incidence in the it has been reported with increasing frequency in individ-
United States of >2.5 cases/100,000 population. The uals >50 years, particularly those with underlying diseases.
epidemiology of bacterial meningitis has changed signif- L. monocytogenes has become an increasingly important
icantly in recent years, reecting a dramatic decline in cause of meningitis in neonates (<1 month), pregnant
the incidence of meningitis due to Haemophilus inuenzae, women, individuals >60 years, and immunocompro-
and a smaller decline in that due to Neisseria meningitidis, mised individuals of all ages. Infection is acquired by
following the introduction and increasingly widespread ingesting foods contaminated by Listeria. Foodborne
use of vaccines for both these organisms. Currently, the human listerial infection has been reported from conta-
organisms most commonly responsible for community- minated coleslaw, milk, soft cheeses, and several types of
acquired bacterial meningitis are Streptococcus pneumoniae ready-to-eat foods, including delicatessen meat and
(~50%), N. meningitidis (~25%), group B streptococci uncooked hotdogs.
(~15%), and Listeria monocytogenes (~10%). H. inuenzae The frequency of H. inuenzae type b meningitis in
now accounts for <10% of cases of bacterial meningitis children has declined dramatically since the introduction
in most series. of the Hib conjugate vaccine, although rare cases of Hib
meningitis in vaccinated children have been reported.
More frequently, H. inuenzae causes meningitis in
ETIOLOGY unvaccinated children and adults.
S. pneumoniae is the most common cause of meningitis Staphylococcus aureus and coagulase-negative staphylococci
in adults >20 years of age, accounting for nearly half the are important causes of meningitis that occurs following
reported cases (1.1 per 100,000 persons per year).There invasive neurosurgical procedures, particularly shunting pro-
are a number of predisposing conditions that increase cedures for hydrocephalus, or as a complication of the use of
the risk of pneumococcal meningitis, the most important subcutaneous Ommaya reservoirs for administration of
of which is pneumococcal pneumonia. Additional risk intrathecal chemotherapy.
PATHOPHYSIOLOGY (WBCs) and relatively small amounts of complement 455
proteins and immunoglobulins. The paucity of the latter
The most common bacteria that cause meningitis, S.
two prevents effective opsonization of bacteria, an essen-
pneumoniae and N. meningitidis, initially colonize the
tial prerequisite for bacterial phagocytosis by neu-
nasopharynx by attaching to nasopharyngeal epithelial
trophils. Phagocytosis of bacteria is further impaired by
cells. Bacteria are transported across epithelial cells in
the uid nature of CSF, which is less conducive to
membrane-bound vacuoles to the intravascular space or
phagocytosis than a solid tissue substrate.
invade the intravascular space by creating separations in
A critical event in the pathogenesis of bacterial
the apical tight junctions of columnar epithelial cells.
meningitis is the inammatory reaction induced by the
Once in the bloodstream, bacteria are able to avoid
invading bacteria. Many of the neurologic manifesta-
phagocytosis by neutrophils and classic complement
tions and complications of bacterial meningitis result
mediated bactericidal activity because of the presence of
from the immune response to the invading pathogen
a polysaccharide capsule. Bloodborne bacteria can reach
rather than from direct bacteria-induced tissue injury. As
the intraventricular choroid plexus, directly infect
a result, neurologic injury can progress even after the
choroid plexus epithelial cells, and gain access to the
CSF has been sterilized by antibiotic therapy.
CSF. Some bacteria, such as S. pneumoniae, can adhere to
The lysis of bacteria with the subsequent release of
cerebral capillary endothelial cells and subsequently
cell-wall components into the subarachnoid space is the

CHAPTER 35
migrate through or between these cells to reach the
initial step in the induction of the inammatory response
CSF. Bacteria are able to multiply rapidly within CSF
and the formation of a purulent exudate in the subarach-
because of the absence of effective host immune
noid space (Fig. 35-2). Bacterial cell-wall components,
defenses. Normal CSF contains few white blood cells

Meningitis, Encephalitis, Brain Abscess, and Empyema

Invasion of SAS by meningeal pathogens

Multiplication of organisms and lysis of organisms by bactericidal antibiotics

Release of bacterial cell wall components (endotoxin, teichoic acid)

Production of inflammatory cytokines

Altered blood-brain Adherence of leukocytes Alterations Production of

barrier permeability to cerebral capillary in cerebral excitatory amino
endothelial cells blood flow acids and reactive
oxygen and
nitrogen species

Permeability of Leukocytes migrate into

blood vessels with CSF, degranulate, and
leakage of plasma release toxic metabolites Cell injury
proteins into CSF and death

Exudate in SAS obstructs

outflow and resorption of
CSF and surrounds
and infiltrates
Cerebral
cerebral vasculature blood flow blood flow
ischemia

Vasogenic Obstructive
Cytotoxic edema,
edema and communicating
stroke, seizures
hydrocephalus and
interstitial edema

Intracranial pressure

Coma

FIGURE 35-2
The pathophysiology of the neurologic complications of bacterial meningitis. SAS,
subarachnoid space; CSF, cerebrospinal uid.
 456 such as the lipopolysaccharide (LPS) molecules of gram- vasogenic, and cytotoxic edema leads to raised ICP and
negative bacteria and teichoic acid and peptidoglycans of coma. Cerebral herniation usually results from the
S. pneumoniae, induce meningeal inammation by stimu- effects of cerebral edema, either focal or generalized;
lating the production of inammatory cytokines and hydrocephalus and dural sinus or cortical vein thrombo-
chemokines by microglia, astrocytes, monocytes, microvas- sis may also play a role.
cular endothelial cells, and CSF leukocytes. In experi-
mental models of meningitis, cytokines including tumor
CLINICAL PRESENTATION
necrosis factor (TNF) and interleukin 1 (IL-1) are pre-
sent in CSF within 12 h of intracisternal inoculation of Meningitis can present as either an acute fulminant illness
LPS. This cytokine response is quickly followed by an that progresses rapidly in a few hours or as a subacute
increase in CSF protein concentration and leukocytosis. infection that progressively worsens over several days.The
Chemokines (cytokines that induce chemotactic migration classic clinical triad of meningitis is fever, headache, and
in leukocytes) and a variety of other proinammatory nuchal rigidity. A decreased level of consciousness occurs
cytokines are also produced and secreted by leukocytes in >75% of patients and can vary from lethargy to coma.
and tissue cells that are stimulated by IL-1 and TNF. Nausea, vomiting, and photophobia are also common
In addition, bacteremia and the inammatory cytokines complaints.
induce the production of excitatory amino acids, reactive Seizures occur as part of the initial presentation of
SECTION III

oxygen and nitrogen species (free oxygen radicals, nitric bacterial meningitis or during the course of the illness
oxide, and peroxynitrite), and other mediators that can in 2040% of patients. Focal seizures are usually due to
induce death of brain cells. focal arterial ischemia or infarction, cortical venous
Much of the pathophysiology of bacterial meningitis thrombosis with hemorrhage, or focal edema. General-
is a direct consequence of elevated levels of CSF ized seizure activity and status epilepticus may be due to
cytokines and chemokines.TNF and IL-1 act synergisti- hyponatremia, cerebral anoxia, or, less commonly, the
Diseases of the Central Nervous System

cally to increase the permeability of the blood-brain toxic effects of antimicrobial agents such as high-dose
barrier, resulting in induction of vasogenic edema and penicillin.
the leakage of serum proteins into the subarachnoid Raised ICP is an expected complication of bacterial
space (Fig. 35-2).The subarachnoid exudate of proteina- meningitis and the major cause of obtundation and coma
ceous material and leukocytes obstructs the ow of CSF in this disease. More than 90% of patients will have a
through the ventricular system and diminishes the CSF opening pressure >180 mm H2O, and 20% have
resorptive capacity of the arachnoid granulations in the opening pressures >400 mm H2O. Signs of increased
dural sinuses, leading to obstructive and communicating ICP include a deteriorating or reduced level of con-
hydrocephalus and concomitant interstitial edema. sciousness, papilledema, dilated poorly reactive pupils,
Inammatory cytokines upregulate the expression of sixth nerve palsies, decerebrate posturing, and the Cush-
selectins on cerebral capillary endothelial cells and leuko- ing reex (bradycardia, hypertension, and irregular respi-
cytes, promoting leukocyte adherence to vascular rations). The most disastrous complication of increased
endothelial cells and subsequent migration into the CSF. ICP is cerebral herniation. The incidence of herniation
The adherence of leukocytes to capillary endothelial cells in patients with bacterial meningitis has been reported to
increases the permeability of blood vessels, allowing for occur in as few as 1% to as many as 8% of cases.
the leakage of plasma proteins into the CSF, which adds Specic clinical features may provide clues to the
to the inammatory exudate. Neutrophil degranulation diagnosis of individual organisms and are discussed in
results in the release of toxic metabolites that contribute more detail in specic chapters devoted to individual
to cytotoxic edema, cell injury, and death. Contrary to pathogens.The most important of these clues is the rash
previous beliefs, CSF leukocytes probably do little to of meningococcemia, which begins as a diffuse erythe-
contribute to the clearance of CSF bacterial infection. matous maculopapular rash resembling a viral exanthem;
During the very early stages of meningitis, there is an however, the skin lesions of meningococcemia rapidly
increase in cerebral blood ow, soon followed by a become petechial. Petechiae are found on the trunk and
decrease in cerebral blood ow and a loss of cerebrovas- lower extremities, in the mucous membranes and con-
cular autoregulation (Chap. 22). Narrowing of the large junctiva, and occasionally on the palms and soles.
arteries at the base of the brain due to encroachment by
the purulent exudate in the subarachnoid space and inl-
DIAGNOSIS
tration of the arterial wall by inammatory cells with
intimal thickening (vasculitis) also occur and may result in When bacterial meningitis is suspected, blood cultures
ischemia and infarction, obstruction of branches of the should be immediately obtained and empirical antimi-
middle cerebral artery by thrombosis, thrombosis of the crobial therapy is initiated without delay (Table 35-1).
major cerebral venous sinuses, and thrombophlebitis of The diagnosis of bacterial meningitis is made by exami-
the cerebral cortical veins.The combination of interstitial, nation of the CSF (Table 35-2). The need to obtain
TABLE 35-1 TABLE 35-2 457
ANTIBIOTICS USED IN EMPIRICAL THERAPY OF CEREBROSPINAL FLUID (CSF) ABNORMALITIES
BACTERIAL MENINGITIS AND FOCAL CNS IN BACTERIAL MENINGITIS
INFECTIONSa
Opening pressure >180 mm H2O
INDICATION ANTIBIOTIC White blood cells 10/L to 10,000/L; neutrophils
predominate
Preterm infants to Ampicillin + Red blood cells Absent in nontraumatic tap
infants <1 month cefotaxime Glucose <2.2 mmol/L (<40 mg/dL)
Infants 13 months Ampicillin + CSF/serum glucose <0.4
cefotaxime or Protein >0.45 g/L (>45 mg/dL)
ceftriaxone Grams stain Positive in >60%
Immunocompetent children Cefotaxime or Culture Positive in >80%
>3 months and adults <55 years ceftriaxone + Latex agglutination May be positive in patients
vancomycin with meningitis due to
Adults >55 years and adults Ampicillin + S. pneumoniae, N. meningitidis,
of any age with alcoholism cefotaxime or H. inuenzae type b, E. coli,
or other debilitating illnesses ceftriaxone + group B streptococci
vancomycin Limulus lysate Positive in cases of gram-

CHAPTER 35
Hospital-acquired meningitis, Ampicillin + negative meningitis
posttraumatic or postneurosurgery ceftazidime + PCR Detects bacterial DNA
meningitis, neutropenic patients, vancomycin
or patients with impaired
Note: PCR, polymerase chain reaction.
cell-mediated immunity
ANTIMICROBIAL TOTAL DAILY DOSE AND
AGENT DOSING INTERVAL

Meningitis, Encephalitis, Brain Abscess, and Empyema

CHILD (>1 MONTH) ADULT
WBC count or glucose concentration, nor is it likely to
Ampicillin 200 (mg/kg)/d, q4h 12 g/d, q4h prevent visualization of organisms by Grams stain or
Cefepime 150 (mg/kg)/d, q8h 6 g/d, q8h
detection of bacterial nucleic acid by polymerase chain
Cefotaxime 200 (mg/kg)/d, q6h 12 g/d, q4h
Ceftriaxone 100 (mg/kg)/d, q12h 4 g/d, q12h
reaction (PCR) assay.
Ceftazidime 150 (mg/kg)/d, q8h 6 g/d, q8h The classic CSF abnormalities in bacterial meningitis
Gentamicin 7.5 (mg/kg)/d, q8hb 7.5 (mg/kg)/d, (Table 35-2) are (1) polymorphonuclear (PMN) leukocytosis
q8h (>100 cells/L in 90%), (2) decreased glucose concentration
Meropenem 120 (mg/kg)/d, q8h 3 g/d, q8h [<2.2 mmol/L (<40 mg/dL) and/or CSF/serum glucose
Metronidazole 30 (mg/kg)/d, q6h 15002000 ratio of <0.4 in ~60%], (3) increased protein concentration
mg/d, q6h [>0.45 g/L (>45 mg/dL) in 90%], and (4) increased open-
Nafcillin 100200 (mg/kg)/d, 912 g/d,
q6h q4h
ing pressure (>180 mm H2O in 90%). CSF bacterial cul-
Penicillin G 400,000 (U/kg)/d, 2024 million tures are positive in >80% of patients, and CSF Grams stain
q4h U/d, q4h demonstrates organisms in >60%.
Vancomycin 60 (mg/kg)/d, q6h 2 g/d, q12hb CSF glucose concentrations <2.2 mmol/L (<40 mg/dL)
are abnormal, and a CSF glucose concentration of zero
a
All antibiotics are administered intravenously; doses indicated can be seen in bacterial meningitis. Use of the CSF/
assume normal renal and hepatic function. serum glucose ratio corrects for hyperglycemia that may
b
Doses should be adjusted based on serum peak and trough levels:
mask a relative decrease in the CSF glucose concentra-
gentamicin therapeutic level: peak: 58 g/mL; trough: <2 g/mL; van-
comycin therapeutic level: peak: 2540 g/mL; trough: 515 g/mL. tion. The CSF glucose concentration is low when the
CSF/serum glucose ratio is <0.6. A CSF/ serum glucose
ratio <0.4 is highly suggestive of bacterial meningitis
but may also be seen in other conditions, including fun-
neuroimaging studies (CT or MRI) prior to LP requires gal, tuberculous, and carcinomatous meningitis. It takes
clinical judgment. In an immunocompetent patient with from 30 min to several hours for the concentration of
no known history of recent head trauma, a normal level CSF glucose to reach equilibrium with blood glucose
of consciousness, and no evidence of papilledema or levels; therefore, administration of 50 mL of 50% glucose
focal neurologic decits, it is considered safe to perform (D50) prior to LP, as commonly occurs in emergency
LP without prior neuroimaging studies. If LP is delayed department settings, is unlikely to alter CSF glucose
in order to obtain neuroimaging studies, empirical concentration signicantly unless more than a few hours
antibiotic therapy should be initiated after blood cul- have elapsed between glucose administration and LP.
tures are obtained. Antibiotic therapy initiated a few A broad-range PCR can detect small numbers of
hours prior to LP will not signicantly alter the CSF viable and nonviable organisms in CSF and is expected
 458 to be useful for making a diagnosis of bacterial meningi- pleocytosis with a normal glucose concentration, in
tis in patients who have been pretreated with oral or contrast to PMN pleocytosis and hypoglycorrhachia
parenteral antibiotics and in whom Grams stain and characteristic of bacterial meningitis. MRI abnormalities
CSF culture are negative.When the broad-range PCR is (other than meningeal enhancement) are not seen in
positive, a PCR that uses specic bacterial primers to uncomplicated bacterial meningitis. By contrast, in HSV
detect the nucleic acid of S. pneumoniae, N. meningitidis, encephalitis, on T2-weighted and uid-attenuated inver-
Escherichia coli, L. monocytogenes, H. inuenzae, and sion recovery (FLAIR) MRI images, high signal inten-
S. agalactiae can be obtained based on the clinical suspi- sity lesions are seen in the orbitofrontal, anterior, and
cion of the meningeal pathogen.The latex agglutination medial temporal lobes in the majority of patients within
(LA) test for the detection of bacterial antigens of 48 h of symptom onset. Some patients with HSV
S. pneumoniae, N. meningitidis, H. inuenzae type b, group encephalitis have a distinctive periodic pattern on EEG
B streptococcus, and E. coli K1 strains in the CSF has (see later).
been useful for making a diagnosis of bacterial meningi- Rickettsial disease can resemble bacterial meningitis.
tis but is being replaced by the CSF bacterial PCR assay. Rocky Mountain spotted fever (RMSF) is transmitted
The CSF LA test has a specicity of 95100% for S. pneu- by a tick bite and caused by the bacteria Rickettsia
moniae and N. meningitidis, so a positive test is virtually rickettsii. The disease may present acutely with high
diagnostic of bacterial meningitis caused by these organ- fever, prostration, myalgia, headache, nausea, and vomit-
SECTION III

isms. However, the sensitivity of the CSF <LA test is ing. Most patients develop a characteristic rash within
only 70100% for detection of S. pneumoniae and 96 h of the onset of symptoms.The rash is initially a dif-
3370% for detection of N. meningitidis antigens, so a fuse erythematous maculopapular rash that may be dif-
negative test does not exclude infection by these organ- cult to distinguish from that of meningococcemia. It
isms.The Limulus amebocyte lysate assay is a rapid diag- progresses to a petechial rash, then to a purpuric rash
nostic test for the detection of gram-negative endotoxin and, if untreated, to skin necrosis or gangrene.The color
Diseases of the Central Nervous System

in CSF and thus for making a diagnosis of gram-nega- of the lesions changes from bright red to very dark red,
tive bacterial meningitis. The test has a specicity of then yellowish-green to black. The rash typically begins
85100% and a sensitivity approaching 100%. Thus, a in the wrist and ankles and then spreads distally and
positive Limulus amebocyte lysate assay occurs in virtu- proximally within a matter of a few hours, involving the
ally all patients with gram-negative bacterial meningitis, palms and soles. Diagnosis is made by immunouores-
but false positives may occur. cent staining of skin biopsy specimens. Ehrlichioses are
Almost all patients with bacterial meningitis will have also transmitted by a tick bite. These are small gram-
neuroimaging studies performed during the course of negative coccobacilli of which two species cause human
their illness. MRI is preferred over CT because of its disease. Anaplasma phagocytophilum causes human granu-
superiority in demonstrating areas of cerebral edema locytic ehrlichiosis (anaplasmosis), and Ehrlichia chaffeensis
and ischemia. In patients with bacterial meningitis, dif- causes human monocytic ehrlichiosis. The clinical and
fuse meningeal enhancement is often seen after the laboratory manifestations of the infections are similar.
administration of gadolinium. Meningeal enhancement Patients present with fever, headache, nausea, and vomit-
is not diagnostic of meningitis but occurs in any CNS ing. Twenty percent of patients have a maculopapular or
disease associated with increased blood-brain barrier petechial rash. There is laboratory evidence of leukope-
permeability. nia, thrombocytopenia and anemia, and mild to moder-
Petechial skin lesions, if present, should be biopsied. ate elevations in alanine aminotransferases, alkaline
The rash of meningococcemia results from the dermal phosphatase, and lactate dehydrogenase. Patients with
seeding of organisms with vascular endothelial damage, RMSF and those with ehrlichial infections may have an
and biopsy may reveal the organism on Grams stain. altered level of consciousness ranging from mild lethargy
to coma, confusion, focal neurologic signs, cranial nerve
palsies, hyperreexia, and seizures.
DIFFERENTIAL DIAGNOSIS
Focal suppurative CNS infections (see later), includ-
Viral meningoencephalitis, and particularly herpes sim- ing subdural and epidural empyema and brain abscess,
plex virus (HSV) encephalitis, can mimic the clinical should also be considered, especially when focal neuro-
presentation of bacterial meningitis (see Encephalitis, logic ndings are present. MRI should be performed
below). HSV encephalitis typically presents with promptly in all patients with suspected meningitis who
headache, fever, altered consciousness, focal neurologic have focal features, both to detect the intracranial infec-
decits (e.g., dysphasia, hemiparesis), and focal or gener- tion and to search for associated areas of infection in the
alized seizures.The ndings on CSF studies, neuroimag- sinuses or mastoid bones.
ing, and electroencephalogram (EEG) distinguish HSV A number of noninfectious CNS disorders can mimic
encephalitis from bacterial meningitis. The typical CSF bacterial meningitis. Subarachnoid hemorrhage (SAH;
prole with viral CNS infections is a lymphocytic Chap. 22) is generally the major consideration. Other
possibilities include chemical meningitis due to rupture meningitis, and particularly meningitis following neuro- 459
of tumor contents into the CSF (e.g., from a cystic surgical procedures, staphylococci and gram-negative
glioma or craniopharyngioma epidermoid or dermoid organisms including P. aeruginosa are the most common
cyst); drug-induced hypersensitivity meningitis; carcino- etiologic organisms. In these patients, empirical therapy
matous or lymphomatous meningitis; meningitis associ- should include a combination of vancomycin and
ated with inammatory disorders such as sarcoid, systemic ceftazidime, cefepime, or meropenem. Ceftazidime,
lupus erythematosus (SLE), and Behets syndrome; cefepime, or meropenem should be substituted for ceftri-
pituitary apoplexy; and uveomeningitic syndromes axone or cefotaxime in neurosurgical patients and in neu-
(Vogt-Koyanagi-Harada syndrome). tropenic patients, as ceftriaxone and cefotaxime do not
On occasion, subacutely evolving meningitis may be provide adequate activity against CNS infection with
considered in the differential diagnosis of acute meningi- P. aeruginosa. Meropenem is a carbapenem antibiotic that
tis.The principal causes include Mycobacterium tuberculosis, is highly active in vitro against L. monocytogenes, has
Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides been demonstrated to be effective in cases of meningitis
immitis, and Treponema pallidum. caused by P. aeruginosa, and shows good activity against
penicillin-resistant pneumococci. In experimental pneu-
mococcal meningitis, meropenem was comparable to

CHAPTER 35
ceftriaxone and inferior to vancomycin in sterilizing CSF
Treatment: cultures.The number of patients with bacterial meningitis
ACUTE BACTERIAL MENINGITIS
enrolled in clinical trials of meropenem has not been suf-
EMPIRICAL ANTIMICROBIAL THERAPY cient to denitively assess the efcacy of this antibiotic.
(Table 35-1) Bacterial meningitis is a medical emergency. SPECIFIC ANTIMICROBIAL THERAPY
The goal is to begin antibiotic therapy within 60 min of a Meningococcal Meningitis (Table 35-3)
patients arrival in the emergency department. Empirical

Meningitis, Encephalitis, Brain Abscess, and Empyema

Although ceftriaxone and cefotaxime provide adequate
antimicrobial therapy is initiated in patients with sus- empirical coverage for N. meningitidis, penicillin G remains
pected bacterial meningitis before the results of CSF the antibiotic of choice for meningococcal meningitis
Grams stain and culture are known. S. pneumoniae and caused by susceptible strains. Isolates of N. meningitidis
N. meningitidis are the most common etiologic organ- with moderate resistance to penicillin have been identi-
isms of community-acquired bacterial meningitis. Due ed, but patients infected with these strains have still
to the emergence of penicillin- and cephalosporin-resis-
tant S. pneumoniae, empirical therapy of community-
acquired suspected bacterial meningitis in children and TABLE 35-3
adults should include a combination of dexamethasone, ANTIMICROBIAL THERAPY OF CNS BACTERIAL
a third-generation cephalosporin (e.g., ceftriaxone or INFECTIONS BASED ON PATHOGENa
cefotaxime) and vancomycin, plus acyclovir, as HSV
ORGANISM ANTIBIOTIC
encephalitis is the leading disease in the differential
diagnosis, and doxycycline during tick season to treat Neisseria meningitides
tick-borne bacterial infections. Ceftriaxone or cefotaxime Penicillin-sensitive Penicillin G or ampicillin
provide good coverage for susceptible S. pneumoniae, Penicillin-resistant Ceftriaxone or cefotaxime
Streptococcus pneumoniae
group B streptococci, and H. inuenzae and adequate
Penicillin-sensitive Penicillin G
coverage for N. meningitidis. Cefepime is a broad-spec- Penicillin-intermediate Ceftriaxone or cefotaxime
trum fourth-generation cephalosporin with in vitro Penicillin-resistant (Ceftriaxone or
activity similar to that of cefotaxime or ceftriaxone cefotaxime) +
against S. pneumoniae and N. meningitidis and greater vancomycin
activity against Enterobacter species and Pseudomonas Gram-negative bacilli Ceftriaxone or cefotaxime
aeruginosa. In clinical trials, cefepime has been demon- (except Pseudomonas spp.)
strated to be equivalent to cefotaxime in the treatment Pseudomonas aeruginosa Ceftazidime or cefepime
or meropenem
of penicillin-sensitive pneumococcal and meningococ-
Staphylococci spp.
cal meningitis, and it has been used successfully in some Methicillin-sensitive Nafcillin
patients with meningitis due to Enterobacter species and Methicillin-resistant Vancomycin
P. aeruginosa. Ampicillin should be added to the empirical Listeria monocytogenes Ampicillin + gentamicin
regimen for coverage of L. monocytogenes in individuals Haemophilus inuenzae Ceftriaxone or cefotaxime
<3 months, those >55 years, or those with suspected Streptococcus agalactiae Penicillin G or ampicillin
impaired cell-mediated immunity because of chronic Bacteroides fragilis Metronidazole
Fusobacterium spp. Metronidazole
illness, organ transplantation, pregnancy, malignancy, or
immunosuppressive therapy. In hospital-acquired a
Doses are as indicated in Table 35-1.
 460 been successfully treated with penicillin. CSF isolates of preferred over the intrathecal route because adequate
N. meningitidis should be tested for penicillin and ampi- concentrations of vancomycin in the cerebral ventricles
cillin susceptibility, and if resistance is found, cefotaxime are not always achieved with intrathecal administration.
or ceftriaxone should be substituted for penicillin.
Listeria Meningitis Meningitis due to L. monocy-
A 7-day course of intravenous antibiotic therapy is ade-
togenes is treated with ampicillin for at least 3 weeks
quate for uncomplicated meningococcal meningitis. The
(Table 35-3). Gentamicin is often added (2 mg/kg load-
index case and all close contacts should receive chemo-
ing dose, then 7.5 mg/kg per day given every 8 h and
prophylaxis with a 2-day regimen of rifampin (600 mg
adjusted for serum levels and renal function). The com-
every 12 h for 2 days in adults and 10 mg/kg every 12 h
bination of trimethoprim [1020 (mg/kg)/d] and sul-
for 2 days in children >1 year). Rifampin is not recom-
famethoxazole [50100 (mg/kg)/d] given every 6 h may
mended in pregnant women. Alternatively, adults can be
provide an alternative in penicillin-allergic patients.
treated with one dose of ciprooxacin (750 mg), one
dose of azithromycin (500 mg), or one intramuscular Staphylococcal Meningitis Meningitis due to
dose of ceftriaxone (250 mg). Close contacts are dened susceptible strains of S. aureus or coagulase-negative
as those individuals who have had contact with oropha- staphylococci is treated with nafcillin (Table 35-3). Van-
ryngeal secretions, either through kissing or by sharing comycin is the drug of choice for methicillin-resistant
toys, beverages, or cigarettes. staphylococci and for patients allergic to penicillin. In
SECTION III

these patients, the CSF should be monitored during

Pneumococcal Meningitis Antimicrobial ther- therapy. If the CSF is not sterilized after 48 h of intra-
apy of pneumococcal meningitis is initiated with a venous vancomycin therapy, then either intraventricular
cephalosporin (ceftriaxone, cefotaxime, or cefepime) or intrathecal vancomycin, 20 mg once daily, can be
and vancomycin. All CSF isolates of S. pneumoniae added.
should be tested for sensitivity to penicillin and the
Gram-Negative Bacillary Meningitis The
Diseases of the Central Nervous System

cephalosporins. Once the results of antimicrobial sus-

ceptibility tests are known, therapy can be modied third-generation cephalosporins (cefotaxime, ceftriaxone,
accordingly (Table 35-3). For S. pneumoniae meningitis, an and ceftazidime) are equally efcacious for the treatment
isolate of S.pneumoniae is considered to be susceptible to of gram-negative bacillary meningitis, with the exception
penicillin with a minimal inhibitory concentration (MIC) of meningitis due to P. aeruginosa, which should be
<0.06 g/mL, to have intermediate resistance when the treated with ceftazidime, cefepime, or meropenem
MIC is 0.11.0 g/mL, and to be highly resistant when (Table 35-3). A 3-week course of intravenous antibiotic
the MIC >1.0 g/mL. Isolates of S. pneumoniae that therapy is recommended for meningitis due to gram-
have cephalosporin MICs 0.5 g/mL are considered negative bacilli.
sensitive to the cephalosporins (cefotaxime, ceftriaxone, Adjunctive Therapy The release of bacterial cell-
cefepime). Those with MICs of 1 g/mL are considered wall components by bactericidal antibiotics leads to the
to have intermediate resistance, and those with MICs production of the inammatory cytokines IL-1 and TNF
2 g/mL are considered resistant. For meningitis due in the subarachnoid space. Dexamethasone exerts its
to pneumococci with cefotaxime or ceftriaxone MICs benecial effect by inhibiting the synthesis of IL-1 and
0.5 g/mL, treatment with cefotaxime or ceftriaxone is TNF at the level of mRNA, decreasing CSF outow resis-
usually adequate. If the MIC >1 g/mL, vancomycin is tance, and stabilizing the blood-brain barrier. The ratio-
the antibiotic of choice. Rifampin can be added to van- nale for giving dexamethasone 20 min before antibiotic
comycin for its synergistic effect but is inadequate as therapy is that dexamethasone inhibits the production
monotherapy because resistance develops rapidly when of TNF by macrophages and microglia only if it is admin-
it is used alone. A 2-week course of intravenous antimi- istered before these cells are activated by endotoxin.
crobial therapy is recommended for pneumococcal Dexamethasone does not alter TNF production once it
meningitis. has been induced. The results of clinical trials of dexam-
Patients with S. pneumoniae meningitis should have ethasone therapy in children, predominantly with
a repeat LP performed 2436 h after the initiation of meningitis due to H. inuenzae and S. pneumoniae, have
antimicrobial therapy to document sterilization of the demonstrated its efcacy in decreasing meningeal
CSF. Failure to sterilize the CSF after 2436 h of antibi- inammation and neurologic sequelae such as the inci-
otic therapy should be considered presumptive evi- dence of sensorineural hearing loss.
dence of antibiotic resistance. Patients with penicillin- A prospective European trial of adjunctive therapy for
and cephalosporin-resistant strains of S. pneumoniae acute bacterial meningitis in 301 adults found that dex-
who do not respond to intravenous vancomycin alone amethasone reduced the number of unfavorable out-
may benet from the addition of intraventricular van- comes (15% vs. 25%, p = .03) including death (7% vs. 15%,
comycin. The intraventricular route of administration is p = .04). The benets were most striking in patients with
 pneumococcal meningitis. Dexamethasone (10 mg intra- headache of viral meningitis is usually frontal or retroor- 461
venously) was administered 1520 min before the rst bital and is often associated with photophobia and pain
dose of an antimicrobial agent, and the same dose was on moving the eyes. Nuchal rigidity is present in most
repeated every 6 h for 4 days. These results were con- cases but may be mild and present only near the limit of
rmed in a second trial of dexamethasone in adults with neck anteexion. Constitutional signs can include malaise,
pneumococcal meningitis. Therapy with dexamethasone myalgia, anorexia, nausea and vomiting, abdominal pain,
should ideally be started 20 min before, or not later than and/or diarrhea. Patients often have mild lethargy or
concurrent with, the rst dose of antibiotics. It is unlikely drowsiness; however, profound alterations in conscious-
to be of signicant benet if started >6 h after antimicro- ness, such as stupor, coma, or marked confusion, are
bial therapy has been initiated. Dexamethasone may unusual in viral meningitis and suggest the presence of
decrease the penetration of vancomycin into CSF, and it encephalitis or other alternative diagnoses. Similarly, seizures
delays the sterilization of CSF in experimental models of or focal neurologic signs or symptoms or neuroimaging
S. pneumoniae meningitis. As a result, its potential benet abnormalities indicative of brain parenchymal involve-
should be carefully weighed when vancomycin is the ment are not typical of viral meningitis and suggest the
antibiotic of choice. Alternatively, vancomycin can be presence of encephalitis or another CNS infectious or
administered by the intraventricular route. inammatory process.

CHAPTER 35
INCREASED INTRACRANIAL PRESSURE
ETIOLOGY
Emergency treatment of increased ICP includes eleva-
tion of the patients head to 3045, intubation and Using a variety of diagnostic techniques, including
hyperventilation (PaCO2 2530 mm Hg), and mannitol. CSF PCR, culture, and serology, a specific viral cause
Patients with increased ICP should be managed in an can be found in 7590% of cases of viral meningitis.
intensive care unit; accurate ICP measurements are best The most important agents are enteroviruses, HSV

Meningitis, Encephalitis, Brain Abscess, and Empyema

obtained with an ICP monitoring device. Treatment of type 2 (HSV-2), and arboviruses (Table 35-4). CSF
increased intracranial pressure is discussed in detail in cultures are positive in 3070% of patients, the fre-
Chap. 22. quency of isolation depending on the specific viral
agent. Approximately two-thirds of culture-negative

PROGNOSIS
TABLE 35-4
Mortality is 37% for meningitis caused by H. inuenzae,
N. meningitidis, or group B streptococci; 15% for that due VIRUSES CAUSING ACUTE MENINGITIS
to L. monocytogenes; and 20% for S. pneumoniae. In gen- AND ENCEPHALITIS IN NORTH AMERICAa
eral, the risk of death from bacterial meningitis increases ACUTE MENINGITIS
with (1) decreased level of consciousness on admission,
(2) onset of seizures within 24 h of admission, (3) signs COMMON LESS COMMON
of increased ICP, (4) young age (infancy) and >50 years, Enteroviruses Varicella zoster virus
(5) the presence of comorbid conditions including (coxsackieviruses, Epstein-Barr virus
shock and/or the need for mechanical ventilation, and echoviruses, and human Lymphocytic
(6) delay in the initiation of treatment. Decreased CSF enteroviruses 6871) choriomeningitis virus
Herpes simplex virus 2
glucose concentration [<2.2 mmol/L (<40 mg/dL)] and
Arthropod-borne viruses
markedly increased CSF protein concentration [>3 g/L HIV
(>300 mg/dL)] have been predictive of increased mor-
tality and poorer outcomes in some series. Moderate or ACUTE ENCEPHALITIS
severe sequelae occur in ~25% of survivors, although the COMMON LESS COMMON
exact incidence varies with the infecting organism.
Common sequelae include decreased intellectual func- Herpesviruses Rabies
tion, memory impairment, seizures, hearing loss and Herpes simplex virus 1 Eastern equine
encephalitis virus
dizziness, and gait disturbances. Varicella zoster virus Western equine
encephalitis virus
ACUTE VIRAL MENINGITIS Epstein-Barr virus Powassan virus
Arthropod-borne viruses Cytomegalovirusa
CLINICAL MANIFESTATIONS La Crosse virus Enterovirusesa
West Nile virus Colorado tick fever
Patients with viral meningitis usually present with St. Louis encephalitis virus Mumps
headache, fever, and signs of meningeal irritation cou-
pled with an inammatory CSF prole (see later). The a
Immunocompromised host.
 462 cases of aseptic meningitis have a specific viral etiology potential discriminators between viral and bacterial
identified by CSF PCR testing (see later). meningitis or as markers of specic types of viral infec-
tion (e.g., infection with HIV), but they remain of
EPIDEMIOLOGY uncertain sensitivity and specicity and are not widely
used for diagnostic purposes.
Viral meningitis is not a nationally reportable disease;
however, it has been estimated that the incidence is Polymerase Chain Reaction Amplication
~75,000 cases per year. In temperate climates, there is a of Viral Nucleic Acid
substantial increase in cases during the summer and early
fall months, reecting the seasonal predominance of Amplication of viral-specic DNA or RNA from CSF
enterovirus and arthropod-borne virus (arbovirus) infec- using PCR amplication has become the single most
tions, with a peak monthly incidence of about 1 reported important method for diagnosing CNS viral infections.
case per 100,000 population. In both enteroviral and HSV infections of the CNS,
PCR has become the diagnostic procedure of choice
and is substantially more sensitive than viral cultures.
LABORATORY DIAGNOSIS HSV PCR is also an important diagnostic test in
CSF Examination patients with recurrent episodes of aseptic meningitis,
SECTION III

many of whom have ampliable HSV DNA in CSF

The most important laboratory test in the diagnosis of
despite negative viral cultures. CSF PCR is also used
viral meningitis is examination of the CSF. The typical
routinely to diagnose CNS viral infections caused by
profile is a lymphocytic pleocytosis (25500 cells/L),
cytomegalovirus (CMV), Epstein-Barr virus (EBV),
a normal or slightly elevated protein concentration
VZV, and human herpesvirus 6 (HHV-6). CSF PCR
[0.20.8 g/L (2080 mg/dL)], a normal glucose
tests are available for WNV but are not as sensitive as
concentration, and a normal or mildly elevated opening
CSF IgM. PCR is also useful in the diagnosis of CNS
Diseases of the Central Nervous System

pressure (100350 mm H2O). Organisms are not seen

infection caused by Mycoplasma pneumoniae, which can
on Grams or acid-fast stained smears or India ink
mimic viral meningitis and encephalitis.
preparations of CSF. Rarely, PMNs may predominate in
the rst 48 h of illness, especially with infections due to
echovirus 9, eastern equine encephalitis (EEE) virus, or Viral Culture
mumps. A pleocytosis of polymorphonuclear neutrophils The sensitivity of CSF cultures for the diagnosis of viral
also occurs in 45% of patients with West Nile virus meningitis and encephalitis, in contrast to its utility in
(WNV) meningitis and can persist for a week or longer bacterial infections, is generally poor. In addition to
before shifting to a lymphocytic pleocytosis. Despite CSF, specic viruses may also be isolated from throat
these exceptions, the presence of a CSF PMN pleocy- swabs, stool, blood, and urine. Enteroviruses and aden-
tosis in a patient with suspected viral meningitis should oviruses may be found in feces; arboviruses, some
always prompt consideration of alternative diagnoses, enteroviruses, and LCMV in blood; mumps and CMV
including bacterial meningitis or parameningeal infec- in urine; and enteroviruses, mumps, and adenoviruses in
tions. The total CSF cell count in viral meningitis is throat washings. During enteroviral infections, viral
typically 25500/L, although cell counts of several shedding in stool may persist for several weeks. The
thousand/L are occasionally seen, especially with presence of enterovirus in stool is not diagnostic and
infections due to lymphocytic choriomeningitis virus may result from residual shedding from a previous
(LCMV) and mumps virus. The CSF glucose concen- enteroviral infection; it also occurs in some asympto-
tration is typically normal in viral infections, although it matic individuals during enteroviral epidemics.
may be decreased in 1030% of cases due to mumps or
LCMV. Rare instances of decreased CSF glucose con-
Serologic Studies
centration occur in cases of meningitis due to
echoviruses and other enteroviruses, HSV-2, and For some viruses, including many arboviruses such as
varicella-zoster virus (VZV). As a rule, a lymphocytic WNV, serologic studies remain a crucial diagnostic tool.
pleocytosis with a low glucose concentration should Serum antibody determination is less useful for viruses
suggest fungal or tuberculous meningitis, Listeria with high seroprevalence rates in the general population
meningoencephalitis, or noninfectious disorders (e.g., such as HSV,VZV, CMV, and EBV. For viruses with low
sarcoid, neoplastic meningitis). seroprevalence rates, diagnosis of acute viral infection
A number of tests measuring levels of various CSF can be made by documenting seroconversion between
proteins, enzymes, and mediatorsincluding C-reactive acute-phase and convalescent sera (typically obtained
protein, lactic acid, lactate dehydrogenase, neopterin, after 24 weeks) or by demonstrating the presence of
quinolinate, IL-1, IL-6, soluble IL-2 receptor, virus-specic IgM antibodies. Documentation of synthesis
2-microglobulin, and TNFhave been proposed as of virus-specic antibodies in CSF, as shown by an
increased IgG index or the presence of CSF IgM anti- PCR (RT-PCR) is the diagnostic procedure of choice 463
bodies, is more useful than serum serology alone and can and is both sensitive (>95%) and specic (>100%).
provide presumptive evidence of CNS infection. Enteroviruses are the most likely cause of viral meningi-
Although serum and CSF IgM antibodies generally per- tis in the summer months, especially in children
sist for only a few months after acute infection, there are (<15 years), although cases occur at reduced frequency
exceptions to this rule. For example, WNV IgM has year round. Although the incidence of enteroviral
been shown to persist in some patients for >1 year fol- meningitis declines with increasing age, some outbreaks
lowing acute infection. Unfortunately, the delay have preferentially affected older children and adults.
between onset of infection and the hosts generation of a Meningitis outside the neonatal period is usually
virus-specic antibody response often means that sero- benign. Patients present with sudden onset of fever;
logic data are useful mainly for the retrospective estab- headache; nuchal rigidity; and often constitutional signs,
lishment of a specic diagnosis, rather than in aiding including vomiting, anorexia, diarrhea, cough, pharyngi-
acute diagnosis or management. tis, and myalgias. The physical examination should
CSF oligoclonal gamma globulin bands occur in include a careful search for stigmata of enterovirus infec-
association with a number of viral infections.The associ- tion, including exanthemata, hand-foot-mouth disease,
ated antibodies are often directed against viral proteins. herpangina, pleurodynia, myopericarditis, and hemor-
Oligoclonal bands occur commonly in certain nonin- rhagic conjunctivitis.The CSF prole is typically a lym-

CHAPTER 35
fectious neurologic diseases (e.g., multiple sclerosis) and phocytic pleocytosis (1001000 cells/L) with normal
may be found in nonviral infections (e.g., neurosyphilis, glucose and normal or mildly elevated protein concen-
Lyme neuroborreliosis). tration. In rare cases, PMNs may predominate during
the rst 48 h of illness. Treatment is supportive, and
patients usually recover without sequelae. Chronic and
Other Laboratory Studies
severe infections can occur in neonates and in individu-

Meningitis, Encephalitis, Brain Abscess, and Empyema

All patients with suspected viral meningitis should have als with hypo- or agammaglobulinemia.
a complete blood count and differential, liver and renal Arbovirus infections occur predominantly in the sum-
function tests, erythrocyte sedimentation rate (ESR) and mer and early fall.Arboviral meningitis should be consid-
C-reactive protein, electrolytes, glucose, creatine kinase, ered when clusters of meningitis and encephalitis cases
aldolase, amylase, and lipase. Neuroimaging studies occur in a restricted geographic region during the sum-
(MRI, CT) are not necessary in patients with uncompli- mer or early fall. In WNV epidemics, avian deaths may
cated viral meningitis but should be performed in serve as sentinel infections for subsequent human disease.
patients with altered consciousness, seizures, focal neuro- A history of tick exposure or travel or residence in the
logic signs or symptoms, or atypical CSF proles. appropriate geographic area should suggest the possibility
of Colorado tick fever virus or Powassan virus infection,
although nonviral tick-borne diseases, including RMSF
DIFFERENTIAL DIAGNOSIS
and Lyme neuroborreliosis, may present similarly.
The most important issue in the differential diagnosis of Arbovirus meningoencephalitis is typically associated
viral meningitis is to consider diseases that can mimic with a CSF lymphocytic pleocytosis, normal glucose
viral meningitis, including (1) untreated or partially concentration, and normal or mildly elevated protein
treated bacterial meningitis; (2) early stages of meningitis concentration. However, 4045% of patients with WNV
caused by fungi, mycobacteria, or Treponema pallidum meningoencephalitis have CSF neutrophilia, which can
(neurosyphilis), in which a lymphocytic pleocytosis is persist for a week or more. The rarity of hypoglycor-
common, cultures may be slow growing or negative, and rhachia in WNV infection as well as the absence of
hypoglycorrhachia may not be present early; (3) meningitis positive Grams stains and the negative cultures helps dis-
caused by agents such as Mycoplasma, Listeria spp., tinguish these patients from those with bacterial menin-
Brucella spp., Coxiella spp., Leptospira spp., and Rickettsia gitis.The presence of increased numbers of plasmacytoid
spp.; (4) parameningeal infections; (5) neoplastic meningi- cells or Mollaret-like large mononuclear cells in the CSF
tis; and (6) meningitis secondary to noninfectious inam- may be a clue to the diagnosis of WNV infection. Den-
matory diseases, including hypersensitivity meningitis, itive diagnosis of arboviral meningoencephalitis is based
SLE and other rheumatologic diseases, sarcoidosis, on demonstration of viral-specic IgM in CSF or sero-
Behets syndrome, and the uveomeningitic syndromes. conversion. CSF PCR tests are available for some viruses
in selected diagnostic laboratories and at the Centers for
Disease Control and Prevention (CDC), but in the case
SPECIFIC VIRAL ETIOLOGIES of WNV, sensitivity (~70%) of CSF PCR is less than that
Enteroviruses are the most common cause of viral menin- of CSF serology.
gitis, accounting for >75% of cases in which a specic HSV-2 meningitis occurs in ~25% of women and 11%
etiology can be identied. CSF reverse transcriptase of men at the time of an initial (primary) episode of
 464 genital herpes. Of these patients, 20% go on to have VIII, are more common in HIV meningitis than in other
recurrent attacks of meningitis. HSV-2 has been increas- viral infections. Diagnosis can be conrmed by detection
ingly recognized as a major cause of viral meningitis in of HIV genome in blood or CSF. Seroconversion may be
adults, and overall it is probably second in importance to delayed, and patients with negative HIV serologies who
enteroviruses as a cause of viral meningitis. Diagnosis of are suspected of having HIV meningitis should be moni-
HSV meningitis is usually by HSV CSF PCR as cul- tored for delayed seroconversion. For further discussion
tures may be negative, especially in patients with recur- of HIV infection, see Chap. 37.
rent meningitis. Demonstration of intrathecal synthesis Mumps should be considered when meningitis occurs
of HSV-specic antibody may also be useful in diagno- in the late winter or early spring, especially in males
sis, although antibody tests are less sensitive and less spe- (male:female ratio 3:1). With the widespread use of the
cic than PCR and may not become positive until after live attenuated mumps vaccine in the United States since
the rst week of infection. In contrast to HSV 1967, the incidence of mumps meningitis has fallen by
encephalitis in adults in which >90% of cases are due to >95%.The presence of parotitis, orchitis, oophoritis, pan-
HSV-1, the overwhelming majority of HSV meningitis creatitis, or elevations in serum lipase and amylase are
is due to HSV-2. Although a history of or the presence suggestive of mumps meningitis; however, their absence
of HSV genital lesions is an important diagnostic clue, does not exclude the diagnosis. Clinical meningitis
many patients with HSV meningitis give no history and occurs in up to 30% of patients with mumps parotitis,
SECTION III

have no evidence of active genital herpes at the time of and CSF pleocytosis occurs in >50%. Mumps infection
presentation. Most cases of recurrent viral or aseptic confers lifelong immunity, so a documented history of
meningitis, including cases previously diagnosed as Mol- previous infection excludes this diagnosis. Patients with
larets meningitis, are likely due to HSV. meningitis have a CSF pleocytosis that can exceed 1000
VZV meningitis should be suspected in the presence cells/L in 25%. Lymphocytes predominate in 75%,
of concurrent chickenpox or shingles. However, it is although CSF neutrophilia occurs in 25%. Hypoglycor-
Diseases of the Central Nervous System

important to recognize that in some series, up to 40% of rhachia, occurs in 1030% of patients and may be a clue
VZV meningitis cases have been reported to occur in to the diagnosis when present. Diagnosis is typically
the absence of rash.The frequency of VZV as a cause of made by culture of virus from CSF or by detecting IgM
meningitis is extremely variable, ranging from as low as antibodies or seroconversion. CSF PCR is available in
3% to as high as 20% in different series. Diagnosis is some diagnostic and research laboratories.The frequency
usually based on CSF PCR, although the sensitivity of of mumps meningitis has declined dramatically with the
this test may not be as high as for the other her- widespread use of the live-attenuated mumps vaccine.
pesviruses. In patients with negative CSF PCR results, Rare cases of vaccine-associated meningitis occur, with a
the diagnosis of VZV CNS infection can be made by frequency of 10100/100,000 doses typically 24 weeks
the demonstration of VZV-specic intrathecal antibody after vaccination.
synthesis and/or the presence of VZV CSF IgM anti- LCMV infection should be considered when aseptic
bodies, or by positive CSF cultures. meningitis occurs in the late fall or winter and in indi-
EBV infections may also produce aseptic meningitis, viduals with a history of exposure to house mice (Mus
with or without associated infectious mononucleosis. musculus), pet or laboratory rodents (e.g., hamsters, rats,
The presence of atypical lymphocytes in the CSF or mice), or their excreta. Some patients have an associated
peripheral blood is suggestive of EBV infection but may rash, pulmonary inltrates, alopecia, parotitis, orchitis, or
occasionally be seen with other viral infections. EBV is myopericarditis. Laboratory clues to the diagnosis of
almost never cultured from CSF. Serum and CSF serol- LCMV, in addition to the clinical ndings noted above,
ogy can help establish the presence of acute infection, may include the presence of leukopenia, thrombocytope-
which is characterized by IgM viral capsid antibodies nia, or abnormal liver function tests. Some cases present
(VCAs), antibodies to early antigens (EA), and the with a marked CSF pleocytosis (>1000 cells/L) and
absence of antibodies to EBV-associated nuclear antigen hypoglycorrachia (<30%). Diagnosis is based on serology
(EBNA). CSF PCR is another important diagnostic test, and/or culture of virus from CSF.
although positive results may reect viral reactivation
associated with other infectious or inammatory
processes.
HIV meningitis should be suspected in any patient pre- Treatment:
senting with a viral meningitis with known or suspected ACUTE VIRAL MENINGITIS
risk factors for HIV infection. Meningitis may occur fol- Treatment of almost all cases of viral meningitis is pri-
lowing primary infection with HIV in 510% of patients marily symptomatic and includes use of analgesics,
and less commonly at later stages of illness. Cranial nerve antipyretics, and antiemetics. Fluid and electrolyte status
palsies, most commonly involving cranial nerves V,VII, or
should be monitored. Patients with suspected bacterial measles infection. A live attenuated VZV vaccine (Vari- 465
meningitis should receive appropriate empirical therapy vax) is available in the United States. Clinical studies
pending culture results (see earlier). Hospitalization may indicate an effectiveness rate of 7090% for this vaccine,
not be required in immunocompetent patients with but a booster may be required to maintain immunity.
presumed viral meningitis and no focal signs or symp- An inactivated varicella vaccine is available for trans-
toms, no signicant alteration in consciousness, and a plant recipients.
classic CSF prole (lymphocytic pleocytosis, normal glu-
cose, negative Grams stain) if adequate provision for
monitoring at home and medical follow-up can be
ensured. Immunocompromised patients; patients with PROGNOSIS
signicant alteration in consciousness, seizures, or the In adults, the prognosis for full recovery from viral
presence of focal signs and symptoms suggesting the meningitis is excellent. Rare patients complain of per-
possibility of encephalitis or parenchymal brain involve- sisting headache, mild mental impairment, incoordina-
ment; and those patients who have an atypical CSF pro- tion, or generalized asthenia for weeks to months. The
le should be hospitalized. Oral or intravenous acyclovir outcome in infants and neonates (<1 year) is less cer-
may be of benet in patients with meningitis caused by tain; intellectual impairment, learning disabilities, hear-

CHAPTER 35
HSV-1 or -2 and in cases of severe EBV or VZV infection. ing loss, and other lasting sequelae have been reported in
Data concerning treatment of HSV, EBV, and VZV menin- some studies.
gitis are extremely limited. Seriously ill patients should
probably receive intravenous acyclovir (1530 mg/kg
per day in three divided doses), which can be followed
VIRAL ENCEPHALITIS
by an oral drug such as acyclovir (800 mg, ve times DEFINITION
daily), famciclovir (500 mg tid), or valacyclovir (1000 mg

Meningitis, Encephalitis, Brain Abscess, and Empyema

tid) for a total course of 714 days. Patients who are less In contrast to viral meningitis, where the infectious process
ill can be treated with oral drugs alone. Patients with HIV and associated inammatory response are limited largely to
meningitis should receive highly active antiretroviral the meninges, in encephalitis the brain parenchyma is also
therapy (Chap. 37). involved. Many patients with encephalitis also have evidence
Patients with viral meningitis who are known to of associated meningitis (meningoencephalitis) and, in
have decient humoral immunity (e.g., X-linked agam- some cases, involvement of the spinal cord or nerve
maglobulinemia) and who are not already receiving roots (encephalomyelitis, encephalomyeloradiculitis).
either intramuscular gamma globulin or intravenous
immunoglobulin (IVIg), should be treated with these CLINICAL MANIFESTATIONS
agents. Intraventricular administration of immunoglob-
ulin through an Ommaya reservoir has been tried in In addition to the acute febrile illness with evidence of
some patients with chronic enteroviral meningitis who meningeal involvement characteristic of meningitis, the
have not responded to intramuscular or intravenous patient with encephalitis commonly has an altered level
immunoglobulin. of consciousness (confusion, behavioral abnormalities),
An investigational drug, pleconaril, has shown efcacy or a depressed level of consciousness, ranging from mild
against a variety of enteroviral infections and has good lethargy to coma, and evidence of either focal or diffuse
oral bioavailability and excellent CNS penetration. Clini- neurologic signs and symptoms. Patients with encephali-
cal trials in patients with enteroviral meningitis indicated tis may have hallucinations, agitation, personality
that pleconaril decreased the duration of symptoms change, behavioral disorders, and, at times, a frankly psy-
compared to placebo. Most cases of enteroviral CNS chotic state. Focal or generalized seizures occur in many
infection are benign and self-limited and do not require patients with encephalitis. Virtually every possible type
specic antiviral therapy. However, pleconaril treatment of focal neurologic disturbance has been reported in
might benet patients with chronic CNS enteroviral viral encephalitis; the signs and symptoms reect the
infections in the setting of agammaglobulinemia or sites of infection and inammation. The most com-
those who develop poliomyelitis as a complication of monly encountered focal ndings are aphasia, ataxia,
polio vaccine administration. Unfortunately, the availabil- upper or lower motor neuron patterns of weakness,
ity of pleconaril for compassionate-use purposes is cur- involuntary movements (e.g., myoclonic jerks, tremor),
rently uncertain. and cranial nerve decits (e.g., ocular palsies, facial
Vaccination is an effective method of preventing the weakness). Involvement of the hypothalamic-pituitary
development of meningitis and other neurologic com- axis may result in temperature dysregulation, diabetes
plications associated with poliovirus, mumps, and insipidus, or the development of the syndrome of inap-
propriate secretion of antidiuretic hormone (SIADH).
 466 Despite the clear neuropathologic evidence that viruses occurs in >95% of patients with documented viral
differ in the regions of the CNS they injure, it is often encephalitis. In rare cases, a pleocytosis may be absent on
impossible to distinguish reliably on clinical grounds the initial LP but present on subsequent LPs. Patients
alone one type of viral encephalitis (e.g., that caused by who are severely immunocompromised by HIV infec-
HSV) from others (see Differential Diagnosis, below). tion, glucocorticoid or other immunosuppressant drugs,
chemotherapy, or lymphoreticular malignancies may fail
ETIOLOGY to mount a CSF inammatory response. CSF cell counts
exceed 500/L in only about 10% of patients with
In the United States, there are ~20,000 reported cases encephalitis. Infections with certain arboviruses (e.g.,
of encephalitis per year, although the actual number of EEE virus or California encephalitis virus), mumps, and
cases is likely to be signicantly larger. Hundreds of LCMV may occasionally result in cell counts >1000/L,
viruses are capable of causing encephalitis, although but this degree of pleocytosis should suggest the possibil-
only a limited subset is responsible for most cases in ity of nonviral infections or other inammatory
which a specic cause is identied (Table 35-4). The processes. Atypical lymphocytes in the CSF may be seen
same organisms responsible for aseptic meningitis are in EBV infection and less commonly with other viruses,
also responsible for encephalitis, although the relative including CMV, HSV, and enteroviruses. Increased num-
frequencies with which specic organisms cause these bers of plasmacytoid or Mollaret-like large mononuclear
SECTION III

two patterns of infection often differ. The most impor- cells have been reported in WNV encephalitis. Polymor-
tant viruses causing sporadic cases of encephalitis in phonuclear pleocytosis occurs in ~40% of patients with
immunocompetent adults are herpesviruses (HSV,VZV, WNV encephalitis. Large numbers of CSF PMNs may
EBV). Epidemics of encephalitis are caused by be present in patients with encephalitis due to EEE
arboviruses, which belong to several different viral tax- virus, echovirus 9, and, more rarely, other enteroviruses.
onomic groups including Alphaviruses (e.g., EEE virus, However, persisting CSF neutrophilia should prompt
western equine encephalitis virus), Flaviviruses (e.g.,
Diseases of the Central Nervous System

consideration of bacterial infection, leptospirosis, amebic

WNV, St. Louis encephalitis virus, Japanese encephalitis infection, and noninfectious processes such as acute hem-
virus, Powassan virus), and Bunyaviruses (e.g., California orrhagic leukoencephalitis. About 20% of patients with
encephalitis virus serogroup, LaCrosse virus). Histori- encephalitis will have a signicant number of red blood
cally, the largest number of cases of arbovirus encephali- cells (>500/L) in the CSF in a nontraumatic tap. The
tis in the United States has been due to St. Louis pathologic correlate of this nding may be a hemor-
encephalitis virus and the California encephalitis virus rhagic encephalitis of the type seen with HSV; however,
serogroup. However, since 2002, WNV has been CSF red blood cells occur with similar frequency and in
responsible for the majority of arbovirus meningitis and similar numbers in patients with nonherpetic focal
encephalitis cases in the United States. The 2003 epi- encephalitides. A decreased CSF glucose concentration is
demic was the largest epidemic of arboviral neuroinva- distinctly unusual in viral encephalitis and should suggest
sive disease (encephalitis + meningitis) ever recorded in the possibility of bacterial, fungal, tuberculous, parasitic,
the United States, with 2860 cases and 264 deaths. leptospiral, syphilitic, sarcoid, or neoplastic meningitis.
Since 2003, WNV has accounted for ~11001300 cases Rare patients with mumps, LCMV, or advanced HSV
of neuroinvasive disease per year and 100120 deaths in encephalitis may have low CSF glucose concentrations.
the United States. New causes of viral CNS infections
are constantly appearing, as evidenced by the recent
outbreak of cases of encephalitis in Southeast Asia CSF PCR
caused by Nipah virus, a newly identied member of CSF PCR has become the primary diagnostic test for
the Paramyxovirus family, and of meningitis in Europe CNS infections caused by CMV, EBV,VZV, HHV-6, and
caused by Toscana virus, an arbovirus belonging to the enteroviruses (see Viral Meningitis, above). The sensitiv-
Bunyavirus family. ity and specicity of CSF PCRs varies with the virus
being tested. The sensitivity (~96%) and specicity
LABORATORY DIAGNOSIS (~99%) of HSV CSF PCR is equivalent to or exceeds
that of brain biopsy. It is important to recognize that
CSF Examination HSV CSF PCR results need to be interpreted after
CSF examination should be performed in all patients considering the likelihood of disease in the patient
with suspected viral encephalitis unless contraindicated by being tested, the timing of the test in relationship to
the presence of severely increased ICP. The characteristic onset of symptoms, and the prior use of antiviral therapy.
CSF prole is indistinguishable from that of viral menin- A negative HSV CSF PCR test performed by a qualied
gitis and typically consists of a lymphocytic pleocytosis, a laboratory at the appropriate time during illness in a
mildly elevated protein concentration, and a normal glu- patient with a high likelihood of HSV encephalitis based
cose concentration. A CSF pleocytosis (>5 cells/L) on clinical and laboratory abnormalities signicantly
reduces the likelihood of HSV encephalitis but does not >1 week in duration and who are CSF PCRnegative 467
exclude it. For example, in a patient with a pretest prob- for HSV. Demonstration of WNV IgM antibodies is
ability of 35% of having HSV encephalitis, a negative diagnostic of WNV encephalitis as IgM antibodies do
HSV CSF PCR reduces the posttest probability to ~2%, not cross the blood-brain barrier, and their presence in
and for a patient with a pretest probability of 60%, a CSF is therefore indicative of intrathecal synthesis.Tim-
negative test reduces the posttest probability to ~6%. In ing of antibody collection may be important as the rate
both situations a positive test makes the diagnosis almost of CSF WNV IgM seropositivity increases by ~10% per
certain (9899%).There have been several recent reports day during the rst week after illness onset.
of initially negative HSV CSF PCR tests that were
obtained early (72 h) following symptom onset, and MRI, CT, EEG
that became positive when repeated 13 days later. The
frequency of positive HSV CSF PCRs in patients with Patients with suspected encephalitis almost invariably
herpes encephalitis also decreases as a function of the undergo neuroimaging studies and often EEG. These
duration of illness, with only ~20% of cases remaining tests help identify or exclude alternative diagnoses and
positive after 14 days. PCR results are generally not assist in the differentiation between a focal, as opposed
affected by 1 week of antiviral therapy. In one study, 98% to a diffuse, encephalitic process. Focal findings in a
of CSF specimens remained PCR-positive during the rst patient with encephalitis should always raise the possi-

CHAPTER 35
week of initiation of antiviral therapy, but the numbers fell bility of HSV encephalitis. Examples of focal findings
to ~50% by 814 days and to ~21% by >15 days after ini- include: (1) areas of increased signal intensity in the
tiation of antiviral therapy. frontotemporal, cingulate, or insular regions of the
The sensitivity and specicity of CSF PCR tests for brain on T2-weighted, FLAIR, or diffusion-weighted
viruses other than herpes simplex have not been deni- MRI images (Fig. 35-3); (2) focal areas of low absorp-
tively characterized. Enteroviral CSF PCR appears to tion, mass effect, and contrast enhancement on CT; or

Meningitis, Encephalitis, Brain Abscess, and Empyema

have a sensitivity and specicity of >95%.The specicity (3) periodic focal temporal lobe spikes on a back-
of EBV CSF PCR has not been established. Positive ground of slow or low-amplitude (flattened) activity
EBV CSF PCRs associated with positive tests for other on EEG. Approximately 10% of patients with PCR-
pathogens have been reported and may reect reactiva- documented HSV encephalitis will have a normal
tion of EBV latent in lymphocytes that enter the CNS as MRI, although nearly 80% will have abnormalities in
a result of an unrelated infectious or inammatory
process. In patients with CNS infection due to VZV, CSF
antibody and PCR studies should be considered comple-
mentary, as patients may have evidence of intrathecal
synthesis of VZV-specic antibodies and negative CSF
PCRs. In the case of WNV infection, CSF PCR appears
to be less sensitive (~70% sensitivity) than detection of
WNV-specic CSF IgM, although PCR testing remains
useful in immunocompromised patients who may not
mount an effective anti-WNV antibody response.

CSF Culture
Attempts to culture viruses from the CSF in cases of
encephalitis are often disappointing. Cultures are nega-
tive in >95% of cases of HSV-1 encephalitis.

Serologic Studies and Antigen Detection

The basic approach to the serodiagnosis of viral
encephalitis is identical to that discussed earlier for viral
meningitis. In patients with HSV encephalitis, both anti- FIGURE 35-3
bodies to HSV-1 glycoproteins and glycoprotein anti- Coronal FLAIR magnetic resonance image from a patient
gens have been detected in the CSF. Optimal detection with herpes simplex encephalitis. Note the area of
of both HSV antibodies and antigen typically occurs increased signal in the right temporal lobe (left side of image)
after the rst week of illness, limiting the utility of these conned predominantly to the gray matter. This patient had
tests in acute diagnosis. Nonetheless, HSV CSF antibody predominantly unilateral disease; bilateral lesions are more
testing is of value in selected patients whose illness is common but may be quite asymmetric in their intensity.
 468 the temporal lobe, and an additional 10% in extratem- this virus to produce a CNS vasculopathy rather than a
poral regions. The lesions are typically hyperintense on true encephalitis. Immunocompromised adult patients
T2-weighted images. CT is less sensitive than MRI with CMV often have enlarged ventricles with areas of
and is normal in up to 33% of patients.The addition of increased T2 signal on MRI outlining the ventricles
FLAIR and diffusion-weighted images to the standard and sub-ependymal enhancement on T1-weighted post-
MRI sequences enhances sensitivity. EEG abnormali- contrast images. Table 35-5 highlights specic diagnos-
ties occur in >90% of PCR-documented cases of HSV tic test results in encephalitis that can be useful in clinical
encephalitis; they typically involve the temporal lobes decision-making.
but are often nonspecific. Some patients with HSV
encephalitis have a distinctive EEG pattern consisting
of periodic, stereotyped, sharp-and-slow complexes Brain Biopsy
originating in one or both temporal lobes and repeat-
Brain biopsy is now generally reserved for patients in
ing at regular intervals of 23 s.The periodic complexes
whom CSF PCR studies fail to lead to a specic diag-
are typically noted between the 2nd and 15th day of the
nosis, who have focal abnormalities on MRI, and who
illness and are present in two-thirds of pathologically
continue to show progressive clinical deterioration
proven cases of HSV encephalitis.
despite treatment with acyclovir and supportive therapy.
Signicant MRI abnormalities are found in only
SECTION III

~50% of patients with WNV encephalitis, a frequency

less than that with HSV encephalitis. When present,
DIFFERENTIAL DIAGNOSIS
abnormalities often involve deep brain structures, includ-
ing the thalamus, basal ganglia, and brainstem, rather than Infection by a variety of other organisms can mimic
the cortex and may only be apparent on FLAIR images. viral encephalitis. In studies of biopsy-proven HSV
EEGs typically show generalized slowing that may be encephalitis, common infectious mimics of focal viral
Diseases of the Central Nervous System

more anteriorly prominent rather than the temporally encephalitis included mycobacteria, fungi, rickettsia,
predominant pattern of sharp or periodic discharges Listeria and other bacteria (including Bartonella sp.), and
more characteristic of HSV encephalitis. Patients with Mycoplasma.
VZV encephalitis may show multifocal areas of hemor- Infection caused by the ameba Naegleria fowleri can
rhagic and ischemic infarction reecting the tendency of also cause acute meningoencephalitis (primary amebic

TABLE 35-5
USE OF DIAGNOSTIC TESTS IN ENCEPHALITIS
The best test for WNV encephalitis is the CSF IgM antibody test. The prevalence of positive CSF IgM tests increases by
about 10%/day after illness onset and reaches 7080% by the end of the rst week. Serum WNV IgM can provide evidence
for recent WNV infection, but in the absence of other ndings does not establish the diagnosis of neuroinvasive disease
(meningitis, encephalitis, acute accid paralysis).
Approximately 80% of patients with proven HSV encephalitis have MRI abnormalities involving the temporal lobes.
This percentage likely increases to >90% when FLAIR and DWI MR sequences are also utilized. The absence of temporal
lobe lesions on MR reduces the likelihood of HSV encephalitis and should prompt consideration of other diagnostic
possibilities.
The CSF HSV PCR test may be negative in the rst 72 h of symptoms of HSV encephalitis. A repeat study should be
considered in patients with an initial early negative PCR in whom diagnostic suspicion of HSV encephalitis remains high
and no alternative diagnosis has yet been established.
Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio corrected for breakdown of the blood-brain
barrier) of HSV-specic antibody may be useful in diagnosis of HSV encephalitis in patients in whom only late (>1 week
post-onset) CSF specimens are available and PCR studies are negative. Serum serology alone is of no value in diagnosis
of HSV encephalitis due to the high seroprevalence rate in the general population.
Negative CSF viral cultures are of no value in excluding the diagnosis of HSV or EBV encephalitis.
VZV CSF IgM antibodies may be present in patients with a negative VZV CSF PCR. Both tests should be performed in
patients with suspected VZV CNS disease.
The specicity of EBV CSF PCR for diagnosis of CNS infection is unknown. Positive tests may occur in patients with a CSF
pleocytosis due to other causes. Detection of EBV CSF IgM or intrathecal synthesis of antibody to VCA supports the
diagnosis of EBV encephalitis. Serological studies consistent with acute EBV infection (e.g., IgM VCA, presence of
antibodies against EA but not against EBNA) can help support the diagnosis.

Note: CSF, cerebrospinal uid; IgM, immunoglobulin M; WNV, West Nile virus; HSV, herpes simplex virus; MRI, magnetic resonance imaging;
FLAIR, uid attenuated inversion recovery; DWI, diffusion-weighted imaging; PCR, polymerase chain reaction; EBV, Epstein-Barr virus; VZV,
varicella-zoster virus; CNS, central nervous system; VCA, viral capsid antibody; EA, early antigen; EBNA, EBV-associated nuclear antigen.
meningoencephalitis), whereas that caused by Acanthamoeba weakness with accid tone, reduced or absent reexes, 469
and Balamuthia more typically produces subacute or and relatively preserved sensation. Despite an aggressive
chronic granulomatous amebic meningoencephalitis. World Health Organization poliovirus eradication initia-
Naegleria thrive in warm, iron-rich pools of water, tive, >1200 cases of wild-type poliovirus-induced
including those found in drains, canals, and both natural poliomyelitis have been reported worldwide in 2006,
and human-made outdoor pools. Infection has typically with 88% occurring in Nigeria and India and >20 cases
occurred in immunocompetent children with a history each from Somalia,Afghanistan, and Namibia.There have
of swimming in potentially infected water. The CSF, in been recent small outbreaks of poliomyelitis associated
contrast to the typical prole seen in viral encephalitis, with vaccine strains of virus that have reverted to viru-
often resembles that of bacterial meningitis with a neu- lence through mutation or recombination with circulating
trophilic pleocytosis and hypoglycorrhachia. Motile wild-type enteroviruses in Hispaniola, China, the Philip-
trophozoites can be seen in a wet mount of warm, fresh pines, and Madagascar.
CSF. No effective treatment has been identied, and Epidemiologic factors may provide important clues
mortality approaches 100%. to the diagnosis of viral meningitis or encephalitis. Par-
Encephalitis can be caused by the raccoon pinworm ticular attention should be paid to the season of the
Baylisascaris procyonis. Clues to the diagnosis include a year; the geographic location and travel history; and pos-
history of raccoon exposure, and especially of playing in sible exposure to animal bites or scratches, rodents, and

CHAPTER 35
or eating dirt potentially contaminated with raccoon ticks. Although transmission from the bite of an infected
feces. Most patients are children, and many have an asso- dog remains the most common cause of rabies world-
ciated eosinophilia. wide, in the United States very few cases of dog rabies
Once nonviral causes of encephalitis have been occur, and the most common risk factor is exposure to
excluded, the major diagnostic challenge is to distinguish batsalthough a clear history of a bite or scratch is
HSV from other viruses that cause encephalitis.This dis- often lacking. The classic clinical presentation of

Meningitis, Encephalitis, Brain Abscess, and Empyema

tinction is particularly important because in virtually encephalitic (furious) rabies is of fever, uctuating con-
every other instance the therapy is supportive, whereas sciousness, and autonomic hyperactivity. Phobic spasms
specic and effective antiviral therapy is available for of the larynx, pharynx, neck muscles, and diaphragm can
HSV, and its efcacy is enhanced when it is instituted be triggered by attempts to swallow water (hydrophobia)
early in the course of infection. HSV encephalitis should or by inspiration (aerophobia). Patients may also present
be considered when clinical features suggesting involve- with paralytic (dumb) rabies characterized by acute
ment of the inferomedial frontotemporal regions of the ascending paralysis. Rabies due to the bite of a bat has a
brain are present, including prominent olfactory or gus- different clinical presentation than classic rabies. Patients
tatory hallucinations, anosmia, unusual or bizarre behav- present with focal neurologic decits, myoclonus,
ior or personality alterations, or memory disturbance. seizures, and hallucinations; phobic spasms are not a typ-
HSV encephalitis should always be suspected in patients ical feature. Patients with rabies have a CSF lymphocytic
with focal ndings on clinical examination, neuroimag- pleocytosis and may show areas of increased T2 signal
ing studies, or EEG. The diagnostic procedure of choice abnormality in the brainstem, hippocampus, and hypo-
in these patients is CSF PCR analysis for HSV. A positive thalamus. Diagnosis can be made by nding rabies virus
CSF PCR establishes the diagnosis, and a negative test antigen in brain tissue or in the neural innervation of
dramatically reduces the likelihood of HSV encephalitis hair follicles at the nape of the neck. PCR amplication
(see earlier). of viral nucleic acid from CSF and saliva or tears may
The anatomic distribution of lesions may provide also enable diagnosis. Serology is frequently negative in
an additional clue to diagnosis. Patients with both serum and CSF in the rst week after onset of
rapidly progressive encephalitis and prominent infection, which limits its acute diagnostic utility. No
brainstem signs, symptoms, or neuroimaging abnormalities specic therapy is available, and cases are almost invari-
may be infected by aviviruses (WNV, St. Louis encephali- ably fatal, with isolated survivors having devastating
tis virus, Japanese encephalitis virus), HSV, rabies, or L. neurologic sequelae.
monocytogenes. Signicant involvement of deep gray mat- State public health authorities provide a valuable resource
ter structures, including the basal ganglia and thalamus, concerning isolation of particular agents in individual
should also suggest possible avivirus infection. These regions. Regular updates concerning the number, type and
patients may present clinically with prominent movement distribution of cases of arboviral encephalitis can be found
disorders (tremor, myoclonus) or parkinsonian features. on the CDC and U.S. Geological Survey (USGS) web
Patients with WNV infection can also present with a sites (http://www.cdc.gov and http://diseasemaps.usgs. gov).
poliomyelitis-like acute accid paralysis, as can patients The major noninfectious etiologies that should be
infected with enterovirus 71 and, less commonly, other included in the differential diagnosis of acute encephali-
enteroviruses. Acute flaccid paralysis is characterized by tis are nonvasculitic autoimmune meningoencephalitis,
the acute onset of a lower motor neuron type of which may or may not be associated with serum
 470 antithyroid microsomal and antithyroglobulin antibod- followed by a repeat CSF PCR test. Neonatal HSV CNS
ies; limbic encephalitis associated with antineuronal infection is less responsive to acyclovir therapy than
antibodies; limbic encephalopathy not associated with HSV encephalitis in adults; it is recommended that
cancer; acute disseminated encephalomyelitis and related neonates with HSV encephalitis receive 20 mg/kg of
fulminant demyelinating disorders (Chap. 34); and lym- acyclovir every 8 h (60 mg/kg per day total dose) for a
phoma. Finally, Creutzfeldt-Jakob disease (Chap. 38) can minimum of 21 days.
rarely present in an explosive fashion mimicking viral Prior to intravenous administration, acyclovir should
encephalitis. be diluted to a concentration 7 mg/mL. (A 70-kg per-
son would receive a dose of 700 mg, which would be
diluted in a volume of 100 mL.) Each dose should be
infused slowly over 1 h rather than by rapid or bolus
Treatment: infusion, to minimize the risk of renal dysfunction. Care
VIRAL ENCEPHALITIS should be taken to avoid extravasation or intramuscu-
Specic antiviral therapy should be initiated when lar or subcutaneous administration. The alkaline pH of
appropriate. Vital functions, including respiration and acyclovir can cause local inammation and phlebitis
blood pressure, should be monitored continuously and (9%). Dose adjustment is required in patients with
supported as required. In the initial stages of encephali- impaired renal glomerular ltration. Penetration into
SECTION III

tis, many patients will require care in an intensive care CSF is excellent, with average drug levels ~50% of
unit. Basic management and supportive therapy should serum levels. Complications of therapy include eleva-
include careful monitoring of ICP, uid restriction, avoid- tions in blood urea nitrogen and creatinine levels (5%),
ance of hypotonic intravenous solutions, and suppres- thrombocytopenia (6%), gastrointestinal toxicity (nau-
sion of fever. Seizures should be treated with standard sea, vomiting, diarrhea) (7%), and neurotoxicity
anticonvulsant regimens, and prophylactic therapy (lethargy or obtundation, disorientation, confusion, agi-
Diseases of the Central Nervous System

should be considered in view of the high frequency of tation, hallucinations, tremors, seizures) (1%). Acyclovir
seizures in severe cases of encephalitis. As with all seri- resistance may be mediated by changes in either the
ously ill, immobilized patients with altered levels of con- viral deoxypyrimidine kinase or DNA polymerase. To
sciousness, encephalitis patients are at risk for aspiration date, acyclovir-resistant isolates have not been a signi-
pneumonia, stasis ulcers and decubiti, contractures, cant clinical problem in immunocompetent individuals.
deep venous thrombosis and its complications, and However, there have been reports of clinically virulent
infections of indwelling lines and catheters. acyclovir-resistant HSV isolates from sites outside the
Acyclovir is of benet in the treatment of HSV and CNS in immunocompromised individuals, including
should be started empirically in patients with suspected those with AIDS.
viral encephalitis, especially if focal features are present, Oral antiviral drugs with efcacy against HSV, VZV,
while awaiting viral diagnostic studies. Treatment should and EBV, including acyclovir, famciclovir, and valacy-
be discontinued in patients found not to have HSV clovir, have not been evaluated in the treatment of
encephalitis, with the possible exception of patients with encephalitis either as primary therapy or as supplemen-
severe encephalitis due to VZV or EBV. HSV, VZV, and EBV tal therapy following completion of a course of par-
all encode an enzyme, deoxypyrimidine (thymidine) enteral acyclovir. A National Institute of Allergy and
kinase, that phosphorylates acyclovir to produce Infectious Disease (NIAID)/National Institute of Neuro-
acyclovir-5-monophosphate. Host cell enzymes then logical Disorders and Strokesponsored phase III trial of
phosphorylate this compound to form a triphosphate supplemental oral valacyclovir therapy (2 g tid for
derivative. It is the triphosphate that acts as an antiviral 3 months) following the initial 14- to 21-day course of
agent by inhibiting viral DNA polymerase and by causing therapy with parenteral acyclovir is ongoing in patients
premature termination of nascent viral DNA chains. The with HSV encephalitis; this may help clarify the role of
specicity of action depends on the fact that uninfected extended oral antiviral therapy.
cells do not phosphorylate signicant amounts of acy- Ganciclovir and foscarnet, either alone or in combi-
clovir to acyclovir-5-monophosphate. A second level of nation, are often utilized in the treatment of CMV-
specicity is provided by the fact that the acyclovir related CNS infections, although their efcacy remains
triphosphate is a more potent inhibitor of viral DNA poly- unproven. Cidofovir (see later) may provide an alterna-
merase than of the analogous host cell enzymes. tive in patients who fail to respond to ganciclovir and
Adults should receive a dose of 10 mg/kg of acyclovir foscarnet, although data concerning its use in CMV CNS
intravenously every 8 h (30 mg/kg per day total dose) infections is extremely limited.
for a minimum of 14 days. CSF PCR can be repeated at Ganciclovir is a synthetic nucleoside analogue of
the completion of the 14-day course, with PCR-positive 2-deoxyguanosine. The drug is preferentially phospho-
patients receiving an additional 7 days of treatment, rylated by virus-induced cellular kinases. Ganciclovir
triphosphate acts as a competitive inhibitor of the CMV on clinical response. Patients must be prehydrated with 471
DNA polymerase, and its incorporation into nascent normal saline (e.g., 1 L over 12 h) prior to each dose
viral DNA results in premature chain termination. Fol- and treated with probenecid (e.g., 1 g 3 h before cido-
lowing intravenous administration, CSF concentrations fovir and 1 g 2 and 8 h after cidofovir). Nephrotoxicity is
of ganciclovir are 2570% of coincident plasma levels. common; the dose should be reduced if renal function
The usual dose for treatment of severe neurologic ill- deteriorates.
nesses is 5 mg/kg every 12 h given intravenously at a Intravenous ribavirin (1525 mg/kg per day in
constant rate over 1 h. Induction therapy is followed by divided doses given every 8 h) has been reported to be
maintenance therapy of 5 mg/kg every day for an indef- of benet in isolated cases of severe encephalitis due to
inite period. Induction therapy should be continued California encephalitis (LaCrosse) virus. Ribavirin might
until patients show a decline in CSF pleocytosis and a be of benet for the rare patients, typically infants or
reduction in CSF CMV DNA copy number on quantita- young children, with severe adenovirus or rotavirus
tive PCR testing (where available). Doses should be encephalitis and in patients with encephalitis due to
adjusted in patients with renal insufciency. Treatment LCMV or other arenaviruses. However, clinical trials are
is often limited by the development of granulocytope- lacking. Hemolysis, with resulting anemia, has been the
nia and thrombocytopenia (2025%), which may major side effect limiting therapy.

CHAPTER 35
require reduction in or discontinuation of therapy. Gas- No specic antiviral therapy of proven efcacy is cur-
trointestinal side effects, including nausea, vomiting, rently available for treatment of WNV encephalitis.
diarrhea, and abdominal pain, occur in ~20% of Patients have been treated with -interferon, ribavirin,
patients. Some patients treated with ganciclovir for CMV WNV-specic antisense oligonucleotides, and an Israeli
retinitis have developed retinal detachment, but the IVIg preparation that contains high-titer anti-WNV anti-
causal relationship to ganciclovir treatment is unclear. body (Omr-IgG-am). WNV chimeric vaccines, in which
Valganciclovir is an orally bioavailable prodrug that can WNV envelope and premembrane proteins are inserted

Meningitis, Encephalitis, Brain Abscess, and Empyema

generate high serum levels of ganciclovir, although into the background of another avivirus, are already
studies of its efcacy in treating CMV CNS infections are undergoing human clinical testing for safety and
limited. immunogenicity. Both chimeric and killed inactivated
Foscarnet is a pyrophosphate analogue that inhibits WNV vaccines have been found to be safe and effective
viral DNA polymerases by binding to the pyrophos- in preventing equine WNV infection, and several effec-
phate-binding site. Following intravenous infusion, CSF tive avivirus vaccines are already in human use, creat-
concentrations range from 15 to 100% of coincident ing optimism that a safe and effective human WNV
plasma levels. The usual dose for serious CMV-related vaccine can also be developed.
neurologic illness is 60 mg/kg every 8 h administered by
constant infusion over 1 h. Induction therapy for 1421
days is followed by maintenance therapy (60120 SEQUELAE
mg/kg per day). Induction therapy may need to be
There is considerable variation in the incidence and
extended in patients who fail to show a decline in CSF
severity of sequelae in patients surviving viral encephali-
pleocytosis and a reduction in CSF CMV DNA copy num-
tis. In the case of EEE virus infection, nearly 80% of sur-
ber on quantitative PCR tests (where available). Approxi-
vivors have severe neurologic sequelae. At the other
mately one-third of patients develop renal impairment
extreme are infections due to EBV, California
during treatment, which is reversible following discon-
encephalitis virus, and Venezuelan equine encephalitis
tinuation of therapy in most, but not all, cases. This is
virus, where severe sequelae are unusual. For example,
often associated with elevations in serum creatinine
approximately 515% of children infected with
and proteinuria and is less frequent in patients who
LaCrosse virus have a residual seizure disorder, and 1%
are adequately hydrated. Many patients experience
have persistent hemiparesis. Detailed information about
fatigue and nausea. Reduction in serum calcium, mag-
sequelae in patients with HSV encephalitis treated with
nesium, and potassium occur in ~15% of patients and
acyclovir is available from the NIAID-CASG trials. Of
may be associated with tetany, cardiac rhythm distur-
32 acyclovir-treated patients, 26 survived (81%). Of the
bances, or seizures.
26 survivors, 12 (46%) had no or only minor sequelae, 3
Cidofovir is a nucleotide analogue that is effective in
(12%) were moderately impaired (gainfully employed
treating CMV retinitis and equivalent or better than
but not functioning at their previous level), and 11
ganciclovir in some experimental models of murine
(42%) were severely impaired (requiring continuous
CMV encephalitis, although data concerning its efcacy
supportive care). The incidence and severity of sequelae
in human CMV CNS disease are limited. The usual dose
were directly related to the age of the patient and the
is 5 mg/kg intravenously once weekly for 2 weeks, then
level of consciousness at the time of initiation of ther-
biweekly for two or more additional doses, depending
apy. Patients with severe neurologic impairment
 472 (Glasgow coma score 6) at initiation of therapy either A localized pulmonary fungal infection can then remain
died or survived with severe sequelae. Young patients dormant in the lungs until there is an abnormality in
(<30 years) with good neurologic function at initiation cell-mediated immunity that allows the fungus to reacti-
of therapy did substantially better (100% survival, 62% vate and disseminate to the CNS. The most common
with no or mild sequelae) compared with their older pathogen causing fungal meningitis is C. neoformans.This
counterparts (>30 years; 64% survival, 57% no or mild fungus is found worldwide in soil and bird excreta. H.
sequelae). Some recent studies using quantitative HSV capsulatum is endemic to the Ohio and Mississippi River
CSF PCR tests indicate that clinical outcome following valleys of the central United States and to parts of Cen-
treatment also correlates with the amount of HSV DNA tral and South America. C. immitis is endemic to the
present in CSF at the time of presentation. Many desert areas of the southwest United States, northern
patients with WNV infection have acute sequelae, Mexico, and Argentina.
including cognitive impairment; weakness; and hyper- Syphilis is a sexually transmitted disease that is mani-
or hypokinetic movement disorders, including tremor, fest by the appearance of a painless chancre at the site of
myoclonus, and parkinsonism. Improvement in these inoculation. T. pallidum invades the CNS early in the
symptoms may occur over the subsequent 612 months, course of syphilis. Cranial nerves VII and VIII are most
although detailed clinical studies of the duration and frequently involved.
severity of WNV sequelae are not yet available.
SECTION III

LABORATORY DIAGNOSIS
SUBACUTE MENINGITIS The classic CSF abnormalities in tuberculous meningitis
are as follows: (1) elevated opening pressure, (2) lympho-
CLINICAL MANIFESTATIONS
cytic pleocytosis (10500 cells/L), (3) elevated protein
Patients with subacute meningitis typically have an concentration in the range of 15 g/L (10500 mg/dL),
Diseases of the Central Nervous System

unrelenting headache, stiff neck, low-grade fever, and and (4) decreased glucose concentration in the range of
lethargy for days to several weeks before they present for 1.12.2 mmol/L (2040 mg/dL). The combination of unre-
evaluation. Cranial nerve abnormalities and night sweats lenting headache, stiff neck, fatigue, night sweats, and fever with
may be present. This syndrome overlaps that of chronic a CSF lymphocytic pleocytosis and a mildly decreased glucose
meningitis, discussed in detail in Chap. 36. concentration is highly suspicious for tuberculous meningitis.
The last tube of uid collected at LP is the best tube to
send for a smear for acid-fast bacilli (AFB). If there is a
ETIOLOGY
pellicle in the CSF or a cobweb-like clot on the surface
Common causative organisms include M. tuberculosis, C. of the uid, AFB can best be demonstrated in a smear of
neoformans, H. capsulatum, C. immitis, and T. pallidum. the clot or pellicle. Positive smears are typically reported
Initial infection with M. tuberculosis is acquired by inhala- in only 1040% of cases of tuberculous meningitis in
tion of aerosolized droplet nuclei.Tuberculous meningitis adults. Cultures of CSF take 48 weeks to identify the
in adults does not develop acutely from hematogenous organism and are positive in ~50% of adults. Culture
spread of tubercle bacilli to the meninges. Rather, millet remains the gold standard to make the diagnosis of
seedsize (miliary) tubercles form in the parenchyma of tuberculous meningitis. PCR for the detection of
the brain during hematogenous dissemination of tuber- M. tuberculosis DNA has a sensitivity of 7080% but is
cle bacilli in the course of primary infection. These limited at the present time by a high rate of false-posi-
tubercles enlarge and are usually caseating. The propen- tive results.
sity for a caseous lesion to produce meningitis is deter- The characteristic CSF abnormalities in fungal
mined by its proximity to the subarachnoid space (SAS) meningitis are a mononuclear or lymphocytic pleocyto-
and the rate at which brous encapsulation develops. sis, an increased protein concentration, and a decreased
Subependymal caseous foci cause meningitis via dis- glucose concentration. There may be eosinophils in the
charge of bacilli and tuberculous antigens into the SAS. CSF in C. immitis meningitis. Large volumes of CSF are
Mycobacterial antigens produce an intense inamma- often required to demonstrate the organism on India ink
tory reaction that leads to the production of a thick smear or grow the organism in culture. If spinal uid
exudate that lls the basilar cisterns and surrounds the examined by LP on two separate occasions fails to yield
cranial nerves and major blood vessels at the base of the an organism, CSF should be obtained by high-cervical
brain. or cisternal puncture.
Fungal infections are typically acquired by the The cryptococcal polysaccharide antigen test is a
inhalation of airborne fungal spores. The initial highly sensitive and specic test for cryptococcal menin-
pulmonary infection may be asymptomatic or gitis. A reactive CSF cryptococcal antigen test establishes
present with fever, cough, sputum production, and chest the diagnosis. The detection of the histoplasma polysac-
pain. The pulmonary infection is often self-limited. charide antigen in CSF establishes the diagnosis of a
fungal meningitis but is not specic for meningitis due monotherapy or intravenous amphotericin B (0.50.7 473
to H. capsulatum. It may be falsely positive in coccid- mg/kg per day) for >4 weeks. Intrathecal amphotericin B
ioidal meningitis. The CSF complement xation anti- (0.250.75 mg/d three times weekly) may be required to
body test is reported to have a specicity of 100% and a eradicate the infection. Lifelong therapy with ucona-
sensitivity of 75% for coccidioidal meningitis. zole (200400 mg daily) is recommended to prevent
The diagnosis of syphilitic meningitis is made when a relapse. AmBisome (5 mg/kg per day) or amphotericin B
reactive serum treponemal test [uorescent treponemal lipid complex (5 mg/kg per day) can be substituted for
antibody absorption test (FTA-ABS) or microhemag- amphotericin B in patients who have or who develop
glutination-T. pallidum (MHA-TP)] is associated with a signicant renal dysfunction. The most common com-
CSF lymphocytic or mononuclear pleocytosis and an plication of fungal meningitis is hydrocephalus. Patients
elevated protein concentration, or when the CSF VDRL who develop hydrocephalus should receive a CSF diver-
(Venereal Disease Research Laboratory) is positive. A sion device. A ventriculostomy can be used until CSF
reactive CSF FTA-ABS is not denitive evidence of fungal cultures are sterile, at which time the ventricu-
neurosyphilis.The CSF FTA-ABS can be falsely positive lostomy is replaced by a ventriculoperitoneal shunt.
from blood contamination. A negative CSF VDRL does Syphilitic meningitis is treated with aqueous peni-
not rule out neurosyphilis. A negative CSF FTA-ABS or cillin G in a dose of 34 million units intravenously
MHA-TP rules out neurosyphilis.

CHAPTER 35
every 4 h for 1014 days. An alternative regimen is
2.4 million units of procaine penicillin G intramuscu-
larly daily with 500 mg of oral probenecid four times
Treatment: daily for 1014 days. Either regimen is followed with
SUBACUTE MENINGITIS 2.4 million units of benzathine penicillin G intramuscu-
Empirical therapy of tuberculous meningitis is often ini- larly once a week for 3 weeks. The standard criterion for
tiated on the basis of a high index of suspicion without treatment success is reexamination of the CSF. The

Meningitis, Encephalitis, Brain Abscess, and Empyema

adequate laboratory support. Initial therapy is a combi- CSF should be reexamined at 6-month intervals for
nation of isoniazid (300 mg/d), rifampin (10 mg/kg per 2 years. The cell count is expected to normalize within
day), pyrazinamide (30 mg/kg per day in divided doses), 12 months, and the VDRL titer to decrease by two dilu-
ethambutol (1525 mg/kg per day in divided doses), tions or revert to nonreactive within 2 years of comple-
and pyridoxine (50 mg/d). If the clinical response is tion of therapy. Failure of the CSF pleocytosis to resolve
good, pyrazinamide and ethambutol can be discontin- or an increase in the CSF VDRL titer by two or more
ued after 8 weeks and isoniazid and rifampin continued dilutions requires retreatment.
alone for the next 612 months. A 6-month course of
therapy is acceptable, but therapy should be prolonged
for 912 months in patients who have an inadequate
CHRONIC ENCEPHALITIS
resolution of symptoms of meningitis or who have posi-
tive mycobacterial cultures of CSF during the course of PROGRESSIVE MULTIFOCAL
therapy. Dexamethasone therapy is recommended for LEUKOENCEPHALOPATHY
patients who develop hydrocephalus.
Meningitis due to C. neoformans is treated with Clinical Features and Pathology
amphotericin B (0.7 mg/kg IV per day) or AmBisome Progressive multifocal leukoencephalopathy (PML) is a
(5 mg/kg per day), plus ucytosine (100 mg/kg per day progressive disorder characterized pathologically by
in four divided doses) for 2 weeks or until CSF culture is multifocal areas of demyelination of varying size distrib-
sterile. This treatment is followed by an 810-week uted throughout the brain but sparing the spinal cord
course of uconazole (400800 mg/d PO). If the CSF cul- and optic nerves. In addition to demyelination, there are
ture is sterile after 10 weeks of acute therapy, the dose characteristic cytologic alterations in both astrocytes and
of uconazole is decreased to 200 mg/d for 6 months to oligodendrocytes. Astrocytes are enlarged and contain
a year. Patients with HIV infection may require indenite hyperchromatic, deformed, and bizarre nuclei and fre-
maintenance therapy. Meningitis due to H. capsulatum is quent mitotic gures. Oligodendrocytes have enlarged,
treated with amphotericin B (0.71.0 mg/kg per day) for densely staining nuclei that contain viral inclusions
412 weeks. A total dose of 30 mg/kg is recommended. formed by crystalline arrays of JC virus (JCV) particles.
Therapy with amphotericin B is not discontinued until Patients often present with visual decits (45%), typically
fungal cultures are sterile. After completing a course of a homonymous hemianopia; mental impairment (38%)
amphotericin B, maintenance therapy with itraconazole (dementia, confusion, personality change); weakness,
200 mg twice daily is initiated and continued for at least including hemi- or monoparesis; and ataxia. Seizures
6 months to a year. C. immitis meningitis is treated with occur in ~20% of patients, predominantly in those with
either high-dose uconazole (1000 mg daily) as lesions abutting the cortex.
 474 Almost all patients have an underlying immunosup- changes, since both antigen and genomic material have
pressive disorder. In recent series, the most common asso- been found in the brains of normal patients.
ciated conditions were AIDS (80%), hematologic malig- Serologic studies are of no utility in diagnosis due to
nancies (13%), transplant recipients (5%), and chronic high basal seroprevalence level (>80%).
inammatory diseases (2%). It has been estimated that up
to 5% of AIDS patients will develop PML. There have
been nearly 2 dozen cases of PML occurring in patients
Treatment:
being treated for multiple sclerosis and inammatory
PROGRESSIVE MULTIFOCAL LEUKOEN-
bowel disease with natalizumab, a humanized mono- CEPHALOPATHY
clonal antibody that inhibits lymphocyte trafcking into
CNS and bowel mucosa by binding to 4 integrins. Risk No effective therapy for PML is available. Intravenous
in these patients has been estimated at 1 PML case per and/or intrathecal cytarabine were not shown to be
1000 treated patients after a mean of 18 months of ther- of benet in a randomized controlled trial in HIV-
apy. The basic clinical and diagnostic features are similar associated PML. Another randomized controlled trial of
in AIDS and non-AIDSassociated PML. cidofovir in HIV-associated PML also failed to show sig-
nicant benet. Some patients with HIV-associated PML
have shown disease stabilization and, in rare cases,
Diagnostic Studies
SECTION III

improvement associated with improvement in their

The diagnosis of PML is frequently suggested by MRI. immune status following institution of HAART. In HIV-
MRI reveals multifocal asymmetric, coalescing white positive patients treated with HAART, 1-year survival is
matter lesions located periventricularly, in the centrum ~50%, although up to 80% of survivors may have signi-
semiovale, in the parietal-occipital region, and in the cant neurologic sequelae. HIV-positive patients with
cerebellum.These lesions have increased signal on T2 and higher CD4 counts (>300 mm3) and low or nonde-
tectable HIV viral loads have a better prognosis than
Diseases of the Central Nervous System

FLAIR images and decreased signal on T1-weighted

images. PML lesions are classically nonenhancing (90%) those with lower CD4 counts and higher viral loads.
but may rarely show ring enhancement, especially in
more immunocompetent patients. PML lesions are not
typically associated with edema or mass effect. CT scans, SUBACUTE SCLEROSING
which are less sensitive than MRI for the diagnosis of PANENCEPHALITIS (SSPE)
PML, often show hypodense nonenhancing white mat- SSPE is a rare chronic, progressive demyelinating disease
ter lesions. of the CNS associated with a chronic nonpermissive
The CSF is typically normal, although mild elevation infection of brain tissue with measles virus. The fre-
in protein and/or IgG may be found. Pleocytosis occurs quency has been estimated at 1 in 100,000500,000
in <25% of cases, is predominantly mononuclear, and measles cases. An average of ve cases per year are
rarely exceeds 25 cells/L. PCR amplication of JCV reported in the United States. The incidence has
DNA from CSF has become an important diagnostic declined dramatically since the introduction of a measles
tool. The presence of a positive CSF PCR for JCV vaccine. Most patients give a history of primary measles
DNA in association with typical MRI lesions in the infection at an early age (2 years), which is followed
appropriate clinical setting is diagnostic of PML, reect- after a latent interval of 68 years by the development of
ing the assays relatively high specicity (92100%); progressive neurologic disorder. Some 85% of patients
however, sensitivity is variable. In HIV-negative patients are between 5 and 15 years of age at diagnosis. Initial
and HIV-positive patients not receiving highly active manifestations include poor school performance and
antiviral therapy (HAART), sensitivity is likely 7090%. mood and personality changes. Typical signs of a CNS
In HAART-treated patients, sensitivity may be closer to viral infection, including fever and headache, do not
60%, reecting the lower JCV CSF viral load in this rel- occur. As the disease progresses, patients develop pro-
atively more immunocompetent group. Studies with gressive intellectual deterioration, focal and/or general-
quantitative JCV CSF PCR indicate that patients with ized seizures, myoclonus, ataxia, and visual disturbances.
low JCV loads (<100 copies/L) have a generally better In the late stage of the illness, patients are unresponsive,
prognosis than those with higher viral loads. Patients quadriparetic, and spastic, with hyperactive tendon
with negative CSF PCR studies may require brain reexes and extensor plantar responses.
biopsy for denitive diagnosis. In biopsy or necropsy
specimens of brain, JCV antigen and nucleic acid can be
detected by immunocytochemistry, in situ hybridization, Diagnostic Studies
or PCR amplication. Detection of JCV antigen or MRI is often normal early, although areas of increased T2
genomic material should only be considered diagnostic signal develop in the white matter of the brain and brain-
of PML if accompanied by characteristic pathologic stem as disease progresses. The EEG may initially show
only nonspecic slowing, but with disease progression, ~0.31.3/100,000 persons per year. Predisposing condi- 475
patients develop a characteristic periodic pattern with tions include otitis media and mastoiditis, paranasal
bursts of high-voltage, sharp, slow waves every 38 s, fol- sinusitis, pyogenic infections in the chest or other body
lowed by periods of attenuated (at) background. The sites, penetrating head trauma or neurosurgical proce-
CSF is acellular with a normal or mildly elevated protein dures, and dental infections. In immunocompetent indi-
concentration and a markedly elevated gamma globulin viduals the most important pathogens are Streptococcus
level (>20% of total CSF protein). CSF antimeasles anti- spp. [anaerobic, aerobic, and viridans (40%)], Enterobac-
body levels are invariably elevated, and oligoclonal teriaceae [Proteus spp., E. coli sp., Klebsiella spp. (25%)],
antimeasles antibodies are often present. Measles virus can anaerobes [e.g., Bacteroides spp., Fusobacterium spp. (30%)],
be cultured from brain tissue using special cocultivation and staphylococci (10%). In immunocompromised hosts
techniques.Viral antigen can be identied immunocyto- with underlying HIV infection, organ transplantation,
chemically, and viral genome can be detected by in situ cancer, or immunosuppressive therapy, most brain
hybridization or PCR amplication. abscesses are caused by Nocardia spp., Toxoplasma gondii,
Aspergillus spp., Candida spp., and C. neoformans. In Latin
America and in immigrants from Latin America, the
most common cause of brain abscess is Taenia solium
Treatment: (neurocysticercosis). In India and the Far East, mycobac-

CHAPTER 35
SUBACUTE SCLEROSING terial infection (tuberculoma) remains a major cause of
PANENCEPHALITIS focal CNS mass lesions.
No denitive therapy for SSPE is available. Treatment
with isoprinosine (Inosiplex, 100 mg/kg per day), alone ETIOLOGY
or in combination with intrathecal or intraventricular
alpha interferon, has been reported to prolong survival A brain abscess may develop (1) by direct spread from a

Meningitis, Encephalitis, Brain Abscess, and Empyema

and produce clinical improvement in some patients but contiguous cranial site of infection, such as paranasal
has never been subjected to a controlled clinical trial. sinusitis, otitis media, mastoiditis, or dental infection; (2)
following head trauma or a neurosurgical procedure; or
(3) as a result of hematogenous spread from a remote
site of infection. In up to 25% of cases, no obvious pri-
PROGRESSIVE RUBELLA mary source of infection is apparent (cryptogenic brain
PANENCEPHALITIS abscess).
This is an extremely rare disorder that primarily affects Approximately one-third of brain abscesses are associ-
males with congenital rubella syndrome, although isolated ated with otitis media and mastoiditis, often with an
cases have been reported following childhood rubella.After associated cholesteatoma. Otogenic abscesses occur pre-
a latent period of 819 years, patients develop progressive dominantly in the temporal lobe (5575%) and cerebel-
neurologic deterioration. The manifestations are similar to lum (2030%). In some series, up to 90% of cerebellar
those seen in SSPE. CSF shows a mild lymphocytic pleo- abscesses are otogenic. Common organisms include strep-
cytosis, slightly elevated protein concentration, markedly tococci, Bacteroides spp., Pseudomonas spp., Haemophilus
increased gamma globulin, and rubella virusspecic oligo- spp., and Enterobacteriaceae. Abscesses that develop as a
clonal bands. No therapy is available. Universal prevention result of direct spread of infection from the frontal, eth-
of both congenital and childhood rubella through the use moidal, or sphenoidal sinuses and those that occur due
of the available live attenuated rubella vaccine would be to dental infections are usually located in the frontal
expected to eliminate the disease. lobes. Approximately 10% of brain abscesses are associ-
ated with paranasal sinusitis, and this association is par-
ticularly strong in young males in their second and third
BRAIN ABSCESS decades of life. The most common pathogens in brain
abscesses associated with paranasal sinusitis are strepto-
DEFINITION
cocci (especially S. milleri), Haemophilus spp., Bacteroides
A brain abscess is a focal, suppurative infection within spp., Pseudomonas spp., and S. aureus. Dental infections
the brain parenchyma, typically surrounded by a vascu- are associated with ~2% of brain abscesses, although it is
larized capsule. The term cerebritis is often employed to often suggested that many cryptogenic abscesses are in
describe a nonencapsulated brain abscess. fact due to dental infections. The most common
pathogens in this setting are streptococci, staphylococci,
Bacteroides spp., and Fusobacterium spp.
EPIDEMIOLOGY
Hematogenous abscesses account for ~25% of brain
A bacterial brain abscess is a relatively uncom- abscesses. Hematogenous abscesses are often multiple,
mon intracranial infection, with an incidence of and multiple abscesses often (50%) have a hematogenous
 476 origin.These abscesses show a predilection for the terri- with the appearance of a ring-enhancing capsule on neu-
tory of the middle cerebral artery (i.e., posterior frontal roimaging studies. The nal stage, late capsule formation
or parietal lobes). Hematogenous abscesses are often (day 14 and beyond), is dened by a well-formed necrotic
located at the junction of the gray and white matter and center surrounded by a dense collagenous capsule. The
are often poorly encapsulated. The microbiology of surrounding area of cerebral edema has regressed, but
hematogenous abscesses is dependent on the primary marked gliosis with large numbers of reactive astrocytes
source of infection. For example, brain abscesses that has developed outside the capsule. This gliotic process
develop as a complication of infective endocarditis are may contribute to the development of seizures as a seque-
often due to viridans streptococci or S. aureus. Abscesses lae of brain abscess.
associated with pyogenic lung infections such as lung
abscess or bronchiectasis are often due to streptococci,
CLINICAL PRESENTATION
staphylococci, Bacteroides spp., Fusobacterium spp., or
Enterobacteriaceae.Abscesses that follow penetrating head A brain abscess typically presents as an expanding
trauma or neurosurgical procedures are frequently due to intracranial mass lesion rather than as an infectious
methicillin-resistant S. aureus (MRSA), S. epidermidis, process. Although the evolution of signs and symptoms
Enterobacteriaceae, Pseudomonas spp., and Clostridium is extremely variable, ranging from hours to weeks or
spp. Enterobacteriaceae and P. aeruginosa are important even months, most patients present to the hospital
SECTION III

causes of abscesses associated with urinary sepsis. Con- 1112 days following onset of symptoms. The classic
genital cardiac malformations that produce a right-to- clinical triad of headache, fever, and a focal neurologic
left shunt, such as tetralogy of Fallot, patent ductus arte- decit is present in <50% of cases. The most common
riosus, and atrial and ventricular septal defects, allow symptom in patients with a brain abscess is headache,
bloodborne bacteria to bypass the pulmonary capillary occurring in >75% of patients. The headache is often
bed and reach the brain. Similar phenomena can occur characterized as a constant, dull, aching sensation, either
Diseases of the Central Nervous System

with pulmonary arteriovenous malformations. The hemicranial or generalized, and it becomes progressively
decreased arterial oxygenation and saturation from the more severe and refractory to therapy. Fever is present in
right-to-left shunt and polycythemia may cause focal only 50% of patients at the time of diagnosis, and its
areas of cerebral ischemia, thus providing a nidus for absence should not exclude the diagnosis. The new
microorganisms that bypassed the pulmonary circulation onset of focal or generalized seizure activity is a present-
to multiply and form an abscess. Streptococci are the ing sign in 1535% of patients. Focal neurologic decits
most common pathogens in this setting. including hemiparesis, aphasia, or visual eld defects are
part of the initial presentation in >60% of patients.
The clinical presentation of a brain abscess depends
PATHOGENESIS AND HISTOPATHOLOGY
on its location, the nature of the primary infection if
Results of experimental models of brain abscess forma- present, and the level of the ICP. Hemiparesis is the most
tion suggest that for bacterial invasion of brain common localizing sign of a frontal lobe abscess. A tem-
parenchyma to occur, there must be preexisting or con- poral lobe abscess may present with a disturbance of
comitant areas of ischemia, necrosis, or hypoxia in brain language (dysphasia) or an upper homonymous quad-
tissue.The intact brain parenchyma is relatively resistant to rantanopia. Nystagmus and ataxia are signs of a cerebel-
infection. Once bacteria have established infection, brain lar abscess. Signs of raised ICPpapilledema, nausea and
abscess frequently evolves through a series of stages, inu- vomiting, and drowsiness or confusioncan be the
enced by the nature of the infecting organism and by the dominant presentation of some abscesses, particularly
immunocompetence of the host.The early cerebritis stage those in the cerebellum. Meningismus is not present
(days 13) is characterized by a perivascular inltration of unless the abscess has ruptured into the ventricle or the
inammatory cells, which surround a central core of infection has spread to the subarachnoid space.
coagulative necrosis. Marked edema surrounds the lesion
at this stage. In the late cerebritis stage (days 49), pus for-
DIAGNOSIS
mation leads to enlargement of the necrotic center, which
is surrounded at its border by an inammatory inltrate Diagnosis is made by neuroimaging studies. MRI
of macrophages and broblasts. A thin capsule of brob- (Fig. 35-4) is better than CT for demonstrating
lasts and reticular bers gradually develops, and the sur- abscesses in the early (cerebritis) stages and is superior
rounding area of cerebral edema becomes more distinct to CT for identifying abscesses in the posterior fossa.
than in the previous stage. The third stage, early capsule Cerebritis appears on MRI as an area of low-signal
formation (days 1013), is characterized by the formation intensity on T1-weighted images with irregular post-
of a capsule that is better developed on the cortical than gadolinium enhancement and as an area of increased
on the ventricular side of the lesion. This stage correlates signal intensity on T2-weighted images. Cerebritis is
 477

A B C

FIGURE 35-4
Pneumococcal brain abscess. Note that the abscess wall gadolinium administration on the coronal T1-weighted image
has hyperintense signal on the axial T1-weighted MRI (C). The abscess is surrounded by a large amount of vaso-
(A, black arrow), hypointense signal on the axial proton den- genic edema and has a small daughter abscess (C, white

CHAPTER 35
sity images (B, black arrow), and enhances prominently after arrow). (Courtesy of Joseph Lurito, MD; with permission.)

often not visualized by CT scan but, when present, of cases overall but may be positive in >85% of patients
appears as an area of hypodensity. On a contrast- with abscesses due to Listeria.
enhanced CT scan, a mature brain abscess appears as a

Meningitis, Encephalitis, Brain Abscess, and Empyema

focal area of hypodensity surrounded by ring enhance-
DIFFERENTIAL DIAGNOSIS
ment with surrounding edema (hypodensity). On con-
trast-enhanced T1-weighted MRI, a mature brain Conditions that can cause headache, fever, focal neuro-
abscess has a capsule that enhances surrounding a logic signs, and seizure activity include brain abscess,
hypodense center and surrounded by a hypodense area subdural empyema, bacterial meningitis, viral menin-
of edema. On T2-weighted MRI, there is a hyperin- goencephalitis, superior sagittal sinus thrombosis, and
tense central area of pus surrounded by a well-defined acute disseminated encephalomyelitis.When fever is absent,
hypointense capsule and a hyperintense surrounding primary and metastatic brain tumors become the major
area of edema. It is important to recognize that the CT differential diagnosis. Less commonly, cerebral infarction
and MR appearance, particularly of the capsule, may be or hematoma can have an MRI or CT appearance
altered by treatment with glucocorticoids. The distinc- resembling brain abscess.
tion between a brain abscess and other focal CNS
lesions such as primary or metastatic tumors may be
facilitated by the use of diffusion-weighted imaging
sequences on which brain abscesses typically show Treatment:
increased signal and low apparent diffusion coefficient. BRAIN ABSCESS
Microbiologic diagnosis of the etiologic agent is most Optimal therapy of brain abscesses involves a combina-
accurately determined by Grams stain and culture of tion of high-dose parenteral antibiotics and neurosurgi-
abscess material obtained by stereotactic needle aspira- cal drainage. Empirical therapy of community-acquired
tion. Aerobic and anaerobic bacterial cultures and brain abscess in an immunocompetent patient typically
mycobacterial and fungal cultures should be obtained. includes a third-generation cephalosporin (e.g., cefo-
Up to 10% of patients will also have positive blood cul- taxime or ceftriaxone) and metronidazole (see Table 35-1
tures. LP should not be performed in patients with for antibiotic dosages). In patients with penetrating
known or suspected focal intracranial infections such as head trauma or recent neurosurgical procedures, treat-
abscess or empyema; CSF analysis contributes nothing ment should include ceftazidime as the third-generation
to diagnosis or therapy, and LP increases the risk of cephalosporin to enhance coverage of Pseudomonas
herniation. spp. and vancomycin for coverage of staphylococci.
Additional laboratory studies may provide clues to Meropenem plus vancomycin also provides good cov-
the diagnosis of brain abscess in patients with a CNS erage in this setting.
mass lesion. About 50% of patients have a peripheral Aspiration and drainage of the abscess under stereo-
leukocytosis, 60% an elevated ESR, and 80% an elevated tactic guidance are benecial for both diagnosis and
C-reactive protein. Blood cultures are positive in ~10%
 478 therapy. Empirical antibiotic coverage should be modi- NONBACTERIAL CAUSES OF
ed based on the results of Grams stain and culture of
INFECTIOUS FOCAL CNS LESIONS
the abscess contents. Complete excision of a bacterial
abscess via craniotomy or craniectomy is generally ETIOLOGY
reserved for multiloculated abscesses or those in which
stereotactic aspiration is unsuccessful. Neurocysticercosis is the most common parasitic disease
Medical therapy alone is not optimal for treatment of of the CNS worldwide. Humans acquire cysticercosis by
brain abscess and should be reserved for patients the ingestion of food contaminated with the eggs of the
whose abscesses are neurosurgically inaccessible, for parasite T. solium. Toxoplasmosis is a parasitic disease
patients with small (<23 cm) or nonencapsulated caused by T. gondii and acquired from the ingestion of
abscesses (cerebritis), and patients whose condition is undercooked meat and from handling cat feces.
too tenuous to allow performance of a neurosurgical
procedure. All patients should receive a minimum of CLINICAL PRESENTATION
68 weeks of parenteral antibiotic therapy. The role, if
any, of supplemental oral antibiotic therapy following
The most common manifestation of neurocysticercosis
is new-onset partial seizures with or without secondary
completion of a standard course of parenteral therapy
generalization. Cysticerci may develop in the brain
has never been adequately studied.
SECTION III

parenchyma and cause seizures or focal neurologic

In addition to surgical drainage and antibiotic therapy,
decits.When present in the subarachnoid or ventricular
patients should receive prophylactic anticonvulsant ther-
spaces, cysticerci can produce increased ICP by interfer-
apy because of the high risk (~35%) of focal or generalized
ence with CSF ow. Spinal cysticerci can mimic the
seizures. Anticonvulsant therapy is continued for at least 3
presentation of intraspinal tumors. When the cysticerci
months after resolution of the abscess, and decisions
rst lodge in the brain, they frequently cause little in the
regarding withdrawal are then based on the EEG. If the EEG
Diseases of the Central Nervous System

way of an inammatory response. As the cysticercal cyst

is abnormal, anticonvulsant therapy should be continued. If
degenerates, it elicits an inammatory response that may
the EEG is normal, anticonvulsant therapy can be slowly
present clinically as a seizure. Eventually the cyst dies, a
withdrawn, with close follow-up and repeat EEG after the
process that may take several years and is typically asso-
medication has been discontinued.
ciated with resolution of the inammatory response
Glucocorticoids should not be given routinely to
and, often, abatement of seizures.
patients with brain abscesses. Intravenous dexametha-
Primary toxoplasma infection is often asymptomatic.
sone therapy (10 mg every 6 h) is usually reserved for
However, during this phase parasites may spread to the
patients with substantial periabscess edema and asso-
CNS, where they become latent. Reactivation of CNS
ciated mass effect and increased ICP. Dexamethasone
infection is almost exclusively associated with immuno-
should be tapered as rapidly as possible to avoid
compromised hosts, particularly those with HIV infec-
delaying the natural process of encapsulation of the
tion. During this phase patients present with headache,
abscess.
fever, seizures, and focal neurologic decits.
Serial MRI or CT scans should be obtained on a
monthly or twice-monthly basis to document resolution
of the abscess. More frequent studies (e.g., weekly) are DIAGNOSIS
probably warranted in the subset of patients who are
The lesions of neurocysticercosis are readily visualized
receiving antibiotic therapy alone. A small amount of
by MRI or CT scans. Lesions with viable parasites
enhancement may remain for months after the abscess
appear as cystic lesions. The scolex can often be visu-
has been successfully treated.
alized on MRI. Lesions may appear as contrast-
enhancing lesions surrounded by edema. A very early
sign of cyst death is hypointensity of the vesicular
fluid on T2-weighted images when compared with
CSF. Parenchymal brain calcifications are the most
PROGNOSIS
common finding and evidence that the parasite is no
The mortality of brain abscess has declined in parallel longer viable. MRI findings of toxoplasmosis consist
with the development of enhanced neuroimaging tech- of multiple lesions in the deep white matter, the thala-
niques, improved neurosurgical procedures for stereotac- mus, and basal ganglia and at the gray-white junction
tic aspiration, and improved antibiotics. In modern in the cerebral hemispheres. With contrast administra-
series, the mortality is typically <15%. Signicant seque- tion, the majority of the lesions enhance in a ringed,
lae, including seizures, persisting weakness, aphasia, or nodular, or homogeneous pattern and are surrounded
mental impairment, occur in 20% of survivors. by edema. In the presence of the characteristic
neuroimaging abnormalities of T. gondii infection, Subdural 479
serum IgG antibody to T. gondii should be obtained empyema
and, when positive, the patient should be treated. Thrombosed
veins

Dura mater

Arachnoid
Treatment:
INFECTIOUS FOCAL CNS LESIONS
Anticonvulsant therapy is initiated when the patient with
neurocysticercosis presents with a seizure. There is con-
troversy about whether or not antihelminthic therapy
should be given to all patients. Such therapy does not
necessarily reduce the risk of seizure recurrence. Cys-
ticerci appearing as cystic lesions or as enhancing lesions
in the brain parenchyma or in the subarachnoid space at
the convexity of the cerebral hemispheres should be

CHAPTER 35
treated with anticysticidal therapy. Cysticidal drugs
accelerate the destruction of the parasites, resulting in a
faster resolution of the infection. Albendazole and prazi- FIGURE 35-5
quantel are used in the treatment of neurocysticercosis. Subdural empyema.
Approximately 85% of parenchymal cysts are destroyed
by a single course of albendazole, and ~75% are
destroyed by a single course of praziquantel. The dose of

Meningitis, Encephalitis, Brain Abscess, and Empyema

predisposing condition and typically involves the frontal
albendazole is 15 mg/kg per day in two doses for 8 days.
sinuses, either alone or in combination with the eth-
The dose of praziquantel is 50 mg/kg per day for 15 days,
moid and maxillary sinuses. Sinusitis-associated empyema
although a number of other dosage regimens are also
has a striking predilection for young men, possibly
frequently cited. Antiepileptic therapy can be stopped
reecting sex-related differences in sinus anatomy and
once the follow-up CT scan shows resolution of the
development. It has been suggested that SDE may com-
lesion. Long-term antiepileptic therapy is recommended
plicate 12% of cases of frontal sinusitis severe enough to
when seizures occur after resolution of edema and
require hospitalization. As a consequence of this epi-
resorption or calcication of the degenerating cyst.
demiology, SDE shows an ~3:1 male:female predomi-
CNS toxoplasmosis is treated with a combination of
nance, with 70% of cases occurring in the second and
sulfadiazine, 1.52.0 g orally qid, plus pyrimethamine,
third decades of life. SDE may also develop as a compli-
100 mg orally to load then 75100 mg orally qd, plus
cation of head trauma or neurosurgery. Secondary infec-
folinic acid, 1015 mg orally qd. Folinic acid is added to
tion of a subdural effusion may also result in empyema,
the regimen to prevent megaloblastic anemia.Therapy is
although secondary infection of hematomas, in the
continued until there is no evidence of active disease on
absence of a prior neurosurgical procedure, is rare.
neuroimaging studies, which typically takes at least
6 weeks, and then the dose of sulfadiazine is reduced to
24 g/d and pyrimethamine to 50 mg/d. Clindamycin
ETIOLOGY
plus pyrimethamine is an alternative therapy for patients
who cannot tolerate sulfadiazine, but the combination of Aerobic and anaerobic streptococci, staphylococci,
pyrimethamine and sulfadiazine is more effective. Enterobacteriaceae, and anaerobic bacteria are the most
common causative organisms of sinusitis-associated
SDE. Staphylococci and gram-negative bacilli are often
the etiologic organisms when SDE follows neurosurgi-
SUBDURAL EMPYEMA cal procedures or head trauma. Up to one-third of cases
are culture-negative, possibly reecting difculty in
A subdural empyema (SDE) is a collection of pus
obtaining adequate anaerobic cultures.
between the dura and arachnoid membranes (Fig. 35-5).

EPIDEMIOLOGY PATHOPHYSIOLOGY
SDE is a rare disorder that accounts for 1525% of focal Sinusitis-associated SDE develops as a result of either retro-
suppurative CNS infections. Sinusitis is the most common grade spread of infection from septic thrombophlebitis of
 480 the mucosal veins draining the sinuses or contiguous spread infarction (see earlier). In untreated SDE, the increasing
of infection to the brain from osteomyelitis in the posterior mass effect and increase in ICP cause progressive deterio-
wall of the frontal or other sinuses. SDE may also develop ration in consciousness, leading ultimately to coma.
from direct introduction of bacteria into the subdural space
as a complication of a neurosurgical procedure.The evolu-
DIAGNOSIS
tion of SDE can be extremely rapid because the subdural
space is a large compartment that offers few mechanical MRI (Fig. 35-6) is superior to CT in identifying SDE
barriers to the spread of infection. In patients with sinusitis- and any associated intracranial infections.The administra-
associated SDE, suppuration typically begins in the upper tion of gadolinium greatly improves diagnosis by
and anterior portions of one cerebral hemisphere and then enhancing the rim of the empyema and allowing the
extends posteriorly. SDE is often associated with other empyema to be clearly delineated from the underlying
intracranial infections, including epidural empyema (40%), brain parenchyma. Cranial MRI is also extremely valu-
cortical thrombophlebitis (35%), and intracranial abscess or able in identifying sinusitis, other focal CNS infections,
cerebritis (>25%). Cortical venous infarction produces cortical venous infarction, cerebral edema, and cerebritis.
necrosis of underlying cerebral cortex and subcortical white CT may show a crescent-shaped hypodense lesion over
matter, with focal neurologic decits and seizures (see later). one or both hemispheres or in the interhemispheric s-
sure. Frequently the degree of mass effect, exemplied by
SECTION III

midline shift, ventricular compression, and sulcal efface-

CLINICAL PRESENTATION
ment, is far out of proportion to the mass of the SDE.
A patient with SDE typically presents with fever and a CSF examination should be avoided in patients with
progressively worsening headache. The diagnosis of SDE known or suspected SDE as it adds no useful informa-
should always be suspected in a patient with known tion and is associated with the risk of cerebral herniation.
sinusitis who presents with new CNS signs or symptoms.
Diseases of the Central Nervous System

Patients with underlying sinusitis frequently have symp-

DIFFERENTIAL DIAGNOSIS
toms related to this infection. As the infection progresses,
focal neurologic decits, seizures, nuchal rigidity, and The differential diagnosis of the combination of
signs of increased ICP commonly occur. Headache is the headache, fever, focal neurologic signs, and seizure activity
most common complaint at the time of presentation; ini- that progresses rapidly to an altered level of consciousness
tially it is localized to the side of the subdural infection, includes subdural hematoma, bacterial meningitis, viral
but then it becomes more severe and generalized. Con- encephalitis, brain abscess, superior sagittal sinus thrombo-
tralateral hemiparesis or hemiplegia is the most common sis, and acute disseminated encephalomyelitis. The pres-
focal neurologic decit and can occur from the direct ence of nuchal rigidity is unusual with brain abscess or
effects of the SDE on the cortex or as a consequence of epidural empyema and should suggest the possibility of
venous infarction. Seizures begin as partial motor seizures SDE when associated with signicant focal neurologic
that then become secondarily generalized. Seizures signs and fever. Patients with bacterial meningitis also
may be due to the direct irritative effect of the SDE on have nuchal rigidity but do not typically have focal
the underlying cortex or result from cortical venous decits of the severity seen with SDE.

A B C
FIGURE 35-6
Subdural empyema. There is marked enhancement of the images (A, B) but markedly hyperintense on the proton
dura and leptomeninges (A, B, straight arrows) along the left densityweighted (C, curved arrow) image. (Courtesy of
medial hemisphere. The pus is hypointense on T1-weighted Joseph Lurito, MD; with permission.)
 infections. A cranial epidural abscess develops as a compli- 481
Treatment: cation of a craniotomy or compound skull fracture or as a
SUBDURAL EMPYEMA result of spread of infection from the frontal sinuses, mid-
SDE is a medical emergency. Emergent neurosurgical dle ear, mastoid, or orbit. An epidural abscess may develop
evacuation of the empyema, either through burr-hole contiguous to an area of osteomyelitis, when craniotomy is
drainage or craniotomy, is the denitive step in the man- complicated by infection of the wound or bone ap, or as
agement of this infection. Empirical antimicrobial ther- a result of direct infection of the epidural space. Infection
apy should include a combination of a third-generation in the frontal sinus, middle ear, mastoid, or orbit can reach
cephalosporin (e.g., cefotaxime or ceftriaxone), van- the epidural space through retrograde spread of infection
comycin, and metronidazole (Table 35-1 for dosages). from septic thrombophlebitis in the emissary veins that
Parenteral antibiotic therapy should be continued for a drain these areas or by way of direct spread of infection
minimum of 4 weeks. Specic diagnosis of the etiologic through areas of osteomyelitis. Unlike the subdural space,
organisms is made based on Grams stain and culture of the epidural space is really a potential rather than an actual
uid obtained via either burr holes or craniotomy; the compartment.The dura is normally tightly adherent to the
initial empirical antibiotic coverage can be modied inner skull table, and infection must dissect the dura away
accordingly. from the skull table as it spreads. As a result, epidural
abscesses are often smaller than SDEs. Cranial epidural

CHAPTER 35
abscesses, unlike brain abscesses, only rarely result from
hematogenous spread of infection from extracranial pri-
PROGNOSIS
mary sites.The bacteriology of a cranial epidural abscess is
Prognosis is inuenced by the level of consciousness of similar to that of SDE (see earlier).The etiologic organisms
the patient at the time of hospital presentation, the size of an epidural abscess that arises from frontal sinusitis, mid-
of the empyema, and the speed with which therapy is dle ear infections, or mastoiditis are usually streptococci or

Meningitis, Encephalitis, Brain Abscess, and Empyema

instituted. Long-term neurologic sequelae, which include anaerobic organisms. Staphylococci or gram-negative
seizures and hemiparesis, occur in up to 50% of cases. organisms are the usual cause of an epidural abscess that
develops as a complication of craniotomy or compound
EPIDURAL ABSCESS skull fracture.

Cranial epidural abscess is a suppurative infection occur-

ring in the potential space between the inner skull table CLINICAL PRESENTATION
and dura (Fig. 35-7). Patients present with fever (60%), headache (40%),
nuchal rigidity (35%), seizures (10%), and focal decits
ETIOLOGY AND PATHOPHYSIOLOGY (5%). Periorbital edema and Potts puffy tumor, reecting
Epidural abscess is less common than either brain abscess underlying associated frontal bone osteomyelitis, are pre-
or SDE and accounts for <2% of focal suppurative CNS sent in ~40%. In patients with a recent neurosurgical
procedure, wound infection is invariably present, but
other symptoms may be subtle and can include
Epidural abscess
DIAGNOSIS
Cranial MRI is the procedure of choice to demon-
strate a cranial epidural abscess.The sensitivity of CT is
limited by the presence of signal artifacts arising from
the bone of the inner skull table. The CT appearance
of an epidural empyema is that of a lens or crescent-
shaped hypodense extraaxial lesion. On MRI, an epidural
empyema appears as a lentiform or crescent-shaped
fluid collection that is hyperintense compared to CSF
FIGURE 35-7 on T2-weighted images. On T1-weighted images, the
Cranial epidural abscess is a collection of pus between the fluid collection has a signal intensity that is intermedi-
dura and the inner table of the skull. altered mental status ate between that of brain tissue and CSF. Following the
(45%), fever (35%), and headache (20%). The diagnosis administration of gadolinium, a significant enhance-
should also be considered when fever and headache follow ment of the dura is seen on T1-weighted images. In
recent head trauma or occur in the setting of frontal sinusitis, distinction to subdural empyema, signs of mass effect
mastoiditis, or otitis media. or other parenchymal abnormalities are uncommon.
 482 Superior
Treatment: sagittal sinus
EPIDURAL ABSCESS
Transverse
Immediate neurosurgical drainage is indicated. Empiri- sinus
cal antimicrobial therapy, pending the results of Grams
stain and culture of the purulent material obtained at Straight
surgery, should include a combination of a third-genera- sinus
tion cephalosporin, vancomycin, and metronidazole Superior
ophthalmic
(Table 35-1). Ceftazidime or meropenem should be sub-
vein
stituted for ceftriaxone or cefotaxime in neurosurgical
patients. When the organism has been identied, antimi- Inferior
Sigmoid ophthalmic
crobial therapy can be modied accordingly. Antibiotics sinus vein
should be continued for at least 3 weeks after surgical
drainage. Internal
jugular Cavernous
vein sinus

FIGURE 35-8
SECTION III

PROGNOSIS Anatomy of the cerebral venous sinuses.

Mortality is <5% in modern series, and full recovery is

the rule in most survivors.
The superior sagittal sinus drains into the transverse
SUPPURATIVE THROMBOPHLEBITIS sinuses (Fig. 35-8). The transverse sinuses also receive
venous drainage from small veins from both the middle
Diseases of the Central Nervous System

DEFINITION ear and mastoid cells. The transverse sinus becomes the
Suppurative intracranial thrombophlebitis is septic sigmoid sinus before draining into the internal jugular
venous thrombosis of cortical veins and sinuses. This vein. Septic transverse/sigmoid sinus thrombosis can be
may occur as a complication of bacterial meningitis; a complication of acute and chronic otitis media or
SDE; epidural abscess; or infection in the skin of the mastoiditis. Infection spreads from the mastoid air cells
face, paranasal sinuses, middle ear, or mastoid. to the transverse sinus via the emissary veins or by direct
invasion. The cavernous sinuses are inferior to the
superior sagittal sinus at the base of the skull. The cav-
ANATOMY AND PATHOPHYSIOLOGY ernous sinuses receive blood from the facial veins via the
The cerebral veins and venous sinuses have no valves; superior and inferior ophthalmic veins. Bacteria in the
therefore, blood within them can ow in either direc- facial veins enter the cavernous sinus via these veins.
tion. The superior sagittal sinus is the largest of the Bacteria in the sphenoid and ethmoid sinuses can spread
venous sinuses (Fig. 35-8). It receives blood from the to the cavernous sinuses via the small emissary veins.
frontal, parietal, and occipital superior cerebral veins and The sphenoid and ethmoid sinuses are the most com-
the diploic veins, which communicate with the meningeal mon sites of primary infection resulting in septic cav-
veins. Bacterial meningitis is a common predisposing con- ernous sinus thrombosis.
dition for septic thrombosis of the superior sagittal sinus.
The diploic veins, which drain into the superior sagittal
sinus, provide a route for the spread of infection from the CLINICAL MANIFESTATIONS
meninges, especially in cases where there is purulent exu- Septic thrombosis of the superior sagittal sinus presents with
date near areas of the superior sagittal sinus. Infection can headache, fever, nausea and vomiting, confusion, and
also spread to the superior sagittal sinus from nearby SDE focal or generalized seizures. There may be a rapid
or epidural abscess. Dehydration from vomiting, hyperco- development of stupor and coma.Weakness of the lower
agulable states, and immunologic abnormalities, including extremities with bilateral Babinski signs or hemiparesis is
the presence of circulating antiphospholipid antibodies, often present. When superior sagittal sinus thrombosis
also contribute to cerebral venous sinus thrombosis. occurs as a complication of bacterial meningitis, nuchal
Thrombosis may extend from one sinus to another, and rigidity and Kernigs and Brudzinskis signs may be
at autopsy thrombi of different histologic ages can often present.
be detected in several sinuses. Thrombosis of the The oculomotor nerve, the trochlear nerve, the
superior sagittal sinus is often associated with thrombo- abducens nerve, the ophthalmic and maxillary branches
sis of superior cortical veins and small parenchymal of the trigeminal nerve, and the internal carotid artery
hemorrhages. all pass through the cavernous sinus (Fig. 29-4). The
symptoms of septic cavernous sinus thrombosis are fever, antibiotics are usually continued for 6 weeks or until 483
headache, frontal and retroorbital pain, and diplopia. there is radiographic evidence of resolution of thrombo-
The classic signs are ptosis, proptosis, chemosis, and sis. Anticoagulation with dose-adjusted heparin has
extraocular dysmotility due to deficits of cranial been reported to be benecial in patients with aseptic
nerves III, IV, and VI; hyperesthesia of the ophthalmic venous sinus thrombosis; it is also used in the treatment
and maxillary divisions of the fifth cranial nerve and a of septic venous sinus thrombosis complicating bacter-
decreased corneal reflex may be detected. There may ial meningitis in patients who are worsening despite
be evidence of dilated, tortuous retinal veins and antimicrobial therapy and intravenous uids. The pres-
papilledema. ence of a small intracerebral hemorrhage from septic
Headache and earache are the most frequent symp- thrombophlebitis is not an absolute contraindication to
toms of transverse sinus thrombosis. A transverse sinus heparin therapy. Successful management of aseptic
thrombosis may also present with otitis media, sixth venous sinus thrombosis has been reported with
nerve palsy, and retroorbital or facial pain (Gradinegos catheter-directed urokinase therapy and with a combi-
syndrome). Sigmoid sinus and internal jugular vein nation of intrathrombus recombinant tissue plasmino-
thrombosis may present with neck pain. gen activator (rtPA) and intravenous heparin, but there
has not been enough experience with these therapies in

CHAPTER 35
DIAGNOSIS septic venous sinus thrombosis to make recommenda-
tions regarding their use.
The diagnosis of septic venous sinus thrombosis is
suggested by an absent flow void within the affected
venous sinus on MRI and confirmed by magnetic FURTHER READINGS
resonance venography, CT angiogram, or the venous DE GANS J,VAN DE BEEK D: Dexamethasone in adults with bacterial
phase of cerebral angiography. The diagnosis of meningitis. N Engl J Med 347:1549, 2002

Meningitis, Encephalitis, Brain Abscess, and Empyema

thrombophlebitis of intracerebral and meningeal veins HONDA H, WARREN DK: Central nervous system infections: menin-
is suggested by the presence of intracerebral hemor- gitis and brain abscess. Infect Dis Clin North Am 23:609, 2009
rhage but requires cerebral angiography for definitive HSU HE et al: Effect of pneumococcal conjugate vaccine on pneu-
diagnosis. mococcal meningitis. N Engl J Med 360:244, 2009
ROSENSTEIN NE et al: Meningococcal disease. N Engl J Med
344:1378, 2001
STEPHENS DS et al: Epidemic meningitis, meningococcaemia, and
Treatment: Neisseria meningitidis. Lancet 369:2196, 2007
SUPPURATIVE THROMBOPHLEBITIS TUNKEL AR et al: Practice guidelines for the management of bacter-
ial meningitis. Clin Infect Dis 39:1267, 2004
Septic venous sinus thrombosis is treated with antibi- _______ et al: The management of encephalitis: clinical practice
otics, hydration, and removal of infected tissue and guidelines by the Infectious Diseases Society of America. Clin
thrombus in septic lateral or cavernous sinus thrombo- Infect Dis 47:303, 2008
sis. The choice of antimicrobial therapy is based on the TYLER KL: Emerging viral infections of the central nervous system:
bacteria responsible for the predisposing or associated part 1.Arch Neurol 66:939, 2009
condition. Optimal duration of therapy is unknown, but YAO K et al: Detection of human herpesvirus 6 in cerebrospinal uid
of patients with encephalitis.Ann Neurol 65:257, 2009
 CHAPTER 36

CHRONIC AND RECURRENT MENINGITIS

Walter J. Koroshetz I Morton N. Swartz

Clinical Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484

The Immunosuppressed Patient . . . . . . . . . . . . . . . . . . . . . . 492
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492

Chronic inammation of the meninges (pia, arachnoid, cerebral ventricles, exits through narrow foramina into
and dura) can produce profound neurologic disability the subarachnoid space surrounding the brain and spinal
and may be fatal if not successfully treated. The condi- cord, circulates around the base of the brain and over
tion is most commonly diagnosed when a characteristic the cerebral hemispheres, and is resorbed by arachnoid
neurologic syndrome exists for >4 weeks and is associ- villi projecting into the superior sagittal sinus. CSF ow
ated with a persistent inammatory response in the provides a pathway for rapid spread of infectious and
cerebrospinal uid (CSF) (white blood cell count other inltrative processes over the brain, spinal cord,
>5/L). The causes are varied, and appropriate treat- and cranial and spinal nerve roots. Spread from the sub-
ment depends on identication of the etiology. Five arachnoid space into brain parenchyma may occur via
categories of disease account for most cases of chronic the arachnoid cuffs that surround blood vessels that pen-
meningitis: (1) meningeal infections, (2) malignancy, etrate brain tissue (Virchow-Robin spaces).
(3) noninfectious inammatory disorders, (4) chemical
meningitis, and (5) parameningeal infections. Intracranial Meningitis
Nociceptive bers of the meninges are stimulated by the
CLINICAL PATHOPHYSIOLOGY
inammatory process, resulting in headache or neck or
Neurologic manifestations of chronic meningitis back pain. Obstruction of CSF pathways at the foramina
(Table 36-1) are determined by the anatomic location or arachnoid villi may produce hydrocephalus and symp-
of the inammation and its consequences. Persistent toms of raised intracranial pressure (ICP), including
headache with or without stiff neck, hydrocephalus, cra- headache, vomiting, apathy or drowsiness, gait instability,
nial neuropathies, radiculopathies, and cognitive or per- papilledema, visual loss, impaired upgaze, or palsy of the
sonality changes are the cardinal features. These can sixth cranial nerve (CN) (Chap. 29). Cognitive and
occur alone or in combination. When they appear in behavioral changes during the course of chronic menin-
combination, widespread dissemination of the inam- gitis may also result from vascular damage, which may
matory process along CSF pathways has occurred. In similarly produce seizures, stroke, or myelopathy. Inam-
some cases, the presence of an underlying systemic ill- matory deposits seeded via the CSF circulation are often
ness points to a specic agent or class of agents as the prominent around the brainstem and cranial nerves and
probable cause. The diagnosis of chronic meningitis is along the undersurface of the frontal and temporal
usually made when the clinical presentation prompts the lobes. Such cases, termed basal meningitis, often present as
astute physician to examine the CSF for signs of inam- multiple cranial neuropathies, with visual loss (CN II),
mation. CSF is produced by the choroid plexus of the facial weakness (CN VII), hearing loss (CN VIII),

484
TABLE 36-1 infection outside the nervous system. Infectious causes 485
SYMPTOMS AND SIGNS OF CHRONIC MENINGITIS are of major concern in the immunosuppressed patient,
especially in patients with AIDS, in whom chronic
SYMPTOM SIGN
meningitis may present without headache or fever.
Chronic headache / Papilledema Noninfectious inammatory disorders often produce
Neck or back pain Brudzinskis or Kernigs sign systemic manifestations, but meningitis may be the ini-
of meningeal irritation tial manifestation. Carcinomatous meningitis may or
Change in personality Altered mental status may not be accompanied by clinical evidence of the pri-
drowsiness, inattention,
disorientation, memory loss,
mary neoplasm.
frontal release signs (grasp,
suck, snout), perseveration
Facial weakness Peripheral seventh CN palsy
Double vision Palsy of CN III, IV, VI Approach to the Patient:
Visual loss Papilledema, optic atrophy CHRONIC MENINGITIS
Hearing loss Eighth CN palsy
Arm or leg weakness Myelopathy or radiculopathy The occurrence of chronic headache, hydrocephalus,
Numbness in arms Myelopathy or radiculopathy cranial neuropathy, radiculopathy, and/or cognitive

CHAPTER 36
or legs decline in a patient should prompt consideration of a
Sphincter dysfunction Myelopathy or radiculopathy lumbar puncture for evidence of meningeal inam-
Frontal lobe dysfunction mation. On occasion the diagnosis is made when an
(hydrocephalus)
imaging study (CT or MRI) shows contrast enhance-
Clumsiness Ataxia
ment of the meninges, which is always abnormal with
the exception of dural enhancement after lumbar
Note: CN, cranial nerve.
puncture, neurosurgical procedures, or spontaneous

Chronic and Recurrent Meningitis

CSF leakage. Once chronic meningitis is conrmed
by CSF examination, effort is focused on identifying
diplopia (CNs III, IV, and VI), sensory or motor abnor- the cause (Tables 36-2 and 36-3) by (1) further
malities of the oropharynx (CNs IX, X, and XII), analysis of the CSF, (2) diagnosis of an underlying sys-
decreased olfaction (CN I), or facial sensory loss and temic infection or noninfectious inammatory con-
masseter weakness (CN V). dition, or (3) pathologic examination of meningeal
biopsy specimens.
Spinal Meningitis Two clinical forms of chronic meningitis exist. In
the rst, the symptoms are chronic and persistent,
Injury may occur to motor and sensory roots as they tra- whereas in the second there are recurrent, discrete
verse the subarachnoid space and penetrate the meninges. episodes of illness. In the latter group, all symptoms,
These cases present as multiple radiculopathies with com- signs, and CSF parameters of meningeal inammation
binations of radicular pain, sensory loss, motor weakness, resolve completely between episodes without specic
and sphincter dysfunction. Meningeal inammation can therapy. In such patients, the likely etiologies include
encircle the cord, resulting in myelopathy. Patients with herpes simplex virus (HSV) type 2; chemical meningi-
slowly progressive involvement of multiple cranial nerves tis due to leakage into CSF of contents from an epi-
and/or spinal nerve roots are likely to have chronic dermoid tumor, craniopharyngioma, or cholesteatoma;
meningitis. Electrophysiologic testing (electromyography, primary inflammatory conditions, including Vogt-
nerve conduction studies, and evoked response testing) Koyanagi-Harada syndrome, Behets syndrome, sys-
may be helpful in determining whether there is involve- temic lupus erythematosus; and drug hypersensitivity
ment of cranial and spinal nerve roots. with repeated administration of the offending agent.
The epidemiologic history is of considerable
Systemic Manifestations importance and may provide direction for selection
of laboratory studies. Pertinent features include a his-
In some patients, evidence of systemic disease provides
tory of tuberculosis or exposure to a likely case; past
clues to the underlying cause of chronic meningitis. A
travel to areas endemic for fungal infections (the San
careful history and physical examination are essential
Joaquin Valley in California and southwestern states
before embarking on a diagnostic workup, which may
for coccidioidomycosis, midwestern states for histo-
be costly, prolonged, and associated with risk from inva-
plasmosis, southeastern states for blastomycosis);
sive procedures. A complete history of travel, sexual
travel to the Mediterranean region or ingestion of
practice, and exposure to infectious agents should be
imported unpasteurized dairy products (Brucella);
sought. Infectious causes are often associated with fever,
time spent in wooded areas endemic for Lyme disease;
malaise, anorexia, and signs of localized or disseminated
 486 TABLE 36-2
INFECTIOUS CAUSES OF CHRONIC MENINGITIS

HELPFUL RISK FACTORS AND SYSTEMIC

CAUSATIVE AGENT CSF FORMULA DIAGNOSTIC TESTS MANIFESTATIONS

Common Bacterial Causes

Partially treated Mononuclear or mixed CSF culture and Gram stain History consistent with
suppurative meningitis mononuclear- acute bacterial meningitis
polymorphonuclear cells and incomplete treatment
Parameningeal infection Mononuclear or mixed Contrast-enhanced CT or Otitis media, pleuropulmonary
polymorphonuclear- MRI to detect parenchymal, infection, right-to-left
mononuclear cells subdural, epidural, or cardiopulmonary shunt for
sinus infection brain abscess; focal
neurologic signs; neck,
back, ear, or sinus
tenderness
Mycobacterium Mononuclear cells except Tuberculin skin test may be Exposure history; previous
tuberculosis polymorphonuclear cells negative; AFB culture of CSF tuberculous illness;
SECTION III

in early infection (commonly (sputum, urine, gastric immunosuppressed or AIDS;

<500 WBC/L); low CSF contents if indicated); young children; fever,
glucose, high protein tuberculostearic acid detection meningismus, night sweats,
in CSF; identify tubercle miliary TB on x-ray or liver
bacillus on acid-fast stain biopsy; stroke due to arteritis
CSF or protein pellicle;
of PCR
Clinical Manifestations of Neurologic Disease

Lyme disease Mononuclear cells; elevated Serum Lyme antibody titer; History of tick bite or
(Bannwarths syndrome) protein Western blot conrmation; appropriate exposure
Borrelia burgdorferi (patients with syphilis may history; erythema chronicum
have false-positive Lyme titer) migrans skin rash; arthritis,
radiculopathy, Bells palsy,
meningoencephalitismultiple
sclerosis-like syndrome
Syphilis (secondary, Mononuclear cells; CSF VDRL; serum VDRL Appropriate exposure history;
tertiary) Treponema elevated protein (or RPR); uorescent HIV seropositive individuals
pallidum treponemal antibody- at increased risk of aggressive
absorbed (FTA) or MHA-TP; infection; dementia; cerebral
serum VDRL may be negative infarction due to endarteritis
in tertiary syphilis

Uncommon Bacterial Causes

Actinomyces Polymorphonuclear cells Anaerobic culture Parameningeal abscess or sinus
tract (oral or dental focus);
pneumonitis
Nocardia Polymorphonuclear; Isolation may require weeks; Associated brain abscess
occasionally mononuclear weakly acid fast may be present
cells; often low glucose
Brucella Mononuclear cells CSF antibody detection; Intake of unpasteurized dairy
(rarely polymorphonuclear); serum antibody detection products; exposure to goats,
elevated protein; often sheep, cows; fever, arthralgia,
low glucose myalgia, vertebral
osteomyelitis
Whipples disease Mononuclear cells Biopsy of small bowel or Diarrhea, weight loss,
Tropherema whippelii lymph node; CSF PCR for arthralgias, fever; dementia,
T. whippelii; brain and ataxia, paresis,
meningeal biopsy ophthalmoplegia,
(with PAS stain and oculomasticatory myoclonus
EM examination)

Rare Bacterial Causes

Leptospirosis (occasionally if left untreated may last 34 weeks)
TABLE 36-2 (CONTINUED) 487
INFECTIOUS CAUSES OF CHRONIC MENINGITIS

HELPFUL RISK FACTORS AND SYSTEMIC

CAUSATIVE AGENT CSF FORMULA DIAGNOSTIC TESTS MANIFESTATIONS

Fungal Causes
Cryptococcus neoformans Mononuclear cells; count India ink or fungal wet AIDS and immune suppression;
not elevated in some mount of CSF (budding pigeon exposure; skin and
patients with AIDS yeast); blood and urine other organ involvement
cultures; antigen detection due to disseminated infection
in CSF
Coccidioides immitis Mononuclear cells Antibody detection in Exposure history
(sometimes 1020% CSF and serum southwestern US;
eosinophils); often increased virulence
low glucose in dark-skinned races
Candida sp. Polymorphonuclear Fungal stain and culture IV drug abuse; post surgery;
or mononuclear of CSF prolonged intravenous
therapy; disseminated

CHAPTER 36
candidiasis
Histoplasma capsulatum Mononuclear cells; Fungal stain and culture of Exposure historyOhio and
low glucose large volumes of CSF; central Mississippi River
antigen detection in CSF, Valley; AIDS; mucosal
serum, and urine; antibody lesions
detection in serum, CSF
Blastomyces dermatitidis Mononuclear cells Fungal stain and culture Midwestern and southeastern

Chronic and Recurrent Meningitis

of CSF; biopsy and culture USA; usually systemic
of skin, lung lesions; infection; abscesses,
antibody detection draining sinus, ulcers
in serum
Aspergillus sp. Mononuclear or CSF culture Sinusitis; granulocytopenia
polymorphonuclear or immunosuppression
Sporothrix schenckii Mononuclear cells Antibody detection in CSF Traumatic inoculation;
and serum; CSF culture IV drug use; ulcerated
skin lesion

Rare Fungal Causes

Xylohypha (formerly Cladosporium) trichoides and other dark-walled (demateaceous) fungi such as Curvularia, Drechslera;
Mucor, Pseudoallescheria boydii

Protozoal Causes
Toxoplasma gondii Mononuclear cells Biopsy or response to Usually with intracerebral
empirical therapy in clinically abscesses; common in
appropriate context HIV seropositive patients
(including presence of
antibody in serum)
Trypanosomiasis Mononuclear cells, Elevated CSF IgM; Endemic in Africa; chancre,
Trypanosoma gambiense, elevated protein identication of lymphadenopathy;
T. rhodesiense trypanosomes in CSF prominent sleep disorder
and blood smear

Rare Protozoal Causes

Acanthamoeba sp. causing granulomatous amebic encephalitis and meningoencephalitis in immunocompromised
and debilitated individuals

Helminthic Causes
Cysticercosis Mononuclear cells; may Indirect hemagglutination Usually with multiple cysts
(infection with cysts have eosinophils; glucose assay in CSF; ELISA in basal meninges and
of Taenia solium) level may be low immunoblotting in serum hydrocephalus; cerebral
cysts, muscle
calcication
(Continued)
 488 TABLE 36-2 (CONTINUED)
INFECTIOUS CAUSES OF CHRONIC MENINGITIS

HELPFUL RISK FACTORS AND SYSTEMIC

CAUSATIVE AGENT CSF FORMULA DIAGNOSTIC TESTS MANIFESTATIONS

Helminthic Causes
Gnathostoma spinigerum Eosinophils, mononuclear Peripheral eosinophilia History of eating raw sh;
cells common in Thailand and
Japan; subarachnoid
hemorrhage; painful
radiculopathy
Angiostrongylus Eosinophils, mononuclear Recovery of worms History of eating raw shellsh;
cantonensis cells from CSF common in tropical Pacic
regions; often benign
Baylisascaris procyonis Eosinophils, mononuclear Infection follows accidental
(raccoon ascarid) cells ingestion of B. procyonis eggs
from raccoon feces; fatal
meningoencephalitis
SECTION III

Rare Helminthic Causes

Trichinella spiralis (trichinosis); Echinococcus cysts; Schistosoma sp. The former may produce a lymphocytic pleocytosis
whereas the latter two may produce an eosinophilic response in CSF associated with cerebral cysts (Echinococcus) or gran-
ulomatous lesions of brain or spinal cord

Viral Causes
Clinical Manifestations of Neurologic Disease

Mumps Mononuclear cells Antibody in serum No prior mumps or

immunization; may produce
meningoencephalitis; may
persist for 34 weeks
Lymphocytic Mononuclear cells Antibody in serum Contact with rodents or
choriomeningitis their excreta; may persist
for 34 weeks
Echovirus Mononuclear cells; Virus isolation from CSF Congenital hypogammaglobu-
may have low glucose linemia; history of recurrent
meningitis
HIV (acute retroviral Mononuclear cells p24 antigen in serum and HIV risk factors; rash, fever,
syndrome) CSF; high level of HIV viremia lymphadenopathy; lymphope-
nia in peripheral blood;
syndrome may persist long
enough to be considered as
chronic meningitis; or chronic
meningitis may develop in later
stages (AIDS) due to HIV
Herpes simplex (HSV) Mononuclear cells PCR for HSV, CMV DNA; Recurrent meningitis due to
CSF antibody for HSV, EBV HSV-2 (rarely HSV-1) often
associated with genital recur-
rences; EBV associated with
myeloradiculopathy, CMV with
polyradiculopathy

Note: AFB, acid-fast bacillus; CMV, cytomegalovirus; CSF, cerebrospinal uid; CT, computed tomography; EBV, Epstein-Barr virus; ELISA,
enzyme-linked immunosorbent assay; EM, electron microscopy; FTA, uorescent treponemal antibody absorption test; HSV, herpes simplex
virus; MHA-TP, microhemagglutination assayT. pallidum; MRI, magnetic resonance imaging; PAS, periodic acidSchiff; PCR, polymerase chain
reaction; RPR, rapid plasma reagin test; TB, tuberculosis; VDRL, Venereal Disease Research Laboratories test.

exposure to sexually transmitted disease (syphilis); residence in Thailand or Japan (Gnathostoma

exposure of an immunocompromised host to spinigerum), Latin America (Paracoccidioides brasiliiensis),
pigeons and their droppings (Cryptococcus); gardening or the South Pacic (Angiostrongylus cantonensis); rural
(Sporothrix schenkii); ingestion of poorly cooked meat residence and raccoon exposure (Baylisascaris procyo-
or contact with a household cat (Toxoplasma gondii); nis); and residence in Latin America, the Philippines,
TABLE 36-3 489
NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS

HELPFUL RISK FACTORS AND SYSTEMIC

CAUSATIVE AGENT CSF FORMULA DIAGNOSTIC TESTS MANIFESTATIONS

Malignancy Mononuclear cells, Repeated cytologic Metastatic cancer of breast,

elevated protein, examination of large volumes lung, stomach, or pancreas;
low glucose of CSF; CSF exam by melanoma, lymphoma,
polarizing microscopy; leukemia; meningeal
clonal lymphocyte markers; gliomatosis; meningeal
deposits on nerve roots or sarcoma; cerebral
meninges seen on myelogram dysgerminoma; meningeal
or contrast-enhanced MRI; melanoma or B cell lymphoma
meningeal biopsy
Chemical compounds Mononuclear or PMNs, Contrast-enhanced CT scan History of recent injection into
(may cause recurrent low glucose, elevated or MRI Cerebral angiogram the subarachnoid space;
meningitis) protein; xanthochromia to detect aneurysm history of sudden onset of
from subarachnoid headache; recent resection

CHAPTER 36
hemorrhage in week prior of acoustic neuroma or
to presentation with craniopharyngioma;
meningitis epidermoid tumor of brain
or spine, sometimes with
dermoid sinus tract; pituitary
apoplexy
Primary inammation

Chronic and Recurrent Meningitis

CNS sarcoidosis Mononuclear cells; elevated Serum and CSF angiotensin- CN palsy, especially of CN VII;
protein; often low glucose converting enzyme levels; hypothalamic dysfunction,
biopsy of extraneural affected especially diabetes insipidus;
tissues or brain lesion/ abnormal chest radiograph;
meningeal biopsy peripheral neuropathy or
myopathy
Vogt-Koyanagi-Harada Mononuclear cells Recurrent meningoencephalitis
syndrome (recurrent with uveitis, retinal
meningitis) detachment, alopecia,
lightening of eyebrows and
lashes, dysacousia, cataracts,
glaucoma
Isolated granulomatous Mononuclear cells, Angiography or meningeal Subacute dementia; multiple
angiitis of the nervous elevated protein biopsy cerebral infarctions; recent
system zoster ophthalmicus
Systemic lupus Mononuclear or PMNs Anti-DNA antibody, Encephalopathy; seizures;
erythematosus antinuclear antibodies stroke; transverse myelopathy;
rash; arthritis
Behets syndrome Mononuclear or PMNs, Oral and genital aphthous
(recurrent meningitis) elevated protein ulcers; iridocyclitis; retinal
hemorrhages; pathergic
lesions at site of skin
puncture
Chronic benign Mononuclear cells Recovery in 26 months,
lymphocytic meningitis diagnosis by exclusion
Mollarets meningitis Large endothelial cells PCR for herpes; MRI/CT to Recurrent meningitis; exclude
(recurrent meningitis) and PMNs in rst hours, rule out epidermoid tumor HSV-2; rare cases due to
followed by mononuclear or dural cyst HSV-1; occasional case
cells associated with dural cyst
Drug hypersensitivity PMNs; occasionally Exposure to ibuprofen,
mononuclear cells or sulfonamides, isoniazid,
eosinophils tolmetin, ciprooxacin,
phenazopyridine; improvement
after discontinuation of drug;
recurrent episodes with
recurrent exposure
(Continued)
 490 TABLE 36-3 (CONTINUED)
NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS

HELPFUL RISK FACTORS AND SYSTEMIC

CAUSATIVE AGENT CSF FORMULA DIAGNOSTIC TESTS MANIFESTATIONS

Wegeners Mononuclear cells Chest and sinus radiographs;

Associated sinus, pulmonary,
granulomatosis urinalysis; ANCA antibodiesor renal lesions; CN palsies;
in serum skin lesions; peripheral
neuropathy
Other: multiple sclerosis, Sjgrens syndrome, neonatal onset multisystemic inammatory disease (NOMID), and rarer forms
of vasculitis (e.g., Cogans syndrome)

Note: ANCA, anti-neutrophil cytoplasmic antibodies; CN, cranial nerve; CSF, cerebrospinal uid; CT, computed tomography; HSV, herpes sim-
plex virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PMNs, polymorphonuclear cells.

or Southeast Asia when eosinophilic meningitis is CSF ow pathways, elevated ICP can still occur due
SECTION III

present (Taenia solium). to impaired resorption of CSF by arachnoid villi. In

The presence of focal cerebral signs in a patient such patients, lumbar puncture is usually safe, but
with chronic meningitis suggests the possibility of a repetitive or continuous lumbar drainage may be
brain abscess or other parameningeal infection; iden- necessary to prevent relatively sudden death from
tication of a potential source of infection (chronic raised ICP. In some patients, especially those with
draining ear, sinusitis, right-to-left cardiac or pul- cryptococcal meningitis, fatal levels of raised ICP can
Clinical Manifestations of Neurologic Disease

monary shunt, chronic pleuropulmonary infection) occur without enlarged ventricles.

supports this diagnosis. In some cases, diagnosis may Contrast-enhanced MRI or CT studies of the
be established by recognition and biopsy of unusual brain and spinal cord can identify meningeal
skin lesions (Behets syndrome, cryptococcosis, blas- enhancement, parameningeal infections (including
tomycosis, SLE, Lyme disease, IV drug use, sporotri- brain abscess), encasement of the spinal cord (malig-
chosis, trypanosomiasis) or enlarged lymph nodes nancy or inammation and infection), or nodular
(lymphoma, tuberculosis, sarcoid, infection with HIV, deposits on the meninges or nerve roots (malignancy
secondary syphilis, or Whipples disease). A careful or sarcoidosis) (Fig. 36-1). Imaging studies are also
ophthalmologic examination may reveal uveitis useful to localize areas of meningeal disease prior to
[Vogt-Koyanagi-Harada syndrome, sarcoid, or central meningeal biopsy.
nervous system (CNS) lymphoma], keratoconjunc- Cerebral angiography may be indicated in patients
tivitis sicca (Sjgrens syndrome), or iridocyclitis with chronic meningitis and stroke to identify cere-
(Behets syndrome) and is essential to assess visual bral arteritis (granulomatous angiitis, other inamma-
loss from papilledema. Aphthous oral lesions, genital tory arteritides, or infectious arteritis).
ulcers, and hypopyon suggest Behets syndrome.
CEREBROSPINAL FLUID ANALYSIS The
Hepatosplenomegaly suggests lymphoma, sarcoid,
CSF pressure should be measured and samples sent
tuberculosis, or brucellosis. Herpetic lesions in the
for bacterial, fungal, and tuberculous culture;Venereal
genital area or on the thighs suggest HSV-2 infection.
Disease Research Laboratories (VDRL) test; cell
A breast nodule, a suspicious pigmented skin lesion,
count and differential; Grams stain; and measurement
focal bone pain, or an abdominal mass directs atten-
of glucose and protein. Wet mount for fungus and
tion to possible carcinomatous meningitis.
parasites, India ink preparation and culture, culture for
IMAGING Once the clinical syndrome is recog- fastidious bacteria and fungi, assays for cryptococcal
nized as a potential manifestation of chronic menin- antigen and oligoclonal immunoglobulin bands, and
gitis, proper analysis of the CSF is essential. However, cytology should be performed. Other specic CSF
if the possibility of raised ICP exists, a brain imaging tests (Tables 36-2 and 36-3) or blood tests and cul-
study should be performed before lumbar puncture. If tures should be ordered as indicated on the basis of
ICP is elevated because of a mass lesion, brain the history, physical examination, or preliminary CSF
swelling, or a block in ventricular CSF outow results (i.e., eosinophilic, mononuclear, or polymor-
(obstructive hydrocephalus), then lumbar puncture phonuclear meningitis). Rapid diagnosis may be facil-
carries the potential risk of brain herniation. itated by serologic tests and polymerase chain reaction
Obstructive hydrocephalus usually requires direct (PCR) testing to identify DNA sequences in the CSF
ventricular drainage of CSF. In patients with open that are specic for the suspected pathogen.
 from a large volume of CSF. The diagnosis of fungal 491
meningitis may require large volumes of CSF for cul-
ture of sediment. If standard lumbar puncture is unre-
warding, a cervical cisternal tap to sample CSF near to
the basal meninges may be fruitful.
LABORATORY INVESTIGATION In addition to
the CSF examination, an attempt should be made to
uncover pertinent underlying illnesses. Tuberculin
skin test, chest radiograph, urine analysis and culture,
blood count and differential, renal and liver function
tests, alkaline phosphatase, sedimentation rate, antinu-
clear antibody, anti-Ro, anti-La antibody and serum
angiotensin-converting enzyme level are often indi-
cated. Liver or bone marrow biopsy may be diagnos-
FIGURE 36-1 tic in some cases of miliary tuberculosis, disseminated
Primary central nervous system lymphoma. A 24-year-old fungal infection, sarcoidosis, or metastatic malignancy.

CHAPTER 36
man, immunosuppressed due to intestinal lymphangiecta- Abnormalities discovered on chest radiograph or
sia, developed multiple cranial neuropathies. CSF ndings chest CT can be pursued by bronchoscopy or
consisted of 100 lymphocytes/L and a protein of 2.5 g/L transthoracic needle biopsy.
(250 mg/dL); cytology and cultures were negative. Gadolin-
ium-enhanced T1 MRI revealed diffuse, multifocal meningeal MENINGEAL BIOPSY A meningeal biopsy should
enhancement surrounding the brainstem (A), spinal cord and be strongly considered in patients who are severely dis-
cauda equina (B). abled, who need chronic ventricular decompression, or

Chronic and Recurrent Meningitis

whose illness is progressing rapidly.The activities of the
surgeon, pathologist, microbiologist, and cytologist
should be coordinated so that a large enough sample is
In most categories of chronic (not recurrent) obtained and the appropriate cultures and histologic
meningitis, mononuclear cells predominate in the and molecular studies, including electron-microscopic
CSF. When neutrophils predominate after 3 weeks of and PCR studies, are performed. The diagnostic yield
illness, the principal etiologic considerations are of meningeal biopsy can be increased by targeting
Nocardia asteroides, Actinomyces israelii, Brucella, Mycobac- regions that enhance with contrast on MRI or CT.
terium tuberculosis (510% of early cases only), various With current microsurgical techniques, most areas of
fungi (Blastomyces dermatitidis, Candida albicans, Histo- the basal meninges can be accessed for biopsy via a
plasma capsulatum, Aspergillus spp., Pseudallescheria boy- limited craniotomy. In a series from the Mayo Clinic
dii, Cladophialophora bantiana), and noninfectious reported by Cheng et al., MRI demonstrated
causes (SLE, exogenous chemical meningitis). When meningeal enhancement in 47% of patients undergo-
eosinophils predominate or are present in limited ing meningeal biopsy. Biopsy of an enhancing region
numbers in a primarily mononuclear cell response in was diagnostic in 80% of patients; biopsy of nonen-
the CSF, the differential diagnosis includes parasitic hancing regions was diagnostic in only 9%; sarcoid
diseases (A. cantonensis, G. spinigerum, B. procyonis, or (31%) and metastatic adenocarcinoma (25%) were the
Toxocara canis infection, cysticercosis, schistosomiasis, most common conditions identied.Tuberculosis is the
echinococcal disease, T. gondii infection), fungal infec- most common condition identied in many reports
tions (620% eosinophils along with a predominantly from outside the United States.
lymphocyte pleocytosis, particularly with coccidioidal
meningitis), neoplastic disease (lymphoma, leukemia, APPROACH TO THE ENIGMATIC CASE In
metastatic carcinoma), or other inammatory processes approximately one-third of patients, the diagnosis is not
(sarcoidosis, hypereosinophilic syndrome). known despite careful evaluation of CSF and potential
It is often necessary to broaden the number of diag- extraneural sites of disease. A number of the organisms
nostic tests if the initial workup does not reveal the that cause chronic meningitis may take weeks to be
cause. In addition, repeated samples of large volumes identied by cultures. In enigmatic cases several options
of CSF may be required to diagnose certain infectious are available, determined by the extent of the clinical
and malignant causes of chronic meningitis. For decits and rate of progression. It is prudent to wait
instance, lymphomatous or carcinomatous meningitis until cultures are nalized if the patient is asympto-
may be diagnosed by examination of sections cut from matic or symptoms are mild and not progressive.
a cell block formed by spinning down the sediment Unfortunately, in many patients progressive neurologic
 492 deterioration occurs, and rapid treatment is required. commonly presents as intracranial abscesses and may
Ventricular-peritoneal shunts may be placed to relieve also be associated with meningitis. Other important
hydrocephalus, but the risk of disseminating the undi- causes of chronic meningitis in AIDS include infection
agnosed inammatory process into the abdomen must with Cryptococcus, Nocardia, Candida, or other fungi;
be considered. syphilis; and lymphoma (Fig. 36-1). Toxoplasmosis,
cryptococcosis, nocardiosis, and other fungal infections
EMPIRICAL TREATMENT Diagnosis of the are important etiologic considerations in individuals
causative agent is essential because effective therapies with immunodeciency states other than AIDS, includ-
exist for many etiologies of chronic meningitis, but if ing those due to immunosuppressive medications. Because
the condition is left untreated, progressive damage to of the increased risk of chronic meningitis and the
the CNS and cranial nerves and roots is likely to attenuation of clinical signs of meningeal irritation in
occur. Occasionally, empirical therapy must be initi- immunosuppressed individuals, CSF examination should
ated when all attempts at diagnosis fail. In general, be performed for any persistent headache or unex-
empirical therapy in the United States consists of plained change in mental state.
antimycobacterial agents, amphotericin for fungal
infection, or glucocorticoids for noninfectious inam-
matory causes. It is important to direct empirical FURTHER READINGS
SECTION III

therapy of lymphocytic meningitis at tuberculosis, GILDEN DH et al: Herpesvirus infections of the nervous system. Nat
particularly if the condition is associated with hypo- Clin Pract Neurol 3:82, 2007
glycorrhachia and sixth and other CN palsies, since HALPERIN JJ et al: Practice parameter: Treatment of nervous system
untreated disease is fatal in 48 weeks. In the Mayo Lyme disease (an evidence-based review): Report of the Quality
Clinic series, the most useful empirical therapy was Standards Subcomittee of the American Academy of Neurology.
administration of glucocorticoids rather than antitu- Neurology 69:91, 2007
LAN SH et al: Cerebral infarction in chronic meningitis: A compari-
Clinical Manifestations of Neurologic Disease

berculous therapy. Carcinomatous or lymphomatous son of tuberculous meningitis and cryptococcal meningitis. Q J
meningitis may be difcult to diagnose initially, but Med 94(5):247, 2001
the diagnosis becomes evident with time. LILIANG PC et al: Use of ventriculoperitoneal shunts to treat uncon-
trollable intracranial hypertension in patients who have cryptococ-
cal meningitis without hydrocephalus. Clin Infect Dis 34(12):E64,
2002
THE IMMUNOSUPPRESSED PATIENT SHAPIRO WR et al: Treatment modalities for leptomeningeal metas-
tases. Semin Oncol 36:S46 2009
Chronic meningitis is not uncommon in the course of TALATI NJ et al: Spectrum of CNS disease caused by rapidly growing
HIV infection. Pleocytosis and mild meningeal signs mycobacteria. Lancet Infect Dis 8:390, 2008
often occur at the onset of HIV infection, and occa- VINNARD C, Macgregor RR:Tuberculous meningitis in HIV-infected
sionally low-grade meningitis persists. Toxoplasmosis individuals. Curr HIV/AIDS Rep 6:139, 2009
 CHAPTER 37

HIV NEUROLOGY

Anthony S. Fauci I H. Clifford Lane

I Aids Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

I Etiologic Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
Morphology of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Replication Cycle of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
I Pathophysiology and Pathogenesis . . . . . . . . . . . . . . . . . . . 497
Neuropathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
I Clinical Manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Neurologic Disease Caused by HIV . . . . . . . . . . . . . . . . . . . . 498
Specic Neurologic Presentations . . . . . . . . . . . . . . . . . . . . . 505
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

Clinical disease of the nervous system accounts for a signi- condition resolves; the same holds true for category C in
cant degree of morbidity in a high percentage of patients relation to category B.
with HIV infection. Neurologic problems occur through- The denition of AIDS is indeed complex and com-
out the course of infection and may be inammatory, prehensive and was established not for the practical care
demyelinating, or degenerative in nature. The problems of patients, but for surveillance purposes.Thus, the clini-
fall into four basic categories: neurologic disease caused by cian should not focus on whether or not the patient ful-
HIV itself, HIV-related neoplasms, opportunistic infections lls the strict denition of AIDS, but should view HIV
of the nervous system, and adverse effects of medical disease as a spectrum ranging from primary infection,
therapy (Table 37-1). with or without the acute syndrome, to the asympto-
matic stage, to advanced disease.
AIDS CLASSIFICATION
ETIOLOGIC AGENT
The current U.S. Centers for Disease Control and Pre-
vention (CDC) classication system for HIV-infected The etiologic agent of AIDS is HIV, which belongs to
adolescents and adults categorizes persons on the basis the family of human retroviruses (Retroviridae) and the
of clinical conditions associated with HIV infection and subfamily of lentiviruses. Nononcogenic lentiviruses
CD4+ T lymphocyte counts. The system is based on cause disease in other animal species, including sheep,
three ranges of CD4+ T lymphocyte counts and three horses, goats, cattle, cats, and monkeys. The four recog-
clinical categories and is represented by a matrix of nine nized human retroviruses belong to two distinct groups:
mutually exclusive categories (Tables 37-2 and 37-3). the human T lymphotropic viruses (HTLV)-I and
Using this system, any HIV-infected individual with a HTLV-II, which are transforming retroviruses; and the
CD4+ T cell count of <200/L has AIDS by denition, human immunodeciency viruses, HIV-1 and HIV-2,
regardless of the presence of symptoms or opportunistic which cause cytopathic effects either directly or indi-
diseases (Table 37-2). Once individuals have had a rectly.The most common cause of HIV disease through-
clinical condition in category B, their disease classica- out the world, and certainly in the United States, is
tion cannot be reverted back to category A, even if the HIV-1, which comprises several subtypes with different
493
 494 TABLE 37-1 external spikes formed by the two major envelope pro-
NEUROLOGIC DISEASES IN PATIENTS WITH HIV teins, the external gp120 and the transmembrane gp41.
INFECTION The virion buds form the surface of the infected cell
Opportunistic infections Myelopathy
and incorporates a variety of host proteins, including
Toxoplasmosis Vacuolar myelopathy major histocompatibility complex (MHC) class I and II
Cryptococcosis Pure sensory ataxia antigens, into its lipid bilayer. The structure of HIV-1 is
Progressive multifocal Paresthesia/dysesthesia schematically diagrammed in Fig. 37-1B.
leukoencephalopathy Peripheral neuropathy
Cytomegalovirus Acute inammatory demyeli-
Syphilis nating polyneuropathy REPLICATION CYCLE OF HIV
Mycobacterium (Guillain-Barr syndrome)
tuberculosis Chronic inammatory HIV is an RNA virus whose hallmark is the reverse
HTLV-I infection demyelinating polyneu- transcription of its genomic RNA to DNA by the
Neoplasms ropathy (CIDP) enzyme reverse transcriptase. The replication cycle of HIV
Primary CNS lymphoma Mononeuritis multiplex begins with the high-afnity binding of the gp120 pro-
Kaposis sarcoma Distal symmetric tein via a portion of its V1 region near the N terminus
Result of HIV-1 infection polyneuropathy to its receptor on the host cell surface, the CD4 mole-
Aseptic meningitis Myopathy
cule (Fig. 37-2). The CD4 molecule is a 55-kDa pro-
SECTION III

HIV-associated neurocogni-
tive impairment, including tein found predominantly on a subset of T lymphocytes
HIV encephalopathy/ that are responsible for helper function in the immune
AIDS dementia complex system. It is also expressed on the surface of mono-
cytes/macrophages and dendritic/Langerhans cells. Once
gp120 binds to CD4, the gp120 undergoes a confor-
geographic distributions. HIV-2 was rst identied in mational change that facilitates binding to one of a
Diseases of the Central Nervous System

1986 in West African patients and was originally con- group of co-receptors. The two major co-receptors for
ned to West Africa. However, a number of cases that HIV-1 are CCR5 and CXCR4. Both receptors belong
can be traced to West Africa or to sexual contacts with to the family of seven-transmembrane-domain G protein
West Africans have been identied throughout the coupled cellular receptors, and the use of one or the
world. Both HIV-1 and HIV-2 are zoonotic infections. other or both receptors by the virus for entry into the
The Pan troglodytes troglodytes species of chimpanzees has cell is an important determinant of the cellular tropism
been established as the natural reservoir of HIV-1 and of the virus. Certain dendritic cells express a diversity of
the most likely source of original human infection. C-type lectin receptors on their surface, one of which is
HIV-2 is more closely related phylogenetically to the called DC-SIGN, that also bind with high afnity to the
simian immunodeciency virus (SIV) found in sooty HIV gp120 envelope protein, allowing the dendritic cell
mangabeys than it is to HIV-1. to facilitate the binding of virus to the CD4+ T cell
upon engagement of dendritic cells with CD4+ T cells.
Following binding of the envelope protein to the CD4
MORPHOLOGY OF HIV
molecule associated with the above-mentioned confor-
Electron microscopy shows that the HIV virion is an mational change in the viral envelope gp120, fusion with
icosahedral structure (Fig. 37-1A) containing numerous the host cell membrane occurs via the newly exposed

TABLE 37-2
1993 REVISED CLASSIFICATION SYSTEM FOR HIV INFECTION
AND EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR
ADOLESCENTS AND ADULTS

CLINICAL CATEGORIES

A ASYMPTOMATIC, B SYMPTOMATIC, C AIDS-

CD4+ T CELL ACUTE (PRIMARY) NOT A OR C INDICATOR
CATEGORIES HIV OR PGLa CONDITIONS CONDITIONS

>500/L A1 B1 C1
200499/L A2 B2 C2
<200/L A3 B3 C3

a
PGL, progressive generalized lymphadenopathy.
Source: MMWR 42(No. RR-17), December 18, 1992.
TABLE 37-3 495
CLINICAL CATEGORIES OF HIV INFECTION
Category A: Consists of one or more of the conditions listed below in an adolescent or adult (>13 years) with documented
HIV infection. Conditions listed in categories B and C must not have occurred.
Asymptomatic HIV infection
Persistent generalized lymphadenopathy
Acute (primary) HIV infection with accompanying illness or history of acute HIV infection
Category B: Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among condi-
tions listed in clinical category C and that meet at least one of the following criteria: (1) The conditions are attributed to HIV
infection or are indicative of a defect in cell-mediated immunity; or (2) the conditions are considered by physicians to have
a clinical course or to require management that is complicated by HIV infection. Examples include, but are not limited to,
the following:
Bacillary angiomatosis
Candidiasis, oropharyngeal (thrush)
Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Constitutional symptoms, such as fever (38.5C) or diarrhea lasting >1 month
Hairy leukoplakia, oral

CHAPTER 37
Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome
Idiopathic thrombocytopenic purpura
Listeriosis
Pelvic inammatory disease, particularly if complicated by tuboovarian abscess
Peripheral neuropathy
Category C: Conditions listed in the AIDS surveillance case denition.
Candidiasis of bronchi, trachea, or lungs

HIV Neurology
Candidiasis, esophageal
Cervical cancer, invasivea
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 months duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcer(s) (>1 months duration); or bronchitis, pneumonia, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 months duration)
Kaposis sarcoma
Lymphoma, Burkitts (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonarya or extrapulmonary)
Mycobacterium, other species or unidentied species, disseminated or extrapulmonary
Pneumocystis jiroveci pneumonia
Pneumonia, recurrenta
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain
Wasting syndrome due to HIV

a
Added in the 1993 expansion of the AIDS surveillance case denition.
Source: MMWR 42(No. RR-17), December 18, 1992.

gp41 molecule penetrating the plasma membrane of the transcription of the genomic RNA into DNA, and the
target cell and then coiling upon itself to bring the virion protein coat opens to release the resulting double-stranded
and target cell together. Following fusion, the preintegra- HIV-DNA. At this point in the replication cycle, the viral
tion complex, composed of viral RNA and viral enzymes genome is vulnerable to cellular factors that can block the
and surrounded by a capsid protein coat, is released into progression of infection. In particular, the cytoplasmic
the cytoplasm of the target cell. As the preintegration TRIM5- protein in rhesus macaque cells blocks SIV
complex traverses the cytoplasm to reach the nucleus, the replication at a point shortly after the virus fuses with the
viral reverse transcriptase enzyme catalyzes the reverse host cell. Although the exact mechanisms of action of
 496 gp41

Matrix
Capsid Lipid
membrane

RNA

gp120 Reverse
transcriptase
SECTION III

FIGURE 37-1
A. Electron micrograph of HIV. Figure illustrates a typical transmembrane components of the envelope, genomic RNA,
virion following budding from the surface of a CD4+ T lym- enzyme reverse transcriptase, p18(17) inner membrane
phocyte, together with two additional incomplete virions in (matrix), and p24 core protein (capsid) (copyright by George
the process of budding from the cell membrane. B. Struc- V. Kelvin). (Adapted from RC Gallo: Sci Am 256:46, 1987.)
ture of HIV-1, including the gp120 outer membrane, gp41
Diseases of the Central Nervous System

TRIM5- remain unclear, the human form is inhibited by is still not clear whether (1) viral replication is inhibited
cyclophilin A and is not effective in restricting HIV repli- by the binding of APOBEC to the virus genome with
cation in human cells. The recently described APOBEC subsequent accumulation of reverse transcripts, or (2) by
family of cellular proteins also inhibits progression of the hypermutations caused by the enzymatic deaminase
virus infection after virus has entered the cell. APOBEC activity of APOBEC proteins. HIV has evolved a powerful
proteins bind to nascent reverse transcripts and deaminate strategy to protect itself from APOBEC. The viral protein
viral cytidine, causing hypermutation of HIV genomes. It Vif targets APOBEC for proteasomal degradation.

Cellular DNA

Unintegrated
linear DNA

Integrase

Reverse gp120
transcriptase
Integrated
proviral DNA CD4
Genomic
mRNA
RNA
Genomic RNA
HIV

Co-receptor

Fusion
Budding Protein synthesis,
processing, and assembly
Mature HIV virion

FIGURE 37-2
The replication cycle of HIV. See text for description. (Adapted from Fauci, 1996.)
 With activation of the cell, the viral DNA accesses receptor for HIV. When the number of CD4+ T cells 497
the nuclear pore and is exported from the cytoplasm to declines below a certain level, the patient is at high risk
the nucleus, where it is integrated into the host cell for developing a variety of opportunistic diseases, particu-
chromosomes through the action of another virally larly the infections and neoplasms that are AIDS-dening
encoded enzyme, integrase. HIV provirus (DNA) selec- illnesses. Some features of AIDS, such as Kaposi sarcoma
tively integrates into the nuclear DNA preferentially and neurologic abnormalities, cannot be explained com-
within introns of active genes and regional hotspots. pletely by the immunosuppressive effects of HIV, since
This provirus may remain transcriptionally inactive these complications may occur prior to the development
(latent) or it may manifest varying levels of gene expres- of severe immunologic impairment.
sion, up to active production of virus.
Cellular activation plays an important role in the NEUROPATHOGENESIS
replication cycle of HIV and is critical to the pathogene-
sis of HIV disease. Following initial binding and internal- Although there has been a remarkable decrease in the
ization of virions into the target cell, incompletely incidence of HIV encephalopathy among those with
reverse-transcribed DNA intermediates are labile in qui- access to treatment in the era of effective ARV therapy,
escent cells and do not integrate efciently into the host HIV-infected individuals can still experience a variety of
cell genome unless cellular activation occurs shortly after neurologic abnormalities due either to opportunistic

CHAPTER 37
infection. Furthermore, some degree of activation of the infections and neoplasms or to direct effects of HIV or
host cell is required for the initiation of transcription of its products. With regard to the latter, HIV has been
the integrated proviral DNA into either genomic RNA demonstrated in the brain and CSF of infected individu-
or mRNA. This latter process may not necessarily be als with and without neuropsychiatric abnormalities.The
associated with the detectable expression of the classic main cell types that are infected in the brain in vivo are
cell surface markers of activation. In this regard, activa- the perivascular macrophages and the microglial cells;

HIV Neurology
tion of HIV expression from the latent state depends on monocytes that have already been infected in the blood
the interaction of a number of cellular and viral factors. can migrate into the brain, where they then reside as
Following transcription, HIV mRNA is translated into macrophages, or macrophages can be directly infected
proteins that undergo modication through glycosyla- within the brain. The precise mechanisms whereby HIV
tion, myristylation, phosphorylation, and cleavage. The enters the brain are unclear; however, they are thought to
viral particle is formed by the assembly of HIV proteins, relate, at least in part, to the ability of virus-infected and
enzymes, and genomic RNA at the plasma membrane of immune-activated macrophages to induce adhesion mol-
the cells. Budding of the progeny virion occurs through ecules such as E-selectin and vascular cell adhesion mole-
specialized regions in the lipid bilayer of the host cell cule-1 (VCAM-1) on brain endothelium. Other studies
membrane known as lipid rafts, where the core acquires have demonstrated that HIV gp120 enhances the expres-
its external envelope. The virally encoded protease then sion of intercellular adhesion molecule-1 (ICAM-1) in
catalyzes the cleavage of the gag-pol precursor to yield glial cells; this effect may facilitate entry of HIV-infected
the mature virion. Progression through the virus replica- cells into the CNS and may promote syncytia formation.
tion cycle is profoundly inuenced by a variety of viral Virus isolates from the brain are preferentially R5 strains
regulatory gene products. Likewise, each point in the as opposed to X4 strains; in this regard, HIV-infected
replication cycle of HIV is a real or potential target for individuals who are heterozygous for CCR5-32 appear
therapeutic intervention. Thus far, the reverse transcrip- to be relatively protected against the development of
tase, protease, and integrase enzymes as well as the process HIV encephalopathy compared to wild-type individuals.
of virustarget cell binding and fusion have proven clini- Distinct HIV envelope sequences are associated with the
cally to be susceptible to pharmacologic disruption. clinical expression of the AIDS dementia complex.There
Inhibitors of the maturation process of virions during is no convincing evidence that brain cells other than
the latter phase of the replication cycle are currently those of monocyte/macrophage lineage can be produc-
being evaluated in clinical trials. tively infected in vivo. Astrocytes have been reported to
be susceptible to HIV infection in vitro despite the fact
PATHOPHYSIOLOGY that they do not express detectable levels of cell-surface
AND PATHOGENESIS CD4 or the main HIV co-receptors. Nonetheless, they
do not support active virus replication. There is no con-
The hallmark of HIV disease is a profound immunode- vincing evidence that oligodendrocytes or neurons can
ciency resulting primarily from a progressive quantitative be infected with HIV (see below).
and qualitative deciency of the subset of T lympho- HIV-infected individuals may manifest white matter
cytes referred to as helper T cells. This subset of T cells is lesions as well as neuronal loss. Given the absence of
dened phenotypically by the presence on its surface of evidence of HIV infection of neurons either in vivo or
the CD4 molecule, which serves as the primary cellular in vitro, it is highly unlikely that direct infection of these
 498 cells accounts for their loss. Rather, the HIV-mediated opportunistic diseases that involve the CNS are toxoplas-
effects on neurons and oligodendrocytes are thought to mosis, cryptococcosis, progressive multifocal leukoen-
involve indirect pathways whereby viral proteins, partic- cephalopathy, and primary CNS lymphoma. Other less
ularly gp120 and Tat, trigger the release of endogenous common problems include mycobacterial infections;
neurotoxins from macrophages and to a lesser extent syphilis; and infection with CMV, HTLV-I, T. cruzi, or
from astrocytes. In addition, it has been demonstrated Acanthamoeba. Overall, secondary diseases of the CNS
that both HIV-1 Nef and Tat can induce chemotaxis of occur in approximately one-third of patients with AIDS.
leukocytes, including monocytes, into the CNS. Neuro- These data antedate the widespread use of combination
toxins can be released from monocytes as a consequence ARV therapy, and this frequency is considerably less in
of infection and/or immune activation. Monocyte- patients receiving effective ARV drugs.
derived neurotoxic factors have been reported to kill
neurons via the N-methyl-d-aspartate (NMDA) receptor.
In addition, HIV gp120 shed by virus-infected mono- NEUROLOGIC DISEASE CAUSED BY HIV
cytes could cause neurotoxicity by antagonizing the HIV-Associated Cognitve Impairment
function of vasoactive intestinal peptide (VIP), by elevat-
ing intracellular calcium levels, and by decreasing nerve The term HIV-associated neurocognitive impairment (HNCI)
growth factor levels in the cerebral cortex. A variety of is used to describe a spectrum of disorders that range from
SECTION III

monocyte-derived cytokines can contribute directly or asymptomatic to apparent only through extensive neu-
indirectly to the neurotoxic effects in HIV infection; ropsychiatric testing to clinically severe.The most severe
these include TNF-, IL-1, IL-6,TGF-, IFN-, platelet- form, the AIDS dementia complex, or HIV encephalopathy,
activating factor, and endothelin. Furthermore, among is considered an AIDS-dening illness. Most HIV-infected
the CC-chemokines, elevated levels of monocyte chemo- patients have some neurologic problem during the course
tactic protein (MCP)1 in the brain and CSF have been of their disease. As noted in the section on pathogenesis,
Diseases of the Central Nervous System

shown to correlate best with the presence and degree of damage to the CNS may be a direct result of viral infec-
HIV encephalopathy. In addition, infection and/or acti- tion of the CNS macrophages or glial cells or may be
vation of monocyte-lineage cells can result in increased secondary to the release of neurotoxins and potentially
production of eicosanoids, nitric oxide, and quinolinic toxic cytokines such as IL-1,TNF-, IL-6, and TGF-.
acid, which may contribute to neurotoxicity. Astrocytes It has been reported that HIV-infected individuals with
may play diverse roles in HIV neuropathogenesis. Reac- the E4 allele for apo E are at increased risk for AIDS
tive gliosis or astrocytosis has been demonstrated in the encephalopathy and peripheral neuropathy. Virtually all
brains of HIV-infected individuals, and TNF- and IL-6 patients with HIV infection have some degree of nervous
have been shown to induce astrocyte proliferation. In system involvement with the virus. This is evidenced by
addition, astrocyte-derived IL-6 can induce HIV expres- the fact that CSF ndings are abnormal in ~90% of
sion in infected cells in vitro. Furthermore, it has been patients, even during the asymptomatic phase of HIV
suggested that astrocytes may downregulate macrophage- infection. CSF abnormalities include pleocytosis (5065%
produced neurotoxins. It has been reported that HIV- of patients), detection of viral RNA (~75%), elevated
infected individuals with the E4 allele for apolipoprotein CSF protein (35%), and evidence of intrathecal synthesis
E (apo E) are at increased risk for AIDS encephalopathy of anti-HIV antibodies (90%). It is important to point
and peripheral neuropathy.The likelihood that HIV or its out that evidence of infection of the CNS with HIV
products are involved in neuropathogenesis is supported does not imply impairment of cognitive function. The
by the observation that neuropsychiatric abnormalities neurologic function of an HIV-infected individual should
may undergo remarkable and rapid improvement upon be considered normal unless clinical signs and symptoms
the initiation of ARV therapy. suggest otherwise.
It has also been suggested that the CNS may serve as HIV encephalopathy, also called HIV-associated demen-
a relatively sequestered site for a reservoir of latently tia or AIDS dementia complex, consists of a constellation
infected cells and for the slow, continual replication of of signs and symptoms of CNS disease. Although this is
HIV that might be a barrier for the eradication of virus generally a late complication of HIV infection that pro-
by ARV therapy. gresses slowly over months, it can be seen in patients
with CD4+ T cell counts >350 cells/L.A major feature
of this entity is the development of dementia, dened as
CLINICAL MANIFESTATIONS a decline in cognitive ability from a previous level. It
may present as impaired ability to concentrate, increased
The neurologic problems that occur in HIV-infected forgetfulness, difculty reading, or increased difculty
individuals may be either primary to the pathogenic performing complex tasks. Initially these symptoms may
processes of HIV infection or secondary to opportunis- be indistinguishable from ndings of situational depres-
tic infections or neoplasms. Among the more frequent sion or fatigue. In contrast to cortical dementia (such
 TABLE 37-4 499
CLINICAL STAGING OF HIV ENCEPHALOPATHY (AIDS DEMENTIA COMPLEX)

STAGE DEFINITION

Stage 0 (normal) Normal mental and motor function

Stage 0.5 (equivocal/ Absent, minimal, or equivocal symptoms without
subclinical) impairment of work or capacity to perform activities of
daily living. Mild signs (snout response, slowed ocular or
extremity movements) may be present. Gait and
strength are normal.
Stage 1 (mild) Able to perform all but the more demanding aspects of
work or activities of daily living but with unequivocal evi-
dence (signs or symptoms that may include performance
on neuropsychological testing) of functional, intellectual,
or motor impairment. Can walk without assistance.
Stage 2 (moderate) Able to perform basic activities of self-care but cannot
work or maintain the more demanding aspects of daily
life. Ambulatory, but may require a single prop.

CHAPTER 37
Stage 3 (severe) Major intellectual incapacity (cannot follow news or
personal events, cannot sustain complex conversation,
considerable slowing of all output) or motor disability
(cannot walk unassisted, usually with slowing and clum-
siness of arms as well).
Stage 4 (end-stage) Nearly vegetative. Intellectual and social comprehension
and output are at a rudimentary level. Nearly or absolutely
mute. Paraparetic or paraplegic with urinary and fecal

HIV Neurology
incontinence.

Source: Adapted from JJ Sidtis, RW Price, Neurology 40:197, 1990.

as Alzheimers disease), aphasia, apraxia, and agnosia are encephalopathy; a commonly used clinical staging sys-
uncommon, leading some investigators to classify HIV tem is outlined in Table 37-4.
encephalopathy as a subcortical dementia. In addition The precise cause of HIV encephalopathy remains
to dementia, patients with HIV encephalopathy may unclear, although the condition is thought to be a result
also have motor and behavioral abnormalities. Among of a combination of direct effects of HIV on the CNS
the motor problems are unsteady gait, poor balance, and associated immune activation. HIV has been found
tremor, and difculty with rapid alternating movements. in the brains of patients with HIV encephalopathy by
Increased tone and deep tendon reexes may be found Southern blot, in situ hybridization, PCR, and electron
in patients with spinal cord involvement. Late stages may microscopy. Multinucleated giant cells, macrophages, and
be complicated by bowel and/or bladder incontinence. microglial cells appear to be the main cell types harbor-
Behavioral problems include apathy and lack of initia- ing virus in the CNS. Histologically, the major changes
tive, with progression to a vegetative state in some are seen in the subcortical areas of the brain and include
instances. Some patients develop a state of agitation or pallor and gliosis, multinucleated giant cell encephalitis,
mild mania.These changes usually occur without signif- and vacuolar myelopathy. Less commonly, diffuse or
icant changes in level of alertness. This is in contrast to focal spongiform changes occur in the white matter.
the nding of somnolence in patients with dementia Areas of the brain involved in motor, language, and
due to toxic/metabolic encephalopathies. judgment are most severely affected.
HIV encephalopathy is the initial AIDS-dening ill- There are no specic criteria for a diagnosis of HIV
ness in ~3% of patients with HIV infection and thus encephalopathy, and this syndrome must be differenti-
only rarely precedes clinical evidence of immunode- ated from a number of other diseases that affect the
ciency. Clinically signicant encephalopathy eventually CNS of HIV-infected patients.The diagnosis of demen-
develops in ~25% of patients with AIDS. As immuno- tia depends upon demonstrating a decline in cognitive
logic function declines, the risk and severity of HIV function. This can be accomplished objectively with the
encephalopathy increase. Autopsy series suggest that use of a Mini-Mental Status Examination (MMSE) in
8090% of patients with HIV infection have histologic patients for whom prior scores are available. For this rea-
evidence of CNS involvement. Several classication son, it is advisable for all patients with a diagnosis of
schemes have been developed for grading HIV HIV infection to have a baseline MMSE. However,
 500 TABLE 37-5
CLINICAL FINDINGS IN THE ACUTE HIV SYNDROME
General Neurologic
Fever Meningitis
Pharyngitis Encephalitis
Lymphadenopathy Peripheral neuropathy
Headache/retroorbital pain Myelopathy
Arthralgias/myalgias Dermatologic
Lethargy/malaise Erythematous maculopapu-
Anorexia/weight loss lar rash
Nausea/vomiting/diarrhea Mucocutaneous ulceration

Source: From B Tindall, DA Cooper: AIDS 5:1, 1991.

this problem is quickly reversible, again supporting at

least a partial role of soluble mediators in the pathogen-
SECTION III

esis. It should also be noted that these patients have an

FIGURE 37-3 increased sensitivity to the side effects of neuroleptic
AIDS dementia complex. Postcontrast CT scan through the drugs.The use of these drugs for symptomatic treatment
lateral ventricles of a 47-year-old man with AIDS, altered is associated with an increased risk of extrapyramidal
mental status, and dementia. The lateral and third ventricles side effects; therefore, patients with HIV encephalopathy
and the cerebral sulci are abnormally prominent. Mild white who receive these agents must be monitored carefully.
matter hypodensity is also seen adjacent to the frontal horns
Diseases of the Central Nervous System

of the lateral ventricles.

Asceptic Meningitis and Encephalitis
Aseptic meningitis may be seen in any but the very late
changes in MMSE scores may be absent in patients with stages of HIV infection. In the setting of acute primary
mild HIV encephalopathy. Imaging studies of the CNS, infection patients may experience a syndrome of headache,
by either MRI or CT, often demonstrate evidence of photophobia, and meningismus (Table 37-5). Rarely, an
cerebral atrophy (Fig. 37-3). MRI may also reveal small acute encephalopathy due to encephalitis may occur.
areas of increased density on T2-weighted images. Lum- Cranial nerve involvement may be seen, predominantly
bar puncture is an important element of the evaluation cranial nerve VII but occasionally V and/or VIII. CSF
of patients with HIV infection and neurologic abnor- ndings include a lymphocytic pleocytosis, elevated pro-
malities. It is generally most helpful in ruling out or tein level, and normal glucose level.This syndrome, which
making a diagnosis of opportunistic infections. In HIV cannot be clinically differentiated from other viral menin-
encephalopathy, patients may have the nonspecic nd- gitides (Chap. 35), usually resolves spontaneously within
ings of an increase in CSF cells and protein level. 24 weeks; however, in some patients, signs and symp-
Although HIV RNA can often be detected in the spinal toms may become chronic. Aseptic meningitis may occur
uid and HIV can be cultured from the CSF, this nd- any time in the course of HIV infection; however, it is
ing is not specic for HIV encephalopathy. There rare following the development of AIDS. This fact sug-
appears to be no correlation between the presence of gests that clinical aseptic meningitis in the context of HIV
HIV in the CSF and the presence of HIV encephalopa- infection is an immune-mediated disease.
thy. Elevated levels of macrophage chemoattractant pro-
tein (MCP-1), 2-microglobulin, neopterin, and quinolinic
HIV Myelopathy
acid (a metabolite of tryptophan reported to cause CNS
injury) have been noted in the CSF of patients with Spinal cord disease, or myelopathy, is present in ~20% of
HIV encephalopathy. These ndings suggest that these patients with AIDS, often as part of HIV encephalopa-
factors as well as inammatory cytokines may be thy. In fact, 90% of the patients with HIV-associated
involved in the pathogenesis of this syndrome. myelopathy have some evidence of dementia, suggest-
Combination ARV therapy is of benet in patients ing that similar pathologic processes may be responsible
with HIV encephalopathy. Improvement in neuropsy- for both conditions. Three main types of spinal cord
chiatric test scores has been noted for both adult and disease are seen in patients with AIDS.The rst of these
pediatric patients treated with ARVs.The rapid improve- is a vacuolar myelopathy, as discussed above under HIV
ment in cognitive function noted with the initiation of encephalopathy. This condition is pathologically similar
ARV therapy suggests that at least some component of to subacute combined degeneration of the cord such as
occurs with pernicious anemia. Although vitamin B12 they should be reserved for severe cases of CIDP refrac- 501
deciency can be seen in patients with AIDS as a pri- tory to other measures. Another autoimmune peripheral
mary complication of HIV infection, it does not appear neuropathy seen in patients with AIDS is mononeuritis
to be responsible for the myelopathy seen in the major- multiplex (Chap. 40) due to a necrotizing arteritis of
ity of patients.Vacuolar myelopathy is characterized by a peripheral nerves. The most common peripheral neu-
subacute onset and often presents with gait distur- ropathy in patients with HIV infection is a distal sen-
bances, predominantly ataxia and spasticity; it may sory polyneuropathy that may be a direct consequence
progress to include bladder and bowel dysfunction. of HIV infection or a side effect of dideoxynucleoside
Physical ndings include evidence of increased deep therapy. Two-thirds of patients with AIDS may be
tendon reexes and extensor plantar responses.The sec- shown by electrophysiologic studies to have some evi-
ond form of spinal cord disease involves the dorsal dence of peripheral nerve disease. Presenting symptoms
columns and presents as a pure sensory ataxia.The third are usually painful burning sensations in the feet and
form is also sensory in nature and presents with pares- lower extremities. Findings on examination include a
thesias and dysesthesias of the lower extremities. In stocking-type sensory loss to pinprick, temperature, and
contrast to the cognitive problems seen in patients with touch sensation and a loss of ankle reexes. Motor
HIV encephalopathy, these spinal cord syndromes do changes are mild and are usually limited to weakness of
not respond well to ARV drugs, and therapy is mainly the intrinsic foot muscles. Response of this condition to

CHAPTER 37
supportive. ARVs has been variable, perhaps because ARVs are
One important disease of the spinal cord that also responsible for the problem in some instances. When
involves the peripheral nerves is a myelopathy and due to dideoxynucleoside therapy, patients with lower
polyradiculopathy seen in association with CMV infection. extremity peripheral neuropathy may complain of a
This entity is generally seen late in the course of HIV sensation that they are walking on ice. Other entities in
infection and is fulminant in onset, with lower extremity the differential diagnosis of peripheral neuropathy

HIV Neurology
and sacral paresthesias, difculty in walking, areexia, include diabetes mellitus, vitamin B12 deficiency, and
ascending sensory loss, and urinary retention.The clinical side effects from metronidazole or dapsone. For distal
course is rapidly progressive over a period of weeks. CSF symmetric polyneuropathy that fails to resolve follow-
examination reveals a predominantly neutrophilic pleo- ing the discontinuation of dideoxynucleosides, therapy
cytosis, and CMV DNA can be detected by CSF PCR. is symptomatic; gabapentin, carbamazepine, tricyclics,
Therapy with ganciclovir or foscarnet can lead to rapid or analgesics may be effective for dysesthesias. Treat-
improvement, and prompt initiation of foscarnet or gan- ment-naive patients may respond to combination ARV
ciclovir therapy is important in minimizing the degree of therapy.
permanent neurologic damage. Combination therapy
with both drugs should be considered in patients who HIV Myopathy
have been previously treated for CMV disease. Other
diseases involving the spinal cord in patients with HIV Myopathy may complicate the course of HIV infection;
infection include HTLV-I-associated myelopathy (HAM), causes include HIV infection itself, zidovudine, and the
neurosyphilis, infection with herpes simplex or varicella- generalized wasting syndrome. HIV-associated myopa-
zoster,TB, and lymphoma. thy may range in severity from an asymptomatic eleva-
tion in creatine kinase levels to a subacute syndrome
characterized by proximal muscle weakness and myal-
HIV Neuropathy
gias. Quite pronounced elevations in creatine kinase
Peripheral neuropathies are common in patients with may occur in asymptomatic patients, particularly after
HIV infection. They occur at all stages of illness and exercise. The clinical signicance of this as an isolated
take a variety of forms. Early in the course of HIV laboratory nding is unclear. A variety of both inam-
infection, an acute inammatory demyelinating polyneu- matory and noninammatory pathologic processes have
ropathy resembling Guillain-Barr syndrome may occur been noted in patients with more severe myopathy,
(Chap. 41). In other patients, a progressive or relapsing- including myober necrosis with inammatory cells,
remitting inflammatory neuropathy resembling chronic nemaline rod bodies, cytoplasmic bodies, and mito-
inammatory demyelinating polyneuropathy (CIDP) has chondrial abnormalities. Profound muscle wasting,
been noted. Patients commonly present with progressive often with muscle pain, may be seen after prolonged
weakness, areexia, and minimal sensory changes. CSF zidovudine therapy. This toxic side effect of the drug is
examination often reveals a mononuclear pleocytosis, dose-dependent and is related to its ability to interfere
and peripheral nerve biopsy demonstrates a perivascular with the function of mitochondrial polymerases. It is
inltrate suggesting an autoimmune etiology. Plasma reversible following discontinuation of the drug. Red
exchange or IVIg has been tried with variable success. ragged bers are a histologic hallmark of zidovudine-
Because of the immunosuppressive effects of glucocorticoids, induced myopathy.
 502 HIV-Related Neoplasms
Systemic Lymphoma
Lymphomas occur with an increased frequency in
patients with congenital or acquired T cell immunode-
ciencies. AIDS is no exception; at least 6% of all patients
with AIDS develop lymphoma at some time during the
course of their illness.This is a 120-fold increase in inci-
dence compared to the general population. In contrast
to the situation with KS, primary CNS lymphoma, and
most opportunistic infections, the incidence of AIDS-
associated systemic lymphomas has not experienced as
dramatic a decrease as a consequence of the widespread
use of effective ARV therapy. Lymphoma occurs in all
risk groups, with the highest incidence in patients with
hemophilia and the lowest incidence in patients from
the Caribbean or Africa with heterosexually acquired FIGURE 37-4
infection. Lymphoma is a late manifestation of HIV Central nervous system lymphoma. Postcontrast
SECTION III

infection, generally occurring in patients with CD4+ T T1-weighted MR scan in a patient with AIDS, an altered men-
cell counts <200/L. As HIV disease progresses, the risk tal status, and hemiparesis. Multiple enhancing lesions, some
of lymphoma increases. In contrast to KS, which occurs ring-enhancing, are present. The left Sylvian lesion shows
at a relatively constant rate throughout the course of gyral and subcortical enhancement, and the lesions in the
HIV disease, the attack rate for lymphoma increases caudate and splenium (arrowheads) show enhancement of
exponentially with increasing duration of HIV infection adjacent ependymal surfaces.
Diseases of the Central Nervous System

and decreasing level of immunologic function. At 3

years following a diagnosis of HIV infection, the risk of Primary CNS lymphoma generally presents with
lymphoma is 0.8% per year; by 8 years after infection, it focal neurologic decits, including cranial nerve nd-
is 2.6% per year. As individuals with HIV infection live ings, headaches, and/or seizures. MRI or CT generally
longer as a consequence of improved ARV therapy and reveals a limited number (one to three) of 3- to 5-cm
better treatment and prophylaxis of opportunistic infec- lesions (Fig. 37-4). The lesions often show ring
tions, it is anticipated that the incidence of lymphomas enhancement on contrast administration and may occur
may increase. in any location. Locations that are most commonly
The clinical presentation of lymphoma in patients involved with CNS lymphoma are deep in the white
with HIV infection is quite varied, ranging from focal matter. Contrast enhancement is usually less pronounced
seizures to rapidly growing mass lesions in the oral than that seen with toxoplasmosis. The main diseases in
mucosa to persistent unexplained fever. At least 80% of the differential diagnosis are cerebral toxoplasmosis and
patients present with extranodal disease, and a similar cerebral Chagas disease. In addition to the 20% of lym-
percentage have B-type symptoms of fever, night sweats, phomas in HIV-infected individuals that are primary
or weight loss. Virtually any site in the body may be CNS lymphomas, CNS disease is also seen in HIV-
involved.The most common extranodal site is the CNS, infected patients with systemic lymphoma. Approxi-
which is involved in approximately one-third of all mately 20% of patients with systemic lymphoma have
patients with lymphoma. Approximately 60% of these CNS disease in the form of leptomeningeal involve-
cases are primary CNS lymphoma. ment. This fact underscores the importance of lumbar
puncture in the staging evaluation of patients with sys-
CNS lymphoma temic lymphoma.
Primary CNS lymphoma accounts for ~20% of the cases Systemic lymphoma is seen at earlier stages of HIV
of lymphoma in patients with HIV infection. In contrast infection than primary CNS lymphoma. In one series
to HIV-associated Burkitts lymphoma, primary CNS the mean CD4+ T cell count was 189/L. In addition
lymphomas are usually positive for EBV. In one study, to lymph node involvement, systemic lymphoma may
the incidence of Epstein-Barr positivity was 100%. This commonly involve the gastrointestinal tract, bone mar-
malignancy does not have a predilection for any particu- row, liver, and lung. Gastrointestinal tract involvement is
lar age group. The median CD4+ T cell count at the seen in ~25% of patients. Any site in the gastrointestinal
time of diagnosis is ~50/L.Thus, CNS lymphoma gen- tract may be involved, and patients may complain of dif-
erally presents at a later stage of HIV infection than sys- culty swallowing or abdominal pain. The diagnosis is
temic lymphoma. This fact may at least in part explain usually suspected on the basis of CT or MRI of the
the poorer prognosis for this subset of patients. abdomen. Bone marrow involvement is seen in ~20% of
 503
300

CD4 (cells/L3)
200
*
*
100
* *
* * * * * *
* * * * *
0
HSV HZos Crp KS Cry Can PCP NHL DEM PML WS Tox CMV PCP2 MAC
Opportunistic illness

FIGURE 37-5 DEM, AIDS dementia complex; HSV, herpes simplex virus
Relationship between CD4+ T cell counts and the devel- infection; HZos, herpes zoster; KS, Kaposis sarcoma; MAC,

CHAPTER 37
opment of opportunistic diseases. Boxplot of the median Mycobacterium avium complex bacteremia; NHL, non-
(line inside the box), rst quartile (bottom of the box), third Hodgkins lymphoma; PCP, primary Pneumocystis jiroveci
quartile (top of the box), and mean (asterisk) CD4+ lympho- pneumonia; PCP2, secondary P. jiroveci pneumonia; PML,
cyte count at the time of the development of opportunistic dis- progressive multifocal leukoencephalopathy; Tox, Toxoplasma
ease. Can, candidal esophagitis; CMV, cytomegalovirus infec- gondii encephalitis; WS, wasting syndrome. (From RD Moore,
tion; Crp, cryptosporidiosis; Cry, cryptococcal meningitis; RE Chaisson: Ann Intern Med 124:633, 1996.)

HIV Neurology
patients and may lead to pancytopenia. Liver and lung such infections correlates well with the CD4+ T cell count
involvement are each seen in ~10% of patients. Pul- (Figure 37-5). A selected group of common and impor-
monary disease may present as either a mass lesion, mul- tant opportunistic infections of the nervous system in
tiple nodules, or an interstitial inltrate. patients with HIV is discussed below.
Both conventional and unconventional approaches
have been employed in an attempt to treat HIV-related Cryptococcosis
lymphomas. Systemic lymphoma is generally treated by C. neoformans is the leading infectious cause of meningi-
the oncologist with combination chemotherapy. Earlier tis in patients with AIDS. It is the initial AIDS-dening
disappointing gures are being replaced with more opti- illness in ~2% of patients and generally occurs in
mistic results for the treatment of systemic lymphoma patients with CD4+ T cell counts <100/L. Crypto-
following the availability of more effective combination coccal meningitis is particularly common in patients
ARV therapy. As in most situations in patients with HIV with AIDS in Africa, occurring in ~20% of patients.
disease, those with the higher CD4+ T cell counts tend Most patients present with a picture of subacute menin-
to do better. Response rates as high as 72% with a goencephalitis with fever, nausea, vomiting, altered men-
median survival of 33 months and disease-free intervals tal status, headache, and meningeal signs. The incidence
up to 9 years have been reported. Treatment of primary of seizures and focal neurologic decits is low. The CSF
CNS lymphoma remains a signicant challenge. Treat- prole may be normal or may show only modest eleva-
ment is complicated by the fact that this illness usually tions in WBC or protein levels and decreases in glucose.
occurs in patients with advanced HIV disease. Palliative In addition to meningitis, patients may develop crypto-
measures such as radiation therapy provide some relief. coccomas and cranial nerve involvement. Approximately
The prognosis remains poor in this group, with a 2-year one-third of patients also have pulmonary disease.
survival of 29%. Uncommon manifestations of cryptococcal infection
include skin lesions that resemble molluscum contagiosum,
lymphadenopathy, palatal and glossal ulcers, arthritis, gas-
HIV-Related Opportunistic Infections
troenteritis, myocarditis, and prostatitis. The prostate
Patients with HIV infection may present with focal neu- gland may serve as a reservoir for smoldering cryptococ-
rologic decits from a variety of causes.The most common cal infection.The diagnosis of cryptococcal meningitis is
causes are toxoplasmosis, progressive multifocal leukoen- made by identication of organisms in spinal uid with
cephalopathy, and CNS lymphoma. Other causes include India ink examination or by the detection of cryptococ-
cryptococcal infections, stroke, and reactivation Chagas cal antigen. A biopsy may be needed to make a diagnosis
disease. A broad spectrum of opportunistic infections has of CNS cryptococcoma. Treatment is with IV ampho-
been described in AIDS patients. The risk of many tericin B, at a dose of 0.7 mg/kg daily, with ucytosine,
 504 25 mg/kg qid for 2 weeks, followed by fluconazole,
400 mg/d PO for 10 weeks, and then fluconazole,
200 mg/d until the CD4+ T cell count has increased to
>200 cells/L for 6 months in response to HAART.
Repeated lumbar puncture may be required to manage
increased intracranial pressure. Symptoms may recur
with initiation of HAART as an immune reconstitution
syndrome. Other fungi that may cause meningitis in
patients with HIV infection are C. immitis and H. capsulatum.
Meningoencephalitis has also been reported due to
Acanthamoeba or Naegleria.

Toxoplasmosis
Toxoplasmosis has been one of the most common causes
of secondary CNS infections in patients with AIDS, but
its incidence is decreasing in the era of HAART. It is
most common in patients from the Caribbean and from FIGURE 37-6
SECTION III

France.Toxoplasmosis is generally a late complication of Central nervous system toxoplasmosis. A coronal post-
contrast T1-weighted MR scan demonstrates a peripheral
HIV infection and usually occurs in patients with
enhancing lesion in the left frontal lobe, associated with an
CD4+ T cell counts <200/L. Cerebral toxoplasmosis is
eccentric nodular area of enhancement (arrow); this so-called
thought to represent a reactivation syndrome. It is 10 times
eccentric target sign is typical of toxoplasmosis.
more common in patients with antibodies to the organism
than in patients who are seronegative. Patients diagnosed
Diseases of the Central Nervous System

with HIV infection should be screened for IgG antibod- sulfadiazine and pyrimethamine with leucovorin as
ies to T. gondii during the time of their initial workup. needed for a minimum of 46 weeks. Alternative thera-
Those who are seronegative should be counseled about peutic regimens include clindamycin in combination with
ways to minimize the risk of primary infection includ- pyrimethamine; atovaquone plus pyrimethamine; and
ing avoiding the consumption of undercooked meat and azithromycin plus pyrimethamine plus rifabutin. Relapses
careful hand washing after contact with soil or changing are common, and it is recommended that patients with a
the cat litter box. The most common clinical presenta- history of prior toxoplasmic encephalitis receive mainte-
tion of cerebral toxoplasmosis in patients with HIV nance therapy with sulfadiazine, pyrimethamine, and
infection is fever, headache, and focal neurologic decits. leucovorin as long as their CD4+ T cell counts remain
Patients may present with seizure, hemiparesis, or aphasia <200 cells/L. Patients with CD4+ T cell counts
as a manifestation of these focal decits or with a picture <100/L and IgG antibody to Toxoplasma should receive
more inuenced by the accompanying cerebral edema primary prophylaxis for toxoplasmosis. Fortunately, the
and characterized by confusion, dementia, and lethargy, same daily regimen of a single double-strength tablet of
which can progress to coma.The diagnosis is usually sus- TMP/SMX used for P. jiroveci prophylaxis provides
pected on the basis of MRI ndings of multiple lesions in adequate primary protection against toxoplasmosis.
multiple locations, although in some cases only a single Secondary prophylaxis/maintenance therapy for toxo-
lesion is seen. Pathologically, these lesions generally exhibit plasmosis may be discontinued in the setting of effec-
inammation and central necrosis and, as a result, demon- tive ARV therapy and increases in CD4+ T cell counts
strate ring enhancement on contrast MRI (Fig. 37-6) to >200/L for 6 months.
or, if MRI is unavailable or contraindicated, on double-
dose contrast CT.There is usually evidence of surround-
ing edema. In addition to toxoplasmosis, the differential Progressive Multifocal
Leukoencephalopathy (PML)
diagnosis of single or multiple enhancing mass lesions in
the HIV-infected patient includes primary CNS lym- JC virus, a human polyomavirus that is the etiologic
phoma (see below) and, less commonly, TB or fungal or agent of progressive multifocal leukoencephalopathy (PML), is
bacterial abscesses.The denitive diagnostic procedure is an important opportunistic pathogen in patients with
brain biopsy. However, given the morbidity than can AIDS. Although ~70% of the general adult population
accompany this procedure, it is usually reserved for the have antibodies to JC virus, indicative of prior infection,
patient who has failed 24 weeks of empirical therapy. <10% of healthy adults show any evidence of ongoing
If the patient is seronegative for T. gondii, the likelihood viral replication. PML is the only known clinical mani-
that a mass lesion is due to toxoplasmosis is <10%. In festation of JC virus infection. It is a late manifestation
that setting, one may choose to be more aggressive and of AIDS and is seen in ~4% of patients with AIDS. The
perform a brain biopsy sooner. Standard treatment is lesions of PML begin as small foci of demyelination in
subcortical white matter that eventually coalesce. The AIDS-dening condition and may be the initial AIDS- 505
cerebral hemispheres, cerebellum, and brainstem may all dening condition. Lesions appear radiographically as
be involved. Patients typically have a protracted course single or multiple hypodense areas, typically with ring
with multifocal neurologic decits, with or without enhancement and edema.They are found predominantly
changes in mental status. Approximately 20% of patients in the subcortical areas, a feature that differentiates them
experience seizures. Ataxia, hemiparesis, visual eld from the deeper lesions of toxoplasmosis. Trypanosoma
defects, aphasia, and sensory defects may occur. MRI cruzi amastigotes, or trypanosomes, can be identied
typically reveals multiple, nonenhancing white matter from biopsy specimens or CSF. Other CSF ndings
lesions that may coalesce and have a predilection for the include elevated protein and a mild (<100 cells/L)
occipital and parietal lobes. The lesions show signal lymphocytic pleocytosis. Organisms can also be identi-
hyperintensity on T2-weighted images and diminished ed by direct examination of the blood.Treatment con-
signal on T1-weighted images. The measurement of JC sists of benzimidazole (2.5 mg/kg bid) or nifurtimox
virus DNA levels in CSF has a diagnostic sensitivity of (2 mg/kg qid) for at least 60 days, followed by mainte-
76% and a specicity of close to 100%. Prior to the nance therapy for the duration of immunodeciency
availability of potent ARV combination therapy, the with either drug at a dose of 5 mg/kg three times a
majority of patients with PML died within 36 months week. As is the case with cerebral toxoplasmosis, success-
of the onset of symptoms. Paradoxical worsening of ful therapy with ARVs may allow discontinuation of

CHAPTER 37
PML has been seen with initiation of HAART as an therapy for Chagas disease.
immune reconstitution syndrome. There is no specic
treatment for PML; however, a minimal median survival
of 18 months and survival of >7 years have been SPECIFIC NEUROLOGIC PRESENTATIONS
reported in patients with PML treated with HAART for Stroke
their HIV disease. Unfortunately only ~50% of patients

HIV Neurology
with HIV infection and PML show neurologic Stroke may occur in patients with HIV infection. In
improvement with HAART. Studies with other antiviral contrast to the other causes of focal neurologic decits
agents such as cidofovir have failed to show clear bene- in patients with HIV infection, the symptoms of a stroke
t. Factors inuencing a favorable prognosis for PML in are sudden in onset. Among the secondary infectious
the setting of HIV infection include a CD4+ T cell diseases in patients with HIV infection that may be asso-
count >100/L at baseline and the ability to maintain ciated with stroke are vasculitis due to cerebral varicella
an HIV viral load of <500 copies per mL. Baseline HIV- zoster or neurosyphilis and septic embolism in associa-
1 viral load does not have independent predictive value tion with fungal infection. Other elements of the dif-
of survival. PML is one of the few opportunistic infec- ferential diagnosis of stroke in the patient with HIV
tions that continues to occur with some frequency infection include atherosclerotic cerebral vascular disease,
despite the widespread use of HAART. thrombotic thrombocytopenic purpura, and cocaine or
amphetamine use.
Chagas Disease
Reactivation American trypanosomiasis may present as acute Seizures
meningoencephalitis with focal neurologic signs, fever, Seizures may be a consequence of opportunistic infec-
headache, vomiting, and seizures. In South America, tions, neoplasms, or HIV encephalopathy (Table 37-6).
reactivation of Chagas disease is considered to be an The seizure threshold is often lower than normal in

TABLE 37-6
CAUSES OF SEIZURES IN PATIENTS WITH HIV INFECTION

OVERALL FRACTION OF
CONTRIBUTION TO PATIENTS WHO
DISEASE FIRST SEIZURE, % HAVE SEIZURES, %

HIV encephalopathy 2447 750

Cerebral toxoplasmosis 28 1540
Cryptococcal meningitis 13 8
Primary central nervous 4 1530
system lymphoma
Progressive multifocal 1
leukoencephalopathy

Source: From DM Holtzman et al: Am J Med 87:173, 1989.

 506 patients with advanced HIV infection due to the fre- indicated in all patients with HIV infection and seizures
quent presence of electrolyte abnormalities. Seizures are unless a rapidly correctable cause is found.While pheny-
seen in 1540% of patients with cerebral toxoplasmosis, toin remains the initial treatment of choice, hypersensi-
1535% of patients with primary CNS lymphoma, 8% tivity reactions to this drug have been reported in >10%
of patients with cryptococcal meningitis, and 750% of of patients with AIDS, and therefore the use of phenobar-
patients with HIV encephalopathy. Seizures may also be bital or valproic acid must be considered as alternatives.
seen in patients with CNS tuberculosis, aseptic menin-
gitis, and progressive multifocal leukoencephalopathy. FURTHER READINGS
Seizures may be the presenting clinical symptom of
BENSON CA et al: Treating opportunistic infections among HIV-
HIV disease. In one study of 100 patients with HIV
infected adults and adolescents. Recommendations from CDC, the
infection presenting with a rst seizure, cerebral mass National Institutes of Health, and the HIV Medicine Association/
lesions were the most common cause, responsible for 32 Infectious Diseases Society of America. MMWR 53(RR-15):1,
of the 100 new-onset seizures. Of these 32 cases, 28 2004. Updates available at http://www.aidsinfo.nih.gov
were due to toxoplasmosis and 4 to lymphoma. HIV BOISSE L et al: HIV infection of the central nervous system: clinical
encephalopathy accounted for an additional 24 new- features and neuropathogenesis. Neurol Clin 26:799, 2008
onset seizures. Cryptococcal meningitis was the third GONZALEZ-SCARANO F, MARTIN-GARCIA J: The neuropathogenesis
of AIDS. Nat Rev Immunol 5:69, 2005
most common diagnosis, responsible for 13 of the 100
SECTION III

KAUL M: HIV-1 associated dementia: update on pathological mecha-

seizures. In 23 cases, no cause could be found, and it is nisms and therapeutic approaches. Curr Opin Neurol 22:315,
possible that these cases represent a subcategory of HIV 2009
encephalopathy. Of these 23 cases, 16 (70%) had two or PRICE RW, SPUDICH S: Antiretroviral therapy and central nervous
more seizures, suggesting that anticonvulsant therapy is system HIV type 1 infection. J Infect Dis 197Suppl3:S294, 2008
Diseases of the Central Nervous System
 CHAPTER 38

PRION DISEASES

Stanley B. Prusiner I Bruce L. Miller

I Spectrum of Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 507 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
I Sporadic and Inherited Prion Diseases . . . . . . . . . . . . . . . . . 511 Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
Human PRNP Gene Polymorphisms . . . . . . . . . . . . . . . . . . . 511 Care of CJD Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
I Infectious Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Decontamination of CJD Prions . . . . . . . . . . . . . . . . . . . . . . 515
Iatrogenic CJD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Prevention and Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . 515
Variant CJD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512

Prions are infectious proteins that cause degeneration of from that of its precursor, PrPC. (4) PrPSc can exist in a
the central nervous system (CNS). Prion diseases are variety of different conformations, each of which seems
disorders of protein conformation, the most common of to specify a particular disease phenotype. How a specic
which in humans is called Creutzfeldt-Jakob disease conformation of a PrPSc molecule is imparted to PrPC
(CJD). CJD typically presents with dementia and during prion replication to produce nascent PrPSc with
myoclonus, is relentlessly progressive, and generally the same conformation is unknown. Additionally, it is
causes death within a year of onset. Most CJD patients unclear what factors determine where in the CNS a
are between 50 and 75 years of age; however, patients as particular PrPSc molecule will be deposited.
young as 17 and as old as 83 have been recorded.
In mammals, prions reproduce by binding to the nor- SPECTRUM OF PRION DISEASES
mal, cellular isoform of the prion protein (PrPC) and
stimulating conversion of PrPC into the disease-causing The sporadic form of CJD is the most common prion dis-
isoform (PrPSc). PrPC is rich in -helix and has little order in humans. Sporadic CJD (sCJD) accounts for ~85%
-structure, while PrPSc has less -helix and a high of all cases of human prion disease, while inherited prion
amount of -structure (Fig. 38-1). This -to- struc- diseases account for 1015% of all cases (Table 38-2).
tural transition in the prion protein (PrP) is the funda- Familial CJD (fCJD), Gerstmann-Strussler-Scheinker
mental event underlying prion diseases (Table 38-1). (GSS) disease, and fatal familial insomnia (FFI) are all
Four new concepts have emerged from studies of pri- dominantly inherited prion diseases that are caused by
ons: (1) Prions are the only known infectious pathogens mutations in the PrP gene. Although infectious prion
that are devoid of nucleic acid; all other infectious agents diseases account for <1% of all cases and infection does
possess genomes composed of either RNA or DNA that not seem to play an important role in the natural history
direct the synthesis of their progeny. (2) Prion diseases of these illnesses, the transmissibility of prions is an
may be manifest as infectious, genetic, and sporadic dis- important biologic feature. Kuru of the Fore people of
orders; no other group of illnesses with a single etiology New Guinea is thought to have resulted from the con-
presents with such a wide spectrum of clinical manifes- sumption of brains from dead relatives during ritualistic
tations. (3) Prion diseases result from the accumulation cannibalism. With the cessation of ritualistic cannibalism
of PrPSc, the conformation of which differs substantially in the late 1950s, kuru has nearly disappeared, with the
507
 508 Helix A exception of a few recent patients exhibiting incubation
periods of >40 years. Iatrogenic CJD (iCJD) seems to be
Helix B the result of the accidental inoculation of patients with
prions.Variant CJD (vCJD) in teenagers and young adults
Helix B Helix C
in Europe is the result of exposure to tainted beef from
cattle with bovine spongiform encephalopathy (BSE).
Helix C Six diseases of animals are caused by prions (Table 38-2).
Scrapie of sheep and goats is the prototypic prion disease.
Mink encephalopathy, BSE, feline spongiform encephalopa-
thy, and exotic ungulate encephalopathy are all thought to
A Recombinant PrP B PrPSc model occur after the consumption of prion-infected foodstuffs.
FIGURE 38-1 The BSE epidemic emerged in Britain in the late 1980s and
Structures of prion proteins. A. NMR structure of Syrian was shown to be due to industrial cannibalism. Whether
hamster recombinant (rec) PrP(90231). Presumably, the BSE began as a sporadic case of BSE in a cow or started
structure of the -helical form of recPrP(90231) resembles with scrapie in sheep is unknown. The origin of chronic
that of PrPC. recPrP(90231) is viewed from the interface wasting disease (CWD), a prion disease endemic in deer
where PrPSc is thought to bind to PrPC. Shown are: -helices and elk in regions of North America, is uncertain.
SECTION III

A (residues 144157), B (172193), and C (200227). Flat rib-

bons depict -strands S1 (129131) and S2 (161163).
( A, from SB Prusiner: N Engl J Med 344:1516, 2006; with EPIDEMIOLOGY
permission.) B. Structural model of PrPSc. The 90160 region CJD is found throughout the world. The incidence of
has been modeled onto a -helical architecture while the sCJD is approximately one case per million population,
COOH terminal helices B and C are preserved as in PrPC. and thus it accounts for about one in every 10,000
(Image prepared by C. Govaerts.)
Diseases of the Central Nervous System

deaths. Because sCJD is an age-dependent neurodegen-

erative disease, its incidence is expected to increase
steadily as older segments of populations in developed
and developing countries continue to expand. Although
TABLE 38-1 many geographic clusters of CJD have been reported,
GLOSSARY OF PRION TERMINOLOGY each has been shown to segregate with a PrP gene
Prion Proteinaceous infectious particle that mutation. Attempts to identify common exposure to
lacks nucleic acid. Prions are composed some etiologic agent have been unsuccessful for both
largely, if not entirely, of PrPSc molecules. the sporadic and familial cases. Ingestion of scrapie-
They can cause scrapie in sheep and infected sheep or goat meat as a cause of CJD in
goats, and related neurodegenerative humans has not been demonstrated by epidemiologic
diseases of humans such as Creutzfeldt- studies, although speculation about this potential route
Jakob disease (CJD).
PrPSc Disease-causing isoform of the prion
of inoculation continues. Of particular interest are deer
protein. This protein is the only identi- hunters who develop CJD, because up to 90% of culled
able macromolecule in puried prepara- deer in some game herds have been shown to harbor
tions of scrapie prions. CWD prions. Whether prion disease in deer or elk can
PrPC Cellular isoform of the prion protein. be passed to cows, sheep, or directly to humans remains
PrPC is the precursor of PrPSc. unknown. Studies with Syrian hamsters demonstrate
PrP 27-30 A fragment of PrPSc, generated by that oral infection with prions can occur, but the process
truncation of the NH2-terminus by limited
is inefcient compared to intracerebral inoculation.
digestion with proteinase K. PrP 27-30
retains prion infectivity and polymerizes
into amyloid. PATHOGENESIS
PRNP PrP gene located on human
chromosome 20. The human prion diseases were initially classied as
Prion rod An aggregate of prions composed largely neurodegenerative disorders of unknown etiology on
of PrP 27-30 molecules. Created by the basis of pathologic changes being conned to the
detergent extraction and limited proteol- CNS. With the transmission of kuru and CJD to apes,
ysis of PrPSc. Morphologically and histo-
investigators began to view these diseases as infectious
chemically indistinguishable from many
amyloids. CNS illnesses caused by slow viruses. Even though the
PrP amyloid Amyloid containing PrP in the brains of familial nature of a subset of CJD cases was well
animals or humans with prion disease; described, the signicance of this observation became
often accumulates as plaques. more obscure with the transmission of CJD to animals.
Eventually the meaning of heritable CJD became clear
 TABLE 38-2 509
THE PRION DISEASES

DISEASE HOST MECHANISM OF PATHOGENESIS

Human
Kuru Fore people Infection through ritualistic cannibalism
iCJD Humans Infection from prion-contaminated hGH,
dura mater grafts, etc.
vCJD Humans Infection from bovine prions
fCJD Humans Germ-line mutations in PRNP
GSS Humans Germ-line mutations in PRNP
FFI Humans Germ-line mutation in PRNP (D178N, M129)
sCJD Humans Somatic mutation or spontaneous
conversion of PrPC into PrPSc?
sFI Humans Somatic mutation or spontaneous
conversion of PrPC into PrPSc?
Animal
Scrapie Sheep, goats Infection in genetically susceptible sheep

CHAPTER 38
BSE Cattle Infection with prion-contaminated MBM
TME Mink Infection with prions from sheep or cattle
CWD Mule deer, elk Unknown
FSE Cats Infection with prion-contaminated beef
Exotic ungulate Greater kudu, Infection with prion-contaminated MBM
encephalopathy nyala, or oryx

Prion Diseases
Note: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease; fCJD, familial Creutzfeldt-Jakob
disease; iCJD, iatrogenic Creutzfeldt-Jakob disease; sCJD, sporadic Creutzfeldt-Jakob disease; vCJD, variant
Creutzfeldt-Jakob disease; CWD, chronic wasting disease; FFI, fatal familial insomnia; sFI, sporadic fatal insom-
nia; FSE, feline spongiform encephalopathy; GSS, Gerstmann-Strussler-Scheinker disease; hGH, human growth
hormone; MBM, meat and bone meal; TME, transmissible mink encephalopathy.

with the discovery of mutations in the PRNP gene of PrP Polypeptide CHO CHO GPI
these patients.The prion concept explains how a disease
can manifest as a heritable as well as an infectious illness. S S
Moreover, the hallmark of all prion diseases, whether
sporadic, dominantly inherited, or acquired by infection, PrPC 209 amino acids

is that they involve the aberrant metabolism of PrP.

A major feature that distinguishes prions from viruses PrPSc 209 amino acids

is the nding that both PrP isoforms are encoded by a

chromosomal gene. In humans, the PrP gene is desig- PrP 27-30 ~142 amino acids
Codon
nated PRNP and is located on the short arm of chro-
mosome 20. Limited proteolysis of PrPSc produces a 1 23 50 94 131 188 231 254
smaller, protease-resistant molecule of ~142 amino acids FIGURE 38-2
designated PrP 27-30; PrPC is completely hydrolyzed Prion protein isoforms. Bar diagram of Syrian hamster PrP,
under the same conditions (Fig. 38-2). In the presence which consists of 254 amino acids. After processing of the
of detergent, PrP 27-30 polymerizes into amyloid. Prion NH2 and COOH termini, both PrPC and PrPSc consist of 209
rods formed by limited proteolysis and detergent extrac- residues. After limited proteolysis, the NH2 terminus of PrPSc
tion are indistinguishable from the laments that aggre- is truncated to form PrP 2730 composed of ~142 amino
gate to form PrP amyloid plaques in the CNS. Both the acids.
rods and the PrP amyloid laments found in brain tissue
exhibit similar ultrastructural morphology and green-
gold birefringence after staining with Congo red dye. in a molecule other than nucleic acid.Various strains of
prions have been dened by incubation times and the
distribution of neuronal vacuolation. Subsequently, the
Prion Strains
patterns of PrPSc deposition were found to correlate
The existence of prion strains raised the question of with vacuolation proles, and these patterns were also
how heritable biologic information can be enciphered used to characterize prion strains.
 510 TABLE 38-3
DISTINCT PRION STRAINS GENERATED IN HUMANS WITH INHERITED PRION DISEASES AND
TRANSMITTED TO TRANSGENIC MICEa

INCUBATION TIME
INOCULUM HOST SPECIES HOST PrP GENOTYPE [DAYS SEM] (n/n0) PrPSc (kDa)

None Human FFI(D178N, M129) 19

FFI Mouse Tg(MHu2M) 206 7 (7/7) 19
FFI Tg(MHu2M) Mouse Tg(MHu2M) 136 1 (6/6) 19
None Human fCJD(E200K) 21
fCJD Mouse Tg(MHu2M) 170 2 (10/10) 21
fCJD Tg(MHu2M) Mouse Tg(MHu2M) 167 3 (15/15) 21

a
Tg(MHu2M) mice express a chimeric mouse-human PrP gene.
Note: Clinicopathologic phenotype is determined by the conformation of PrPSc in accord with the results of the transmission of
human prions from patients with FFI to transgenic mice. FFI, fatal familial insomnia; fCJD, familial Creutzfeldt-Jakob disease.
SECTION III

Persuasive evidence that strain-specic information is New strains of prions were also generated from
enciphered in the tertiary structure of PrPSc comes from recombinant (rec) PrP produced in bacteria. In these
transmission of two different inherited human prion dis- studies, recPrP was polymerized into amyloid brils and
eases to mice expressing a chimeric human-mouse PrP inoculated into transgenic mice expressing very high
transgene. In FFI, the protease-resistant fragment of levels of truncated mouse PrPC; about 500 days later, the
PrPSc after deglycosylation has a molecular mass of 19 mice died of prion disease. These synthetic prions
Diseases of the Central Nervous System

kDa, whereas in fCJD and most sporadic prion diseases, were found to be much more stable than any prions
it is 21 kDa (Table 38-3). This difference in molecular previously isolated from animals or humans with natu-
mass was shown to be due to different sites of prote- rally occurring prion diseases. Surprisingly, studies of
olytic cleavage at the NH2 termini of the two human synthetic and naturally occurring prions indicate that
PrPSc molecules, reecting different tertiary structures. the incubation time is directly proportional to the stabil-
These distinct conformations were not unexpected ity of the prion. As the stability increases, the incubation
because the amino acid sequences of the PrPs differ. time lengthens; thus, less-stable prions replicate more
Extracts from the brains of patients with FFI transmit- rapidly.These studies also showed that PrPSc can adopt a
ted disease into mice expressing a chimeric human-mouse continuum of conformational states, each of which
PrP transgene and induced formation of the 19-kDa enciphers a distinct incubation-time phenotype.
PrPSc, whereas brain extracts from fCJD and sCJD
patients produced the 21-kDa PrPSc in mice expressing
Species Barrier
the same transgene. On second passage, these differences
were maintained, demonstrating that chimeric PrPSc can Studies on the role of the primary and tertiary structures
exist in two different conformations based on the sizes of PrP in the transmission of prion disease have given
of the protease-resistant fragments, even though the new insights into the pathogenesis of these maladies.The
amino acid sequence of PrPSc is invariant. amino acid sequence of PrP encodes the species of the
This analysis was extended when patients with spo- prion, and the prion derives its PrPSc sequence from
radic fatal insomnia (sFI) were identied. Although they the last mammal in which it was passaged. While the
did not carry a PRNP gene mutation, the patients primary structure of PrP is likely to be the most impor-
demonstrated a clinical and pathologic phenotype that tant or even sole determinant of the tertiary structure of
was indistinguishable from that of patients with FFI. PrPC, PrPSc seems to function as a template in determin-
Furthermore, 19-kDa PrPSc was found in their brains, ing the tertiary structure of nascent PrPSc molecules as
and on passage of prion disease to mice expressing a they are formed from PrPC. In turn, prion diversity
chimeric human-mouse PrP transgene, 19-kDa PrPSc appears to be enciphered in the conformation of PrPSc,
was also found. These ndings indicate that the disease and thus prion strains seem to represent different con-
phenotype is dictated by the conformation of PrPSc and formers of PrPSc.
not the amino acid sequence. PrPSc acts as a template for In general, transmission of prion disease from one
the conversion of PrPC into nascent PrPSc. On the pas- species to another is inefcient, in that not all intracere-
sage of prions into mice expressing a chimeric hamster- brally inoculated animals develop disease, and those that
mouse PrP transgene, a change in the conformation of fall ill do so only after long incubation times that can
PrPSc was accompanied by the emergence of a new approach the natural life span of the animal.This species
strain of prions. barrier to transmission is correlated with the degree of
similarity between the amino acid sequences of PrPC in condition indistinguishable from sCJD to a slowly pro- 511
the inoculated host and of PrPSc in the prion inoculum. gressive dementing illness of many years duration to an
The importance of sequence similarity between the host early-age-of-onset disorder that is similar to Alzheimers
and donor PrP argues that PrPC directly interacts with disease. A mutation at codon 178 resulting in substitu-
PrPSc in the prion conversion process. tion of asparagine for aspartic acid produces FFI if a
methionine is encoded at the polymorphic 129 residue
on the same allele. Typical CJD is seen if a valine is
SPORADIC AND INHERITED encoded at position 129 of the same allele.
PRION DISEASES
Several different scenarios might explain the initiation of HUMAN PRNP GENE POLYMORPHISMS
sporadic prion disease: (1) A somatic mutation may be Polymorphisms inuence the susceptibility to sporadic,
the cause and thus follow a path similar to that for inherited, and infectious forms of prion disease. The
germ-line mutations in inherited disease. In this situa- methionine/valine polymorphism at position 129 not
tion, the mutant PrPSc must be capable of targeting only modulates the age of onset of some inherited
wild-type PrPC, a process known to be possible for some prion diseases but can also determine the clinical phe-
mutations but less likely for others. (2) The activation notype. The nding that homozygosity at codon 129

CHAPTER 38
barrier separating wild-type PrPC from PrPSc could be predisposes to sCJD supports a model of prion produc-
crossed on rare occasions when viewed in the context of tion that favors PrP interactions between homologous
a population. Most individuals would be spared while proteins.
presentations in the elderly with an incidence of ~1 per Substitution of the basic residue lysine at position 218
million would be seen. (3) PrPSc may be present at very in mouse PrP produced dominant-negative inhibition of
low levels in some normal cells, where it performs some prion replication in transgenic mice. This same lysine at
important, as yet unknown, function. The level of PrPSc

Prion Diseases
position 219 in human PrP has been found in 12% of
in such cells is hypothesized to be sufciently low as to the Japanese population, and this group appears to be
be not detected by bioassay. In some altered metabolic resistant to prion disease. Dominant-negative inhibition
states, the cellular mechanisms for clearing PrPSc might of prion replication was also found with substitution of
become compromised and the rate of PrPSc formation the basic residue arginine at position 171; sheep with
would then begin to exceed the capacity of the cell to arginine are resistant to scrapie prions but are susceptible
clear it. The third possible mechanism is attractive since to BSE prions that were inoculated intracerebrally.
it suggests PrPSc is not simply a misfolded protein, as
proposed for the rst and second mechanisms, but that it
is an alternatively folded molecule with a function. INFECTIOUS PRION DISEASES
Moreover, the multitude of conformational states that
PrPSc can adopt, as described above, raises the possibility IATROGENIC CJD
that PrPSc or another prion-like protein might function Accidental transmission of CJD to humans appears to
in a process like short-term memory where information have occurred with corneal transplantation, contami-
storage occurs in the absence of new protein synthesis. nated electroencephalogram (EEG) electrode implanta-
More than 30 different mutations resulting in non- tion, and surgical procedures. Corneas from donors with
conservative substitutions in the human PRNP gene inapparent CJD have been transplanted to apparently
have been found to segregate with inherited human healthy recipients who developed CJD after prolonged
prion diseases. Missense mutations and expansions in the incubation periods. The same improperly decontami-
octapeptide repeat region of the gene are responsible for nated EEG electrodes that caused CJD in two young
familial forms of prion disease. Five different mutations patients with intractable epilepsy caused CJD in a chim-
of the PRNP gene have been linked genetically to heri- panzee 18 months after their experimental implantation.
table prion disease. Surgical procedures may have resulted in accidental
Although phenotypes may vary dramatically within inoculation of patients with prions, presumably because
families, specic phenotypes tend to be observed with some instrument or apparatus in the operating theater
certain mutations. A clinical phenotype indistinguishable became contaminated when a CJD patient underwent
from typical sCJD is usually seen with substitutions at surgery. Although the epidemiology of these studies is
codons 180, 183, 200, 208, 210, and 232. Substitutions at highly suggestive, no proof for such episodes exists.
codons 102, 105, 117, 198, and 217 are associated with
the GSS variant of prion disease.The normal human PrP
Dura Mater Grafts
sequence contains ve repeats of an eight-amino-acid
sequence. Insertions from two to nine extra octarepeats More than 160 cases of CJD after implantation of dura
frequently cause variable phenotypes ranging from a mater grafts have been recorded. All of the grafts were
 512 thought to have been acquired from a single manufac- conformation and glycosylation of PrPSc. One scenario
turer whose preparative procedures were inadequate to suggests that a particular conformation of bovine PrPSc
inactivate human prions. One case of CJD occurred was selected for heat resistance during the rendering
after repair of an eardrum perforation with a peri- process and was then reselected multiple times as cattle
cardium graft. infected by ingesting prion-contaminated meat and
bone meal (MBM) were slaughtered and their offal ren-
Human Growth Hormone and Pituitary dered into more MBM.
Gonadotropin Therapy
The possibility of transmission of CJD from contami- NEUROPATHOLOGY
nated human growth hormone (hGH) preparations Frequently the brains of patients with CJD have no rec-
derived from human pituitaries has been raised by the ognizable abnormalities on gross examination. Patients
occurrence of fatal cerebellar disorders with dementia in who survive for several years have variable degrees of
>180 patients ranging from 10 to 41 years of age.These cerebral atrophy.
patients received injections of hGH every 24 days for On light microscopy, the pathologic hallmarks of
412 years. If it is assumed that these patients developed CJD are spongiform degeneration and astrocytic gliosis.
CJD from injections of prion-contaminated hGH The lack of an inammatory response in CJD and other
SECTION III

preparations, the possible incubation periods range from prion diseases is an important pathologic feature of these
4 to 30 years. Even though several investigations argue degenerative disorders. Spongiform degeneration is
for the efcacy of inactivating prions in hGH fractions characterized by many 1- to 5-m vacuoles in the neu-
prepared from human pituitaries with 6 M urea, it seems ropil between nerve cell bodies. Generally the spongi-
doubtful that such protocols will be used for purifying form changes occur in the cerebral cortex, putamen,
hGH because recombinant hGH is available. Four cases caudate nucleus, thalamus, and molecular layer of the
Diseases of the Central Nervous System

of CJD have occurred in women receiving human pitu- cerebellum. Astrocytic gliosis is a constant but nonspe-
itary gonadotropin. cic feature of prion diseases. Widespread proliferation
of brous astrocytes is found throughout the gray matter
VARIANT CJD of brains infected with CJD prions. Astrocytic processes
lled with glial laments form extensive networks.
The restricted geographic occurrence and chronology Amyloid plaques have been found in ~10% of CJD
of vCJD raised the possibility that BSE prions have been cases. Puried CJD prions from humans and animals
transmitted to humans through the consumption of exhibit the ultrastructural and histochemical characteris-
tainted beef. More than 190 cases of vCJD have tics of amyloid when treated with detergents during
occurred, with >90% of these in Britain. vCJD has also limited proteolysis. In rst passage from some human
been reported in people either living in or originating Japanese CJD cases, amyloid plaques have been found in
from France, Ireland, Italy, Netherlands, Portugal, Spain, mouse brains. These plaques stain with antibodies raised
Saudi Arabia, United States, Canada, and Japan. against PrP.
Because the number of vCJD cases is still small, it not The amyloid plaques of GSS disease are morpholog-
possible to decide if we are at the beginning of a prion ically distinct from those seen in kuru or scrapie. GSS
disease epidemic in Europe, similar to those seen for BSE plaques consist of a central dense core of amyloid sur-
and kuru, or if the number of vCJD cases will remain rounded by smaller globules of amyloid. Ultrastruc-
small. What is certain is that prion-tainted meat should turally, they consist of a radiating fibrillar network of
be prevented from entering the human food supply. amyloid fibrils, with scant or no neuritic degeneration.
The most compelling evidence that vCJD is caused by The plaques can be distributed throughout the brain
BSE prions was obtained from experiments in mice but are most frequently found in the cerebellum. They
expressing the bovine PrP transgene. Both BSE and vCJD are often located adjacent to blood vessels. Con-
prions were efciently transmitted to these transgenic gophilic angiopathy has been noted in some cases of
mice and with similar incubation periods. In contrast to GSS disease.
sCJD prions, vCJD prions did not transmit disease ef- In vCJD, a characteristic feature is the presence of
ciently to mice expressing a chimeric human-mouse PrP orid plaques.These are composed of a central core of
transgene. Earlier studies with nontransgenic mice sug- PrP amyloid, surrounded by vacuoles in a pattern sug-
gested that vCJD and BSE might be derived from the gesting petals on a ower.
same source because both inocula transmitted disease
with similar but very long incubation periods.
Attempts to determine the origin of BSE and vCJD
CLINICAL FEATURES
prions have relied on passaging studies in mice, some of Nonspecic prodromal symptoms occur in about a third
which are described above, as well as studies of the of patients with CJD and may include fatigue, sleep
disturbance, weight loss, headache, malaise, and ill- usually a prominent and presenting feature, with demen- 513
dened pain. Most patients with CJD present with tia occurring late in the disease course. GSS disease typi-
decits in higher cortical function. These decits almost cally presents earlier than CJD (mean age 43 years) and
always progress over weeks or months to a state of pro- is typically more slowly progressive than CJD; death
found dementia characterized by memory loss, impaired usually occurs within 5 years of onset. FFI is character-
judgment, and a decline in virtually all aspects of intel- ized by insomnia and dysautonomia; dementia occurs
lectual function. A few patients present with either only in the terminal phase of the illness. Rare sporadic
visual impairment or cerebellar gait and coordination cases have been identied. vCJD has an unusual clinical
decits. Frequently the cerebellar decits are rapidly fol- course, with a prominent psychiatric prodrome that may
lowed by progressive dementia. Visual problems often include visual hallucinations and early ataxia, while
begin with blurred vision and diminished acuity, rapidly frank dementia is usually a late sign of vCJD.
followed by dementia.
Other symptoms and signs include extrapyramidal DIFFERENTIAL DIAGNOSIS
dysfunction manifested as rigidity, masklike facies, or
choreoathetoid movements; pyramidal signs (usually Many conditions may mimic CJD supercially. Demen-
mild); seizures (usually major motor) and, less com- tia with Lewy bodies (Chap. 23) is the most common
monly, hypoesthesia; supranuclear gaze palsy; optic atro- disorder to be mistaken for CJD. It can present in a sub-

CHAPTER 38
phy; and vegetative signs such as changes in weight, tem- acute fashion with delirium, myoclonus, and extrapyra-
perature, sweating, or menstruation. midal features. Other neurodegenerative disorders to
consider include AD, frontotemporal dementia, progres-
sive supranuclear palsy, ceroid lipofuscinosis (Chap. 23),
Myoclonus and myoclonic epilepsy with Lafora bodies (Chap. 20).
The absence of abnormalities on diffusion-weighted and
Most patients (~90%) with CJD exhibit myoclonus that

Prion Diseases
FLAIR MRI will usually distinguish these dementing
appears at various times throughout the illness. Unlike
conditions from CJD.
other involuntary movements, myoclonus persists during
Hashimotos encephalopathy, which presents as a sub-
sleep. Startle myoclonus elicited by loud sounds or bright
acute progressive encephalopathy with myoclonus and
lights is frequent. It is important to stress that myoclonus
periodic triphasic complexes on the EEG, should be
is neither specic nor conned to CJD. Dementia with
excluded in every case of suspected CJD. It is diagnosed
myoclonus can also be due to Alzheimers disease (AD)
by the nding of high titers of antithyroglobulin or
(Chap. 23), dementia with Lewy bodies (Chap. 23), cryp-
antithyroid peroxidase (antimicrosomal) antibodies in
tococcal encephalitis, or the myoclonic epilepsy disorder
the blood and improves with glucocorticoid therapy.
Unverricht-Lundborg disease (Chap. 20).
Unlike CJD, uctuations in severity typically occur in
Hashimotos encephalopathy.
Clinical Course Intracranial vasculitides may produce nearly all of the
symptoms and signs associated with CJD, sometimes
In documented cases of accidental transmission of CJD without systemic abnormalities. Myoclonus is excep-
to humans, an incubation period of 1.52.0 years pre- tional with cerebral vasculitis, but focal seizures may con-
ceded the development of clinical disease. In other cases, fuse the picture. Prominent headache, absence of
incubation periods of up to 30 years have been sug- myoclonus, stepwise change in decits, abnormal CSF,
gested. Most patients with CJD live 612 months after and focal white matter changes on MRI or angiographic
the onset of clinical signs and symptoms, whereas some abnormalities all favor vasculitis.
live for up to 5 years. Paraneoplastic conditions, particularly limbic encephali-
tis and cortical encephalitis, can also mimic CJD. In many
of these patients, dementia appears prior to the diagnosis
DIAGNOSIS
of a tumor, and in some, no tumor is ever found. Detec-
The constellation of dementia, myoclonus, and periodic tion of the paraneoplastic antibodies is often the only way
electrical bursts in an afebrile 60-year-old patient gener- to distinguish these cases from CJD.
ally indicates CJD. Clinical abnormalities in CJD are Other diseases that can simulate CJD include neu-
conned to the CNS. Fever, elevated sedimentation rate, rosyphilis, AIDS dementia complex (Chap. 37), progressive
leukocytosis in blood, or a pleocytosis in cerebrospinal multifocal leukoencephalopathy (Chap. 35), subacute scle-
uid (CSF) should alert the physician to another etiol- rosing panencephalitis, progressive rubella panencephalitis,
ogy to explain the patients CNS dysfunction. herpes simplex encephalitis, diffuse intracranial tumor
Variations in the typical course appear in inherited (gliomatosis cerebri; Chap. 32), anoxic encephalopathy,
and transmitted forms of the disease. fCJD has an earlier dialysis dementia, uremia, hepatic encephalopathy, and
mean age of onset than sCJD. In GSS disease, ataxia is lithium or bismuth intoxication.
 514 LABORATORY TESTS
The only specic diagnostic tests for CJD and other
human prion diseases measure PrPSc. The most widely
used method involves limited proteolysis that generates
PrP 27-30, which is detected by immunoassay after
denaturation. The conformation-dependent immunoas-
say (CDI) is based on immunoreactive epitopes that are
exposed in PrPC but buried in PrPSc. The CDI is
extremely sensitive and quantitative and is likely to nd
wide application in both the post- and antemortem
detection of prions. In humans, the diagnosis of CJD
can be established by brain biopsy if PrPSc is detected. If
no attempt is made to measure PrPSc, but the constella-
tion of pathologic changes frequently found in CJD is
seen in a brain biopsy, then the diagnosis is reasonably
secure (see Neuropathology, above). Because PrPSc is
SECTION III

not uniformly distributed throughout the CNS, the FIGURE 38-3

apparent absence of PrPSc in a limited sample such as a T2-weighted (FLAIR) MRI showing hyperintensity in the cor-
biopsy does not rule out prion disease. At autopsy, suf- tex in a patient with sporadic CJD. This so-called cortical
cient brain samples should be taken for both PrPSc ribboning along with increased intensity in the basal ganglia
immunoassay, preferably by CDI, and immunohisto- on T2 or diffusion-weighted imaging can aid in the diagnosis
chemistry of tissue sections. of CJD.
To establish the diagnosis of either sCJD or familial
Diseases of the Central Nervous System

prion disease, sequencing the PRNP gene must be per-

formed. Finding the wild-type PRNP gene sequence
permits the diagnosis of sCJD if there is no history to stereotyped periodic bursts of <200 ms duration, occur-
suggest infection from an exogenous source of prions. ring every 12 s, makes the diagnosis of CJD very likely.
The identication of a mutation in the PRNP gene These discharges are frequently but not always symmet-
sequence that encodes a nonconservative amino acid ric; there may be a one-sided predominance in ampli-
substitution argues for familial prion disease. tude. As CJD progresses, normal background rhythms
CT may be normal or show cortical atrophy. MRI is become fragmentary and slower.
valuable for distinguishing sCJD from most other condi-
tions. On FLAIR sequences and diffusion-weighted
CARE OF CJD PATIENTS
imaging, ~90% of patients show increased intensity in
the basal ganglia and cortical ribboning (Fig. 38-3).This Although CJD should not be considered either conta-
pattern is not seen with other neurodegenerative disor- gious or communicable, it is transmissible. The risk of
ders but has been seen infrequently with viral accidental inoculation by aerosols is very small; nonethe-
encephalitis, paraneoplastic syndromes, or seizures.When less, procedures producing aerosols should be performed
the typical MRI pattern is present, in the proper clinical in certied biosafety cabinets. Biosafety level 2 practices,
setting, diagnosis is facilitated. However, some cases of containment equipment, and facilities are recommended
sCJD do not show this typical pattern, and other early by the Centers for Disease Control and Prevention and
diagnostic approaches are still needed. the National Institutes of Health. The primary problem
CSF is nearly always normal but may show protein in caring for patients with CJD is the inadvertent infec-
elevation and, rarely, mild pleocytosis. Although the tion of health care workers by needle and stab wounds.
stress protein 14-3-3 is elevated in the CSF of some The transmission of prions through the air has never
patients with CJD, similar elevations of 14-3-3 are found been documented. Electroencephalographic and elec-
in patients with other disorders; thus this elevation is not tromyographic needles should not be reused after studies
specic. on patients with CJD have been performed.
The EEG is often useful in the diagnosis of CJD, There is no reason for pathologists or other morgue
although only about 60% of individuals show the typical employees to resist performing autopsies on patients
pattern. During the early phase of CJD, the EEG is usu- whose clinical diagnosis was CJD. Standard microbio-
ally normal or shows only scattered theta activity. In logic practices outlined here, along with specic recom-
most advanced cases, repetitive, high-voltage, triphasic, mendations for decontamination, seem to be adequate
and polyphasic sharp discharges are seen, but in many precautions for the care of patients with CJD and the
cases their presence is transient. The presence of these handling of infected specimens.
DECONTAMINATION OF CJD PRIONS such antibodies in mice, either administered by injection 515
or produced from a transgene, have been shown to pre-
Prions are extremely resistant to common inactivation
vent prion disease when prions are introduced by a
procedures, and there is some disagreement about the
peripheral route, such as intraperitoneal inoculation.
optimal conditions for sterilization. Some investigators
Unfortunately, the antibodies were ineffective in mice
recommend treating CJD-contaminated materials once
inoculated intracerebrally with prions. Several drugs,
with 1 N NaOH at room temperature, but we believe
including pentosan polysulfate and porphyrin deriva-
this procedure may be inadequate for sterilization. Auto-
tives, delay the onset of disease in animals inoculated
claving at 134C for 5 h or treatment with 2 N NaOH
intracerebrally with prions if the drugs are given intrac-
for several hours is recommended for sterilization of
erebrally beginning soon after inoculation.
prions. The term sterilization implies complete destruc-
Structure-based drug design predicated on dominant-
tion of prions; any residual infectivity can be hazardous.
negative inhibition of prion formation has produced
Recent studies show that sCJD prions bound to stainless
several promising compounds. Modied quinacrine
steel surfaces are resistant to inactivation by autoclaving
compounds that are more potent than the parent drug
at 134C for 2 h; exposure of bound prions to an acidic
have been found. Whether improving the efcacy of
detergent solution prior to autoclaving rendered prions
such small molecules will provide general methods for
susceptible to inactivation.
developing novel therapeutics for other neurodegenera-

CHAPTER 38
tive disorders, including AD and Parkinsons disease as
PREVENTION AND THERAPEUTICS well as amyotrophic lateral sclerosis (ALS), remains to be
established.
There is no known effective therapy for preventing or
Disclosure: SBP has a nancial interest in InPro Biotech-
treating CJD. The nding that phenothiazines and
nology, Inc.
acridines inhibit PrPSc formation in cultured cells led to
clinical studies of quinacrine in CJD patients. Although

Prion Diseases
quinacrine seems to slow the rate of decline in some
FURTHER READINGS
CJD patients, no cure of the disease has been observed.
In wild-type mice, quinacrine treatment has been inef- HEAD MW, IRONSIDE JW: Sporadic Creutzfeldt-Jakob disease: dis-
fective. Recent studies indicate that inhibition of the crete subtypes or a spectrum of disease? 132:2627, 2009
PRUSINER SB: Prions, in Fields Virology, 5th ed., DM Knipe, PM
P-glycoprotein (Pgp) transport system results in substan-
Howley (eds.), Philadelphia, Lippincott Williams & Wilkins,
tially increased quinacrine levels in the brains of mice. 2007, pp 30593092
Whether such an approach can be used to treat CJD SAFAR JG et al: Diagnosis of human prion disease. Proc Natl Acad Sci
remains to be established. USA 102:3501, 2005
Like the acridines, anti-PrP antibodies have been WILL RG et al: Diagnosis of new variant Creutzfeldt-Jakob disease.
shown to eliminate PrPSc from cultured cells. Additionally, Ann Neurol 47:575, 2000
 CHAPTER 39

PARANEOPLASTIC NEUROLOGIC SYNDROMES

Josep Dalmau I Myrna R. Rosenfeld

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516 Paraneoplastic Peripheral Neuropathies . . . . . . . . . . . . . . . . 523

Paraneoplastic Encephalomyelitis and Focal Encephalitis . . . 519 Lambert-Eaton Myasthenic Syndrome . . . . . . . . . . . . . . . . . 523
Paraneoplastic Cerebellar Degeneration . . . . . . . . . . . . . . . . 521 Myasthenia Gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
Paraneoplastic Opsoclonus-Myoclonus Syndrome . . . . . . . . 521 Polymyositis-Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . 523
Paraneoplastic Syndromes of the Spinal Cord . . . . . . . . . . . 522 Acute Necrotizing Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . 524
Paraneoplastic Stiff-Person Syndrome . . . . . . . . . . . . . . . . . 522 Paraneoplastic Visual Syndromes . . . . . . . . . . . . . . . . . . . . . 524
Paraneoplastic Sensory Neuronopathy or Dorsal Root I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
Ganglionopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522

Paraneoplastic neurologic disorders (PNDs) are cancer- function and leading to neuronal apoptosis. In addition
related syndromes that can affect any part of the nervous to onconeuronal antibodies, most PNDs of the CNS are
system (Table 39-1). They are remote effects of cancer, associated with inltrates of CD4+ and CD8+ T cells,
caused by mechanisms other than metastasis or by any of microglial activation, gliosis, and variable neuronal loss.
the complications of cancer such as coagulopathy, stroke, The inltrating T cells are often in close contact with
metabolic and nutritional conditions, infections, and side neurons undergoing degeneration, suggesting a primary
effects of cancer therapy. In 60% of patients the neuro- pathogenic role. T cellmediated cytotoxicity may con-
logic symptoms precede the cancer diagnosis. Overall, tribute directly to cell death in these PNDs. Thus both
clinically disabling PNDs occur in 0.51% of all cancer humoral and cellular immune mechanisms participate
patients, but they occur in 23% of patients with neu- in the pathogenesis of many PNDs. This complex
roblastoma or small cell lung cancer (SCLC), and in immunopathogenesis may underlie the resistance of many
3050% of patients with thymoma or sclerotic of these conditions to therapy.
myeloma. Neuronal cell-surface antigens can be the target of
antibodies in some patients with paraneoplastic
encephalitis. A few of these antigens have been identi-
PATHOGENESIS
ed, including the NR1/NR2 subunits of NMDA
Most PNDs are mediated by immune responses triggered receptors (Fig. 39-1) and voltage-gated potassium chan-
by neuronal proteins (onconeuronal antigens) expressed nels (VGKC). These disorders are more responsive to
by tumors. In PNDs of the central nervous system immunotherapy than those associated with immune
(CNS), many antibody-associated immune responses have responses to intracellular antigens.
been identied (Table 39-2). These antibodies usually Only four of the antibodies listed in Table 39-2 have
react with the patients tumor, and their detection in been shown to play a direct pathogenic role in PNDs; all
serum or cerebrospinal uid (CSF) strongly predicts the produce distinctive disorders of the peripheral nervous
presence of cancer. The target antigens are usually intra- system. These are: antibodies to P/Q-type voltage-gated
cellular proteins with roles in neuronal development and calcium channels (VGCC) in patients with the Lambert-
function. Some of the antibodies react with epitopes Eaton myasthenic syndrome (LEMS); antibodies to
located in critical protein domains, disrupting protein acetylcholine receptors in patients with myasthenia

516
TABLE 39-1 In addition, many patients with typical PND syndromes 517
PARANEOPLASTIC SYNDROMES OF THE NERVOUS are antibody-negative.
SYSTEM For still other PNDs, the cause remains quite obscure.
Syndromes of the brain, brainstem, and cerebellum
These include, among others, several neuropathies that
Focal encephalitis occur in the terminal stages of cancer and a number of
Cortical encephalitis neuropathies associated with plasma cell dyscrasias or
Limbic encephalitis lymphoma without evidence of inammatory inltrates
Brainstem encephalitis or deposits of immunoglobulin, cryoglobulin, or amyloid.
Cerebellar dysfunction
Autonomic dysfunction
Paraneoplastic cerebellar degeneration
Opsoclonus-myoclonus
Syndromes of the spinal cord Approach to the Patient:
Subacute necrotizing myelopathy PARANEOPLASTIC NEUROLOGIC
Motor neuron dysfunction DISORDERS
Myelitis
The diagnosis and management of PNDs may be dif-
Stiff-person syndrome
Syndromes of dorsal root ganglia
cult for several reasons. First, it is common for

CHAPTER 39
Sensory neuronopathy symptoms to appear before the presence of a tumor is
Multiple levels of involvement known. Second, the neurologic syndrome can evolve
Encephalomyelitisa, sensory neuronopathy, autonomic in a rapidly progressive fashion, producing a severe
dysfunction and usually irreversible neurologic decit in a short
Syndromes of peripheral nerve period of time. There is evidence that prompt tumor
Chronic and subacute sensorimotor peripheral control improves the course of PNDs. Therefore, the
neuropathy
major concern of the physician is to recognize a dis-

Paraneoplastic Neurologic Syndromes

Vasculitis of nerve and muscle
Neuropathy associated with malignant monoclonal order promptly as paraneoplastic in order to identify
gammopathies and treat the tumor.
Peripheral nerve hyperexcitability
Autonomic neuropathy PND OF THE CENTRAL NERVOUS SYSTEM
Syndromes of the neuromuscular junction AND DORSAL ROOT GANGLIA When symp-
Lambert-Eaton myasthenic syndrome toms involve brain, spinal cord, or dorsal root ganglia,
Myasthenia gravis
the suspicion of PND is usually based on a combina-
Syndromes of the muscle
Polymyositis/dermatomyositis
tion of clinical, radiologic, and CSF ndings. In these
Acute necrotizing myopathy cases, a biopsy of the affected tissue is often difcult to
Syndromes affecting the visual system obtain, and although useful to rule out other disorders
Cancer-associated retinopathy (CAR) (e.g., metastasis, infection), neuropathologic ndings
Melanoma-associated retinopathy (MAR) are not specic for PND. Furthermore, there are no
Uveitis (usually in association with encephalomyelitis) specic radiologic or electrophysiologic tests that are
diagnostic of PND.The presence of antineuronal anti-
a
Includes cortical, limbic, or brainstem encephalitis, cerebellar dys- bodies (Table 39-2) may help in the diagnosis with
function, myelitis.
the following caveats: (1) antibodies are detected in
only 6070% of PNDs of the CNS; (2) antibodies
may be present in both the serum and CSF, but in
some patients only the CSF is positive (especially with
gravis; antibodies to VGKC in some patients with antibodies to Tr and Ma proteins); (3) antibodies (usu-
peripheral nerve hyperexcitability (neuromyotonia); and ally at low titer) are present in a variable proportion of
antibodies to ganglionic acetylcholine receptors in some cancer patients without PND; (4) there is an imperfect
patients with autonomic neuropathy. Common features correlation between antibody titers and the course of
of these four antibodies are that they target cell-surface the neurologic disorder; (5) several antibodies may
molecules and that their passive transfer to animals repro- associate with a similar syndrome, with the antibody
duces the disorders. Plasma exchange or immunomodu- specicity often correlating with the tumor type (e.g.,
lation with intravenous immunoglobulin (IVIg) usually cerebellar degeneration is associated with anti-Tr anti-
produces neurologic improvement. Each of these disor- bodies if the tumor is Hodgkins disease but with anti-
ders can occur without cancer, and therefore detection of Yo antibodies if the tumor is ovarian or breast cancer);
these antibodies does not predict the presence of cancer. and (6) several antibodies may be present in the serum
Other PNDs are likely immune-mediated, although or CSF of the same patient (e.g., anti-Hu and anti-
their antigens are unknown. These include several CV2/CRMP5).
syndromes of inammatory neuropathies and myopathies.
 518 TABLE 39-2
PARANEOPLASTIC ANTINEURONAL ANTIBODIES, ASSOCIATED SYNDROMES AND CANCERS

ANTIBODY SYNDROME ASSOCIATED CANCERS

Anti-Hu (ANNA-1) PEM (including cortical, limbic, brainstem SCLC, other neuroendocrine tumors
encephalitis, cerebellar dysfunction,
myelitis), PSN, autonomic dysfunction
Anti-Yo (PCA-1) PCD Ovary and other gynecologic cancers, breast
Anti-Ri (ANNA-2) PCD, brainstem encephalitis, Breast, gynecological, SCLC
opsoclonus-myoclonus
Anti-Tr PCD Hodgkins lymphoma
Anti-Zic PCD, encephalomyelitis SCLC and other neuroendocrine tumors
Anti-CV2/CRMP5 PEM, PCD, chorea, peripheral SCLC, thymoma, other
neuropathy, uveitis
Anti-Ma proteinsa Limbic, hypothalamic, brainstem Germ-cell tumors of testis, lung cancer,
encephalitis (infrequently PCD) other solid tumors
Anti-NR1/NR2 subunits Encephalitis with prominent psychiatric Ovarian teratoma
of NMDA receptor symptoms, seizures, hypoventilation
Anti-amphiphysin Stiff-person syndrome, PEM Breast, SCLC
SECTION III

Anti-VGCCb LEMS, PCD SCLC, lymphoma

Anti-AChRb MG Thymoma
Anti-VGKCb Peripheral nerve hyperexcitability Thymoma, SCLC, others
(neuromyotonia), limbic encephalitis
Anti-recoverin Cancer-associated retinopathy (CAR) SCLC and other
Anti-bipolar cells of the retina Melanoma-associated retinopathy (MAR) Melanoma
Diseases of the Central Nervous System

a
Patients with antibodies to Ma2 are usually men with testicular cancer. Patients with additional antibodies to other Ma proteins are men or
women with a variety of solid tumors.
b
These antibodies can occur with or without a cancer association.
Note: PEM: paraneoplastic encephalomyelitis; PCD, paraneoplastic cerebellar degeneration; PSN, paraneoplastic sensory neuronopathy; LEMS,
Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; VGCC, voltage-gated calcium channel; AChR, acetylcholine receptor; VGKC,
voltage-gated potassium channel; SCLC, small-cell lung cancer; NMDA, N-methyl-D-aspartate.

FIGURE 39-1
Antibodies to NR1/NR2 subunits of the NMDA receptor layer, which is highly enriched in dendritic processes.
in a patient with paraneoplastic encephalitis and ovarian Panel B shows the antibody reactivity with cultures of rat
teratoma. Panel A is a section of dentate gyrus of rat hip- hippocampal neurons; the intense green immunolabeling is
pocampus immunolabeled (brown staining) with the patients due to the antibodies against the NR1/NR2 subunits of
antibodies. The reactivity predominates in the molecular NMDA receptors.
 MRI and CSF studies are important to rule out cancer screenings in this situation. Serum and urine 519
neurologic complications due to the direct spread of immunoxation studies should be considered in
cancer, particularly metastatic and leptomeningeal dis- patients with peripheral neuropathy of unknown
ease. In most PNDs the MRI ndings are nonspecic. cause; detection of a monoclonal gammopathy suggests
Paraneoplastic limbic encephalitis is usually associated the need for additional studies to uncover a B cell or
with characteristic MRI abnormalities in the mesial plasma cell malignancy. In paraneoplastic neuropathies,
temporal lobes (see later), but similar ndings can diagnostically useful antineuronal antibodies are limited
occur with other disorders [e.g., nonparaneoplastic to anti-CV2/CRMP5 and anti-Hu.
limbic encephalitis with antibodies to VGKC, human For any type of PND, if antineuronal antibodies are
herpesvirus (HHV) 6 encephalitis] (Fig. 39-2). The negative, the diagnosis relies on the demonstration of
CSF prole of patients with PND of the CNS or dor- cancer and the exclusion of other cancer-related or
sal root ganglia typically consists of mild to moderate independent neurologic disorders. Body PET scans
pleocytosis (<200 mononuclear cells, predominantly often uncover tumors undetected by other tests.
lymphocytes), an increase in the protein concentra-
tion, intrathecal synthesis of IgG, and a variable pres-
ence of oligoclonal bands.

CHAPTER 39
PND OF NERVE AND MUSCLE If symptoms SPECIFIC PARANEOPLASTIC
involve peripheral nerve, neuromuscular junction, or NEUROLOGIC SYNDROMES ( Table 39-3)
muscle, the diagnosis of a specic PND is usually
PARANEOPLASTIC ENCEPHALOMYELITIS
established on clinical, electrophysiologic, and patho-
AND FOCAL ENCEPHALITIS
logic grounds. The clinical history, accompanying
symptoms (e.g., anorexia, weight loss), and type of syn- The term encephalomyelitis describes an inammatory

Paraneoplastic Neurologic Syndromes

drome dictate the studies and degree of effort needed process with multifocal involvement of the nervous sys-
to demonstrate a neoplasm. For example, the frequent tem, including brain, brainstem, cerebellum, and spinal
association of LEMS with SCLC should lead to a chest cord. It is often associated with dorsal root ganglia and
and abdomen CT or body positron emission tomogra- autonomic dysfunction. For any given patient, the clini-
phy (PET) scan and, if negative, periodic tumor cal manifestations are determined by the area or areas
screening for at least 3 years after the neurologic diag- predominantly involved, but pathology almost always
nosis. In contrast, the weak association of polymyositis reveals abnormalities (inammatory inltrates, neuronal
with cancer calls into question the need for repeated loss, gliosis) beyond the symptomatic regions. Several
clinicopathologic syndromes may occur alone or in
combination: (1) cortical encephalitis, which may present as
epilepsia partialis continua; (2) limbic encephalitis, char-
acterized by confusion, depression, agitation, anxiety,
severe short-term memory decits, partial complex
seizures, and dementia; the MRI usually shows unilateral
or bilateral medial temporal lobe abnormalities, best
seen with T2 and uid-attenuated inversion recovery
sequences, and occasionally enhancing with gadolinium;
(3) brainstem encephalitis, resulting in eye movement dis-
orders (nystagmus, opsoclonus, supranuclear or nuclear
paresis), cranial nerve paresis, dysarthria, dysphagia, and
central autonomic dysfunction; (4) cerebellar gait and limb
ataxia; (5) myelitis, which may cause lower or upper
motor neuron symptoms, myoclonus, muscle rigidity,
and spasms; and (6) autonomic dysfunction as a result of
involvement of the neuraxis at multiple levels, including
hypothalamus, brainstem, and autonomic nerves (see
autonomic neuropathy). Cardiac arrhythmias, postural
hypotension, or central hypoventilation are frequent
FIGURE 39-2 causes of death in patients with encephalomyelitis.
Fluid-attenuated inversion recovery sequence MRI of a Paraneoplastic encephalomyelitis and focal encephali-
patient with limbic encephalitis and voltage-gated potassium tis are usually associated with SCLC, but many other
channel antibodies. Note the abnormal hyperintensity involv- cancers have also been reported. Patients with SCLC
ing the medial aspect of the temporal lobes. and these syndromes usually have anti-Hu antibodies in
 520 TABLE 39-3
a
ANTIBODY-ASSOCIATED PARANEOPLASTIC AND NONPARANEOPLASTIC SYNDROMES

ANTIBODIES

PARANEOPLASTIC

SYNDROME FREQUENT INFREQUENT NONPARANEOPLASTIC

Limbic encephalitis Ma2, Hu, CV2/CRMP5, Tr, VGKC VGKC

anti-NR1/NR2 of
NMDA receptor
Cerebellar degeneration Yo, Tr, P/Q VGCC, Hu, Zic, mGluR1, MAZ Gliadin, GAD
Ri, CV2/CRMP5, Ma1-2
Hypothalamic, Ma2, Hu CV2/CRMP5
brainstem encephalitis
Encephalomyelitis Hu, Zic CV2/CRMP5, Ri, amphiphysin
Chorea CV2/CRMP5
Opsoclonus-myoclonus Ri Hu, Ma2, Yo,
SECTION III

Stiff-person syndrome Amphiphysin Gephyrin, Ri GAD

PNH (neuromyotonia) VGKC VGKC
Myasthenia gravis AChR AChR, MuSK
LEMS P/Q-type VGCC MysB P/Q-type VGCC
Sensory neuronopathy Hu
Axonal sensorimotor Hu, CV2/CRMP5 Monoclonal gammopathy
neuropathy (M protein)b
Diseases of the Central Nervous System

Autonomic neuropathy Hu CV2/CRMP5, ganglionic AChR Ganglionic AChR

Predominant sensory MAG, ganglioside antibodies: MAG, ganglioside antibodies,
demyelinating often present with often present with MGUS
neuropathy Waldenstrms
macroglobulinemia
Paraneoplastic Recoverin (CAR), Tubby-like protein 1, PNR Anti-enolase
retinopathy anti-bipolar cell
antibodies (MAR),
anti-enolase

a
Antibodies have been validated by more than one laboratory and/or the protein sequence of the target antigen is known.
b
The M protein usually does not have specic antibody activity.
Note: Italics indicate that commercial testing for these antibodies is not available. PNH, peripheral nerve hyperexcitability; CAR, cancer-associ-
ated retinopathy; MAR, melanoma-associated retinopathy; PNR, photoreceptor-specic nuclear receptor; MGUS, monoclonal gammopathy of
uncertain signicance; VGKC, voltage-gated potassium channel; GAD, glutamic acid decarboxylase; AChR, acetylcholine receptor; LEMS, Lam-
bert-Eaton myasthenic syndrome; VGCC, voltage-gated calcium channel; MAG, myelin-associated glycoprotein; NMDA, N-methyl-D-aspartate.

serum and CSF. Anti-CV2/CRMP5 antibodies occur less

frequently; some of these patients may develop chorea or Treatment:
uveitis. Antibodies to Ma proteins are associated with ENCEPHALITIS
limbic, hypothalamic and brainstem encephalitis and AND ENCEPHALOMYELITIS
occasionally with cerebellar symptoms (Fig. 39-3); some Most types of paraneoplastic encephalitis and
patients develop hypersomnia, cataplexy, and severe encephalomyelitis respond poorly to treatment. Stabiliza-
hypokinesia. MRI abnormalities are frequent, including tion of symptoms or partial neurologic improvement may
those described with limbic encephalitis and variable occasionally occur, particularly if there is a satisfactory
involvement of the hypothalamus, basal ganglia, or upper response of the tumor to treatment. The roles of plasma
brainstem. Antibodies to NR1/NR2 subunits of the exchange, IVIg, and immunosuppression have not been
NMDA receptor associate with a severe, potentially established. Approximately 30% of patients with anti-
lethal, but treatment-responsive encephalitis.The affected Ma2-associated encephalitis respond to treatment of the
patients are young women who develop combinations of tumor (usually a germ-cell neoplasm of the testis) and
psychiatric symptoms, seizures, dyskinesias, stupor and immunotherapy. Two other syndromes that are respon-
hypoventilation.The oncologic associations of these anti- sive to treatment of the tumor and immunotherapy are
bodies are shown in Table 39-2.
 521

FIGURE 39-3
MRI and tumor of a patient with anti-Ma2-associated brainstem. Panel C corresponds to a section of the patients
encephalitis. Panels A and B are uid-attenuated inversion orchiectomy incubated with a specic marker (Oct4) of
recovery MRI sequences showing abnormal hyperintensities germ-cell tumors. The positive (brown) cells correspond to
in the medial temporal lobes, hypothalamus and upper an intratubular germ-cell neoplasm.

CHAPTER 39
the encephalitis that associates with antibodies to the
Treatment:
NR1/NR2 subunits of NMDA receptors in patients with CEREBELLAR DEGENERATION
teratoma of the ovary, and the encephalitis that associ-
ates with VGKC antibodies in some patients with thy- A number of single case reports have described neu-

Paraneoplastic Neurologic Syndromes

moma or SCLC. rologic improvement after tumor removal, plasma
exchange, IVIg, cyclophosphamide, rituximab, or glu-
cocorticoids. However, large series of patients with
antibody-positive paraneoplastic cerebellar degenera-
PARANEOPLASTIC CEREBELLAR tion show that this disorder rarely improves with any
DEGENERATION treatment.
This disorder is often preceded by a prodrome that may
include dizziness, oscillopsia, blurry or double vision,
nausea, and vomiting. A few days or weeks later,
PARANEOPLASTIC OPSOCLONUS-
dysarthria, gait and limb ataxia, and variable dysphagia
MYOCLONUS SYNDROME
can appear.The examination usually shows downbeating
nystagmus and, rarely, opsoclonus. Brainstem dysfunc- Opsoclonus is a disorder of eye movement characterized
tion, upgoing toes, or a mild neuropathy may occur, but by involuntary, chaotic saccades that occur in all direc-
more often the symptoms and signs are restricted to the tions of gaze; it is frequently associated with myoclonus
cerebellum. Early in the course, MRI studies are usually and ataxia. Opsoclonus-myoclonus may be cancer-
normal; later, the MRI typically reveals cerebellar atro- related or idiopathic. When the cause is paraneoplastic,
phy. The disorder results from extensive degeneration of the tumors involved are usually cancer of the lung and
Purkinje cells, with variable involvement of other cere- breast in adults and neuroblastoma in children. The
bellar cortical neurons, deep cerebellar nuclei, and spin- pathologic substrate of opsoclonus-myoclonus is unclear.
ocerebellar tracts. The tumors more frequently involved Most SCLC patients do not have detectable antineu-
are SCLC, cancer of the breast and ovary, and Hodgkins ronal antibodies. A small subset of patients with ataxia,
lymphoma. opsoclonus, and other eye movement disorders develop
Anti-Yo antibodies in patients with breast and gyne- anti-Ri antibodies; in rare instances muscle rigidity,
cologic cancers and anti-Tr antibodies in patients with autonomic dysfunction, and dementia also occur. The
Hodgkins lymphoma are the two paraneoplastic anti- tumor most frequently involved in anti-Ri-associated
bodies typically associated with prominent or pure cere- syndromes is breast cancer.
bellar degeneration. Antibodies to P/Q-type VGCC If the tumor is not successfully treated, the paraneo-
occur in some patients with SCLC and cerebellar dys- plastic opsoclonus-myoclonus syndrome in adults often
function; only some of these patients develop LEMS. Of progresses to encephalopathy, coma, and death. In addi-
note, a variable degree of cerebellar dysfunction can be tion to treating the tumor, symptoms may respond to
associated with virtually any type of antibody-related immunotherapy (glucocorticoids, plasma exchange, and/
PND of the CNS (Table 39-2). or IVIg).
 522 At least 50% of children with opsoclonus-myoclonus sleep and general anesthetics. Electrophysiologic studies
have an underlying neuroblastoma. Hypotonia, ataxia, demonstrate continuous motor unit activity. Antibodies
behavioral changes, and irritability are frequent accom- associated with the stiff-person syndrome target proteins
panying symptoms. Many patients harbor antibodies to [glutamic acid decarboxylase (GAD), amphiphysin]
neuronal cell surface antigens of unknown identity. involved in the function of inhibitory synapses utilizing
Neurologic symptoms often improve with treatment of -aminobutyric acid (GABA) or glycine as neurotrans-
the tumor (including chemotherapy) and with glucocor- mitters. Paraneoplastic stiff-person syndrome and
ticoids, adrenocorticotropic hormone (ACTH), plasma amphiphysin antibodies are often related to breast can-
exchange, IVIg, and rituximab. Many patients are left cer. By contrast, antibodies to GAD may occur in some
with psychomotor retardation and behavioral and sleep cancer patients but are much more frequently present in
problems. the nonparaneoplastic disorder.

PARANEOPLASTIC SYNDROMES
OF THE SPINAL CORD Treatment:
The number of reports of paraneoplastic spinal cord STIFF-PERSON SYNDROME
syndromes, such as subacute motor neuronopathy and acute Optimal treatment of stiff-person syndrome requires
SECTION III

necrotizing myelopathy, has decreased in recent years. This therapy of the underlying tumor, glucocorticoids, and
may represent a true decrease in incidence, due to symptomatic use of drugs that enhance GABA-ergic
improved and prompt oncologic interventions, or may transmission (diazepam, baclofen, sodium valproate,
be because of the identication of nonparaneoplastic tiagabine, vigabatrin). A benet of IVIg has been demon-
etiologies. strated for the nonparaneoplastic disorder but remains
Some patients with cancer develop upper or lower to be established for the paraneoplastic syndrome.
Diseases of the Central Nervous System

motor neuron dysfunction or both, resembling amyotrophic

lateral sclerosis. It is unclear whether these disorders
have a paraneoplastic etiology or simply coincide with PARANEOPLASTIC SENSORY
the presence of cancer.There are isolated case reports of NEURONOPATHY OR DORSAL
cancer patients with motor neuron dysfunction who ROOT GANGLIONOPATHY
had neurologic improvement after tumor treatment. A This syndrome is characterized by sensory deficits that
more than coincidental association occurs between lym- may be symmetric or asymmetric, painful dysesthesias,
phoma and motor neuron dysfunction. A search for radicular pain, and decreased or absent reflexes. All
lymphoma should be undertaken in patients with a modalities of sensation and any part of the body includ-
motor neuron syndrome who are found to have a mon- ing face and trunk can be involved. Specialized sensations
oclonal protein in serum or CSF. such as taste and hearing can also be affected. Electro-
Paraneoplastic myelitis may present with upper or lower physiologic studies show decreased or absent sensory
motor neuron symptoms, segmental myoclonus, and nerve potentials with normal or near-normal motor
rigidity. This syndrome can appear as the presenting conduction velocities. Symptoms result from an inam-
manifestation of encephalomyelitis and may be associ- matory, likely immune-mediated, process that targets the
ated with SCLC and serum anti-Hu, anti-CV2/CRMP5, dorsal root ganglia, causing neuronal loss, proliferation of
or anti-amphiphysin antibodies. satellite cells, and secondary degeneration of the poste-
Paraneoplastic myelopathy can also produce several rior columns of the spinal cord. The dorsal nerve roots,
syndromes characterized by prominent muscle stiffness and less frequently the anterior nerve roots and periph-
and rigidity. The spectrum ranges from focal symptoms eral nerves, may also be involved.
in one or several extremities (stiff-limb syndrome or stiff-
person syndrome) to a disorder that also affects the brain-
stem (known as encephalomyelitis with rigidity) and likely Treatment:
has a different pathogenesis. SENSORY NEUROPATHY
This disorder often precedes or is associated with
PARANEOPLASTIC STIFF-PERSON encephalomyelitis and autonomic dysfunction and has
SYNDROME the same immunologic and oncologic associations, e.g.,
anti-Hu antibodies and SCLC. As with anti-Hu-associated
This disorder is characterized by progressive muscle
encephalomyelitis, the therapeutic approach focuses on
rigidity, stiffness, and painful spasms triggered by audi-
prompt treatment of the tumor. Glucocorticoids occa-
tory, sensory, or emotional stimuli. Rigidity mainly
sionally produce clinical stabilization or improvement.
involves the lower trunk and legs, but it can affect the
The benet of IVIg and plasma exchange is not proved.
upper extremities and neck. Symptoms improve with
PARANEOPLASTIC PERIPHERAL tumors involved. Pathology demonstrates axonal degen- 523
NEUROPATHIES eration and T cell inltrates involving the small vessels of
the nerve and muscle. Immunosuppressants (glucocorti-
These disorders may develop any time during the
coids and cyclophosphamide) often result in neurologic
course of the neoplastic disease. Neuropathies occurring
improvement.
at late stages of cancer or lymphoma usually cause mild
Peripheral nerve hyperexcitability (neuromyotonia, or Isaacs
to moderate sensorimotor decits due to axonal degen-
syndrome) is characterized by spontaneous and continuous
eration of unclear etiology.These neuropathies are often
muscle ber activity of peripheral nerve origin. Clinical
masked by concurrent neurotoxicity from chemotherapy
features include cramps, muscle twitching (fascicula-
and other cancer therapies. In contrast, the neuropathies
tions or myokymia), stiffness, delayed muscle relaxation
that develop in the early stages of cancer often show a
(pseudomyotonia), and spontaneous or evoked carpal or
rapid progression, sometimes with a relapsing and remit-
pedal spasms.The involved muscles may be hypertrophic,
ting course, and evidence of inammatory inltrates and
and some patients develop paresthesias and hyperhydrosis.
axonal loss or demyelination in biopsy studies. If
CNS dysfunction, including mood changes, sleep disor-
demyelinating features predominate (Chap. 34), IVIg or
der, or hallucinations, may occur. The electromyogram
glucocorticoids may improve symptoms. Occasionally
(EMG) shows brillations; fasciculations; and doublet,
anti-CV2/CRMP5 antibodies are present; detection of
triplet, or multiplet single unit (myokymic) discharges that

CHAPTER 39
anti-Hu suggests concurrent dorsal root ganglionitis.
have a high intraburst frequency. An immune pathogenesis
Guillain-Barr syndrome and brachial plexitis have occa-
is suggested by the frequent presence of serum antibod-
sionally been reported in patients with lymphoma, but
ies to VGKC.The disorder often occurs without cancer;
there is no clear evidence of a paraneoplastic association.
if paraneoplastic, benign and malignant thymomas and
Malignant monoclonal gammopathies include: (1) multiple
SCLC are the usual tumors. Phenytoin, carbamazepine,
myeloma and sclerotic myeloma associated with IgG
and plasma exchange improve symptoms.
or IgA monoclonal proteins; and (2) Waldenstrms

Paraneoplastic Neurologic Syndromes

Paraneoplastic autonomic neuropathy usually develops as a
macroglobulinemia, B cell lymphoma, and chronic B cell
component of other disorders, such as LEMS and
lymphocytic leukemia associated with IgM monoclonal
encephalomyelitis. It may rarely occur as a pure or pre-
proteins.These disorders may cause neuropathy by a vari-
dominantly autonomic neuropathy with adrenergic or
ety of mechanisms, including compression of roots and
cholinergic dysfunction at the pre- or postganglionic
plexuses by metastasis to vertebral bodies and pelvis,
levels. Patients can develop several life-threatening com-
deposits of amyloid in peripheral nerves, and paraneo-
plications, such as gastrointestinal paresis with pseudoob-
plastic mechanisms.The paraneoplastic variety has several
struction, cardiac dysrhythmias, and postural hypotension.
distinctive features. Approximately half of patients with
Other symptoms include dry mouth, erectile dysfunction,
sclerotic myeloma develop a sensorimotor neuropathy
anhidrosis, and sphincter dysfunction; abnormal pupillary
with predominantly motor decits, resembling a chronic
responses may be found. The disorder has been reported
inammatory demyelinating neuropathy (Chap. 41); some
to occur in association with several tumors, including
patients develop elements of the POEMS syndrome
SCLC, cancer of the pancreas or testis, carcinoid tumors,
(polyneuropathy, organomegaly, endocrinopathy, M protein,
and lymphoma. Because autonomic symptoms can also be
skin changes). Treatment of the plasmacytoma or sclerotic
the presenting feature of encephalomyelitis, serum anti-
lesions usually improves the neuropathy. In contrast, the
Hu and anti-CV2/CRMP5 antibodies should also be
sensorimotor or sensory neuropathy associated with multi-
sought. Serum antibodies to ganglionic acetylcholine
ple myeloma rarely responds to treatment. Between 5 and
receptors have been reported in this syndrome, but they
10% of patients with Waldenstrms macroglobulinemia
also occur without a cancer association. (See Chap. 28.)
develop a distal symmetric sensorimotor neuropathy with
predominant involvement of large sensory bers. These
patients may have IgM antibodies in their serum against LAMBERT-EATON MYASTHENIC
myelin-associated glycoprotein and various gangliosides SYNDROME
(Chap. 41). In addition to treating the Waldenstrms LEMS is discussed in Chap. 42.
macroglobulinemia, other therapies may improve the neu-
ropathy, including plasma exchange, IVIg, chlorambucil,
cyclophosphamide, udarabine, or rituximab. MYASTHENIA GRAVIS
Vasculitis of the nerve and muscle causes a painful sym- Myasthenia gravis is discussed in Chap. 42.
metric or asymmetric distal sensorimotor neuropathy
with variable proximal weakness. It predominantly
POLYMYOSITIS-DERMATOMYOSITIS
affects elderly men and is associated with an elevated ery-
throcyte sedimentation rate and increased CSF protein Polymyositis and dermatomyositis are discussed in detail
concentration. SCLC and lymphoma are the primary in Chap. 44.
 524 ACUTE NECROTIZING MYOPATHY photopsias that often progress to visual loss. The ERG
demonstrates reduction in the b-wave amplitude. Parane-
Patients with this syndrome develop myalgias and rapid
oplastic optic neuritis and uveitis are very uncommon
progression of weakness involving the extremities and
and can develop in association with encephalomyelitis.
the pharyngeal and respiratory muscles, often resulting
Some patients with paraneoplastic uveitis harbor anti-
in death. Serum muscle enzymes are elevated, and mus-
CV2/CRMP5 antibodies.
cle biopsy shows extensive necrosis with minimal or
Some paraneoplastic retinopathies are associated with
absent inammation and sometimes deposits of comple-
serum antibodies that specically react with the subset
ment.The disorder occurs as a paraneoplastic manifesta-
of retinal cells undergoing degeneration, supporting an
tion of a variety of cancers including SCLC and cancer
immune-mediated pathogenesis (Tables 39-2 and 39-3).
of the gastrointestinal tract, breast, kidney, and prostate,
Paraneoplastic retinopathies usually fail to improve with
among others. Glucocorticoids or treatment of the
treatment, although rare responses to glucocorticoids,
underlying tumor rarely control the disorder.
plasma exchange, and IVIg have been reported.
PARANEOPLASTIC VISUAL SYNDROMES
This group of disorders involves the retina and, less fre- FURTHER READINGS
quently, the uvea and optic nerves. The term cancer-
SECTION III

ANTOINE JC, CAMDESSANCH JP: Peripheral nervous system involve-

associated retinopathy is used to describe paraneoplastic cone ment in patients with cancer. Lancet Neurol 6:75, 2007
and rod dysfunction characterized by photosensitivity, pro- DALMAU J et al: Anti-NMDA-receptor encephalitis: case series and
gressive loss of vision and color perception, central or ring analysis of the effects of antibodies. Lancet Neurol. 8:1091, 2008
scotomas, night blindness, and attenuation of photopic and MATHEW RM et al: Orchiectomy for suspected microscopic tumor
scotopic responses in the electroretinogram (ERG). The in patients with anti-Ma2-associated encephalitis. Neurology
68:900, 2007
most commonly associated tumor is SCLC. Melanoma- ROSENFELD MR: Paraneoplastic syndromes of the CNS. Lancet
Diseases of the Central Nervous System

associated retinopathy affects patients with metastatic Neurol 7:327, 2008

cutaneous melanoma. Patients develop the acute onset of VEDELER CA, STORSTEIN A: Autoimmune limbic encephalitis. Acta
night blindness and shimmering, ickering, or pulsating Neurol Scand Suppl 189:63, 2009
 CHAPTER 40

PERIPHERAL NEUROPATHY

Vinay Chaudhry

Electrophysiologic Studies (See Chap. 3) . . . . . . . . . . . . . . . 529 Other Inherited Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . 544

Mononeuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530 Special Peripheral Neuropathy Presentations . . . . . . . . . . . . 546
Mononeuropathy Multiplex . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Autonomic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Polyneuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Pure Motor Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Diabetic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Pure Sensory Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Toxic Including Chemotherapy-Induced Neuropathies . . . . . . 535 Plexopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Nutritional Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538 Peripheral Nerve Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548
Infections and Peripheral Neuropathy . . . . . . . . . . . . . . . . . . 539 Peripheral Nerve Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Inherited Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . . . . . . . . 541

Peripheral neuropathy describes disorders of peripheral

nerves, including the dorsal or ventral nerve roots; dorsal Approach to the Patient:
root ganglia; brachial or lumbosacral plexus; cranial PERIPHERAL NEUROPATHY
nerves (except I and II); and other sensory, motor, auto- A stepwise approach to diagnosis is presented in
nomic, or mixed nerves; the term peripheral indicates that Fig. 40-1.The following questions should be addressed
the disorder is outside the central nervous system (brain initially:
and spinal cord). Peripheral neuropathy affects ~28% of
adults; the incidence increases with age. Evaluation 1. Is this a peripheral neuropathy? The initial symptoms
begins with a history focusing on the time course of the of peripheral neuropathy are often intermittent,
illness, symptoms, medical conditions that predispose to and examination can be normal. Patients may pre-
neuropathy (e.g., diabetes mellitus, connective tissue dis- sent with positive and/or negative symptoms
ease, nutritional deciency), toxic exposures (drug or (Table 40-1). In most situations, sensory symp-
environmental), and family history. Physical examination toms precede motor symptoms. Small-ber neu-
assesses the function of small sensory bers (pain and ropathies often present with dysesthesias and pares-
temperature), large sensory bers (vibration, propriocep- thesias, terms used interchangeably to describe
tion, reex changes), and/or motor nerves (weakness). unpleasant, unusual, or abnormal sensations such
The distribution of sensory, motor, and reex changes as burning or cutting pain, electric shocklike
determines whether the neuropathy is asymmetric or sensations, tingling, pins and needles, formication,
symmetric. Electrodiagnostic studies (EDx) help to clas- prickly feelings such as a limb falling asleep, or
sify the neuropathy into one of three major categories: cramp-like sensations (Chap. 12). Large-ber neu-
axonal, demyelinating, or neuronal. Focused laboratory ropathies can present as numbness, tingling, or a
tests are then performed based on the history, examina- gait disturbance (sensory ataxia). In most cases, the
tion, and EDx. An underlying cause can be identied in abnormal sensation originates in the toes and feet
~75% of neuropathies. and ascends proximally to the legs in a stocking

525
 526
Patient Complaint: Neuropathy

History and examination compatible with neuropathy?

Yes No

Evaluation of other
Mononeuropathy Mononeuropathy multiplex Polyneuropathy disorder or
reassurance and
follow up
EDx EDx EDx

Is the lesion axonal Axonal Demyelinating Axonal Demyelinating

or demyelinating? with focal
Is entrapment or conduction block
compression present? Consider
Is a contributing systemic vasculitis or
disorder present? other multifocal Subacute Chronic
Consider Uniform slowing, Nonuniform slowing,
process multifocal course (months) course (years)
chronic conduction block
SECTION III

form of
Decision on need CIDP
for surgery (nerve repair, Possible
transposition, or release Review history for toxins; Test for paraprotein,
nerve If chronic or If acute: GBS
procedure) test for associated if negative
biopsy Test for paraprotein, subacute: CIDP
systemic disease or
HIV, Lyme disease intoxication
Review family IVIg or
Treatment appropriate history; examine Treatment plasmapheresis;
for specific diagnosis If tests are family members; for CIDP; supportive
negative, consider Treatment appropriate genetic testing see Ch.41 care including
Diseases of the Central Nervous System

treatment for for specific diagnosis respiratory assistance

CIDP
Genetic counseling if appropriate

FIGURE 40-1
Approach to the evaluation of peripheral neuropathies. CIDP, chronic inammatory demyelinating polyradiculoneuropathy;
GBS, Guillain-Barr syndrome.

TABLE 40-1
SYMPTOMS, SIGNS, AND TESTS IN PERIPHERAL NEUROPATHY

LARGE FIBER SMALL FIBER MOTOR AUTONOMIC

Symptoms
Numbness Pain: burning, shock-like, Cramps Decreased or increased
Pins and needles stabbing, prickling, Weak grip sweating
Tingling shooting, lancinating Footdrop Dry eyes, mouth,
Poor balance Allodynia Twitching Erectile dysfunction
Gastroparesis/diarrhea
Faintness, light-headedness
Signs
Decreased Decreased Reduced Orthostasis
Vibration Pin prick Strength Unequal pupil size
Joint-position sense Temperature sensation Reexes
Reexes
Tests
NCS-EMG Skin biopsy NCS-EMG QSART
Nerve biopsy QST Tilt table
LP Nerve biopsy R-R interval
Valsalva

Note: NCS-EMG, nerve conduction studies/electromyography; QSART, quantitative sudomotor axon reex testing;
QST, quantitative sensory test; LP, lumbar puncture.
 distribution. Only when the sensation reaches the 3. Which bers are affected? In a polyneuropathy, mani- 527
level of the knee or thigh do symptoms appear in festations can be classied as small-ber sensory,
the hands, producing a length-dependent, or large-ber sensory, motor, and/or autonomic
stocking-glove, pattern. Paresthesias that begin in (Table 40-3). Often there is overlap, but if there is
one hand suggest an entrapment neuropathy such predominant involvement of one ber group, the
as carpal tunnel syndrome. differential diagnosis and evaluation can be nar-
Motor symptoms usually have a later onset than rowed. For example, if a patient has burning pain in
sensory symptoms. In long-standing inherited neu- the feet, a small-ber neuropathy is likely and dia-
ropathies, patients may present with isolated weak- betes mellitus is a possible etiology. If a patient has
ness of the feet without sensory symptoms; the sensory ataxia, large bers are likely affected and
ankle jerk, the most distal deep tendon reex, is Sjgrens syndrome or a paraneoplastic process
invariably absent. When confronted with a length- should be considered.
dependent pattern of sensory symptoms, the diag- 4. What is the anatomic pattern? Clinical evaluation is
nosis of a peripheral neuropathy is not difcult. often helpful in categorizing a neuropathy as axonal,
However, in cases with pure motor weakness or
wasting, localization may be difcult, and in such
TABLE 40-3

CHAPTER 40
cases the presence of distal weakness is helpful in
differentiating a peripheral neuropathy from muscle CLASSIFICATION OF NEUROPATHY BY FIBER TYPE
or neuromuscular junction disorders, which typi- Small-ber sensory (painful neuropathies and dissociated
cally present with proximal weakness. Motor neu- sensory loss)
ron disease can also present with distal weakness Hereditary sensory neuropathies (early)
and wasting; however, the ndings are not in the Lepromatous leprosy
distribution of an individual nerve. Diabetic (includes glucose intolerance) small-ber

Peripheral Neuropathy
neuropathy
2. What is its distribution? Polyneuropathy involves
Amyloidosis
widespread and symmetric dysfunction of the Analphalipoproteinemia (Tangier disease)
peripheral nerves; mononeuropathy involves a single Fabrys disease (pain predominates)
peripheral nerve; multiple mononeuropathy involves Dysautonomia (Riley-Day syndrome)
multiple individual peripheral nerves (Table 40-2 HIV and antiretroviral therapy neuropathy
and Fig. 40-1). Mononeuropathies are usually due Large-ber sensory (ataxic-neuropathies)
to compression, trauma, or vascular causes. Multiple Sjgrens syndrome
mononeuropathies (also referred to as mononeuropa- Vitamin B12 neuropathy (from dorsal column involvement)
Cisplatin neuropathy
thy multiplex) can be a result of multiple entrap- Pyridoxine toxicity
ments, inltration, or vasculitis. Plexopathies (brachial Friedreichs ataxia
or lumbosacral) also involve multiple peripheral Small- and large-ber: Global sensory loss
nerves, in an asymmetric fashion. Carcinomatous sensory neuropathy
Hereditary sensory neuropathies (recessive and dominant)
Diabetic sensory neuropathy
Vacor intoxication
TABLE 40-2 Xanthomatous neuropathy of primary biliary cirrhosis
CLASSIFICATION OF NEUROPATHY BY LOCATION (tabes dorsalis)
Motor-predominant neuropathies
Polyneuropathy Multiple Mononeuropathy Immune neuropathies: acute (Guillain-Barr syndrome);
Fairly symmetric In distribution of single relapsing
Distal stocking-glove nerve(s) Heritable motor-sensory neuropathies
May or may not be painful Setting: diabetes, Acute intermittent porphyria
Sensorimotor pressure, vasculitis Diphtheritic neuropathy
Symmetrically decreased May or may not be painful Lead neuropathy
reexes Isolated reex loss Brachial neuritis
Plexopathy Not a Neuropathy Diabetic lumbosacralplexus neuropathy (diabetic
Asymmetric Upper motor neuron signs amyotrophy)
Painful onset (brisk reexes) Autonomic
Multiple nerves in a Prominent bladder and Acute: Acute pandysautonomic neuropathy, botulism,
single limb bowel involvement porphyria, GBS, vacore, amiodarone, vincristine
Rapid onset of weakness, Unilateral (arm, leg, face) Chronic: Amyloid, diabetes, Sjgrens, HSAN I and III
atrophy symptoms (Riley-Day), Chagas, paraneoplastic
Isolated reex loss Sensory level
Hyperventilation Note: GBS, Guillain-Barr syndrome; HSAN, hereditary sensory and
autonomic neuropathy.
 528 TABLE 40-4
CLASSIFICATION OF NEUROPATHY BY HISTOPATHOLOGY

DEMYELINATING AXONAL NEURONAL

Pattern Proximal = distal Distal > proximal; length- Non-length-dependent;

dependent UE, LE, face
Onset Acute/subacute Slow evolution Rapid
Symptoms Paresthesia and weakness Dysesthesias and distal Paresthesias, gait ataxia
weakness
Sensory signs Vibration and proprio- Pain and temperature Vibration and proprio-
ception > pain and affected > vibration and ception > pain and
temperature proprioception temperature
Motor Distal and proximal Distal weakness Proprioceptive weakness
weakness
DTRs Areexia Distal areexia Areexia
NCS Velocity affected > Amplitudes affected > Sensory amplitudes
amplitude velocity affected; radial > sural
Nerve biopsy Demyelination and Axonal degeneration and Axonal degeneration but
remyelination regeneration no regeneration
SECTION III

Prognosis Rapid recovery Slow recovery Poor recovery

Causes GBS, diphtheria, CIDP, Toxic, metabolic, HIV, Sjgrens, cisplatin,
DM, MMN CMT2, DM pyridoxine

Note: UE, LE, upper, lower extremities; DTRs, deep tendon reexes; NCS, nerve conduction studies; GBS, Guillain-Barr
syndrome; CIDP, chronic inammatory demyelinating neuropathy; DM, diabetes mellitus; MMN, multifocal motor neuropathy;
CMT, Charcot-Marie-Tooth.
Diseases of the Central Nervous System

TABLE 40-5
demyelinating, or neuronal [dorsal root ganglion
(DRG)] (Table 40-4). Most axonal neuropathies CLASSIFICATION OF NEUROPATHY BY TIME COURSE
follow a length-dependent (stocking-glove) pat- Acute
tern with sensory (small fiber more than large GBS, porphyria, toxic (triorthocresyl phosphate, vacor,
fiber) symptoms and signs predominating over thallium), diphtheria, brachial neuritis
motor manifestations; distal reflexes are absent. In Subacute
contrast, most demyelinating neuropathies affect Toxic (hexacarbon, acrylamid), angiopathic, nutritional,
alcoholic
motor fibers and sensory fibers (large fiber Chronic
more than small fiber) equally, and areflexia or Diabetic, CIDP, paraneoplastic, paraprotein
hyporeflexia is more generalized. DRG lesions Longstanding heritable
involve purely sensory fibers in a non-length- CMT, Friedreichs ataxia
dependent fashion; sensory ataxia and general- Recurrent
ized loss of reflexes are usually found. EDx studies Relapsing CIDP, porphyria, Refsums disease, HNPP
are also important in defining the anatomy of a
neuropathy. Note: GBS, Guillain-Barr syndrome; CIDP, chronic inammatory
demyelinating neuropathy; CMT, Charcot-Marie-Tooth (disease);
5. What is the time course? Rapidly evolving peripheral HNPP, hereditary neuropathy with pressure palsies.
neuropathies are usually inammatory [Guillain-
Barr syndrome (GBS)] or toxic in origin. Suba-
cute evolution suggests an inammatory, toxic, or
nutritional cause (Table 40-5). Chronic neu- chronic inflammatory demyelinating neuropathy
ropathies, especially those that are long-standing (CIDP), multifocal motor neuropathy, anti-myelin-
over many years, are usually hereditary, such as associated glycoprotein (MAG) neuropathy]; hered-
Charcot-Marie-Tooth (CMT) disease. itary (CMT); toxic (HIV drugs, anticancer drugs,
6. What is the likely etiology? It is helpful to consider alcohol, heavy metals, tick bite); vasculitic (pol-
potential etiologies by category: metabolic (diabetes yarteritis nodosa, Churg-Strauss syndrome, cryo-
mellitus, renal failure, amyloid, porphyria); infec- globulinemia, isolated vasculitis of the peripheral
tious [HIV, Lyme disease, cytomegalovirus (CMV), nervous system); paraneoplastic (especially lung);
syphilis, leprosy, diphtheria]; immune-mediated [GBS, nutritional (vitamin B12, B1, B6 deciencies); and
 TABLE 40-6 529
miscellaneous causes (celiac disease, Fabry disease,
hypothyroidism). TREATMENT OF PAINFUL NEUROPATHY
7. What tests are indicated? These may include fast- FIRST-LINE THERAPY
ing blood glucose and hemoglobin A1C (HbA1C);
serum vitamin B12; tests for systemic vasculitis or Antidepressants
Tricyclic
collagen vascular disease; measurement of neu- Amitriptyline, nortriptyline, imipramine, desimipramine,
ropathy-associated autoantibodies; urine screen doxepin (10150 mg qd)
for heavy metals; spinal fluid analysis; autonomic Serotonin-noradrenaline reuptake inhibitors (SNRI)
function testing (Chap. 28); and genetic tests for Duloxetine (60120 mg qd)
hereditary neuropathies. An impaired glucose Venlafaxine (150225 mg qd)
tolerance test is found in more than half of Antiepileptics
patients with idiopathic sensory neuropathy and Carbamazepine 100800 mg qd
Oxcarabazepine 12002400 mg qd
is more sensitive than tests of fasting glucose or
Lamotrigine 200400 mg qd
HbA1C. Diagnostic tests to further characterize Topiramate 300400 mg qd
the neuropathy include quantitative sensory test- Gabapentin 9003600 mg qd
ing, EDx studies, sural nerve biopsy, and muscle Pregabalin 150600 mg qd

CHAPTER 40
biopsy. Diagnostic tests and procedures are more Valproic acid 10001200 mg qd
likely to be informative in patients with asym- SECOND-LINE THERAPY
metric, motor-predominant, rapid-onset or Opioids
demyelinating neuropathies than in patients with Oxycodone 40160 mg qd
slowly evolving length-dependent sensory > Morphine 90360 mg qd PO
motor types. Tramadol 50400 mg qd
8. What treatment is appropriate? Treatment of the Fentanyl patch 2575 g/h q 3 days

Peripheral Neuropathy
underlying disorder, pain management, and support- Antiarrhythmics
ive care to protect and rehabilitate damaged tissue all Mexilitine 6001200 mg qd
Topical
need to be considered. Examples of therapies Capsaicin 0.075% topical tid or qid
directed at the underlying etiology include glycemic Lidocaine 5% patch bid
control for diabetic neuropathy, vitamin replacement Isosorbide dinitrate spray 30 mg qhs
for B12 deciency, immunosuppression for vasculitis, Others
surgery for entrapment neuropathy, enzyme replace- Clonidine 0.12.4 mg qd
ment for Fabry disease, liver or bone marrow trans- Memantine 55 mg qd
plant for amyloid neuropathy, and treatment for Dextromethorphan 400 mg
Levodopa 100 mg tid
immune-mediated neuropathies (Chap. 41).
Alpha-lipoic acid (thioctic acid) 600 mg
Pain management usually begins with tricyclic Spinal cord stimulator
antidepressants (TCAs) such as amitriptyline, Transcutaneous electrical nerve stimulation (TENS)
imipramine, and desipramine, which can reduce Alternative
burning, aching, sharp, throbbing, and stinging Acupuncture
(Table 40-6; see also Table 5-1). Duloxetine Pain psychologist/counselor
hydrochloride, a dual reuptake inhibitor of sero-
tonin and norepinephrine, is approved for the
management of neuropathic pain from diabetes. denervated/immobile extremity, combined with
Tramadol is also effective for painful diabetic neu- recurrent, unnoticed, painless trauma, predisposes to
ropathy. Anticonvulsants such as phenytoin, carba- skin ulceration, poor healing, tissue resorption, neu-
mazepine, clonazepam, gabapentin, topiramate, rogenic arthropathy, and mutilation; amputation may
lamotrigine, and pregabalin are effective for lanci- be required. This unfortunate sequence of events is
nating pains. Topical anesthetic agents including avoidable with proper care of the denervated areas.
lidocaine, mexiletine, and capsaicin creams pro-
vide transient relief for focal neuropathic pain.
Narcotics may be required for severe cases of ELECTROPHYSIOLOGIC STUDIES
refractory neuropathic pain. Treatment of pain is (SEE CHAP. 3)
discussed in detail in Chap. 5.
The role of physical therapy, occupational Electrophysiologic studies serve as an extension of the
therapy, and assistive devices (such as a foot brace) neurologic examination and thus play an important role
should not be overlooked. Trophic changes in a in the evaluation of peripheral neuropathies.The following
 530 information should be obtained from nerve conduction permanent injury can result. Intrinsic factors such as
studies and electromyography (NCS-EMG): arthritis, uid retention (pregnancy), amyloid, tumors,
and diabetes mellitus may make nerves at entrapment
1. Is the process axonal or demyelinating? This deter- sites more susceptible to injury. Often both extrinsic
mination is one of the main goals of an NCS-EMG and intrinsic factors contribute to neuropathy, e.g., an
study since approaches to management and progno- anatomically narrowed region coupled with repetitive
sis hinge largely on this distinction. In general, activity, poor posture or position. Common entrapment
axonal processes affect sensory bers more than neuropathies include the median nerve at the wrist
motor bers, whereas equal involvement is charac- (carpal tunnel), ulnar nerve at the cubital tunnel or in
teristic of most demyelinating processes. the ulnar groove, lower trunk of the brachial plexus at
2. Are the ndings focal or generalized and are they the thoracic outlet, common peroneal nerve at the
symmetric or asymmetric? bular head, posterior tibial nerve at the tarsal tunnel,
3. Is this a length-dependent neuropathy? A distal and lateral femoral cutaneous nerve at the inguinal liga-
axonopathy generally gives rise to length-dependent ment. Symptoms and signs of various entrapment neu-
ndings. The order of nerves affected, as measured ropathies are listed in Table 40-7. Histologic changes of
by sensory NCS, for example, is sural, followed by subacute compression consist of a mixture of segmental
ulnar, median, and radial. By contrast, a neuronopa- demyelination and Wallerian degeneration reecting
SECTION III

thy (or ganglionopathy) may affect the radial nerve retrograde axonal injury.
before the sural or ulnar nerve. Since most entrapped nerves contain both motor and
4. How severe is the lesion? The complete absence of a sensory bers, both types of symptoms occur, usually in
response may reect complete loss of bers or com- the distribution of the affected nerve. Sensory symptoms
plete conduction block. may include numbness, pins and needles, tingling, prick-
5. What is the approximate age of the lesion? In ling, burning, or electric shock sensations. Light touch is
axonal processes, the compound muscle action
Diseases of the Central Nervous System

often more affected than pinprick, and subtle sensory

potential amplitudes are lost early (7 days) compared abnormalities may be revealed by measuring two-point
with sensory amplitudes (10 days). In demyelinating discrimination. Aching and nondescript pain can also
lesions it is often useful to follow progression of occur proximal to the site of nerve compression. In mild
ndings with serial studies (Chap. 41). cases, no motor symptoms are evident, but in more
6. Is this a hereditary or acquired neuropathy? A uni- affected patients, weakness, wasting, or fasciculations
form slowing of NCS suggests a hereditary neu- may occur. Knowledge of the anatomy of individual
ropathy, although exceptions exist, such as x-linked nerves is important to be able to localize the site of the
CMT and hereditary neuropathy with liability to lesion to the root, plexus, or nerves or their branches.
pressure palsies (HNPP). Sensory testing may occasionally provoke paresthesias.
7. Is there a subclinical neuropathy? In patients receiv- Reexes are generally unaffected since most entrapped
ing chemotherapy or other potentially neurotoxic nerves are distal to the deep tendon reexes typically
drugs, directed examination and limited NCS may examined. Percussion of the nerve at the affected site
help the physician adjust therapy before a signicant may induce paresthesias (Tinels sign); however, this may
neuropathy develops. also occur in normal individuals and is not a reliable
8. What is the prognosis? For both demyelinating and sign. Placing the limb in a posture known to aggravate
axonal neuropathies, the degree of axonal loss serves the compression may accentuate symptoms (e.g.,
as a guide to prognosis. Phalens sign evoked by exing the wrist for carpal tun-
It is important to recognize that EDx studies have nel syndrome).
limitations, and that not all patients with neuropathic EDx studies conrm the clinical diagnosis and provide
symptoms will have informative ndings. information about location, severity, and prognosis. Focal
demyelination is detected as a focally reduced nerve con-
duction velocity along the length of the sensory and/or
MONONEUROPATHIES motor bers. Wallerian degeneration is reected in a
reduction of distal amplitudes and as denervation poten-
Mononeuropathy (Table 40-7) refers to disease or dam- tials. The latter is associated with a relatively poor prog-
age of a single nerve. The most common causes are nosis for recovery. Bone or joint abnormalities and soft
compression, entrapment, and trauma. Extrinsic com- tissue masses can be revealed by appropriate imaging
pression usually occurs when a limb is maintained in a techniques. MR neurography and ultrasonography are
xed position that produces sustained pressure on the useful in identifying thickening of nerves at sites of com-
nerve. The neuropathy is often reversible if the posi- pression; these studies are useful for proximal entrap-
tion is changed. However, if the patient is unable to ments (brachial plexus, lumbosacral plexus, or sciatic or
move (e.g., during anesthesia or with intoxication), gluteal nerve lesions).
TABLE 40-7 531
MONONEUROPATHIES

PRECIPITATING DIFFERENTIAL
SYMPTOMS ACTIVITIES EXAMINATION ELECTRO-DIAGNOSIS DIAGNOSIS TREATMENT

Carpal tunnel Numbness, pain Sleep or repeti-Sensory loss in thumb, Slowing of sensory C6 radiculopathy Splint
syndrome or paresthesias tive hand second, and third ngers and motor conduc- Surgery denitive
in ngers activity Weakness in thenar tion across carpal treatment
muscles; inability to tunnel
make a circle with
thumb and index nger
Tinel and Phalen signs
Ulnar nerve Numbness or Elbow exion Sensory loss in the little Focal slowing of Thoracic outlet Elbow pads
entrapment paresthesias in during sleep; nger and ulnar half of nerve conduction syndrome Avoid further injury
at the elbow ulnar aspect of elbow resting ring nger velocity at the elbow C8-T1 radicu- Surgery when con-
(UNE) hand on desk Weakness of the lopathy servative treatment
interossei and thumb fails
adductor; claw-hand
Ulnar nerve Numbness or Unusual hand Like UNE but sensory Prolongation of distal UNE Avoid precipitating
entrapment weakness in the activities with examination spares motor latency in the activities

CHAPTER 40
at the wrist ulnar distribu- tools, bicycling dorsum of the hand, hand
tion in the hand and selected hand
muscles affected
Radial neu- Wrist drop Sleeping on arm Wrist drop with sparing Earlyconduction Posterior cord Splint
ropathy at after inebriation of elbow extension block along the spi- lesion; deltoid Spontaneous
the spiral with alcohol (triceps sparing); nger ral groove also weak recovery provided
groove Saturday night and thumb extensors Latedenervation in Posterior no ongoing injury
palsy paralyzed; sensory loss radial muscles; interosseous

Peripheral Neuropathy
in radial region of wrist reduced radial SNAP nerve (PIN); iso-
lated nger drop
C7 radiculopathy
Thoracic Numbness, Lifting heavy Sensory loss resembles Absent ulnar sensory UNE Surgery if correctable
outlet paresthesias in objects with ulnar nerve and motor response and lesion present
syndrome medial arm, the hand loss resembles median reduced median
forearm, hand, nerve motor response
and ngers
Femoral Buckling of knee, Abdominal hys- Wasting and weakness EMG of quadriceps, L2-4 radiculopa- Physiotherapy to
neuropathy numbness or terectomy; litho- of quadriceps; absent iliopsoas, paraspinal thy strengthen quadri-
tingling in tomy position; knee jerk; sensory loss muscles, adductor Lumbar ceps and mobilize
thigh/medial leg hematoma, in medial thigh and muscles plexopathy hip joint
diabetes lower leg Surgery if needed
Obturator Weakness of the Stretch during Weakness of hip adduc- EMGdenervation L3-4 radiculopa- Conservative
neuropathy leg, thigh hip surgery; tors; sensory loss in limited to hip adduc- thy management
numbness pelvic fracture; upper medial thigh tors sparing the Lumbar Surgery if needed
childbirth quadriceps plexopathy
Meralgia Pain or numb- Standing or Sensory loss in the Sometimes slowing of L2 radiculopathy Usually resolves
paresthetica ness in the ante- walking pocket of the pant sensory response spontaneously
rior lateral thigh Recent weight distribution can be demon-
gain strated across the
inguinal ligament
Peroneal Footdrop Usually an acute Weak dorsiexion, ever- Focal slowing of L5 radiculopathy Foot brace; remove
nerve compressive sion of the foot nerve conduction external source of
entrapment episode identi- Sensory loss in the across bular head compression
at the bular able; weight anterolateral leg and Denervation in tibialis
head loss dorsum of the foot anterior and peroneus
longus muscles
Sciatic Flail foot and Injection injury; Weakness of hamstring, NCSabnormal sural, L5-S1 radicu- Conservative follow
neuropathy numbness fracture/dislo- plantar and dorsiexion peroneal, and tibial lopathies up for partial sci-
in foot cation of hip; of foot; sensory loss in amplitudes Common per- atic nerve injuries
prolonged tibial and peroneal EMGdenervation in oneal neuropa- Brace and physio-
pressure on hip nerve distribution sciatic nerve distrib- thy (partial sci- therapy
(comatose ution sparing glutei atic nerve injury) Surgical exploration
patient) and paraspinal LS plexopathies if needed
Tarsal tunnel Pain and paresthe- At the end of the Sensory loss in the sole Reduced amplitude in Polyneuropathy, Surgery if no exter-
syndrome sias in the sole day after stand- of the foot sensory or motor foot deformity, nal cause identied
of the foot but ing or walking; Tinels sign at tarsal components of medial poor circulation
not in the heel nocturnal tunnel and planter nerves

Note: UE, LE, upper, lower extremities; DTRs, deep tendon reexes; NCS, nerve conduction studies; GBS, Guillain-Barr syndrome; CIDP,
chronic inammatory demyelinating neuropathy; DM, diabetes mellitus; MMN, multifocal motor neuropathy; CMT, Charcot-Marie-Tooth.
 532 be tapered by 5 mg every 24 weeks. The cytotoxic
Treatment:
agent is usually continued for 1 year. Therapy of hyper-
MONONEUROPATHIES
sensitivity vasculitis is focused primarily upon removal of
Treatment for acute and subacute compressive neu- the offending antigen trigger. Treatment of localized vas-
ropathies consists of identifying and removing extrinsic culitis restricted to the peripheral nervous system can be
contributors and the use of splints to avoid further com- less aggressive than for systemic vasculitis because the
pression. In patients with chronic compressive neu- risk of death from untreated disease is very low.
ropathies, exacerbating factors should be identied and Monotherapy with either oral glucocorticoids or a brief
treated before surgical correction is considered. The use course of cyclophosphamide (36 months) may be suf-
of splints, a change of work habits to avoid activities or cient. A tissue diagnosis of vasculitis should be obtained
movements that precipitate the neuropathy, or anti- before initiating therapy; a positive nerve biopsy helps to
inammatory medication for tenosynovitis may be help- justify long-term immunosuppressive treatment, and
ful (see later). pathologic conrmation of the diagnosis is often difcult
Surgical treatment may be required for management after treatment has commenced.
of chronic compressive neuropathies when conserva-
tive measures have failed and the site of entrapment is
clearly delineated. Studies of surgery in carpal tunnel
SECTION III

syndrome have been encouraging.

POLYNEUROPATHIES
DIABETIC NEUROPATHY
MONONEUROPATHY MULTIPLEX Diabetes mellitus is associated with various neuropathy
syndromes that differ in their etiology, natural history,
Mononeuropathy multiplex refers to the multifocal and treatment. The overall prevalence of neuropathy is
Diseases of the Central Nervous System

involvement of individual peripheral nerves. Although 66% for type 1 and 59% for type 2 diabetes. Neuropathy
multiple compressive neuropathies can present in this can be broadly divided into symmetric and asymmetric
manner, more often an inammatory cause is responsi- types, although a great deal of overlap exists between
ble, and in such cases the disorder is referred to as these categories. Symmetric neuropathies may present as
mononeuritis multiplex. Both systemic (67%) and nonsys- small-ber involvement (e.g., dysesthesias in the feet) or
temic (33%) vasculitis may present as mononeuritis mul- autonomic dysfunction (e.g., sexual impotence), but
tiplex; less commonly, vasculitic neuropathy can present often both occur together; examination usually reveals
as an asymmetric or distal symmetric neuropathy. additional evidence of large-ber involvement and of an
Among the systemic vasculitides, polyarteritis nodosa, underlying generalized neuropathy.
rheumatoid arthritis, systemic lupus erythematosus The asymmetric neuropathies are divided into those
(SLE), Churg-Strauss syndrome,Wegeners granulomato- with acute onset and those with gradual onset. Asym-
sis, and hypersensitivity vasculitis should be considered; metric abrupt-onset neuropathies include diabetic trun-
these are often associated with constitutional symptoms cal radiculoneuropathy (DTRN), diabetic lumbosacral
such as fever and weight loss.The common bular nerve radiculoplexus neuropathy (DLSRPN), and oculomotor
(previously called the common peroneal nerve) is (third or sixth nerve) neuropathy. These monophasic
affected in ~75% of patients with vasculitic neuropathy; conditions are thought to be due to vascular causes
symptoms consist of a painful foot drop. The ulnar, such as infarction. Neuropathies of more gradual onset
median, and radial nerves may also be involved. are usually caused by entrapment or compression and
include median neuropathy at the wrist, ulnar neuropa-
thy at the elbow, peroneal neuropathy at the bular
head, and lateral cutaneous neuropathy at the thigh at
Treatment:
the inguinal ligament (meralgia paresthetica).
MONONEURITIS MULTIPLEX
Therapy of the necrotizing systemic vasculitides can sta-
bilize and in some cases improve the neuropathy. Gluco- Symmetric Diabetic Neuropathy
corticoids [prednisone (1.5 mg/kg per day)] plus a cyto-
toxic agent (usually oral cyclophosphamide at 2 mg/kg By far the most common form of diabetic neuropathy is
per day) is the treatment of choice. Aggressive therapy is a length-dependent diabetic sensorimotor polyneuropa-
warranted since the prognosis for survival of untreated thy (DSPN). The lifetime prevalence is ~55% for type 1
patients is poor. Prednisone can be changed to an alter- and 45% for type 2 diabetes. DSPN is a mixed neuropa-
nate-day regimen after 1 month to minimize side effects. thy with small- and large-ber sensory, autonomic, and
Once a clinical response is documented, prednisone may motor nerve involvement in various combinations,
although sensory and autonomic symptoms are more
prominent than motor ones (Table 40-1). Proposed 533
criteria for the diagnosis of DSPN are two or more of Treatment:
the following: symptoms or signs of neuropathy, abnor- DIABETIC SENSORIMOTOR
mal EDx studies, quantitative sensation test abnormali- POLYNEUROPATHY
ties, heart rate decrease with deep breathing or Valsalva Treatment consists of strict glucose control, which pre-
maneuver. vents the neuropathy from worsening; established neu-
DSPN has an insidious, progressive course. Initial ropathy does not usually reverse. Aldose reductase
symptoms may consist of numbness, tingling, buzzing, inhibitors to treat and prevent diabetic neuropathy have
burning, or prickling sensation affecting the toes and been studied in >30 trials. Although controlled trials of
feet. Paresthesias ascend up to the legs and then hands in the aldose reductase inhibitors sorbinol and tolrestat
a stocking-glove distribution. Over time, gait distur- were found to improve electrophysiologic or morpho-
bance and distal weakness may occur. Painful or insensi- metric markers of DSPN, any clinically meaningful
tive extremities predispose to foot ulcers; amputation is improvement in pain or sensation has been inconsis-
sometimes required. Examination shows a distal sensory tent. Treatment with recombinant nerve growth factor
loss to pin, temperature, touch, and vibration sense. was ineffective. Alpha lipoic acid (thioctic acid), an
Ankle reexes are invariably reduced or absent. Weak- antioxidant, has been shown to improve experimental
ness, if present, is mild and involves toe exors and diabetic neuropathy, and a meta-analysis of clinical trials

CHAPTER 40
extensors. The length-dependent pattern of neuropathy suggested that the treatment (600 mg/d IV for 3 weeks)
is evident in the stocking-glove sensory loss, and some is safe and improves symptoms and signs of neuropa-
patients also show sensory loss in the anterior abdominal thy. Pancreatic transplantation can halt progression of
region in a wedge-shaped distribution. Autonomic DSPN but is a realistic therapy only for patients who
symptoms including impotence, nocturnal diarrhea, dif- have renal failure and are undergoing combined kidney
culty voiding, abnormalities of sweating, and abnormal and pancreas transplantation.

Peripheral Neuropathy
fullness after eating and orthostatic hypotension may be Glycemic control is essential for the prevention of
present. diabetic autonomic neuropathy. Once neuropathy is
The diagnosis of DSPN is usually straightforward, established, few effective treatments exist.
although other contributors to the neuropathy should
be excluded, including nutritional (vitamins B1 and B12
and folate deficiencies), toxic (alcohol, vitamin B6
toxicity), immune-mediated (paraprotein), and inherited Asymmetric Diabetic Neuropathy
causes. An alternative diagnosis should be sought in Cranial Neuropathies
patients with rapidly progressive or asymmetric weak- The oculomotor nerves (in decreasing order of fre-
ness, a family history of neuropathy, exposure to toxins, quency the sixth, third, and rarely fourth nerves) are
or prior malignancy. A glucose tolerance test is indicated most often affected. In general, cranial neuropathy
in all patients presenting with neuropathy. EDx studies occurs in patients older than 50 years who already have
show mixed ndings of axonal loss and demyelination in evidence of DSPN. Abducens (sixth) nerve palsy mani-
a length-dependent pattern. Nerve biopsy and lumbar fests as the sudden onset of painless double vision, and
puncture are not necessary unless alternative diagnoses examination shows paralysis of abduction on the
are being considered. affected side (Chap. 17). In a patient with diabetes who
Various hypotheses have been invoked to account for has no other clinical ndings the diagnosis is straight-
DSPN. Increased neuronal concentrations of glucose forward. Spontaneous recovery typically occurs within
induce the conversion of glucose to sorbitol by aldose 35 months and no treatment except an eye patch or
reductase using NADPH as a coenzyme. Sorbitol prism is necessary. Diabetic third nerve palsy is also
decreases levels of myo-inositol and phosphoinositides, abrupt in onset but is often heralded by intense retroor-
leading to a decrease in diacylglycerol, protein kinase C, bital pain that may be present for several days. Symp-
and Na+, K+, ATPase activity. This sequence of events toms include double vision, unilateral ptosis, and
leads to axonal loss and demyelination and is the basis of restriction of medial gaze and upgaze. Unlike compres-
trials using aldose reductase inhibitors and high myo- sive etiologies (e.g., aneurysms of the superior cerebel-
inositol diets. A second hypothesis proposes insufcient lar or posterior communicating arteries), which present
blood ow: increased aldose reductase activity results in with an enlarged (blown) pupil, the pupil is nearly
competitive inhibition of nitric oxide synthetase for always spared in diabetic third nerve palsy. This is due
NADPH, resulting in decreased nitric oxide and reduced to the fact that pupillomotor bers are present on the
blood ow in the vasa nervorum. Altered metabolism of outer layers of the third nerve fascicle, and an ischemic
fatty acids, reduced concentrations of nerve growth fac- lesion tends to involve the center of the fascicle. In
tor, and oxidative stress are possible additional contribut- atypical cases, such as those with pupillary involvement
ing factors. or without pain, a neuroimaging study, usually MRI or
 534 MR angiography (MRA), is indicated to exclude an Diabetic amyotrophy (femoral neuropathy; proximal
aneurysm. Most patients improve spontaneously in diabetic neuropathy) occurs in older patients, usually
36 months without any treatment. Symptomatic treat- with type 2 diabetes. Patients present with the abrupt
ment with eye prisms is often helpful. Idiopathic neu- onset of severe pain affecting the anterior thigh. But-
ropathy of the facial nerve (seventh; Bells palsy) is also tock and lower back pain may also be present.The pain
more common in older diabetics than in nondiabetics. is worse at night and is described as burning. Weakness
The clinical features and prognosis are similar to the and wasting in the thigh muscles leads to difculty
nondiabetic form (Chap. 29). climbing stairs and walking. Males are more likely to be
affected, and weight loss, at times dramatic, is invariably
Limb Mononeuropathies present. Although symptoms may be bilateral, one side
Diabetics are also susceptible to entrapment neuropathies, is more severely affected than the other. Examination
including median neuropathy at the wrist (carpal tunnel shows prominent wasting of the quadriceps muscle uni-
syndrome), ulnar neuropathy at the elbow, fibular laterally with weakness of the knee extensor and hip
(peroneal) neuropathy at the bular head, and lateral exor and, variably, ankle dorsiexor, accompanied by
cutaneous neuropathy at the inguinal ligament (meralgia sensory loss in the thigh and leg in the distribution of
paresthetica). The special susceptibility of diabetic nerves the femoral nerve, and a reduced knee jerk on the
may be related to endoneurial edema and vascular fac- affected side. The syndrome progresses over weeks to
SECTION III

tors. Patients typically present with several weeks or months, then stabilizes and gradually improves. EDx
months of pain, numbness, or weakness in the distribu- studies show ndings of radiculopathy (L2-4), lumbar
tion of the affected nerve.The approach to these entrap- plexopathy, or femoral neuropathy along with a distal
ments is similar to that in individuals without diabetes. sensorimotor neuropathy. An MRI of the lumbosacral
Decompressive surgery may be needed if there is associ- spine and plexus is indicated to exclude a compressive
ated weakness, numbness, or pain in the distribution of cause. Cerebrospinal uid (CSF) examination and nerve
Diseases of the Central Nervous System

the affected nerves and if no reversible extrinsic source of biopsy should be considered whenever the diagnosis is
compression (position/habits) can be identied. uncertain. The level of CSF protein is often elevated,
and biopsy of the intermediate femoral cutaneous nerve
Radiculopathies and Plexopathies may show microvasculitis. The condition may be quite
Diabetic truncal radiculoneuropathy occurs in diabetics in painful and require opiates for pain control.Treatment with
middle or later life, usually in association with underly- high-dose glucocorticoids or intravenous immunoglobulin
ing DSPN. Patients present with an abrupt onset, typi- (IVIg) has been effective in case reports, although con-
cally over days to weeks, of severe pain in the thoracic trolled trials have not shown clear benet. Physiother-
spine, ank, rib cage, or upper abdomen. The pain is apy and orthotic devices are helpful. The prognosis is
described as burning, stabbing, or belt-like. Contact generally favorable; improvement occurs over several
hyperesthesia is present in the area of pain. Associated, months in most patients treated with symptomatic
sometimes profound, weight loss is often described; this measures only. A similar condition may also occur in
can also be seen in diabetic amyotrophy (see later). nondiabetic patients.
Examination may be normal or may reveal variable sen-
sory loss in the distribution of one or several intercostal
Uncommon Diabetic Neuropathies
nerves and their branches. Anterior abdominal wall
weakness may be noted as focal bulging of the weak- Diabetic neuropathic cachexia (acute painful neuropathy of
ened region when the patient attempts to sit up. A diabetes) is an uncommon painful sensory neuropathy
needle EMG of the affected muscles may conrm den- occurring in type 1 diabetics in the setting of poor glu-
ervation in the abdominal or intercostal muscles; the cose control and weight loss. Manifestations include
paraspinal muscles may be spared. This nding, and a severe pain in the feet ascending up to the legs and
reduced ber density measured by skin biopsy from trunk with associated allodynia. Examination may reveal
symptomatic regions, suggests that the injury in diabetic distal sensory loss to pinprick and vibration and reduced
truncal radiculoneuropathy is at, or distal to, the sensory or absent ankle jerks. Strength is preserved. EDx studies
ganglion. The differential diagnosis in this elderly popu- may show a distal neuropathy. Unlike DSPN, the prog-
lation should include herpes zoster infection (without nosis is favorable with glucose control. The painful
rash) and an abdominal malignancy. Most patients symptoms reverse over months to a year.
improve spontaneously, although the pain may persist for Insulin neuritis describes a painful neuropathy seen
weeks to months. Pain management may be difcult and with initiation of insulin treatment for diabetes. The
includes topical capsaicin and narcotics. The abrupt clinical presentation is similar to the acute painful neu-
onset and spontaneous recovery suggest a vascular cause ropathy of diabetes, and most patients improve.
to this syndrome, although an inammatory etiology can A reversible sensory and motor polyneuropathy has
not be excluded. been reported in association with diabetic ketoacidosis.
Most patients also have upper and lower motor neuron neuropathy may do so acutely when used at higher doses; 535
signs, as well as a preexisting neuropathy.The etiology is examples include arsenic, thallium, and pyridoxine. The
not clear; critical illness neuropathy may be the underly- combination of two toxic drugs, commonly seen with
ing cause. Finally, chronic inammatory demyelinating anticancer therapy (e.g., paclitaxel and cisplatin), may
neuropathy (CIDP) occurs in diabetics; the disease produce greater nerve toxicity than either one alone.
resembles that seen in nondiabetics. Patients with underlying conditions may be predisposed
to neuropathy when exposed to some compounds, e.g.,
TOXIC INCLUDING CHEMOTHERAPY- vitamin B12decient patients who receive nitrous oxide
INDUCED NEUROPATHIES anesthesia, or patients with porphyria who receive bar-
biturates. Usually, however, toxic neuropathy is subacute
Most toxic neuropathies are distal axonal degenerations in onset, developing over a period of months. Vin-
that develop gradually over time. The causes are varied, cristine, amiodarone, nitrofurantoin, isoniazid, dimethy-
including drugs, heavy metals, and industrial and envi- laminopropionitrile (DMAPN), inorganic mercury, and
ronmental substances (Table 40-8). Novel anticancer thallium all cause a subacute neuropathy. The insidious
drugs and antiretroviral agents are the most common onset of a chronic neuropathy occurs with exposure to
drugs implicated, although over-the-counter medica- industrial toxins at low dosages over a prolonged period
tions (especially pyridoxine) can also cause neuropathy. of time. Examples include acrylamide, allyl chloride,

CHAPTER 40
A temporal relationship between introduction of the hexacarbons, carbon disulde, ethylene oxide, lead, and
toxic substance and the onset of neuropathy is usually arsenic. In addition to preexisting neuropathy, other host
noted, as is a dose-response relationship. In general, a factors, including diabetes, hepatic or renal impairment,
lower dose over a longer period of time is less toxic than and alcohol abuse, may reduce the threshold for neuro-
a higher dose for a short period, even if the eventual toxicity. The neuropathy may be predominantly motor
cumulative doses are similar. Onset following introduc- with lead, inorganic mercury, organophosphates, buck-

Peripheral Neuropathy
tion of the agent and reversal or at least arrest following thorn, dapsone, and vincristine; small-ber sensory with
its removal provide the best evidence of a toxic neu- DMAPN, thallium, nucleoside analogue reverse tran-
ropathy, along with the symptoms and signs typically scriptase inhibitors (dideoxycytidine ddC, dideoxyino-
caused by the suspected agent.The neuropathy may rst sine ddI, stavudine d4T), ethionamide, metronidazole,
manifest or may continue to progress after discontinuing and taxane; or large-ber sensory with cisplatin, high
the substance; this phenomenon, known as coasting, is doses of taxol, pyridoxine, or acrylamide. Autonomic
seen with the platinum cancer drugs, hexacarbons, dysfunction can occur with vincristine, vacor, perhexi-
nucleoside analogue reverse transcriptase inhibitors, and line, high dose-pyridoxine, and platinum. Other toxins
pyridoxine. that may involve autonomic nerves include acrylamide
Clinical evaluation includes a history focusing on (acral and pedal hyperhidrosis), DMAPN (urologic and
the temporal relationship between exposure and onset sexual dysfunction), and hexacarbons (hyperhidrosis and
of sensory or motor symptoms, comorbid diseases that impotence). Some toxic neuropathies also involve the
may cause neuropathy, and symptoms of systemic toxi- cranial nerves. These include trichloroethylene, which
city. Nerve biopsy occasionally demonstrates pathog- causes acute dysfunction of the cranial nerves V,VII, III,
nomonic features such as osmiophillic Schwann cell and II; thallium and acute fulminant vacor poisonings,
inclusions in amiodarone, perhexiline and chloroquine which cause facial diplegia with generalized neuropathy
neuropathies, and paranodal giant axonal swellings in resembling Guillain-Barr syndrome; perhexiline, which
hexacarbon neuropathies. Levels of some toxins can be causes facial diplegia and perioral numbness; vincristine
measured in certain tissues: heavy metals such as lead, and paclitaxel, which may be associated with numbness
arsenic, and thallium can be measured in urine; arsenic in the trigeminal nerve distribution; and chlorampheni-
can be measured in hair or nails. Blood levels of drugs col, ethambutol, and nitrous oxide, all of which may
are also useful. cause optic neuropathy. Asymmetric neuropathy or
Table 40-8 lists some of the better-documented neu- mononeuritis multiplex is rare but may be seen with
rotoxic substances. Awareness of the types of indus- lead, which may cause unilateral wrist drop; or with
tries in which toxic exposure can occur is important in DMAPN, which causes sacral dermatomal sensory loss.
identifying occupational exposure. Lower dosages and Signs of toxicity to kidney, liver, or other organs can in
shorter durations of exposure may produce neuropathy in some cases alert the clinician to the possibility that a
susceptible individuals such as those with underlying neuropathy could be toxic in origin.
inherited neuropathy. An acute onset of neuropathy
occurs with drugs such as paclitaxel, suramin, and vacor,
Cisplatin
and with biologic agents such as ciguatera, puffer sh
(tetrodotoxin), and buckthorn. Some toxic agents that Cisplatin (cis-diaminodichloroplatinum) is a heavy metal
otherwise require long-term exposure to produce chronic used to treat a variety of solid tumors. Cisplatin is toxic
 536 TABLE 40-8
TOXIC NEUROPATHIES

CIRCUMSTANCES OF TOXICITY NEUROPATHY COMMENTS

AXONOPATHY

Nonpharmaceutical toxins
Acrylamide monomer Flocculators, grouting agents Sensory ataxia; large ber Numbness, excessive sweating,
exfoliative dermatitis
Allyl chloride Epoxy resin, glycerin Dysesthesia and distal weakness
Arsenic (inorganic) Copper/lead smelting, contaminant in S > M; painful; usually subacute Skin: hyperkeratosis, rain-drop pig-
recreational drugs, suicide/homicide or chronic; may be acute follow- mentation of skin, Mees line in nails
(herbicide/insecticide) ing large doses
Carbon disulphide Viscose rayon, cellophane; airborne SM Slow NCS
industrial exposure
Dimethylaminopropi- Polyurethane foam SM Small-ber neuropathy with prominent
onitrile (DMAPN) bladder symptoms and impotence
Ethylene oxide Sterilization of biomedicals
Hexacarbons (paranodal Solvents, adhesives SM Neurolament swelling of axons; CNS
giant axonal) Substance abuse (glues and thinners)
SECTION III

Lead Batteries, smelting metal ores, paints M > S; wrist drop Burtons line, anemia, basophilic
stippling
Mercury (inorganic) Environmental/workplace CNS > PNS; neuropathy Tremor, insomnia, behavioral change
uncommon
Methyl bromide Fumigant, insecticide, refrigerant, re Variable recovery Encephalitis, ataxia
extinguisher
Organophosphorus Insecticide, petroleum, plastics SM Acute toxicity presents as cholinergic
esters crisis
Diseases of the Central Nervous System

Thallium (rat poison) Rodenticides, insecticides Painful SM Thallium (alopecia, Mees line,
hyperkeratosis)
Vacor Rodenticide, suicide Rapid onset of severe axonopa- Diabetic ketoacidosis a feature of
thy and autonomic dysfunction acute toxicity
Pharmaceutical agents
Chloramphenicol Mean cumulative dose 255 g, duration S>M Also optic neuropathy
Colchicine Chronic dosing at 1.2 mg/d especially Distal paresthesias and Also myopathy with elevated serum CK
in the presence of renal dysfunction proximal weakness
Dapsone 200400 mg/d over many months Pure motor, especially upper limbs May look like motor neuron disease
Disulram 250500 mg/d after several months SM Difcult to distinguish from alcohol
used for alcoholism neuropathy
Ethambutol >20 mg/kg per day over many months Sensory neuropathy Also optic neuropathy
Ethionamide >15 mg/kg Sensory neuropathy Limited by GI, dermatologic and CNS
side effects
Gold Controversial, as rheumatoid arthritis S > M with myokymia Rash, pruritus
can cause neuropathy
Not dose dependent
Isoniazid >5 mg/kg over weeks or about 6 months, Dose-dependent SM neuropathy Add pyridoxine 50 mg/d when using
depending on acetylator status INH
Metronidazole Cumulative dose > 30 g Sensory (small and large ber)
Misonidazole Cumulative dose > 18 g/m2 Sensory axonopathy Dose-limiting side effect
Nitrofurantoin Standard dose of 200 mg/day over Mild SM neuropathy
a few weeks
Nitrous oxide Dental surgery, anesthesia, substance S >> M Toxic myeloneuropathy resembles
abuse cobalamine deciency
Nucleoside analogues >12.5 mg/kg per day for ddI, 0.02 mg/kg Painful sensory neuropathy Difcult to distinguish from HIV neu-
(ddC, ddI, 4dT) per day for ddC, and 0.5 mg/kg per ropathy
day for 4dT
Pyridoxine >200 mg a day over several months Length-dependent axonopathy Neuronopathy at higher doses
Suramin Peak serum concentration of 350 g/mL S > M; may be demyelinating
Taxol Cumulative dose of >1500 mg/m2 S>M Higher single doses may cause
neuronopathy
Thalidomide 100 mg/d for 6 months. S>M Thalidomide (brittle nails, palmar
erythema)
Vincristine and other Almost all patients S > M but autonomic bers also Vacuolar myopathy
vinca alkaloids affected
TABLE 40-8 (CONTINUED) 537
TOXIC NEUROPATHIES

CIRCUMSTANCES OF TOXICITY NEUROPATHY COMMENTS

Myelinopathy
Amiodarone 400 mg/day for 636 months, serum SM; dose-dependent Tremor
concentration of 2.4 mg/L
Perhexiline Not dose-related S (large ber) and M, facial, auto- Hepatic toxicity
nomic
Polychlorinated biphenyls Plasticizers, electrical insulators SM Acne, brown nails
Suramin Not dose-related Demyelinating like subacute
GBS
Trichloroethylene Dry-cleaning, rubber, degreasing Mainly cranial nerves: trigeminal, Limbs rarely affected
agent facial, oculomotor, optic
Sensory Neuronopathy
Platinum compounds, Cumulative dose more than Large-ber sensory Irreversible
e.g., cisplatin 900 mg/m2
High-dose pyridoxine Massive parenteral doses in Sensory neuronopathy; gait May be irreversible
grams over days ataxia, pseudoathetosis
Taxol Single dose of 250 mg/m2 Sensory ataxia May be irreversible

CHAPTER 40
Note: S, sensory; M, motor; SM, sensorimotor; NCS, nerve conduction studies; CNS/PNS, central/peripheral nervous system; CK, creatine
kinase; GI, gastrointestinal; GBS, Guillain-Barr syndrome; EDx, electrodiagnosis; CSF, cerebrospinal uid; CMV, cytomegalovirus; DSPN, dia-
betic sensory polyneuropathy.

to dorsal root ganglia neurons, producing a dose-related those caused by cisplatin, oxaliplatin neuropathy is more

Peripheral Neuropathy
large-ber sensory neuropathy (neuronopathy). It also likely to be reversible.
injures hair cells of the cochlea, causing hearing loss.
Peripheral neuropathy is the dose-limiting toxicity of cis-
Paclitaxel
platin. A cumulative cisplatin dose of at least 300 mg/m2
may lead to paresthesias in the extremities and numbness. Paclitaxel, a diterpene alkaloid drug, is widely used as a
Lhermittes sign, an electric shocklike sensation evoked chemotherapeutic agent. Peripheral neuropathy, which
by exion of the neck, may occur due to retrograde can be severe, is the dose-limiting toxicity. A symmet-
degeneration of axons in the posterior columns of the ric, length-dependent neuropathy with prominent sen-
spinal cord. Patients with preexisting neuropathy and sory (large more than small ber) and minor motor
those who receive combination chemotherapy may manifestations, is typically present. Preexisting neuropa-
develop symptoms after lower cumulative doses. Sensory thy is a risk factor. The neuropathy is dose-dependent,
ataxia may be disabling in patients who have severe neu- and both single and cumulative doses are important.
ropathy. Small-ber sensation (e.g., pain and temperature) The drug affects microtubule assembly, causing disrup-
and strength are generally spared. tion of axonal transport and a dying back axonal
neuropathy.
Oxaliplatin
Vincristine
Oxaliplatin can cause an early acute and a late chronic
neuropathy. The acute neuropathy begins during the Vincristine, an alkaloid derived from the pericuwinkle
infusion, within minutes to hours, or within 12 days of plant, vinca rosea, causes a dose-dependent sensorimotor
administration. Patients complain of paresthesias in the neuropathy. Lower cumulative doses (419 mg) cause
hands or feet, mouth, or throat along with myalgias, only reex changes, while higher doses progressively
cramps, or stiffness. Shortness of breath or difculty cause paresthesias, sensory loss (upper extremity more
swallowing may occur. Symptoms are often triggered by than lower), weakness with footdrop, and hand weakness
exposure to cold. Neuromyotonia may be seen on and clumsiness. Autonomic neuropathy can manifest as
EMG. Although this acute toxicity occurs in >90% of cardiac arrhythmias, orthostasis, urinary bladder dysfunc-
patients, it is often self-limited and resolves within days. tion, constipation, or paralytic ileus. Cranial neu-
A channelopathy is thought to be the underlying mech- ropathies have also been described.
anism. A chronic large-ber ataxic neuropathy, similar to
that caused by cisplatin, occurs with cumulative doses
Suramin
780 mg/m2, generally after eight or nine treatment
cycles. Even though the signs and symptoms (paresthe- Suramin is a polysulfonated naphthylurea that has been
sias, distal sensory loss, and loss of reexes) are similar to used as an antineoplastic agent and as a treatment for
 538 certain parasitic diseases. Suramin causes a length- Prognosis for recovery depends on both the site of
dependent distal axonal neuropathy in over half of pathology and the severity of the neuropathy. Involve-
patients and a subacute inflammatory demyelinating ment of the dorsal root ganglion is associated with a
neuropathy in ~15% of patients. Neuropathy occurs poor prognosis. Severe axonopathy requires years for
with peak plasma concentrations >300 g/mL. recovery. Demyelinating disorders, if detected early,
generally are associated with a relatively rapid recovery.
Thalidomide Most toxic neuropathies, even if advanced, will at least
stabilize, and some will improve, when exposure to the
Peripheral neuropathy remains the dose-limiting toxic-
toxic agent is stopped.
ity of thalidomide, which causes a length-dependent
painful sensory axonal neuropathy; a sensory neuronopa-
thy has also been reported. Peripheral neuropathy
occurs in up to 75% of patients and is dose-dependent, NUTRITIONAL NEUROPATHIES
rarely occurring with cumulative doses <20 g, but Thiamine (Vitamin B1 ) (Dry Beriberi)
invariably noted at cumulative doses >100 g. The risk
of neuropathy is minimized at doses 150 mg/d. Serial Thiamine deciency can be a result of inadequate
sensory action potential measurements are important in intake, as may occur in alcoholism, anorexia, intentional
SECTION III

the early detection of the neuropathy. Symptoms often, dieting, starvation, or bulimia. Protracted vomiting, e.g.,
though not always, improve with cessation or dose in patients receiving chemotherapy or in pregnant
reduction.The neuropathy develops at a lower dose and women with hyperemesis gravidarum, may also cause
is typically more severe in patients with a preexisting thiamine deciency. Neuropathy from thiamine de-
diabetic neuropathy. ciency presents as the acute or subacute onset of pares-
thesias, dysesthesias, and mild weakness in the legs. On
examination a stocking-glove sensory loss, distal weak-
Diseases of the Central Nervous System

Bortezomib ness in the legs, and loss of ankle jerks is typical. Nerve
Bortezomib (Velcade), a novel proteosome inhibitor conduction tests and sural nerve biopsies show axonal
used in the treatment of multiple myeloma, induces a degeneration. Erythrocyte transketolase activity is
length-dependent, sensory more than motor, axonal reduced in the blood.Treatment consists of oral thiamine
polyneuropathy that is dose-dependent, increasing with replacement, 100 mg/d. Alcohol-induced neuropathy
increasing cycles of treatment. Both small- and large- develops in some patients without any identiable
ber sensory symptoms occur. In a few patients the nutritional deciencies, suggesting that alcohol itself
symptoms stabilize or improve after stopping treatment. may cause sensory neuropathy. It predominantly affects
A toxic acquired demyelinating neuropathy has also small bers and is painful, but there is considerable over-
been reported. lap with thiamine deciency neuropathy.

Pyridoxine (Vitamin B6 )
Treatment: A subacute length-dependent axonal neuropathy occurs
TOXIC NEUROPATHIES as a result of pyridoxine deciency. Causes include
Removal of the toxic substance is the most important step. dietary deciency and drugs such as isoniazid, cycloserine,
Specic treatments are available for some toxic neu- and penicillamine, which act as pyridoxine antagonists
ropathies. Treatment for heavy metal toxicity includes by combining to the aldehyde moiety of the vitamin.
chelation therapy: penicillamine or calcium-EDTA for Dietary deciency of pyridoxine is uncommon,
lead toxicity; penicillamine or British anti-Lewisite (BAL) although the requirement is increased in pregnancy.
for arsenic toxicity; and potassium chloride or Prussian Measurement of xanthurenic acid after tryptophan load-
blue for thallium toxicity. Pyridoxine (1050 mg/d) can ing can help conrm the diagnosis.Treatment consists of
be used to prevent and treat isoniazid neurotoxicity. oral pyridoxine, 30 mg/d. Pyridoxine supplements are
Niacin and pyridoxine are recommended for ethion- recommended for prophylaxis during pregnancy and for
amide neurotoxicity. There may be some benet from patients taking isoniazid. Overzealous treatment with
the use of neuroprotective agents. Vitamin E (toco- pyridoxine should be avoided, as high doses of pyridox-
pherol) was reported to be neuroprotective in one ine cause a toxic sensory neuronopathy.
small, unblinded study, but these results have not been
conrmed. Org 2766, glutathione, diethyldithiocarba- Vitamin B12 (Cobalamin)
mate, and amifostine have also been tried without con-
clusive outcomes. Studies are under way to evaluate the
Peripheral neuropathy is a minor part of the vitamin B12
possible efcacy of nerve growth factor.
deciency syndrome; subacute combined degeneration of
the spinal cord is more prominent. Distal sensory loss
predominantly involving large-ber modalities, dysequi- malnourished eld workers and prisoners of war. Distal 539
librium, Lhermittes sign, and the combination of an sensory loss with hyporeexia at the ankles (peripheral
absent ankle jerk and upgoing toe may be present. Pancy- nerve lesion), combined with hyperreexia at the knees
topenia, megaloblastic anemia, and glossitis are other and an ataxic gait (spinal cord involvement), indicate the
signs. The principal dietary sources of vitamin B12 are combined peripheral and central axonal loss that is char-
meat and dairy products; enteric processing and absorp- acteristic of this deciency state. Treatment with vitamin
tion typically occur in the terminal ileum. Common B complex frequently improves the symptoms.
causes of vitamin B12 deciency include inadequate
intake, malabsorption (including post-gastrectomy), and Vitamin E Deciency
pernicious anemia. Borderline vitamin B12 deciency may
Vitamin E deficiency can occur from fat malabsorption
develop after exposure to nitrous oxide during anesthesia
or from abetalipoproteinemia. The clinical features of
or with chronic recreational use. Diagnosis of vitamin B12
vitamin E deficiency resemble those of Friedreichs
deciency is made by low serum cobalamin levels and
ataxia (Chap. 26), with severe large-fiber loss and a
raised levels of methylmalonic acid and homocysteine.
non-length-dependent reduction of sensory nerve
Autoantibodies to intrinsic factor and gastric parietal cells
action potentials suggestive of dorsal root ganglionopa-
are present in pernicious anemia. Treatment is with par-
thy. The diagnosis is confirmed by measurement of
enteral administration of cobalamin (vitamin B12) .
serum tocopherol and the ratio of vitamin E to total

CHAPTER 40
serum lipids. Treatment consists of administration of
Riboavin, Nicotinic Acid and Other tocopherol (400 mg bid), which may reverse or prevent
B-Group Vitamins progression of the sensory neuronopathy.
Riboavin and nicotinic acid deciencies have been
incriminated in neuropathies, usually in association with INFECTIONS AND PERIPHERAL

Peripheral Neuropathy
deciencies of other water-soluble vitamins. Peripheral NEUROPATHY
neuropathy may be accompanied by dermatitis, diarrhea,
HIV Infection
and dementia (pellagra).The diagnosis is made on clinical
grounds, and treatment consists of administration of (See also Chap. 37) HIV infection is associated with
40250 mg niacin daily. Strachans syndrome is character- polyradiculopathies, distal symmetric polyneuropathies,
ized by a painful sensory neuropathy associated with oro- inammatory demyelinating polyneuropathies, multifo-
genital dermatitis, amblyopia, and deafness. This syn- cal mononeuropathies, cranial neuropathies, and neu-
drome was rst reported in Jamaica and later in ropathies induced by antiretroviral drugs (Table 40-9).

TABLE 40-9
NEUROPATHIES ASSOCIATED WITH HIV INFECTION

TYPICAL CD4
HIV NEUROPATHY SYMPTOMS AND SIGNS COUNTS, CELLS/L DIAGNOSTIC TESTS

Distal symmetric Painful paresthesias, <200 EDx studies

polyneuropathy distal sensory loss, Skin biopsy
absent ankle jerk
GBS, CIDP Progressive weakness, <500; >50 EDx studies
areexia, numbness CSF studies:
elevated protein,
variable pleocytosis
Mononeuropathy multi- Footdrop, wrist drop, <500; >50 EDx studies, nerve
plex (cryoglobulinemia, facial weakness biopsy
hepatitis C)
CMV polyradiculopathy Flaccid paraparesis, <50 EDx, CSF studies
saddle anesthesia,
urinary retention
Herpes zoster, tubercu- Depends on specic <50 EDx, CSF studies
losis, lymphoma etiology Nerve biopsy
Toxic neuropathy Similar to DSPN <500 Eliminate drug: stavu-
dine (d4T), didanosine
(ddI), zalcidabine (ddC)

Note: GBS, Guillain-Barr syndrome; CIDP, chronic inflammatory demyelinating polyneuropathy; EDx, electrodiag-
nosis; CSF, cerebrospinal fluid; CMV, cytomegalovirus; DSPN, diabetic sensory polyneuropathy.
 540 Lumbosacral polyradiculopathies are usually due to Serum lactate concentrations are elevated and acetylcarni-
CMV infection and occur with advanced HIV/AIDS. tine levels are reduced as a result of mitochondrial dys-
These present with pain, incontinence, and rapidly pro- function. Dideoxynucleosides have also been shown in
gressive asymmetric lower extremity weakness leading vitro to inhibit gamma DNA polymerase, whereas
to paraplegia. Saddle anesthesia is always present. Deep zidovudine, lamivudine, and abacavir (drugs that are not
tendon reexes are often preserved. EMG reveals nd- associated with neuropathy) have only limited effects on
ings of both peripheral neuropathy and lumbosacral this enzyme.
radiculopathy. CSF analysis shows pleocytosis with
polymorphonuclear cells; polymerase chain reaction
for CMV is positive. The differential diagnosis
Treatment:
includes GBS; other infections including herpes viruses,
TOXIC NEUROPATHY FROM
treponema, or tuberculosis; and carcinomatous meningo- ANTIRETROVIRAL DRUGS
radiculitis from lymphoma. Aggressive and rapid treat-
ment with ganciclovir, foscanet, or cidofovir should be Treatment consists of discontinuing the offending
considered. dideoxynucleoside and changing the highly active anti-
retroviral therapy (HAART) regimen, provided that there
Distal Symmetric Polyneuropathy Associated is another regimen to offer. Failing this, a patient may
SECTION III

with HIV need to continue the regimen with the addition of pain-
HIV distal sensory symmetric polyneuropathy presents modifying drugs. Prescribing patterns have changed in
as a painful, predominantly small-ber neuropathy. This the developed world to limit the use of specic
syndrome cannot be distinguished reliably from neu- dideoxynucleosides. However, in resource-limited coun-
ropathy caused by antiretroviral drugs (nucleoside tries, generic antiretroviral combinations typically con-
reverse transcriptase inhibitors); its onset with respect to tain d4T. After discontinuation of a toxic dideoxynucleo-
side, symptomatic improvement can be expected in
Diseases of the Central Nervous System

exposure to the offending drugs may be the only clue. It

is estimated that ~30% of hospitalized patients with most individuals within ~3 months.
AIDS and 100% of individuals dying with AIDS have Various pain-modifying drugs have been tried with-
evidence of neuropathy. The prevalence is lower in less out success, including tricyclic antidepressants and anti-
advanced HIV infection, occurring in only 3% of those convulsants. Lamotrigine was reported to be efcacious
with CD4 cell counts >200/L. Older age, associated in a subgroup of patients in one class I trial, but results
nutritional deciencies, and toxic exposures are addi- of a smaller class II trial were contradictory. Some posi-
tional risk factors for AIDS-related neuropathy. Most tive results have been achieved with topical capsaicin or
patients present with painful burning, tingling, and topical lidocaine, especially in patients with symptoms
numbness in the feet. Symptoms are typically bilateral, conned to the feet. Patients with severe neuropathies
gradual in onset, and worse at night (features common may require narcotic analgesics for pain relief, and long-
to all painful neuropathies). Examination usually shows acting narcotics such as transdermal fentanyl, mor-
distal loss to pin and temperature sensation and absent phine, or oxycodone preparations are particularly
or decreased ankle jerk. Weakness is either not detected useful. Specic prescribing guidelines should be used,
or is conned to the intrinsic foot muscles. Asymmetric particularly if there is any history of substance abuse.
presentations suggest the possibility of vasculitis (nerve Regenerative strategies, including trials of recombinant
biopsy indicated) or an entrapment neuropathy. The human nerve growth factor, have been attempted.
possibility of a confounding neuropathy from diabetes,
alcohol, nutritional causes, or toxin exposure should
always be considered.
Nerve biopsy shows a length-dependent axonal
Neuropathies with Lyme Disease
degeneration of sensory bers, with little evidence of
nerve-ber regeneration. Both large myelinated and A focal or multifocal radiculoneuropathy may occur
unmyelinated nerve bers are lost. Inammatory inl- with Borrelia burgdorferi infection. Subacute cranial neu-
trates of lymphocytes and activated macrophages and ropathy (especially VII) or painful radiculopathy may
reduced numbers of DRG neurons may be seen. occur in the acute phase of Lyme disease, with or
without associated meningitis. The radiculitis is dyses-
Toxic Neuropathy from Antiretroviral Drugs thetic or painful and is variable in distribution. CSF
A toxic neuropathy follows exposure to specic pleocytosis with intrathecal production of B. burgdorferi
dideoxynucleosides (d4T, ddI, and especially ddC), partic- antibodies is typical. Most patients improve either
ularly in advanced HIV disease. Sural nerve biopsy shows spontaneously or after IV ceftriaxone treatment. In the
severe axonal destruction, most prominently in unmyeli- chronic phase, a mild, chronic distal polyneuropathy
nated bers, along with mitochondrial abnormalities. (sensory more than motor) has been described; however,
the CSF is normal and the association may be auricular nerve in the neck, median and ulnar nerves, 541
coincidental. and peroneal nerves can all be involved. Over the long
term, untreated leprosy leads to claw hand deformity
(from ulnar and median nerve weakness), footdrop, and
Herpes Zoster
inability to close the eyelids due to orbicularis oculi
Reactivation of varicella zoster virus (VZV) in dorsal weakness.
root ganglia produces lancinating pain and hyperalgesia
in a dermatomal distribution. The pain is followed
34 days later by the appearance of a blistering skin INHERITED NEUROPATHIES
rash. The inflammation may at times involve the adja- CHARCOT-MARIE-TOOTH DISEASE
cent motor nerve roots, causing weakness and wasting.
Ophthalmoplegic zoster causes weakness in the divi- Clinical Features
sion of one or more oculomotor nerves; facial zoster CMT neuropathy is the most common heritable neu-
causes facial palsy (Ramsay Hunt syndrome); thora- romuscular disorder with an estimated incidence of
columbar zoster causes rash and sensory loss in a tho- 1740 cases per 100,000 (Table 40-10). It is a chronic
racic or lumbar nerve root. Although pain usually distal sensory and motor neuropathy presenting as long-
subsides after a few days to a week, it sometimes persists standing gait difculty with frequent tripping, followed

CHAPTER 40
(postherpetic neuralgia). Herpes zoster and posther- by difculty with buttoning, handling keys, turning
petic neuralgia both occur more commonly in the elderly door knobs, and opening jars. There is often a history
and in immunosuppressed individuals. In the acute set- of clumsiness, frequent ankle injuries, inability to jump
ting acyclovir, famciclovir, or valacyclovir are equally well or to keep up with other children in races, and
effective, although acyclovir must be given five times a being unathletic. In some patients the history suggests a
day as opposed to three times a day for the other more recent onset. If carefully sought, a family history

Peripheral Neuropathy
two drugs. Glucocorticoids are of unproven benefit. can often be obtained.Wasting and weakness of the dis-
Treatment of postherpetic neuralgia includes tricyclic tal muscles of the legs (inverted champagne bottle
antidepressants, duloxetin, gabapentin, pregabalin, oxy- appearance) with hammer toes and high arched feet
codone, morphine sulfate, tramodol, lidocaine patch, (pes cavus) are commonly present, along with steppage
and topical capsaicin. A zoster vaccine (Zostavax) has gait, distal sensory loss, and distal loss of reexes. Pes
been approved to prevent VZV in elderly patients; the cavus and hammer toes indicate that the neuropathy
incidence of shingles is reduced by 50% and posther- dates from early life. An inability to walk on the heels
petic neuralgia by 67%. or perform tandem gait is often present.The differential
diagnosis is limited if there is an early age of onset, a
Leprous Neuritis positive family history, and longstanding symptoms. If
the EDx ndings indicate a demyelinating process, the
Mycobacterium leprae causes mononeuropathy multiplex diagnosis of CMT can be made with condence,
affecting peripheral nerves in cooler regions of the body, although genetic testing may be needed to conrm the
reecting the predilection for this bacterium to thrive at precise genotype. If the EDx ndings are axonal, or if
cooler temperatures. The deformities caused by the family history is uncertain or negative, CMT
untreated leprous neuritis have led to the fear and becomes a diagnosis of exclusion. Diabetes, as well as
stigma attached to this disease. Although the incidence nutritional, toxic, endocrine, inammatory, paraprotein-
of leprous neuritis has declined, it remains a leading associated, and infectious causes, may all need to be
cause of neuropathy worldwide. Leprosy is classied into excluded. Physical examination and EDx studies of at-
tuberculoid, lepromatous, and borderline types; periph- risk family members can be more useful diagnostically
eral nerves may be affected in all three types, and than additional laboratory testing of the patient. Treat-
involved nerves are often palpably thickened. In tuber- ment is supportive; patients often need foot braces but
culoid leprosy, a single patch of hypesthetic or anesthetic rarely, if ever, become wheelchair dependent. CMT
skin may occur in any location. The area is generally does not reduce the life span and only rarely involves
hypopigmented, thickened, or red. A mononeuropathy respiratory muscles.
involving a nearby supercial nerve may occur. Lepro-
matous leprosy produces more widespread skin thicken-
Classication
ing, hypesthesia, and anhidrosis affecting the pinnae of
ears, dorsum of hands or feet, dorsomedial surfaces of Demyelinating forms of CMT are classied as CMT1,
the forearm, and anteromedial aspects of the legs. The and axonal forms as CMT2. Patients with nerve con-
sensory loss spares the midline of the trunk anteriorly, duction velocities (NCVs) intermediate between CMT1
the groin, axilla, and scalp; these are the warmer regions and CMT2 are classied as having intermediate CMT,
of the body.The fth and seventh cranial nerves, greater and most of these cases are X-linked. CMT is usually
 542 TABLE 40-10 Charcot-Marie-Tooth 1 (CMT1) Demyelinating
FORMS OF CHARCOT-MARIE-TOOTH DISEASE Neuropathies
(HEREDITARY MOTOR AND SENSORY NEUROPATHY)
CMT1 is the most common of the heritable neu-
AND RELATED DISORDERS
ropathies; inheritance is autosomal dominant. Distal
DISORDER LOCUS GENE INHERITANCE weakness, wasting, and sensory loss with distal reduction
of tendon reexes and foot deformities occur as with
Charcot-Marie-Tooth Type 1
other forms of CMT. The onset is in the rst or second
(HMSNI) decade of life, although patients may not come to atten-
CMT1A 17p11.2-p12 PMP22 AD tion until much later in life. EDx studies show a pattern
CMT1B 1q22-q23 P0 AD
of generalized demyelination with NCVs that are uni-
CMT1C 16p12-p13 SIMPLE AD
CMT1D 10q21-q22 EGR2 AD/AR
formly and proportionately slowed in distal, intermedi-
CMT1X Xq13.1 GJB1 X-linked ate, and proximal segments of the same nerve on the
CMT5X Xq21.32-24 PRPS1 X-linked opposite side, and in adjacent nerves. Findings suggestive
CMT4A 8q13-q21 GDAP1 AR of heterogeneous demyelination, such as conduction
CMT4B1 11q22 MTMR2 AR block or dispersion, are not seen. Electrophysiologic evi-
CMT4B2 11p15 SBF2 AR dence of demyelination may be prominent even in
CMT4D 8q24 NDRG1 AR patients who are clinically asymptomatic. Nerve biopsies
SECTION III

(HMSN-Lom)
CMT4E 10q21.1-q22.1 EGR2 AR
show evidence of repeated bouts of demyelination and
CMT4F 19q13 PRX AR remyelination. Proliferation of Schwann cells occurs in
CMT4J 6q21 FIG4 AR an attempt to remyelinate; the supernumerary Schwann
Charcot-Marie-Tooth Type 2 cells are concentrically arranged around demyelinated
and remyelinated axons, giving a characteristic onion
(HMSNII) bulb appearance. There is also increased collagen
Diseases of the Central Nervous System

CMT2A 1p35-p36 KIF1B AD

CMT2B 3q13-q22 RAB7 AD
between the layers of Schwann cells leading to palpably
CMT2C 12q23-q24 Unknown AD thickened nerves.
CMT2D 7p14 GARS AD CMT1 is classified into several genetically distinct
CMT2E 8p21 NEF-L AD subtypes (Table 40-10), all of which are clinically simi-
CMT2B1 11q21 LMNA AR lar. In addition, distinct phenotypes with overlapping
Djerine-Sottas genotypes are identified. These include HNPP; infan-
(HMSNIII)
tile-onset or severe childhood forms, which include
DSS 17p11.2-p12 PMP22 AD Djerine-Sottas syndrome (DSS) and congenital
1q22-p23 P0 AD hypomyelinating neuropathies (CHN); and Roussy-
10q21-q22 EGR2 AD/AR Lvy syndrome.
19q13 PRX AD
Congenital Hypomyelination CMT1A
CHN 1q22-23 P0 AD This is the most common form; it is associated with the
10q21-q22 EGR2 AR/AD 17p11.2-p12 duplication in the PMP22 gene expressed
Hereditary Neuropathy with Pressure Palsies by Schwann cells. The duplication involves a large seg-
ment of DNA (~1.4 Mb) encoding a 160-amino-acid
HNPP 17p11.2-p12 PMP22 AD
protein localized to compact myelin in peripheral
Note: HMSN, hereditary motor and sensory neuropathies; PMP22, nerves. CMT1A accounts for up to 90% of CMT1 and
peripheral myelin protein 22; P0, myelin protein zero; SIMPLE, small 50% of all CMT. Deletion of the PMP22 gene produces
integral membrane protein of late endosome; Cx32, connexin32; a different phenotypeHNPP (see later). Commercial
EGR2 (Krox-20) early growth response 2 gene; GDAP1, ganglioside-
testing for PMP22 duplication/deletion is widely avail-
induced differentiation-associated protein-1; MTMR2, myotubularin-
related protein-2; SBF2, SET binding factor 2; NDRG1, N-myc able. PMP22 appears to be important in the initiation of
downstream regulated gene1; PRX, periaxin; KIF1B, kinesin family myelin spirals; regulation and growth of Schwann cells;
member 1B; RAB7, ras-associated protein 7; GARS, Glycyl-tRNA and control of thickness, stability, and maintenance of
synthetase; NEFL, neurolament, light polypeptide; LMNA, lamin A.
myelin sheaths.

transmitted as an autosomal dominant trait, but X-linked- CMT1B

dominant CMT is responsible for ~10% of CMT cases. CMT1B accounts for <5% of CMT1 cases. It is due to
Rare autosomal recessive forms, designated CMT4, tend a mutation in the myelin protein zero (MPZ, or P0)
to have an early onset and are more severe than the gene. Different mutations in the same gene can produce
dominant types. In total, ~35 different loci and >24 a wide spectrum of phenotypes including DSS, CHN,
genes have been identied in CMT. or CMT2. P0 is quantitatively the major structural
protein of peripheral nerve myelin and is important in entrapment sites is preferred over surgical release or 543
myelin compaction. CMT1B is clinically indistinguish- transposition.
able from CMT1A; a late adult-onset form with foot-
drop can occur. Genetic testing is available. Djerine-Sottas Syndrome and Congenital
Hypomyelinating Neuropathy
CMT1X These are severe childhood forms of CMT1. DSS and
This is an X-linked dominant form of CMT that can CHN both present with muscle weakness at birth or
also affect heterozygote females. It is responsible for up infancy, with absent or very slow NCVs. Delayed motor
to 10% of CMT. Males are more often affected, and milestones are noted in early childhood. Patients either
female carriers are usually mildly affected or asympto- never ambulate or lose their ability to ambulate in
matic. Male-to-male transmission does not occur. Onset infancy or childhood. NCVs are markedly slow (typi-
in males is between 5 and 20 years of age; symptoms cally 10 m/s); CSF protein is elevated. Clinically DSS
include difculty running, sprained ankles, footdrop, and CHN are indistinguishable. DSS can be either auto-
distal wasting, weakness, sensory loss, and reduced somal dominant or recessive; CHN is autosomal reces-
reexes. These features do not distinguish CMT1X sive. Nerve biopsy can distinguish the two, with DSS
from other forms of CMT1. Signs of central nervous showing a thin myelin sheath surrounded by onion
system (CNS) involvement, including ataxia, dysarthria, bulbs composed of concentric layers of basal lamina

CHAPTER 40
weakness, aphasia, disorientation, and hearing loss, may (Schwann cells are degenerated leaving the basal lam-
be present, especially in males. Spontaneously resolving ina), while CHN shows lack of onion bulbs and absent
conuent white matter changes may be seen on MRI. myelin sheaths. DSS may be caused by mutations of
NCVs are in an intermediate range, although males PMP22, myelin protein zero (MPZ), or early growth
have slower conduction velocities (2545 m/s), which response gene (ERG2); EGR2 or MPZ mutations
may be nonuniform with conduction block and disper- underlie CHN.

Peripheral Neuropathy
sion. This nonuniform pattern may mimic ndings of
an acquired disorder such as CIDP. The mutated gene, Roussy-Lvy Syndrome
GJB1, encodes the gap junction protein connexin-32, This describes a combination of demyelinating CMT
which is expressed at the paranodal regions and at the with postural and action tremor. The original family
Schmidt-Lanterman incisures of noncompact myelin. members had the MPZ mutation, but mutations in
PMP22 (CMT1A), MPZ (CMT1B), or GJB1 (CMT1X)
Hereditary Neuropathy with Liability to Pres- genes may also cause this syndrome.
sure Palsies
This is also called tomaculous neuropathy. It is an autoso-
mal dominant disorder that presents as recurrent Charcot-Marie-Tooth 2 (CMT2) Axonal
Neuropathies
episodes of focal entrapment neuropathy with attacks of
numbness and weakness in peroneal, ulnar, radial, and CMT2, an autosomal dominant neuropathy, is responsi-
median nerves (in descending order) or in a brachial ble for one-third of CMT disease, although the number
plexus distribution. Malposition of a limb or trauma of patients is increasing as more genetic abnormalities
may provoke episodes of neuropathy. Some patients pre- are being identied. CMT2 has a later age of onset than
sent with a progressive length-dependent polyneuropa- CMT1; family members may be affected subclinically.
thy rather than with recurrent mononeuropathies, and Although typical length-dependent sensory and motor
others remain entirely asymptomatic. Increased distal loss develops over the years, intrinsic hand weakness and
latencies in median and peroneal nerves and reduced atrophy, present in CMT1, do not develop.
velocities across the elbow of the ulnar and bular head CMT2A (classic CMT2) is caused by mutations in
segment of the peroneal nerves may be found. Tomacu- MFN2 and represents 10% of dominant CMT2;
lae are sausage-shaped bodies that indicate segmental CMT2B is caused by mutations in RAB7, a member of
demyelination. CMT1A and HNPP are both associated the Rab family of ras-related GTPases that function in
with copy number changes in the PMP22 genea intracellular membrane trafcking; it presents with
duplication causing CMT1A and deletion causing severe sensory involvement and limb ulcerations.
HNPP. Hence, CMT1A and HNPP are the reciprocal CMT2B overlaps with hereditary sensory neuropathy
products of unequal crossing-over during meiosis.When (HSN) type I with prominent sensory loss and severe
HNPP presents as a painless brachial plexus neuropathy, sensory loss to touch and pain (see later). CMT2C is
it should be distinguished from brachial plexus neuritis associated with vocal cord and respiratory (diaphragm)
and from hereditary neuralgic amyotrophy, a familial dis- involvement; the genetic defects have not been identi-
order with painful weakness and sensory loss in the ed. CMT2D is an axonal CMT with upper limb pre-
brachial plexus distribution.Treatment for HNPP is sup- dominance associated with mutations in the glycyl-tRNA
portive. Avoiding further compression or trauma to the synthetase gene; predominant hand involvement with
 544 atrophy of distal hand muscles in a patient with a posi- duplication. Most CMT1 and CMT2 pedigrees are
tive family history suggests CMT2D. autosomal dominant. X-linked inheritance should be
suspected if males are more often affected, there is no
male-to-male transmission, and EDx studies show het-
Autosomal Recessive Forms of CMT erogeneous ndings. Sporadic cases are difcult to eval-
Autosomal recessive CMTs account for <10% of inher- uate since family members may not be available. Testing
ited neuropathy cases in the Western world but may be for the CMT1A duplication/deletion and for GJB1
more common in regions of the world where consan- mutation can diagnose ~80% of all cases of CMT.
guinity is common. Several genes have been identied,
especially in inbred families. Demyelinating autosomal OTHER INHERITED NEUROPATHIES
recessive forms, designated CMT4, are usually character-
Hereditary Motor Neuropathies (HMN)
ized by early onset and more severe involvement, with
congenital or delayed motor milestones, facial weakness, The distal HMNs present with distal motor weakness
bulbar weakness, sensorineural deafness, diaphragm with sparing of sensory bers. Seven subtypes have been
weakness, and vocal cord paralysis. described based on the age of onset and mode of inheri-
tance, which is usually autosomal dominant or recessive.
The common HMNs present as footdrop with severe
SECTION III

Molecular Testing wasting and weakness distally. Some variants may mani-
The phenotype, the inheritance pattern, and electro- fest with predominantly upper limb involvement, vocal
physiologic data guide the approach to the diagnosis of cord paralysis, or with upper motor neuron signs mimic-
an inherited neuropathy. Figure 40-2 summarizes an king amyotrophic lateral sclerosis (Chap. 27); the prog-
approach to genetic testing for CMT. If the proband has nosis is relatively good.
CMT1, a single nerve study (median motor forearm
Diseases of the Central Nervous System

conduction velocity) in family members is a quick

Hereditary Sensory Neuropathies (HSN)
screening tool. However, if the proband has axonal
CMT (CMT2), more detailed evaluation of family HSNs, also called hereditary sensory and autonomic
members may be required. Evaluation for HNPP neuropathies (HSANs), are a heterogeneous group of dis-
employs the same molecular test as for the CMT1A orders affecting the sensory and/or autonomic neurons.

Suspected CMT

HNPP Distal wasting, Infancy/early childhood

(multiple entrapments) weakness, sensory (DSS or CHN) < 10 m/s

PMP22 deletion Demyelinating Intermediate Axonal PMP22 mutation

(CMT1) 1038 m/s 2545 m/s (CMT2) > 38 m/s

MPZ mutation
PMP22 duplication MFN2 (CMT2) EGR2
GJB1 (CMT1X)
(CMT1A) GJB1 (CMT1X) PRX
GJB1 (CMT1X)

MPZ (CMT1B) MPZ (CMT1B) MPZ (CMT1B)

Sequence
PMP22 (CMT1A)

Upper limb > lower limb: CMT2D Severe sensory loss and ataxia: CMT4F (periaxin)
Sensory > motor: axonal CMT2 (MPZ or RAB7) Vocal cord/diaphragm: CMT2C
Proximal weakness (wheelchair: DI CMT1B) Deafness: CMT1E
Pyramidal features: HMSN V CMT with optic atrophy: MFN2 gene (HMSN VI)
Tonic pupil: CMT2J (MPZ) Scoliosis: CMT4C

FIGURE 40-2
Diagnostic approach to Charcot-Marie-Tooth disease (CMT). Djerine-Sottas syndrome; CHN, congenital hypomyelinating
HNPP, hereditary neuropathy with pressure palsies; DSS, neuropathy; HMSN, hereditary motor and sensory neuropathy.
The predominant clinical presentation is of progressive peripheral neuropathy. Nearly 100 different mutations 545
distal sensory loss, although some weakness and wasting have been identied in the TTR gene, the most com-
is also observed. The classification of HSN and HSAN mon being the Val30Met mutation. Liver transplanta-
is based on the age of onset and mode of inheritance. tion halts disease progression.
Five subtypes are described. The most common is
HSN 1 (also called HSAN 1), an autosomal dominant
Tangier Disease (TD)
neuropathy presenting with predominant small-fiber
sensory involvement with lancinating pain, loss of pain This is a rare syndrome caused by a severe deficiency
and temperature sensation, and foot ulceration. Of of high-density lipoproteins (HDL) in plasma. Peripheral
note, CMT2B (see earlier) also presents with predomi- neuropathy is the most disabling feature of TD and
nantly sensory loss to all modalities and foot ulcera- affects ~50% of patients. Three patterns are recognized:
tions. HSN 25 are all autosomal recessive. HSN 2 pre- a transient or relapsing, often asymmetric neuropathy
sents in the first two decades of life with prominent (including isolated cranial nerve deficits); a slowly
sensory loss and mutilation in hands and feet. HSN 3 progressive symmetric neuropathy most marked in the
(HSAN 3), also called Riley-Day syndrome, has promi- distal upper limbs (syringomyelia-like); and a slowly
nent dysautonomia. HSN 4 (HSAN 4) presents with progressive symmetric sensory motor neuropathy
episodic fever, anhidrosis, and reduced response to most marked in the lower limbs. Mononeuropathies

CHAPTER 40
painful stimuli. HSAN 5 presents with congenital involving the oculomotor nerve, long thoracic nerve,
insensitivity to pain; mutations in a sodium channel or any of the limb nerves may occur.The syringomyelic
(SCN1.7) are causative. presentation includes wasting of hand muscles, loss
of pain and temperature sensation, and facial diplegia.
The length-dependent sensorimotor neuropathy pat-
Refsum Disease
tern is the least common variant. Deposits of choles-

Peripheral Neuropathy
This is an autosomal recessive hypertrophic neuropathy terol esters in tonsils, liver, spleen, rectal mucosa, and
caused by defective oxidation of phytanic acid, a cornea lead to the other non-neurologic manifestations
branched-chain fatty acid found in dairy products, beef, of TD.There is no treatment available; a low-cholesterol
lamb, and sh. The onset is in late childhood or adoles- diet or other dietary changes do not modify the
cence, with a slowly progressive course of a sensorimo- natural history. Gene therapy may be possible in the
tor demyelinating neuropathy with sensorineural deaf- future.
ness, cerebellar ataxia, and anosmia. Retinitis pigmentosa
presenting as night blindness often precedes the onset of Porphyric Neuropathy
neuropathy. Thickened skin (ichthyosis), syndactyly and
shortening of the fourth toe, cardiomyopathy, and Peripheral neuropathy accompanies the inherited
cataracts are other features. CSF protein is typically ele- hepatic porphyrias. The triad of acute neuropathy, psy-
vated. Abnormally high plasma and urinary levels of chiatric symptoms, and abdominal involvement are simi-
phytanic acid are diagnostic. Although a diet low in phy- lar in all hepatic porphyrias. Variegate porphyria and
tanic acid may prevent the onset of some of the compli- hereditary coproporphyria are characterized by addi-
cations, compliance with this diet is usually poor. Plasma tional skin lesions (blisters and bullae) in ~50% of
exchange and dialysis may be helpful for episodes of patients. Most patients with porphyria are asymptomatic
worsening. between attacks. Attacks can occur spontaneously or be
precipitated by certain drugs, stress, hormonal factors,
and reduced caloric intake. Abdominal pain, constipa-
Familial Amyloid Neuropathy
tion, vomiting, and mental changes frequently herald the
This is an autosomal dominant disorder in which there attacks. Peripheral neuropathy has an acute onset and
is extracellular deposition of amyloid in peripheral may be preceded or accompanied by autonomic mani-
nerves and other organs. A painful sensory neuropathy festations such as tachycardia, hypertension, and postural
with early involvement of autonomic nerves and car- hypotension. The neuropathy is usually subacutely pro-
diomyopathy is typically present. Age of onset can vary gressive (over 24 weeks) with diffuse weakness (often
from 1883 years. Small bers (pain and temperature) proximal more than distal) and areexia. Sensory loss is
are more affected than large bers (vibration and pro- generally mild and may be more prominent proximally
prioception); anhidrosis, gastrointestinal disturbances in a bathing trunk distribution. Porphyric neuropathy
(diarrhea alternating with constipation), impotence, should be considered in the differential diagnosis of
orthostatic intolerance, visual changes, and arrhythmias GBS, the most common cause of rapidly progressive
are additional features. Mutations in transthyretin (FAP ascending paralysis.
1 and 2), apolipoprotein A1 (FAP 3) or gelosin (FAP 4) CSF is acellular but the protein level is elevated,
are responsible.Transthyretin is most often implicated in similar to that in GBS. Acute attacks are invariably
 546 associated with increased urinary excretion of neuromuscular blockade) are purely motor and can be
aminolevulinic acid and/or porphobilinogen. Measur- recognized and localized electrodiagnostically (Chap. 42).
ing 24-h urinary excretion of porphobilinogen and
aminolevulinic acid and 24-h fecal excretion of proto-
PURE SENSORY NEUROPATHY
porphyrin and coproporphyrin during a symptomatic
period is the most helpful method of determining Causes include Friedreichs ataxia, idiopathic sensory
whether symptoms are due to acute porphyria. Since neuropathy, sensory neuropathy associated with Sjgren
porphyrins are light sensitive, specimens must be stored syndrome, vitamin B12 neuropathy (dorsal column
in the dark and tested as soon as possible. involvement is the major factor), pyridoxine toxicity,
Treatment is largely supportive during the acute cri- and cisplatin neuropathy. The most severe and wide-
sis and includes fluid management, ventilatory support, spread of these pure sensory syndromes exhibit poor or
management of heart rate and blood pressure (auto- no recovery, suggesting irreversible lesions of nerve cell
nomic dysfunction), and avoidance of medications that bodies in dorsal root and trigeminal ganglia (neu-
are known to precipitate an acute attack. Oral and IV ronopathy). A painful sensory neuropathy is an early
glucose and heme arginate are the mainstays of treat- feature of hereditary sensory neuropathies, lepromatous
ment. Recovery from an acute attack may take several leprosy, diabetic small-ber neuropathy, amyloidosis,
months. TD, Fabrys disease, and dysautonomia. Global sensory
SECTION III

loss can occur with carcinomatous sensory neuropathy,

hereditary sensory neuropathies, diabetic sensory neu-
Critical Illness Neuropathy ropathy, vacor intoxication, and xanthomatous neuropa-
See Chap. 22. thy of primary biliary cirrhosis.

PLEXOPATHY
Diseases of the Central Nervous System

SPECIAL PERIPHERAL
NEUROPATHY PRESENTATIONS This refers to disorders of either the brachial or the
lumbosacral plexus. Brachial plexopathy is a broad term
AUTONOMIC NEUROPATHY used to dene any injury, traumatic or otherwise, to the
brachial plexus. Causes include birth injury, trauma,
Symptoms may include orthostatic hypotension (syncope,
neoplasm, radiation, and familial and immune-mediated
light headedness, dizziness, fatigue, and lethargy), heat
processes (Fig. 40-3; Table 40-11). Trauma to the
intolerance, abnormal (reduced or increased) sweating,
plexus is responsible for up to 70% of brachial plexus
constipation, diarrhea, incontinence, sexual dysfunction,
lesions; the upper plexus is the most vulnerable. Brachial
dry eyes, dry mouth, or visual blurriness. Autonomic
neuritis (neuralgic amyotrophy; Chap. 7), characterized
neuropathy is usually a manifestation of a more general-
by sudden onset of pain in the shoulder region followed
ized polyneuropathy, as in diabetes, GBS, and alcoholic
by weakness and atrophy, is the second most common
polyneuropathy, but occasionally syndromes of pure
cause. In this disorder, the shoulder girdle muscles are
pandysautonomia are encountered. Other causes include
most frequently affected, and individual peripheral
amyloidosis and multiple drugs and toxins. Autonomic
nerves tend to be more commonly involved. Other
neuropathies are discussed in detail in Chap. 28.
causes include a cervical rib or band, inltration by
malignant tumor, or prior radiation therapy.
Brachial plexus lesions demonstrate characteristic
PURE MOTOR NEUROPATHY
motor and sensory signs. When the upper parts of the
Examples of predominantly motor neuropathies include brachial plexus (cervical roots 57) are affected, weak-
acute inammatory neuropathies such as GBS; chronic ness and atrophy of shoulder girdle and upper arm mus-
neuropathies such as CIDP and multifocal motor neu- cles occurs. Injuries to the lower brachial plexus (C8-T1
ropathy (MMN) (Chap. 41); some inherited neu- roots) produce distal arm weakness, atrophy, and focal
ropathies; brachial neuropathy; diabetic lumbosacral sensory decits in the forearm and hand. In general,
radiculoplexus neuropathy (diabetic amyotrophy); and idiopathic brachial neuritis, irradiation with >60 Gy
neuropathy due to spinal muscular atrophy, acute inter- (6000 rad), and specic types of trauma (arm jerked
mittent porphyria, diphtheria, lead, and dapsone. Motor downward) result in damage to the upper portions of
neuronopathies include the lower-motor form of amy- the brachial plexus. In contrast, inltration by malignant
otrophic lateral sclerosis, poliomyelitis, hereditary spinal tumor, a cervical rib or band, and specic types of
muscular atrophies, and an adult variant of hex- trauma (arm jerked upward) cause damage to the lower
osaminidase A deciency (Chap. 27). Neuromuscular brachial plexus.
junction disorders (e.g., Lambert-Eaton myasthenic syn- The lumbosacral plexus is formed by the ventral pri-
drome, tick bite paralysis, and other types of toxic mary rami of L1-S4. Although often considered as a
 Dorsal scapular 547
Lateral
Upper anterior
subscapular thoracic Suprascapular C5
L
Axillary
Musculocutaneous C6
Radial P Subclavius
C7
Median
C8
Ulnar
M
Medial Medial
antibrachial anterior
T1
cutaneous Thoracodorsal thoracic
Lower
Medial subscapular
Long thoracic
brachial
cutaneous

PERIPHERAL NERVES CORDS DIVISIONS TRUNKS ROOTS

CHAPTER 40
Anterior Posterior
FIGURE 40-3
Brachial plexus anatomy. L, lateral; M, medial; P, poste- Electromyography. Baltimore, Williams and Wilkins, 1974,
rior. (From J Goodgold: Anatomical Correlates of Clinical p. 126; with permission.)

TABLE 40-11

Peripheral Neuropathy
BRACHIAL PLEXUS LESIONS

SITE OF NERVES/NERVE MUSCLES

INJURY ROOTS AFFECTED SENSORY LOSS COMMON CAUSES

Upper trunk C-5 and C-6 Weakness of shoulder Small patch of skin Birth injury during difcult
abduction (supraspinatus overlying the deltoid delivery (Erb-Duchenne
& deltoid), external rota- palsy); brachial neuritis,
tion (infraspinatus) and also called neuralgica
elbow exion (biceps) myotrophy (Parsonage-
Turner syndrome)
Lower trunk C-8 and T-1 Weakness and wasting Ulnar border of the Birth injury, especially
of small muscles of hand and inner breech delivery (Djerine-
the hand (claw-hand forearm Klumpke paralysis), com-
deformity) pression by cervical rib or
band (thoracic outlet syn-
drome), tumor inltration
Lateral cord Musculocutaneous Weakness of exion and Radial border of Trauma, stretch
nerve and lateral pronation of forearm forearm and hand
part of median
nerve
Medial cord Medial part of Weakness and wasting Ulnar border of the Trauma
median nerve of small muscles of hand and inner
and ulnar nerve the hand (claw hand forearm
deformity)
Posterior cord Axillary and radial Deltoid, extensors of Outer aspect of Trauma, shoulder
nerves elbow, wrist, and ngers upper arm dislocation

single entity, it can be divided into a lumbar plexus the main nerves formed by the sacral plexus. The lum-
(ventral rami of L1L4) and a sacral plexus (lum- bosacral plexus courses near the paravertebral psoas
bosacral trunk L4 and L5 and ventral rami of S1S4) muscle and the sacroiliac notch and sacral ala, where it
(Figs. 40-4 and 40-5). The femoral and obturator is relatively well protected from injury, unlike its upper
nerves are the main nerves formed from the lumbar extremity counterpart. Disorders affecting the lum-
plexus, and the sciatic, gluteal, and pudendal nerves are bosacral plexus include: trauma, intraoperative damage,
 548 degrees of pain, sensory deficits, and weakness in the
T12 lower limbs, generally in an asymmetric distribution.
T12 The onset may be acute, subacute, or insidious depend-
L1
Iliohypogastric n. ing on the etiology; the course may vary from being
L2 monophasic, stepwise, or progressive. EDx studies are
Ilioinguinal n. invaluable aids for diagnosis and localization.
L3

L4 Genito-femoral n. PERIPHERAL NERVE INJURY

Lateral femoral
cutaneous n. L5
Physical damage to peripheral nerves may result from
sudden compression, crush, transection, or stretching of
Femoral n. Obturator n. a nerve. The mildest form of nerve injury results when
a stretch or pressure injury distorts the myelin overly-
Lumbosacral trunk
ing the nodes of Ranvier and produces focal conduc-
FIGURE 40-4
tion block. This type of injury, with conduction block
Lumbar plexus. Posterior divisions are in orange, anterior divi-
sions are in yellow. (From J Goodgold: Anatomical Correlates
but without Wallerian degeneration, is referred to as
of Clinical Electromyography. Baltimore, Williams and Wilkins,
neurapraxia, or class 1 injury. This results in a transient
SECTION III

1974, p. 126; with permission.) sensation of numbness in an extremity, as occurs after

lying or sitting in a certain position. Nerve injury that
interrupts the axons continuity and results in Wallerian
degeneration of the nerve distal to the lesion is consid-
L4 ered moderate or severe. If the endoneurium is pre-
served, the lesion is considered moderate and is called
Diseases of the Central Nervous System

axonotmesis, or class 2 injury. If the endoneurium is

L5 destroyed, the lesion is considered severe and is called
neurotmesis. Peripheral nerve lesions are often mixed;
neurapraxia and axonotmesis may coexist. Similarly,
one fascicle may be completely disrupted while
S1
another is only partially affected. If the clinical and
Superior gluteal electrophysiologic examinations show that the lesion is
complete, and if the mechanism of injury is known to
S2 be a clean laceration, then surgical repair should be
Inferior gluteal considered within 24 h of the injury. If the mechanism
of injury is contusion, stretch, traction, or compression,
nerve conduction studies to determine whether the
S3 lesion is neurapraxic or axonotmesic should be delayed
for 3 weeks. If neurapraxic, a return of function can be
expected, provided care is taken to ensure that there is
S4 no ongoing compressive injury. If clinical and electro-
physiologic examinations (no motor units seen by
Common EMG) fail to reveal evidence of return of function
Sciatic
peroneal after 3 months, the lesion was most likely neurotmesic,
Tibial and exploration and surgical repair may need to be
To sphincter
Pudendal
ani externus
undertaken. If the lesion is incomplete, follow-up evalua-
FIGURE 40-5 tions should be performed monthly; if no improvement
Lumbosacral plexus. Posterior divisions are in orange, ante- is seen, then surgery may be required. Approximately
rior divisions are in yellow. (From J Goodgold: Anatomical 80% of closed injuries resolve spontaneously, because
Correlates of Clinical Electromyography. Baltimore, Williams these lesions are in continuity. The appearance of an
and Wilkins, 1974, p. 126; with permission.) advancing Tinels sign in the distribution of the injured
nerve indicates that the nerve is in continuity and jus-
tifies postponement of surgery. The growth rate of
retroperitoneal hemorrhage, radiotherapy, neoplastic regenerating axons is about 2.5 cm/month. The time
invasion, diabetes mellitus, pregnancy and labor, required for regeneration is dependent on the distance
retroperitoneal abscess or hemorrhage, abdominal aor- from the site of injury to the first muscle innervated
tic aneurysm, and idiopathic lumbosacral plexopathy below the lesion. Since this distance is greater for
(Table 40-12). Most patients present with varying proximal nerve lesions, severe proximal injuries are
TABLE 40-12 549
LUMBOSACRAL PLEXUS LESIONS

SITE NERVE ROOTS MUSCLES SENSORY LOSS COMMON CAUSES

Upper plexus L-2, L-3, L4 Weakness of thigh exion Anterior thigh and Diabetic amyotrophy;
(psoas), thigh adduction, medial leg; absent abdominal surgeryeither
and knee extension knee jerk directly/retraction, or due
(quadriceps) to positioning; lum-
bosacral plexitis
Lower plexus L-4, L-5, S-1, and S-2 Weakness of thigh extension Posterior thigh, lateral Lumbosacral plexitis,
(glutei), knee exion leg, and entire foot; perioperative, cancer
(hamstrings), foot dorsiex- absent ankle jerk inltration, radiation
ion and plantar exion

CHAPTER 40
associated with poor recovery. Brachial plexus injuries FURTHER READINGS
during birth carry a better prognosis for spontaneous BROMBERG MB, SMITH AG (eds): Handbook of Peripheral Neuropathy.
recovery than do those in adults. Taylor & Francis Group, FL, 2005
DYCK PJ et al (eds): Peripheral Neuropathy. Saunders, Philadelphia, 2005
ENGLAND JD et al: Practice parameter: Evaluation of distal symmetric
PERIPHERAL NERVE TUMORS polyneuropathy: Role of autonomic testing, nerve biopsy, and
Peripheral nerve tumors, which can present as periph- skin biopsy (an evidence-based review): Report of the American

Peripheral Neuropathy
Academy of Neurology, American Association of Neuromuscular
eral neuropathy, are mostly benign and can arise in any and Electrodiagnostic Medicine, and American Academy of
nerve trunk or nerve twig. Although peripheral nerve Physical Medicine and Rehabilitation. Neurology 72:177, 2009
tumors can occur anywhere in the body, including the _________ et al: Practice parameter: Evaluation of distal symmetric
spinal roots and cauda equina, many are subcutaneous polyneuropathy: Role of laboratory and genetic testing (an
in location and present as a soft swelling, sometimes evidence-based review): Report of the American Academy of
with a purplish discoloration of the skin. Symptoms Neurology, American Association of Neuromuscular and
can include tingling or pain when the lesion is Electrodiagnostic Medicine, and American Academy of Physical
Medicine and Rehabilitation. Neurology 72:185, 2009
touched. Diagnostic studies may include imaging
HARATI Y (ed): Neurologic Clinics. Peripheral Neuropathies. Elsevier
(CT/MRI), EMG and nerve conduction studies, and Saunders, Philadelphia, 2007, pp 1330
tumor biopsy.Two major categories of peripheral nerve JANI-ACSADI A et al: Charcot-Marie-Tooth neuropathies: diagnosis
tumors are recognized: neurilemmoma (schwannoma) and management. Semin Neurol 28:185, 2008
and neurofibroma. Neurilemmomas are usually solitary JARVIK JG et al: Surgery versus non-surgical therapy for carpal tunnel
and grow in the nerve sheath, rendering the tumor rel- syndrome:A randomised parallel-group trial. Lancet 374:1074, 2009
atively easy to dissect free. In contrast, neurofibromas MYGLAND A: Approach to the patient with chronic polyneuropathy.
Acta Neurol Scand Suppl 187:15, 2007
tend to be multiple and grow in the endoneurial sub-
PRESTON DC, SHAPIRO BE (eds): Electromyography and Neuromuscular
stance, which renders them difficult to dissect. They Disorders, Clinical Electrophysiological Correlations, 2d ed. Elsevier,
may undergo malignant changes. Neurofibromas are Butterworth Heinemann, Philadelphia, 2005
the hallmark of von Recklinghausens neurofibromato- SAID G: Diabetic neuropathya review. Nat Clin Pract Neurol
sis (NF1) (Chap. 32). 3:331, 2007
 CHAPTER 41
GUILLAIN-BARR SYNDROME AND OTHER
IMMUNE-MEDIATED NEUROPATHIES
Stephen L. Hauser I Arthur K. Asbury

I Guillain-Barr Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 550

I Chronic Inammatory Demyelinating Polyneuropathy . . . . . . 555
I Multifocal Motor Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . 556
I Neuropathies with Monoclonal Gammopathy . . . . . . . . . . . . 557
Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Monoclonal Gammopathy of Undetermined Signicance . . . 557
I Vasculitic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
I Anti-Hu Paraneoplastic Neuropathy . . . . . . . . . . . . . . . . . . . 558
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 558

occurring in ~50% of patients. Most patients require hos-

GUILLAIN-BARR SYNDROME pitalization, and almost 30% require ventilatory assistance
Guillain-Barr syndrome (GBS) is an acute, frequently at some time during the illness. Fever and constitutional
severe, and fulminant polyradiculoneuropathy that is symptoms are absent at the onset and, if present, cast doubt
autoimmune in nature. It occurs year-round at a rate of on the diagnosis. Deep tendon reexes attenuate or disap-
about one case per million per month, or ~3500 cases pear within the rst few days of onset. Cutaneous sensory
per year in the United States and Canada. Men are at decits (e.g., loss of pain and temperature sensation) are
1.5-fold higher risk for GBS than women, and in west- usually relatively mild, but functions subserved by large
ern countries adults are more frequently affected than sensory bers, such as deep tendon reexes and proprio-
children. ception, are more severely affected. Bladder dysfunction
may occur in severe cases but is usually transient. If bladder
dysfunction is a prominent feature and comes early in the
Clinical Manifestations
course, diagnostic possibilities other than GBS should be
GBS manifests as rapidly evolving areexic motor paralysis considered, particularly spinal cord disease. Once clinical
with or without sensory disturbance. The usual pattern is worsening stops and the patient reaches a plateau (almost
an ascending paralysis that may be rst noticed as rubbery always within 4 weeks of onset), further progression is
legs. Weakness typically evolves over hours to a few days unlikely.
and is frequently accompanied by tingling dysesthesias in Autonomic involvement is common and may occur
the extremities.The legs are usually more affected than the even in patients whose GBS is otherwise mild. The usual
arms, and facial diparesis is present in 50% of affected indi- manifestations are loss of vasomotor control with wide uc-
viduals. The lower cranial nerves are also frequently tuation in blood pressure, postural hypotension, and cardiac
involved, causing bulbar weakness with difculty handling dysrhythmias. These features require close monitoring and
secretions and maintaining an airway; the diagnosis in management and can be fatal. Pain is another common fea-
these patients may initially be mistaken for brainstem ture of GBS; in addition to the acute pain described above, a
ischemia. Pain in the neck, shoulder, back, or diffusely over deep aching pain may be present in weakened muscles that
the spine is also common in the early stages of GBS, patients liken to having overexercised the previous day.

550
TABLE 41-1 551
SUBTYPES OF GUILLAIN-BARR SYNDROME (GBS)

SUBTYPE FEATURES ELECTRODIAGNOSIS PATHOLOGY

Acute inammatory Adults affected more than Demyelinating First attack on Schwann myelin
demyelinating children; 90% of cases in cell surface; widespread
polyneuropathy western world; recovery damage, macrophage
(AIDP) rapid; anti-GM1 antibodies activation, and lymphocytic
(<50%) inltration; variable secondary
axonal damage
Acute motor axonal Children and young adults; Axonal First attack at motor nodes of
neuropathy (AMAN) prevalent in China and Ranvier; macrophage activation,
Mexico; may be seasonal; few lymphocytes, frequent
recovery rapid; anti-GD1a periaxonal macrophages; extent
antibodies of axonal damage highly variable
Acute motor sensory Mostly adults; uncommon; Axonal Same as AMAN, but also affects
axonal neuropathy recovery slow, often sensory nerves and roots;
(AMSAN) incomplete; closely axonal damage usually severe

CHAPTER 41
related to AMAN
M. Fisher syndrome Adults and children; Demyelinating Few cases examined; resembles
(MFS) uncommon; ophthalmoplegia, AIDP
ataxia, and areexia;
anti-GQ1b antibodies (90%)

Guillain-Barr Syndrome and Other Immune-Mediated Neuropathies

Other pains in GBS include dysesthetic pain in the that 2030% of all cases occurring in North America,
extremities as a manifestation of sensory nerve ber Europe, and Australia are preceded by infection or reinfec-
involvement. These pains are self-limited and often tion with Campylobacter jejuni. A similar proportion is pre-
respond to standard analgesics (Chap. 5). ceded by a human herpes virus infection, often CMV or
Several subtypes of GBS are recognized, as determined Epstein-Barr virus. Other viruses and also Mycoplasma
primarily by electrodiagnostic and pathologic distinctions pneumoniae have been identied as agents involved in
(Table 41-1). These include the axonal variants, which antecedent infections, as have recent immunizations. The
are often clinically severeeither acute motor axonal swine inuenza vaccine, administered widely in the
neuropathy (AMAN) or acute motor sensory axonal United States in 1976, is the most notable example;
neuropathy (AMSAN). In addition, a range of limited or inuenza vaccines in use from 19921994, however,
regional GBS syndromes are also encountered. Notable resulted in only one additional case of GBS per million
among these is the Miller Fisher syndrome (MFS; persons vaccinated. Older-type rabies vaccine, prepared in
Table 41-1), which presents as rapidly evolving ataxia and nervous system tissue, is implicated as a trigger of GBS in
areexia of limbs without weakness, and ophthalmoplegia, developing countries where it is still used; the mechanism
often with pupillary paralysis. The MFS variant accounts is presumably immunization against neural antigens. GBS
for ~5% of all cases and is strongly associated with anti- also occurs more frequently than can be attributed to
bodies to the ganglioside GQ1b (see Immunopathogene- chance alone in patients with lymphoma (including
sis, below). Other regional variants of GBS include (1) Hodgkins disease), in HIV-seropositive individuals, and in
pure sensory forms; (2) ophthalmoplegia with anti-GQ1b patients with systemic lupus erythematosus (SLE). C. jejuni
antibodies as part of severe motor-sensory GBS; (3) GBS has also been implicated in summer outbreaks of AMAN
with severe bulbar and facial paralysis, sometimes associ- among children and young adults exposed to chickens in
ated with antecedent cytomegalovirus (CMV) infection rural China.
and anti-GM2 antibodies; and (4) acute pandysautonomia
(Chap. 28).
Immunopathogenesis
Several lines of evidence support an autoimmune basis
Antecedent Events
for acute inammatory demyelinating polyneuropathy
Approximately 70% of cases of GBS occur 13 weeks after (AIDP), the most common and best-studied type of
an acute infectious process, usually respiratory or gastroin- GBS; the concept extends to all of the subtypes of GBS
testinal. Culture and seroepidemiologic techniques show (Table 41-1).
 552 It is likely that both cellular and humoral immune agents, vaccines) that misdirect to host nerve tissue
mechanisms contribute to tissue damage in AIDP. T cell through a resemblance-of-epitope (molecular mimicry)
activation is suggested by the nding that elevated levels of mechanism (Fig. 41-1). The neural targets are likely to
cytokines and cytokine receptors are present in serum be glycoconjugates, specically gangliosides (Table 41-2;
[interleukin (IL) 2, soluble IL-2 receptor] and in cere- Fig. 41-2). Gangliosides are complex glycosphingolipids
brospinal uid (CSF) (IL-6, tumor necrosis factor , inter- that contain one or more sialic acid residues; various gan-
feron- ).AIDP is also closely analogous to an experimental gliosides participate in cell-cell interactions (including
T cellmediated immunopathy designated experimental those between axons and glia), modulation of receptors,
allergic neuritis (EAN); EAN is induced in laboratory ani- and regulation of growth. They are typically exposed on
mals by immune sensitization against protein fragments the plasma membrane of cells, rendering them suscepti-
derived from peripheral nerve proteins, and in particular ble to an antibody-mediated attack. Gangliosides and
against the P2 protein. Based on analogy to EAN, it was other glycoconjugates are present in large quantity in
initially thought that AIDP was likely to be primarily a human nervous tissues and in key sites, such as nodes of
T cellmediated disorder; however, abundant data now Ranvier. Antiganglioside antibodies, most frequently to
suggest that autoantibodies directed against nonprotein GM1, are common in GBS (2050% of cases), particularly
determinants may be central to many cases. in those preceded by C. jejuni infection. Furthermore, iso-
Circumstantial evidence suggests that all GBS results lates of C. jejuni from stool cultures of patients with GBS
SECTION III

from immune responses to nonself antigens (infectious have surface glycolipid structures that antigenically cross

Regional Nodes/ Peripheral Nerves/

Gut/Peyer's Patches Roots/Ganglia
Circulation
Diseases of the Central Nervous System

IL 3,4,5,10

Ganglioside
(GM-1 and others)
CD4 B cell B cell

O
TCR
lgG

A
MHC II Cj

Cj

Cjj
C Myelin
Schwann cell sheath
Cj
Cj plasmalemma

Antigen Plasma cell

presenting cell Blood/Nerve
Barrier

FIGURE 41-1
Postulated immunopathogenesis of GBS associated with regional lymph nodes. Activated T cells probably also func-
C. jejuni infection. B cells recognize glycoconjugates on tion to assist in opening of the blood-nerve barrier, facilitating
C. jejuni (Cj) (triangles) that cross-react with ganglioside pre- penetration of pathogenic autoantibodies. The earliest
sent on Schwann cell surface and subjacent peripheral nerve changes in myelin (right) consist of edema between myelin
myelin. Some B cells, activated via a T cellindependent lamellae and vesicular disruption (shown as circular blebs) of
mechanism, secrete primarily IgM (not shown). Other B cells the outermost myelin layers. These effects are associated
(upper left side) are activated via a partially T celldependent with activation of the C5b-C9 membrane attack complex and
route and secrete primarily IgG; T cell help is provided by probably mediated by calcium entry; it is possible that the
CD4 cells activated locally by fragments of Cj proteins that macrophage cytokine tumor necrosis factor (TNF) also par-
are presented on the surface of antigen-presenting cells ticipates in myelin damage. B, B cell; MHC II, class II major
(APC). A critical event in the development of GBS is the histocompatibility complex molecule; TCR, T cell receptor; A,
escape of activated B cells from Peyers patches into axon; O, oligodendrocyte.
TABLE 41-2 553
PRINCIPAL ANTI-GLYCOLIPID ANTIBODIES IMPLICATED IN IMMUNE NEUROPATHIES

CLINICAL PRESENTATION ANTIBODY TARGET USUAL ISOTYPE

Acute Immune Neuropathies (Guillain-Barr Syndrome)

Acute inammatory demyelinating No clear patterns GM1 most common IgG (polyclonal)
polyneuropathy (AIDP)
Acute motor axonal neuropathy (AMAN) GD1a, GM1, GM1b, GalNAcGD1a IgG (polyclonal)
(<50% for any)
Miller Fisher syndrome (MFS) GQ1b (>90%) IgG (polyclonal)
Acute pharyngeal cervicobrachial GT1a (Most) IgG (polyclonal)
neuropathy (APCBN)
Chronic Immune Neuropathies
Chronic inammatory demyelinating Po in some No clear pattern
polyneuropathy (CIDP) (75%)
CIDPa (MGUS associated) (25%) Neural binding sites IgG, IgA (monoclonal)
Chronic sensory > motor neuropathy SPGP, SGLPG (on MAG) (50%) IgM (monoclonal)

CHAPTER 41
Uncertain (50%) IgM (monoclonal)
Multifocal motor neuropathy (MMN) GM1, GalNAcGD1a, others IgM (polyclonal, monoclonal)
(2550%)
Chronic sensory ataxic neuropathy GD1b, GQ1b, and other b-series IgM (monoclonal)
gangliosides

Note: MGUS, monoclonal gammopathy of undetermined signicance; MAG, myelin-associated glycoprotein.

Guillain-Barr Syndrome and Other Immune-Mediated Neuropathies

Source: Modied from HJ Willison, N Yuki: Brain 125:2591, 2002.

disorders. Between 5 and 15 days after injection some

recipients developed acute motor axonal GBS with high
GM1 GM1b
titers of anti-GM1 antibodies that recognized epitopes
at nodes of Ranvier and motor endplates. Experimen-
GD1a GD1b tally, anti-GM1 antibodies can trigger complement-
mediated injury at paranodal axon-glial junctions, dis-
rupting the clustering of sodium channels and likely
GaINAc-GD1a GQ1b contributing to conduction block (see Pathophysiology,
below).
Anti-GQ1b IgG antibodies are found in >90% of
GT1a SGPG patients with MFS (Table 41-2; Fig. 41-2), and titers of
SO3
IgG are highest early in the course. Anti-GQ1b antibod-
ies are not found in other forms of GBS unless there is
LM1 SGLPG extraocular motor nerve involvement. A possible expla-
SO3
nation for this association is that extraocular motor
nerves are enriched in GQ1b gangliosides in compari-
son to limb nerves. In addition, a monoclonal anti-
N-acetylneuraminic acid N-acetylgalactosamine Glucose GQ1b antibody raised against C. jejuni isolated from a
patient with MFS blocked neuromuscular transmission
N-acetylglucosamine Glucuronic acid Galactose Ceramide experimentally.
Taken together, these observations provide strong but
FIGURE 41-2 still inconclusive evidence that autoantibodies play an
Glycolipids implicated as antigens in immune-mediated important pathogenic role in GBS. Although anti-gan-
neuropathies. (Modied from HJ Willison, N Yuki: Brain 125: glioside antibodies have been studied most intensively,
2591, 2002.) other antigenic targets may also be important. One
report identied IgG antibodies against Schwann cells
react with gangliosides, including GM1, concentrated in and neurons (nerve growth cone region) in some GBS
human nerves. Another line of evidence is derived from cases. Proof that these antibodies are pathogenic requires
experience in Europe with parenteral use of puried bovine that they be capable of mediating disease following
brain gangliosides for treatment of various neuropathic direct passive transfer to nave hosts; this has not yet
 554 been demonstrated, although one case of apparent axonal pathology, the principal electrodiagnostic nding is
maternal-fetal transplacental transfer of GBS has been reduced amplitude of compound action potentials without
described. conduction slowing or prolongation of distal latencies.
In ADEM, an early step in the induction of tissue
damage appears to be complement deposition along the Diagnosis
outer surface of the Schwann cell. Activation of comple-
ment initiates a characteristic vesicular disintegration of GBS is a descriptive entity. The diagnosis is made by
the myelin sheath, and also leads to recruitment of acti- recognizing the pattern of rapidly evolving paralysis
vated macrophages, which participate in damage to with areexia, absence of fever or other systemic symp-
myelin and axons. In AMAN, the pattern is different in toms, and characteristic antecedent events (Table 41-3).
that complement is deposited along with IgG at the Other disorders that may enter into the differential diag-
nodes of Ranvier along large motor axons. nosis include acute myelopathies (especially with pro-
longed back pain and sphincter disturbances); botulism
(pupillary reactivity lost early); diphtheria (early oropha-
Pathophysiology ryngeal disturbances); Lyme polyradiculitis and other
In the demyelinating forms of GBS, the basis for accid tick-borne paralyses; porphyria (abdominal pain, seizures,
paralysis and sensory disturbance is conduction block. psychosis); vasculitic neuropathy (check erythrocyte sedi-
SECTION III

This nding, demonstrable electrophysiologically, implies mentation rate, described below); poliomyelitis (fever and
that the axonal connections remain intact. Hence, recov- meningismus common); CMV polyradiculitis (in imm-
ery can take place rapidly as remyelination occurs. In unocompromised patients); critical illness neuropathy;
severe cases of demyelinating GBS, secondary axonal neuromuscular disorders such as myasthenia gravis; poi-
degeneration usually occurs; its extent can be estimated sonings with organophosphates, thallium, or arsenic; tick
electrophysiologically. More secondary axonal degenera- paralysis; paralytic shellsh poisoning; or severe hypophos-
Diseases of the Central Nervous System

tion correlates with a slower rate of recovery and a phatemia (rare). Laboratory tests are helpful primarily to
greater degree of residual disability. When a severe pri- exclude mimics of GBS. Electrodiagnostic features may
mary axonal pattern is encountered electrophysiologi- be minimal, and the CSF protein level may not rise until
cally, the implication is that axons have degenerated and the end of the rst week. If the diagnosis is strongly sus-
become disconnected from their targets, specically the pected, treatment should be initiated without waiting
neuromuscular junctions, and must therefore regenerate for evolution of the characteristic electrodiagnostic and
for recovery to take place. In motor axonal cases in CSF ndings to occur. Both tau and 14-3-3 protein levels
which recovery is rapid, the lesion is thought to be local-
ized to preterminal motor branches, allowing regenera-
tion and reinnervation to take place quickly. Alternatively,
TABLE 41-3
in mild cases, collateral sprouting and reinnervation from
surviving motor axons near the neuromuscular junction DIAGNOSTIC CRITERIA FOR GUILLAIN-BARR
may begin to reestablish physiologic continuity with SYNDROME
muscle cells over a period of several months. Required
1. Progressive weakness of 2 or more limbs due to neu-
Laboratory Features ropathy a
2. Areexia
CSF ndings are distinctive, consisting of an elevated CSF 3. Disease course <4 weeks
protein level [110 g/L (1001000 mg/dL)] without 4. Exclusion of other causes [e.g., vasculitis (polyarteritis
accompanying pleocytosis. The CSF is often normal nodosa, systemic lupus erythematosus, Churg-Strauss
when symptoms have been present for 48 h; by the end syndrome), toxins (organophosphates, lead), botulism,
of the rst week the level of protein is usually elevated. A diphtheria, porphyria, localized spinal cord or cauda
transient increase in the CSF white cell count equina syndrome]
(10100/L) occurs on occasion in otherwise typical Supportive
GBS; however, a sustained CSF pleocytosis suggests an 1. Relatively symmetric weakness
alternative diagnosis (viral myelitis) or a concurrent diag- 2. Mild sensory involvement
nosis such as unrecognized HIV infection. Electrodiag- 3. Facial nerve or other cranial nerve involvement
nostic features are mild or absent in the early stages of 4. Absence of fever
5. Typical CSF prole (acellular, increase in protein level)
GBS and lag behind the clinical evolution. In cases with
6. Electrophysiologic evidence of demyelination
demyelination (Table 41-1), prolonged distal latencies,
conduction velocity slowing, evidence of conduction a
Excluding M. Fisher and other variant syndromes.
block, and temporal dispersion of compound action Source: Modied from AK Asbury, DR Cornblath: Ann Neurol
potential are the usual features. In cases with primary 27:S21, 1990.
are reported to be elevated early (during the rst few although minor ndings on examination (such as are- 555
days of symptoms) in some cases of GBS. Tau increases exia) may persist.The mortality rate is <5% in optimal
in CSF may reect axonal damage and predict a residual settings; death usually results from secondary pulmonary
decit. GBS patients with risk factors for HIV or with complications. The outlook is worst in patients with
CSF pleocytosis should have a serologic test for HIV. severe proximal motor and sensory axonal damage. Such
axonal damage may be either primary or secondary in
nature (see Pathophysiology, above), but in either case
successful regeneration cannot occur. Other factors that
Treatment: worsen the outlook for recovery are advanced age, a ful-
GUILLAIN-BARR SYNDROME minant or severe attack, and a delay in the onset of treat-
In the vast majority of patients with GBS, treatment ment. Between 5 and 10% of patients with typical GBS
should be initiated as soon after diagnosis as possible. have one or more late relapses; such cases are then classi-
Each day counts; ~2 weeks after the rst motor symp- ed as chronic inammatory demyelinating polyneu-
toms, immunotherapy is no longer effective. Either ropathy (CIDP).
high-dose intravenous immune globulin (IVIg) or
plasmapheresis can be initiated, as they are equally
effective. A combination of the two therapies is not sig-
CHRONIC INFLAMMATORY

CHAPTER 41
nicantly better than either alone. IVIg is often the initial
DEMYELINATING POLYNEUROPATHY
therapy chosen because of its ease of administration CIDP is distinguished from GBS by its chronic course.
and good safety record. IVIg is administered as ve daily In other respects, this neuropathy shares many features
infusions for a total dose of 2 g/kg body weight. There is with the common demyelinating form of GBS, includ-
some evidence that GBS autoantibodies are neutralized ing elevated CSF protein levels and the electrodiagnostic
by anti-idiotypic antibodies present in IVIg preparations, ndings of acquired demyelination. Most cases occur in

Guillain-Barr Syndrome and Other Immune-Mediated Neuropathies

perhaps accounting for the therapeutic effect. A course adults, and men are affected slightly more often than
of plasmapheresis usually consists of ~4050 mL/kg women. The incidence of CIDP is lower than that of
plasma exchange (PE) four times over a week. Meta- GBS, but due to the protracted course the prevalence is
analysis of randomized clinical trials indicates that treat- greater.
ment reduces the need for mechanical ventilation by
nearly half (from 27% to 14% with PE), and increases the
likelihood of full recovery at 1 year (from 55% to 68%). In
Clinical Manifestations
patients who are treated early in the course of GBS and Onset is usually gradual, sometimes subacute; in a few, the
improve, relapse may occur in the second or third week. initial attack is indistinguishable from that of GBS. An
Brief retreatment with the original therapy is usually acute-onset form of CIDP should be considered when
effective. Glucocorticoids have not been found to be GBS deteriorates >9 weeks after onset or relapses at least
effective in GBS. Occasional patients with very mild three times. Symptoms are both motor and sensory in
forms of GBS, especially those who appear to have most cases.Weakness of the limbs is usually symmetric but
already reached a plateau when initially seen, may be can be strikingly asymmetric. There is considerable vari-
managed conservatively without IVIg or PE. ability from case to case. Some patients experience a
In the worsening phase of GBS, most patients require chronic progressive course, whereas others, usually
monitoring in a critical care setting, with particular younger patients, have a relapsing and remitting course.
attention to vital capacity, heart rhythm, blood pressure, Some have only motor ndings, and a small proportion
nutrition, deep vein thrombosis prophylaxis, cardiovas- present with a relatively pure syndrome of sensory ataxia.
cular status, early consideration (after 2 weeks of intuba- Tremor occurs in ~10% and may become more promi-
tion) of tracheotomy, and chest physiotherapy. As noted, nent during periods of subacute worsening or improve-
~30% of patients with GBS require ventilatory assis- ment. A small proportion have cranial nerve ndings,
tance, sometimes for prolonged periods of time (several including external ophthalmoplegia. CIDP tends to ame-
weeks or longer). Frequent turning and assiduous skin liorate over time with treatment; the result is that many
care are important, as are daily range-of-motion exer- years after onset nearly 75% of patients have reasonable
cises to avoid joint contractures and daily reassurance functional status. Death from CIDP is uncommon.
as to the generally good outlook for recovery.
Diagnosis
The diagnosis rests on characteristic clinical, CSF, and elec-
Prognosis and Recovery
trophysiologic ndings.The CSF is usually acellular with an
Approximately 85% of patients with GBS achieve a full elevated protein level, sometimes several times normal. Elec-
functional recovery within several months to a year, trodiagnostically, variable degrees of conduction slowing,
 556 prolonged distal latencies, temporal dispersion of com- spontaneous remission. Controlled studies have shown
pound action potentials, and conduction block are that high-dose IVIg, PE, and glucocorticoids are all more
the principal features. In particular, the presence of effective than placebo. Initial therapy is usually with IVIg,
conduction block is a certain sign of an acquired demyeli- administered as 0.4 g/kg body weight daily for 5 days;
nating process. Evidence of axonal loss, presumably sec- most patients require periodic re-treatment at ~6-week
ondary to demyelination, is present in >50% of patients. intervals. PE, which appears to be as effective as IVIg, is
Serum protein electrophoresis with immunoxation is initiated at two to three treatments per week for 6
indicated to search for monoclonal gammopathy and weeks; periodic re-treatment may also be required.
associated conditions (see Monoclonal Gammopathy of Treatment with glucocorticoids is another option
Undetermined Signicance, below). In all patients with (6080 mg prednisone PO daily for 12 months, fol-
presumptive CIDP, it is also reasonable to exclude vas- lowed by a gradual dose reduction of 10 mg per month
culitis, collagen vascular disease (especially SLE), chronic as tolerated), but long-term adverse effects including
hepatitis, HIV infection, and diabetes mellitus. Other bone demineralization, gastrointestinal bleeding, and
associated conditions include inammatory bowel disease cushingoid changes are problematic. Anecdotal experi-
and Hodgkins lymphoma. ence suggested that glucocorticoids might be harmful
to some patients with a purely motor form of CIDP, thus
Pathogenesis glucocorticoids should probably be avoided when sen-
SECTION III

sory ndings are absent. Approximately one-half of

Although there is evidence of immune activation in CIDP,
patients with CIDP fail to respond adequately to the ini-
the precise mechanisms of pathogenesis are unknown.
tial therapy chosen; a different treatment should then
Biopsy typically reveals little inammation and onion-bulb
be tried. Patients who fail therapy with IVIg, PE, and glu-
changes (imbricated layers of attenuated Schwann cell
cocorticoids may benet from treatment with immuno-
processes surrounding an axon) that result from recurrent
suppressive agents such as azathioprine, methotrexate,
Diseases of the Central Nervous System

demyelination and remyelination (Fig. 41-1).The response

cyclosporine, and cyclophosphamide, either alone or as
to therapy suggests that CIDP is immune-mediated; CIDP
adjunctive therapy. Early experience with anti-CD20
responds to glucocorticoids, whereas GBS does not. Pas-
(rituximab) has also shown promise. Use of these thera-
sive transfer of demyelination into experimental animals
pies requires periodic reassessment of their risks and
has been accomplished using IgG puried from the serum
benefits.
of some patients with CIDP, lending support for a
humoral autoimmune pathogenesis. Although the target
antigen or antigens in CIDP have not yet been identied,
the myelin protein Po has been implicated as a potential MULTIFOCAL MOTOR NEUROPATHY
autoantigen in some patients. It is also of interest that a
CIDP-like illness developed spontaneously in the Multifocal motor neuropathy (MMN) is a distinctive
nonobese diabetic (NOD) mouse when the immune co- but uncommon neuropathy that presents as slowly pro-
stimulatory molecule B7-2 (CD86) was genetically gressive motor weakness and atrophy evolving over years
deleted; this suggests that CIDP can result from altered in the distribution of selected nerve trunks, associated
triggering of T cells by antigen-presenting cells. with sites of persistent focal motor conduction block in
Approximately 25% of patients with clinical features the same nerve trunks. Sensory bers are relatively
of CIDP also have a monoclonal gammopathy of unde- spared. The arms are affected more frequently than the
termined signicance (MGUS). Cases associated with legs, and >75% of all patients are men. Some cases have
monoclonal IgA or IgG usually respond to treatment as been confused with lower motor neuron forms of amy-
favorably as cases without a monoclonal gammopathy. otrophic lateral sclerosis (Chap. 27). Approximately 50%
Patients with IgM monoclonal gammopathy tend to of patients present with high titers of polyclonal IgM
have more sensory ndings, a more protracted course, antibody to the ganglioside GM1. It is uncertain how
and may have a less satisfactory response to treatment, this nding relates to the discrete foci of persistent motor
although this is an area of controversy. conduction block, but high concentrations of GM1 gan-
gliosides are normal constituents of nodes of Ranvier in
peripheral nerve bers. Pathology reveals demyelination
and mild inammatory changes at the sites of conduc-
Treatment: tion block.
CHRONIC INFLAMMATORY
Most patients with MMN respond to high-dose IVIg
DEMYELINATING POLYNEUROPATHY
(dosages as for CIDP, above); periodic re-treatment is
Most authorities initiate treatment for CIDP when pro- required in more than half of responders to maintain the
gression is rapid or walking is compromised. If the disor- benet. Some refractory patients have responded to cyclo-
der is mild, management can be expectant, awaiting phosphamide. Glucocorticoids and PE are not effective.
 monoclonal IgM immunoglobulin binds to a normal 557
NEUROPATHIES WITH MONOCLONAL peripheral nerve constituent, myelin-associated glycopro-
GAMMOPATHY tein (MAG), found in the paranodal regions of Schwann
cells. Binding appears to be specic for a polysaccharide
MULTIPLE MYELOMA
epitope that is also found in other normal peripheral
Clinically overt polyneuropathy occurs in ~5% of patients nerve myelin glycoproteins, P0 and PMP22, and also in
with the commonly encountered type of multiple other normal nerve-related glycosphingolipids (Fig. 41-1).
myeloma, which exhibits either lytic or diffuse osteo- In the MAG-positive cases, IgM paraprotein is incorpo-
porotic bone lesions. These neuropathies are sensorimo- rated into the myelin sheaths of affected patients and
tor, are usually mild and slowly progressive but may be widens the spacing of the myelin lamellae, thus produc-
severe, and generally do not reverse with successful sup- ing a distinctive ultrastructural pattern. Demyelination
pression of the myeloma. In most cases, electrodiagnostic and remyelination are the hallmarks of the lesions. The
and pathologic features are consistent with a process of chronic demyelinating neuropathy appears to result from
axonal degeneration. a destabilization of myelin metabolism rather than activa-
In contrast, myeloma with osteosclerotic features, tion of an immune response.Therapy with chlorambucil,
although representing only 3% of all myelomas, is associ- or cyclophosphamide combined with glucocorticoids or
ated with polyneuropathy in one-half of cases. These PE, often results in improvement of the neuropathy asso-

CHAPTER 41
neuropathies, which may also occur with solitary plas- ciated with a prolonged reduction in the levels in the
macytoma, are distinct because they (1) are usually circulating paraprotein; chronic use of these alkylating
demyelinating in nature; (2) often respond to radiation agents is associated with signicant risks. Recent prelimi-
therapy or removal of the primary lesion; (3) are associ- nary data also suggest that anti-CD20 (rituximab) ther-
ated with different monoclonal proteins and light chains apy may be effective. In a small proportion of patients
(almost always lambda as opposed to primarily kappa in (30% at 10 years), MGUS will in time evolve into frankly

Guillain-Barr Syndrome and Other Immune-Mediated Neuropathies

the lytic type of multiple myeloma); and (4) may occur malignant conditions such as multiple myeloma or
in association with other systemic ndings including lymphoma.
thickening of the skin, hyperpigmentation, hypertri-
chosis, organomegaly, endocrinopathy, anasarca, and
clubbing of ngers. These are features of the POEMS VASCULITIC NEUROPATHY
syndrome (polyneuropathy, organomegaly, endocrinopa-
thy, M protein, and skin changes). The pathogenesis of Peripheral nerve involvement is common in polyarteritis
this uncommon syndrome and the explanation for its asso- nodosa (PAN), appearing in half of all cases clinically
ciation with lambda light chains are unknown. Treatment and in 100% of cases at postmortem studies. The
of the neuropathy is best directed at the osteosclerotic most common pattern is multifocal (asymmetric) motor-
myeloma using surgery, radiotherapy, or chemotherapy, as sensory neuropathy (mononeuropathy multiplex) due to
indicated. ischemic lesions of nerve trunks and roots; however,
Neuropathies are also encountered in other systemic some cases of vasculitic neuropathy present as a distal,
conditions with gammopathy including Waldenstrms symmetric sensorimotor polyneuropathy. Symptoms of
macroglobulinemia, primary systemic amyloidosis, and neuropathy are a common presenting complaint in
cryoglobulinemic states (mixed essential cryoglobuline- patients with PAN. The electrodiagnostic ndings are
mia, some cases of hepatitis C). those of an axonal process. Small- to medium-sized
arteries of the vasa nervorum, particularly the epineural
vessels, are affected in PAN, resulting in a widespread
MONOCLONAL GAMMOPATHY
ischemic neuropathy. A high frequency of neuropathy
OF UNDETERMINED SIGNIFICANCE
occurs in allergic angiitis and granulomatosis (Churg-
Chronic polyneuropathies occurring in association with Strauss syndrome).
MGUS are usually associated with the immunoglobulin Systemic vasculitis should always be considered when a
isotypes IgG, IgA, and IgM. From a clinical standpoint, subacute or chronically evolving mononeuropathy multi-
many of these patients are indistinguishable from patients plex occurs in conjunction with constitutional symptoms
with CIDP without monoclonal gammopathy (see (fever, anorexia, weight loss, loss of energy, malaise, and
Chronic Inammatory Demyelinating Polyneuropathy, nonspecic pains). Diagnosis of suspected vasculitic neu-
above), and their response to immunosuppressive agents ropathy is made by a combined nerve and muscle biopsy,
is also similar. An exception is the syndrome of IgM with serial section or skip-serial techniques.
kappa monoclonal gammopathy associated with an indo- Approximately one-third of biopsy-proven cases of
lent, longstanding, sometimes static sensory neuropathy, vasculitic neuropathy are nonsystemic in that the vas-
frequently with tremor and sensory ataxia. Most patients culitis appears to affect only peripheral nerves. Constitu-
are men and older than 50 years. In the majority, the tional symptoms are absent, and the course is more
 558 indolent than that of PAN. The erythrocyte sedimenta- binding proteins (HuD, HuC, and Hel-N1) that in nor-
tion rate may be elevated, but other tests for systemic mal tissues are only expressed by neurons. The same
disease are negative. Nevertheless, clinically silent proteins are usually expressed by SCLC, triggering in
involvement of other organs is likely, and vasculitis is fre- some patients an immune response characterized by
quently found in muscle biopsied at the same time as antibodies and cytotoxic T cells that cross-react with
nerve. the Hu proteins of the dorsal root ganglion neurons,
Vasculitic neuropathy may also be seen as part of the resulting in immune-mediated neuronal destruction. An
vasculitis syndrome occurring in the course of other con- encephalomyelitis may accompany the sensory neu-
nective tissue disorders. The most frequent is rheumatoid ronopathy and presumably has the same pathogenesis.
arthritis, but ischemic neuropathy due to involvement of Neurologic symptoms usually precede, by 6 months,
vasa nervorum may also occur in mixed cryoglobulinemia, the identication of SCLC. The sensory neuronopathy
Sjgrens syndrome, Wegeners granulomatosis, hypersensi- runs its course in a few weeks or months and stabilizes,
tivity angiitis, and progressive systemic sclerosis. Manage- leaving the patient disabled. Most cases are unresponsive
ment of these neuropathies, including the nonsystemic to treatment with glucocorticoids, IVIg, PE, or
vasculitic neuropathy, consists of treatment of the underlying immunosuppressant drugs.
condition as well as the aggressive use of glucocorticoids
and other immunosuppressant drugs. One reasonable start-
SECTION III

ing regimen is daily prednisone (initial dose 1 mg/kg per FURTHER READINGS
day PO with a gradual taper after 1 month) plus IV pulse BURNS TM et al: Vasculitic neuropathies. Neurol Clin 25:89, 2007
(or daily oral) cyclophosphamide for 36 months. HADDEN RDM et al: European Federation of Neurological Soci-
eties/Peripheral Nerve Society guideline on management of
paraproteinemic demyelinating neuropathies: Report of a joint
ANTI-HU PARANEOPLASTIC task force of the European Federation of Neurological Societies
NEUROPATHY
Diseases of the Central Nervous System

and the Peripheral Nerve Society. Eur J Neurol 13:809, 2006

HUGHES RAC et al: European Federation of Neurological Societies/
This uncommon immune-mediated disorder manifests Peripheral Nerve Society guideline on management of chronic
as a sensory neuronopathy (i.e., selective damage to inammatory demyelinating polyradiculoneuropathy: Report of
sensory nerve bodies in dorsal root ganglia). The onset a joint task force of the European Federation of Neurological
Societies and the Peripheral Nerve Society. Eur J Neurol 13:326,
is often asymmetric with dysesthesias and sensory loss 2006
in the limbs that soon progress to affect all limbs, the __________ et al: Immunotherapy for Guillain-Barre Syndrome: A
torso, and face. Marked sensory ataxia, pseudoathetosis, systematic review. Brain 130:2245, 2007
and inability to walk, stand, or even sit unsupported are LUNN MP, WILLISON HJ: Diagnosis and treatment in inammatory
frequent features and are secondary to the extensive neuropathies. J Neurol Neurosurg Psychiatry 80:249, 2009
deafferentation. Subacute sensory neuronopathy may be MULEY SA, PARRY GJ: Inammatory demyelinating neuropathies.
idiopathic, but more than half of cases are paraneoplastic, Curr Treat Options Neurol 11:221, 2009
SUSUKI K et al: Anti-GM1 antibodies cause complement-mediated
primarily related to lung cancer, and most of those are
disruption of sodium channel clusters in peripheral motor nerve
small cell lung cancer (SCLC). Diagnosis of the under- bers. J Neurosci 27:3956, 2007
lying SCLC requires awareness of the association, para- VAN SCHAIK IN et al: European Federation of Neurological Societies/
neoplastic testing, and often PET scanning for the Peripheral Nerve Society guideline on management of multifocal
tumor. The target antigens are a family of RNA motor neuropathy. Eur J Neurol 13:802, 2006
 CHAPTER 42
MYASTHENIA GRAVIS AND OTHER DISEASES
OF THE NEUROMUSCULAR JUNCTION
Daniel B. Drachman

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
Diagnosis and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
Patient Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567

Myasthenia gravis (MG) is a neuromuscular disorder synaptic folds, and by diffusion of ACh away from the
characterized by weakness and fatigability of skeletal mus- receptor.
cles.The underlying defect is a decrease in the number of In MG, the fundamental defect is a decrease in the
available acetylcholine receptors (AChRs) at neuromus- number of available AChRs at the postsynaptic muscle
cular junctions due to an antibody-mediated autoim- membrane. In addition, the postsynaptic folds are at-
mune attack. Treatment now available for MG is highly tened, or simplied. These changes result in decreased
effective, although a specic cure has remained elusive. efciency of neuromuscular transmission. Therefore,
although ACh is released normally, it produces small end-
plate potentials that may fail to trigger muscle action
PATHOPHYSIOLOGY
potentials. Failure of transmission at many neuromuscular
In the neuromuscular junction (Fig. 42-1), acetylcholine junctions results in weakness of muscle contraction.
(ACh) is synthesized in the motor nerve terminal and The amount of ACh released per impulse normally
stored in vesicles (quanta). When an action potential declines on repeated activity (termed presynaptic rundown).
travels down a motor nerve and reaches the nerve ter- In the myasthenic patient, the decreased efciency of
minal, ACh from 150200 vesicles is released and com- neuromuscular transmission combined with the normal
bines with AChRs that are densely packed at the peaks rundown results in the activation of fewer and fewer mus-
of postsynaptic folds. The structure of the AChR has cle bers by successive nerve impulses and hence increas-
been fully elucidated; it consists of ve subunits (2, 1, ing weakness, or myasthenic fatigue. This mechanism also
1, and 1 or ) arranged around a central pore. When accounts for the decremental response to repetitive nerve
ACh combines with the binding sites on the subunits stimulation seen on electrodiagnostic testing.
of the AChR, the channel in the AChR opens, permit- The neuromuscular abnormalities in MG are brought
ting the rapid entry of cations, chiey sodium, which about by an autoimmune response mediated by specic
produces depolarization at the end-plate region of the anti-AChR antibodies. The anti-AChR antibodies
muscle ber. If the depolarization is sufciently large, it reduce the number of available AChRs at neuromuscu-
initiates an action potential that is propagated along the lar junctions by three distinct mechanisms: (1) acceler-
muscle ber, triggering muscle contraction. This process ated turnover of AChRs by a mechanism involving
is rapidly terminated by hydrolysis of ACh by acetyl- cross-linking and rapid endocytosis of the receptors; (2)
cholinesterase (AChE), which is present within the blockade of the active site of the AChR, i.e., the site that

559
 560
Axon

Mitochondria

Vesicle
Release site
Nerve
terminal

Muscle AChR

AChE

A Normal B MG
FIGURE 42-1
Diagrams of (A) normal and (B) myasthenic neuromuscular AChRs (stippling); attened, simplied postsynaptic folds; and
junctions. AChE, acetylcholinesterase. See text for descrip- a widened synaptic space. (Modied from DB Drachman: N
SECTION III

tion of normal neuromuscular transmission. The MG junction Engl J Med 330:1797, 1994; with permission.)
demonstrates a normal nerve terminal; a reduced number of

normally binds ACh; and (3) damage to the postsynaptic increased myasthenic weakness and may precipitate
muscle membrane by the antibody in collaboration with crisis (see later).
complement. An immune response to muscle-specic The distribution of muscle weakness often has a
Diseases of the Central Nervous System

kinase (MuSK) can also result in myasthenia gravis, pos- characteristic pattern. The cranial muscles, particularly
sibly by interfering with AChR clustering. The patho- the lids and extraocular muscles, are often involved
genic antibodies are IgG and are T cell dependent.Thus, early in the course of MG, and diplopia and ptosis are
immunotherapeutic strategies directed against T cells are common initial complaints. Facial weakness produces a
effective in this antibody-mediated disease. snarling expression when the patient attempts to
How the autoimmune response is initiated and main- smile. Weakness in chewing is most noticeable after
tained in MG is not completely understood. However, prolonged effort, as in chewing meat. Speech may have
the thymus appears to play a role in this process. The a nasal timbre caused by weakness of the palate or a
thymus is abnormal in ~75% of patients with MG; in dysarthric mushy quality due to tongue weakness.
~65% the thymus is hyperplastic, with the presence of Difficulty in swallowing may occur as a result of weak-
active germinal centers detected histologically, though ness of the palate, tongue, or pharynx, giving rise to
the hyperplastic thymus is not necessarily enlarged. An nasal regurgitation or aspiration of liquids or food.
additional 10% of patients have thymic tumors (thymo- Bulbar weakness is especially prominent in MuSK
mas). Muscle-like cells within the thymus (myoid cells), antibodypositive MG. In ~85% of patients, the weak-
which bear AChRs on their surface, may serve as a ness becomes generalized, affecting the limb muscles as
source of autoantigen and trigger the autoimmune reac- well. If weakness remains restricted to the extraocular
tion within the thymus gland. muscles for 3 years, it is likely that it will not become
generalized, and these patients are said to have ocular
MG. The limb weakness in MG is often proximal and
CLINICAL FEATURES
may be asymmetric. Despite the muscle weakness, deep
MG is not rare, having a prevalence of 17 in 10,000. tendon reflexes are preserved. If weakness of respiration
It affects individuals in all age groups, but peaks of becomes so severe as to require respiratory assistance,
incidence occur in women in their twenties and thir- the patient is said to be in crisis.
ties and in men in their fifties and sixties. Overall,
women are affected more frequently than men, in a
DIAGNOSIS AND EVALUATION
ratio of ~3:2. The cardinal features are weakness and
fatigability of muscles. The weakness increases during (Table 42-1) The diagnosis is suspected on the basis of
repeated use (fatigue) and may improve following rest weakness and fatigability in the typical distribution
or sleep. The course of MG is often variable. Exacer- described above, without loss of reexes or impairment
bations and remissions may occur, particularly during of sensation or other neurologic function.The suspected
the first few years after the onset of the disease. diagnosis should always be conrmed denitively before
Remissions are rarely complete or permanent. Unre- treatment is undertaken; this is essential because (1)
lated infections or systemic disorders often lead to other treatable conditions may closely resemble MG,
TABLE 42-1 to do during early development. There is also evidence 561
DIAGNOSIS OF MYASTHENIA GRAVIS (MG) that MG patients without demonstrable antibodies to
either AChR or MuSK have otheras yet undened
History
Diplopia, ptosis, weakness
antibodies that impair neuromuscular transmission.
Weakness in characteristic distribution
Fluctuation and fatigue: worse with repeated activity, Electrodiagnostic Testing
improved by rest
Effects of previous treatments Repetitive nerve stimulation often provides helpful
Physical examination diagnostic evidence of MG. Anti-AChE medication is
Ptosis, diplopia stopped 624 h before testing. It is best to test weak
Motor power survey: quantitative testing of muscle muscles or proximal muscle groups. Electric shocks are
strength delivered at a rate of two or three per second to the
Forward arm abduction time (5 min) appropriate nerves, and action potentials are recorded
Vital capacity
from the muscles. In normal individuals, the amplitude
Absence of other neurologic signs
Laboratory testing of the evoked muscle action potentials does not change
Anti-AChR radioimmunoassay: ~85% positive in at these rates of stimulation. However, in myasthenic
generalized MG; 50% in ocular MG; denite diagnosis patients there is a rapid reduction of >1015% in the

CHAPTER 42
if positive; negative result does not exclude MG. amplitude of the evoked responses. As a further test, a
~40% of AChR antibody-negative patients with single dose of edrophonium may be given to prevent or
generalized MG have anti-MuSK antibodies. diminish this decremental response.
Repetitive nerve stimulation; decrement of >15% at
3 Hz: highly probable
Single-ber electromyography: blocking and jitter, with Anticholinesterase Test
normal ber density; conrmatory, but not specic Drugs that inhibit the enzyme AChE allow ACh to interact
Edrophonium chloride (Tensilon) 2 mg + 8 mg IV; highly

Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

probable diagnosis if unequivocally positive
repeatedly with the limited number of AChRs, producing
For ocular or cranial MG: exclude intracranial lesions improvement in the strength of myasthenic muscles.
by CT or MRI Edrophonium is used most commonly for diagnostic test-
ing because of the rapid onset (30 s) and short duration
Note: AChR, acetylcholine receptor; MuSK, muscle-specic tyrosine (~5 min) of its effect. An objective end-point must be
kinase. selected to evaluate the effect of edrophonium, such as
Source: From RT Johnson, JW Grifn (eds): Current Therapy in weakness of extraocular muscles, impairment of speech,
Neurologic Disease, 4th ed. St. Louis, Mosby Year Book, 1994; with
permission.
or the length of time that the patient can maintain the
arms in forward abduction. An initial IV dose of 2 mg of
edrophonium is given. If denite improvement occurs,
the test is considered positive and is terminated. If there
and (2) the treatment of MG may involve surgery and is no change, the patient is given an additional 8 mg IV.
the prolonged use of drugs with adverse side effects. The dose is administered in two parts because some
patients react to edrophonium with side effects such as
Antibodies to AChR or MuSK nausea, diarrhea, salivation, fasciculations, and rarely with
severe symptoms of syncope or bradycardia. Atropine
As noted above, anti-AChR antibodies are detectable in (0.6 mg) should be drawn up in a syringe, ready for IV
the serum of ~85% of all myasthenic patients but in only administration if these symptoms become troublesome.
about 50% of patients with weakness conned to the False-positive tests occur in occasional patients with
ocular muscles. The presence of anti-AChR antibodies is other neurologic disorders, such as amyotrophic lateral
virtually diagnostic of MG, but a negative test does not sclerosis, and in placebo-reactors. False-negative or equivo-
exclude the disease. The measured level of anti-AChR cal tests may also occur. In some cases it is helpful to use a
antibody does not correspond well with the severity of longer-acting drug such as neostigmine (15 mg PO), since
MG in different patients. However, in an individual this permits more time for detailed evaluation of strength.
patient, a treatment-induced fall in the antibody level The edrophonium test is now reserved for patients with
often correlates with clinical improvement. Antibodies to clinical ndings that are suggestive of MG but who have
MuSK have been found to be present in ~40% of AChR negative antibody and electrodiagnostic test results.
antibody-negative patients with generalized MG, and
their presence is a useful diagnostic test in these patients.
Inherited Myasthenic Syndromes
MuSK antibodies are rarely present in AChR antibody-
positive patients or in patients with MG limited to ocular The congenital myasthenic syndromes (CMS) com-
muscles.These antibodies may interfere with clustering of prise a heterogeneous group of disorders of the neuro-
AChRs at neuromuscular junctions, as MuSK is known muscular junction that are not autoimmune but rather
 562 TABLE 42-2
THE CONGENITAL MYASTHENIC SYNDROMES

CLINICAL END-PLATE
TYPE FEATURES ELECTROPHYSIOLOGY GENETICS EFFECTS TREATMENT

Slow channel Most common; Repetitive muscle Autosomal Excitotoxic Quinidine:

weak forearm response on nerve dominant; , , end-plate decreases
extensors; onset stimulation; prolonged AChR mutations myopathy; end-plate
2d to 3d decade; channel opening and decreased damage; made
variable severity MEPP duration AChRs; worse by
postsynaptic anti-AChE
damage
Low-afnity Onset early; Brief and infrequent Autosomal Normal end-plate 3,4-DAP;
fast channel moderately severe; channel openings; recessive; may structure anti-AChE
ptosis, EOM opposite of slow be heteroallelic
involvement; channel syndrome
weakness and
fatigue
SECTION III

Severe AChR Early onset; Decremental Autosomal Increased length Anti-AChE;

deciencies variable severity; response to recessive; of end plates; 3,4-DAP
fatigue; typical repetitive nerve mutations most variable synaptic
MG features stimulation; common; many folds
decreased different mutations
MEPP amplitudes
AChE deciency Early onset; Decremental response Mutant gene for Small nerve Worse with
variable severity; to repetitive nerve AChEs collagen terminals; anti-AChE
Diseases of the Central Nervous System

scoliosis; may have stimulation anchor degenerated drugs

normal EOM, absent junctional folds
pupillary responses

Note: AChR, acetylcholine receptor; AChE, acetylcholinesterase; EOM, extraocular muscles; MEPP, miniature end-plate potentials; 3,4-DAP,
3-4-diaminopyridine.

are due to genetic mutations in which virtually any

Differential Diagnosis
component of the neuromuscular junction may be
affected. Alterations in function of the presynaptic Other conditions that cause weakness of the cranial
nerve terminal or in the various subunits of the AChR and/or somatic musculature include the nonautoimmune
or AChE have been identified in the various forms of CMS discussed above, drug-induced myasthenia, Lambert-
CMS. These disorders share many of the clinical fea- Eaton myasthenic syndrome (LEMS), neurasthenia, hyper-
tures of autoimmune MG, including weakness and fati- thyroidism, botulism, intracranial mass lesions, and
gability of skeletal muscles, in some cases involving progressive external ophthalmoplegia. Treatment with
extraocular muscles (EOMs), lids, and proximal mus- penicillamine (used for scleroderma or rheumatoid arthri-
cles, similar to the distribution in autoimmune MG. tis) may result in true autoimmune MG, but the weakness
CMS should be suspected when symptoms of myasthe- is usually mild, and recovery occurs within weeks or
nia have begun in infancy or childhood and AChR months after discontinuing its use.Aminoglycoside antibi-
antibody tests are consistently negative. Features of four otics or procainamide can cause exacerbation of weakness
of the most common forms of CMS are summarized in myasthenic patients; very large doses can cause neuro-
in Table 42-2. Although clinical features and electrodi- muscular weakness in normal individuals.
agnostic and pharmacologic tests may suggest the cor- LEMS is a presynaptic disorder of the neuromuscular
rect diagnosis, molecular analysis is required for precise junction that can cause weakness similar to that of MG.
elucidation of the defect; this may lead to helpful treat- The proximal muscles of the lower limbs are most com-
ment as well as genetic counseling. In the forms that monly affected, but other muscles may be involved as
involve the AChR, a wide variety of mutations have well. Cranial nerve ndings, including ptosis of the eye-
been identified in each of the subunits, but the sub- lids and diplopia, occur in up to 70% of patients and
unit is affected in ~75% of these cases. In most of the resemble features of MG. However, the two conditions
recessively inherited forms of CMS, the mutations are are readily distinguished, since patients with LEMS have
heteroallelic; that is, different mutations affecting each depressed or absent reexes, experience autonomic
of the two alleles are present. changes such as dry mouth and impotence, and have
incremental rather than decremental responses on repet- power on repeated effort. Hyperthyroidism is readily 563
itive nerve stimulation. LEMS is caused by autoantibodies diagnosed or excluded by tests of thyroid function, which
directed against P/Q type calcium channels at the should be carried out routinely in patients with sus-
motor nerve terminals, which can be detected in ~85% pected MG.Abnormalities of thyroid function (hyper- or
of LEMS patients by radioimmunoassay. These autoan- hypothyroidism) may increase myasthenic weakness. Bot-
tibodies result in impaired release of ACh from nerve ulism can cause myasthenic-like weakness, but the pupils
terminals. Most patients with LEMS have an associated are often dilated, and repetitive nerve stimulation gives
malignancy, most commonly small cell carcinoma of the an incremental response. Diplopia resembling that in MG
lung, which may express calcium channels that stimulate may occasionally be due to an intracranial mass lesion
the autoimmune response. The diagnosis may signal that compresses nerves to the EOMs (e.g., sphenoid
the presence of a tumor long before it would otherwise ridge meningioma), but MRI of the head and orbits usu-
be detected, permitting early removal. Treatment of ally reveals the lesion.
LEMS involves plasmapheresis and immunosuppression, Progressive external ophthalmoplegia is a rare condi-
as for MG. 3,4-Diaminopyridine (3,4-DAP) and pyri- tion resulting in weakness of the EOMs, which may be
dostigmine may also be symptomatically helpful. 3,4- accompanied by weakness of the proximal muscles of
DAP acts by blocking potassium channels, which results the limbs and other systemic features. Most patients with
in prolonged depolarization of the motor nerve termi- this condition have mitochondrial disorders that can be

CHAPTER 42
nals and thus enhances ACh release. Pyridostigmine pro- detected on muscle biopsy (Chap. 43).
longs the action of ACh, allowing repeated interactions
with AChRs. Search for Associated Conditions
Botulism is due to a potent bacterial toxin produced
by Clostridium botulinum. The toxin interferes with the (Table 42-3) Myasthenic patients have an increased inci-
release of acetylcholine from the presynaptic neuromus- dence of several associated disorders.Thymic abnormali-

Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

cular junction, thereby interfering with neuromuscular ties occur in ~75% of patients, as noted above. Neoplas-
transmission. The most common form is food-borne tic change (thymoma) may produce enlargement of the
botulism from ingestion of food containing toxin; in thymus, which is detected by CT or MRI scanning of
wound and intestinal botulism spores germinate and
give rise to organisms that produce toxin. Patients pre-
sent with bulbar weakness (e.g., diplopia, dysarthria, TABLE 42-3
dysphagia), but lack sensory symptoms and signs; deep DISORDERS ASSOCIATED WITH MYASTHENIA
tendon reexes are preserved early in the disease course. GRAVIS AND RECOMMENDED LABORATORY TESTS
Weakness generalizes to the limbs and may result in res- Associated disorders
piratory failure; reexes may be diminished as the disease Disorders of the thymus: thymoma, hyperplasia
progresses. Mentation is normal. Autonomic ndings Other autoimmune disorders: Hashimotos thyroiditis,
include paralytic ileus, constipation, urinary retention, Graves disease, rheumatoid arthritis, lupus erythe-
dilated or poorly reactive pupils, and dry mouth. The matosus, skin disorders, family history of autoimmune
disorder
demonstration of toxin in serum by bioassay is deni-
Disorders or circumstances that may exacerbate
tive, but may be negative. Nerve conduction studies myasthenia gravis: hyperthyroidism or hypothy-
reveal ndings of presynaptic neuromuscular blockade roidism, occult infection, medical treatment for other
with reduced compound muscle action potentials conditions (see Table 42-4)
(CMAPs) that increase in amplitude following high fre- Disorders that may interfere with therapy: tuberculosis,
quency repetitive stimulation. Treatment may include diabetes, peptic ulcer, gastrointestinal bleeding, renal
intubation for airway protection, ventilatory support, or disease, hypertension, asthma, osteoporosis, obesity
aggressive inpatient supportive care (e.g., nutrition, DVT Recommended laboratory tests or procedures
CT or MRI of mediastinum
prophylaxis). Equine antitoxin is given rapidly before the Tests for lupus erythematosus, antinuclear antibody,
results of laboratory studies are available. The prognosis rheumatoid factor, antithyroid antibodies
is better among patients with type B infection who are Thyroid-function tests
under the age of 60 years. A vaccine is available for PPD skin test
highly exposed individuals. Chest radiography
Neurasthenia is the historic term for a myasthenia-like Fasting blood glucose measurement, hemoglobin A1c
fatigue syndrome without an organic basis.These patients Pulmonary-function tests
Bone densitometry in older patients
may present with subjective symptoms of weakness and
fatigue, but muscle testing usually reveals the jerky
Note: PPD, puried protein derivative.
release or give-away weakness characteristic of nonor- Source: From RT Johnson, JW Grifn (eds): Current Therapy in
ganic disorders; the complaint of fatigue in these patients Neurologic Disease, 4th ed. St. Louis, Mosby Year Book, 1993, p 379;
means tiredness or apathy rather than decreasing muscle with permission.
 564 the anterior mediastinum. A thymic shadow on CT scan MANAGEMENT OF MG
may normally be present through young adulthood, but
Establish diagnosis unequivocally (see Table 42-1)
enlargement of the thymus in a patient >40 years old is
highly suspicious of thymoma. Hyperthyroidism occurs
in 38% of patients and may aggravate the myasthenic Search for associated conditions (see Table 42-3)

weakness. Thyroid function tests should be obtained in

all patients with suspected MG. Because of the associa-
tion of MG with other autoimmune disorders, blood Ocular only Generalized Crisis

tests for rheumatoid factor and antinuclear antibodies

should also be carried out. Chronic infection of any MRI of brain
(if positive, Anticholinesterase
kind can exacerbate MG and should be sought carefully. reassess) (pyridostigmine)
Finally, measurements of ventilatory function are valu-
able because of the frequency and seriousness of respira- Anticholinesterase Intensive care
(pyridostigmine) (respiratory
tory impairment in myasthenic patients. infection, fluids)
Because of the side effects of glucocorticoids and other Evaluate for thymectomy
immunosuppressive agents used in the treatment of MG, a (indications: thymoma or
generalized MG);
thorough medical investigation should be undertaken, evaluate surgical risk, FVC
SECTION III

searching specically for evidence of chronic or latent

infection (such as tuberculosis or hepatitis), hypertension, Good risk Poor risk Plasmapheresis
diabetes, renal disease, and glaucoma. (good FVC) (low FVC) or intravenous Ig

then
If unsatisfactory
Thymectomy Improved If not
Treatment:
Diseases of the Central Nervous System

improved
MYASTHENIA GRAVIS Evaluate clinical status; if indicated,
go to immunosuppression
The prognosis has improved strikingly as a result of
advances in treatment; virtually all myasthenic patients
Immunosuppression
can be returned to full productive lives with proper
therapy. The most useful treatments for MG include anti-
See text for short-term, intermediate,
cholinesterase medications, immunosuppressive agents, and long-term treatments
thymectomy, and plasmapheresis or intravenous
immunoglobulin (IVIg) (Fig. 42-2).
FIGURE 42-2
A N T I C H O L I N E S T E R A S E M E D I C AT I O N S Algorithm for the management of myasthenia gravis.
Anticholinesterase medication produces at least partial FVC, forced vital capacity.
improvement in most myasthenic patients, although
improvement is complete in only a few. Pyridostigmine
is the most widely used anticholinesterase drug. As a
may limit the dose tolerated. Atropine/diphenoxylate or
rule, the benecial action of oral pyridostigmine begins
loperamide is useful for the treatment of gastrointestinal
within 1530 min and lasts for 34 h, but individual
symptoms.
responses vary. Treatment is begun with a moderate
dose, e.g., 3060 mg 34 times daily. The frequency and THYMECTOMY Two separate issues should be dis-
amount of the dose should be tailored to the patients tinguished: (1) surgical removal of thymoma, and (2)
individual requirements throughout the day. For exam- thymectomy as a treatment for MG. Surgical removal of
ple, patients with weakness in chewing and swallowing a thymoma is necessary because of the possibility of
may benet by taking the medication before meals so local tumor spread, although most thymomas are histo-
that peak strength coincides with mealtimes. Long-acting logically benign. In the absence of a tumor, the available
pyridostigmine may occasionally be useful to get the evidence suggests that up to 85% of patients experi-
patient through the night but should never be used for ence improvement after thymectomy; of these, ~35%
daytime medication because of variable absorption. achieve drug-free remission. However, the improvement
The maximum useful dose of pyridostigmine rarely is typically delayed for months to years. The advantage
exceeds 120 mg every 36 h during daytime. Overdosage of thymectomy is that it offers the possibility of long-
with anticholinesterase medication may cause increased term benet, in some cases diminishing or eliminating
weakness and other side effects. In some patients, the need for continuing medical treatment. In view
muscarinic side effects of the anticholinesterase med- of these potential benets and of the negligible risk in
ication (diarrhea, abdominal cramps, salivation, nausea) skilled hands, thymectomy has gained widespread
acceptance in the treatment of MG. It is the consensus 2- to 3-day intervals), until there is marked clinical 565
that thymectomy should be carried out in all patients improvement or a dose of 5060 mg/d is reached. This
with generalized MG who are between puberty and at dose is maintained for 13 months and then is gradually
least 55 years of age. Whether thymectomy should be modied to an alternate-day regimen over the course of
recommended in children, in adults >55 years, and in an additional 13 months; the goal is to reduce the dose
patients with weakness limited to the ocular muscles is on the off day to zero or to a minimal level. Generally,
still a matter of debate. There is also evidence that patients begin to improve within a few weeks after
patients with MuSK antibodypositive MG may not reaching the maximum dose, and improvement contin-
respond to thymectomy. Thymectomy must be carried ues to progress for months or years. The prednisone
out in a hospital where it is performed regularly and dosage may gradually be reduced, but usually months
where the staff is experienced in the pre- and postoper- or years may be needed to determine the minimum
ative management, anesthesia, and surgical techniques effective dose, and close monitoring is required. Few
of total thymectomy. patients are able to do without immunosuppressive
agents entirely. Patients on long-term glucocorticoid
IMMUNOSUPPRESSION Immunosuppression
therapy must be followed carefully to prevent or treat
using glucocorticoids, azathioprine, and other drugs is
adverse side effects. The most common errors in gluco-
effective in nearly all patients with MG. The choice of

CHAPTER 42
corticoid treatment of myasthenic patients include (1)
drugs or other immunomodulatory treatments should
insufcient persistenceimprovement may be delayed
be guided by the relative benets and risks for the indi-
and gradual; (2) too early, too rapid, or excessive taper-
vidual patient and the urgency of treatment. It is helpful
ing of dosage; and (3) lack of attention to prevention
to develop a treatment plan based on short-term, inter-
and treatment of side effects.
mediate-term, and long-term objectives. For example, if
immediate improvement is essential either because of
Other Immunosuppressive Drugs Mycophe-

Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

the severity of weakness or because of the patients
nolate mofetil, azathioprine, cyclosporine, tacrolimus,
need to return to activity as soon as possible, IVIg
and occasionally cyclophosphamide are effective in
should be administered or plasmapheresis should be
many patients, either alone or in various combinations.
undertaken. For the intermediate term, glucocorticoids
Mycophenolate mofetil has become one of the most
and cyclosporine or tacrolimus generally produce clini-
widely used drugs in the treatment of MG because of its
cal improvement within a period of 13 months. The
effectiveness and relative lack of side effects. A dose of
benecial effects of azathioprine and mycophenolate
11.5 g bid is recommended. Its mechanism of action
mofetil usually begin after many months (up to a year),
involves inhibition of purine synthesis by the de novo
but these drugs have advantages for the long-term
pathway. Since lymphocytes lack the alternative salvage
treatment of patients with MG. For the occasional
pathway that is present in all other cells, mycophenolate
patient with MG that is genuinely refractory to optimal
inhibits proliferation of lymphocytes but not proliferation
treatment with conventional immunosuppressive
of other cells. It does not kill or eliminate preexisting
agents, a course of high-dose cyclophosphamide may
autoreactive lymphocytes, and therefore clinical improve-
induce long-lasting (possibly permanent) benet by
ment may be delayed for many months to a year, until the
rebooting the immune system. At high doses,
preexisting autoreactive lymphocytes die spontaneously.
cyclophosphamide eliminates mature lymphocytes, but
The advantage of mycophenolate lies in its relative lack of
hematopoietic precursors (stem cells) are spared,
adverse side effects, with only occasional production of
because they express the enzyme aldehyde dehydroge-
diarrhea and rare development of leukopenia. This drug
nase, which hydrolyzes cyclophosphamide. At present,
has become the choice for long-term treatment of myas-
this procedure is reserved for refractory patients and
thenic patients. Unfortunately, the cost of mycophenolate
should be administered only in a facility fully familiar
is still very high (~$6400 U.S. annually for 1g bid).
with this approach.
Until recently, azathioprine has been the most widely
Glucocorticoid Therapy Glucocorticoids, when used of these drugs because of its relative safety in
used properly, produce improvement in myasthenic most patients and long track record. Its therapeutic
weakness in the great majority of patients. To minimize effect may add to that of glucocorticoids and/or allow
adverse side effects, prednisone should be given in a the glucocorticoid dose to be reduced. However, up to
single dose rather than in divided doses throughout 10% of patients are unable to tolerate azathioprine
the day. The initial dose should be relatively low because of idiosyncratic reactions consisting of ulike
(1525 mg/d) to avoid the early weakening that symptoms of fever and malaise, bone marrow depres-
occurs in about one-third of patients treated initially sion, or abnormalities of liver function. An initial dose of
with a high-dose regimen. The dose is increased step- 50 mg/d should be used to test for adverse side effects.
wise, as tolerated by the patient (usually by 5 mg/d at If this dose is tolerated, it is increased gradually until the
 566 white blood count falls to ~30004000/L. In patients during treatment, or within a week, and continuing for
who are receiving glucocorticoids concurrently, leuko- weeks to months. The mechanism of action of IVIg is not
cytosis precludes the use of this measure. A reduction of known; the treatment has no consistent effect on the
the lymphocyte count to <1000/L and/or an increase measurable amount of circulating AChR antibody.
of the mean corpuscular volume of red blood cells may Adverse reactions are generally not serious but include
be used as indications of adequacy of azathioprine headache, uid overload, and rarely aseptic meningitis
dosage. The typical dosage range is 23 mg/kg total or renal failure. IVIg should rarely be used as a long-term
body weight. The benecial effect of azathioprine takes treatment in place of rationally managed immunosup-
at least 36 months to begin and even longer to peak. In pressive therapy. Unfortunately, there is a tendency for
patients taking azathioprine, allopurinol should never physicians unfamiliar with immunosuppressive treat-
be used to treat hyperuricemia, because the two drugs ments to rely on repeated IVIg infusions, which are
share a common degradation pathway; the result may inconvenient, usually produce only intermittent benet,
be severe bone marrow depression due to increased and are costly. The intermediate and long-term treat-
effects of the azathioprine. ment of myasthenic patients requires other methods of
The calcineurin inhibitors cyclosporine and tacrolimus therapy outlined earlier in this chapter.
(FK506) are approximately as effective as azathioprine
and are being used increasingly in the management of MANAGEMENT OF MYASTHENIC CRISIS
SECTION III

MG.Their benecial effect appears more rapidly than that Myasthenic crisis is dened as an exacerbation of weak-
of azathioprine. Either drug may be used alone, but they ness sufcient to endanger life; it usually consists of res-
are usually used as an adjunct to glucocorticoids to per- piratory failure caused by diaphragmatic and intercostal
mit reduction of the glucocorticoid dose. The usual dose muscle weakness. Crisis rarely occurs in properly man-
of cyclosporine is 45 mg/kg per day, and the average aged patients. Treatment should be carried out in inten-
dose of tacrolimus is 0.1 mg/kg per day, given in two sive care units staffed with teams experienced in the
Diseases of the Central Nervous System

equally divided doses (to minimize side effects). Side management of MG, respiratory insufciency, infectious
effects of these drugs include hypertension and nephro- disease, and uid and electrolyte therapy. The possibility
toxicity, which must be closely monitored.Trough blood that deterioration could be due to excessive anti-
levels are measured 12 h after the evening dose.The ther- cholinesterase medication (cholinergic crisis) is best
apeutic range for cyclosporine is 150200 ng/L, and for excluded by temporarily stopping anticholinesterase
tacrolimus it is 515 ng/L. drugs. The most common cause of crisis is intercurrent
Cyclophosphamide is reserved for occasional infection. This should be treated immediately, because
patients refractory to the other drugs (see earlier for dis- the mechanical and immunologic defenses of the
cussion of high-dose cyclophosphamide treatment). patient can be assumed to be compromised. The myas-
thenic patient with fever and early infection should be
PLASMAPHERESIS AND INTRAVENOUS treated like other immunocompromised patients. Early
IMMUNOGLOBULIN Plasmapheresis has been and effective antibiotic therapy, respiratory assistance,
used therapeutically in MG. Plasma, which contains the and pulmonary physiotherapy are essentials of the
pathogenic antibodies, is mechanically separated from treatment program. As discussed above, plasmapheresis
the blood cells, which are returned to the patient. A or IVIg is frequently helpful in hastening recovery.
course of ve exchanges (34 L per exchange) is gener-
ally administered over a 10- to 14-day period. Plasma- D R U G S T O AV O I D I N M YA S T H E N I C
pheresis produces a short-term reduction in anti-AChR PATIENTS Many drugs have been reported to have
antibodies, with clinical improvement in many patients. adverse effects in patients with MG (Table 42-4). How-
It is useful as a temporary expedient in seriously ever, not all patients react adversely to all these drugs.
affected patients or to improve the patients condition Conversely, not all safe drugs can be used with
prior to surgery (e.g., thymectomy). impunity in patients with MG. As a rule, the listed drugs
The indications for the use of IVIg are the same as should be avoided whenever possible, and myasthenic
those for plasma exchange: to produce rapid improve- patients should be followed closely when any new drug
ment to help the patient through a difcult period of is introduced.
myasthenic weakness or prior to surgery. This treatment
has the advantages of not requiring special equipment
or large-bore venous access. The usual dose is 2 g/kg,
which is typically administered over 5 days (400 mg/kg PATIENT ASSESSMENT
per day). If tolerated, the course of IVIg can be short-
In order to evaluate the effectiveness of treatment as
ened to administer the entire dose over a 3-day period.
well as drug-induced side effects, it is important to assess
Improvement occurs in ~70% of patients, beginning
the patients clinical status systematically at baseline and
TABLE 42-4 History
Myasthenia Gravis Worksheet
567
DRUGS WITH INTERACTIONS IN MYASTHENIA
General Normal Good Fair Poor
GRAVIS (MG)
Diplopia None Rare Occasional Constant
Drugs that May Exacerbate mg
Antibiotics Ptosis None Rare Occasional Constant
Aminoglycosides: e.g., streptomycin, tobramycin, Arms Normal Slightly Some ADL Definitely
kanamycin limited impairment limited
Quinolones: e.g., ciprooxacin, levooxacin, ooxacin, Legs Normal Walks/runs Can walk limited Minimal
gatioxacin fatigues distances walking
Macrolides: e.g., erythromycin, azithromycin, Speech Normal Dysarthric Severely Unintelligible
dysarthric
telithromycin
Nondepolarizing muscle relaxants for surgery Voice Normal Fades Impaired Severely impaired
D-Tubocurarine (curare), pancuronium, vecuronium,
Chew Normal Fatigue on Fatigue on Feeding tube
atracurium normal foods soft foods
Beta-blocking agents
Swallow Normal Normal foods Soft foods only Feeding tube
Propranalol, atenolol, metoprolol
Local anesthetics and related agents Respiration Normal Dyspnea on Dyspnea on Dyspnea

CHAPTER 42
Procaine, xylocaine in large amounts unusual effort any effort at rest
Procainamide (for arrhythmias)
Botulinum toxin Examination
BP Pulse Wt Arm abduction time R L
Botox exacerbates weakness
Edema Deltoids R L
Quinine derivatives Vital capacity Biceps R L
Quinine, quinidine, chloroquine, meoquine (Lariam) Cataracts? R L Triceps R L
EOMS Grip R L
Magnesium
Ptosis time Iliopsoas R L
Decreases ACh release

Myasthenia Gravis and Other Diseases of the Neuromuscular Junction

Face Quadriceps R L
Penicillamine Hamstrings R L
May cause MG Other R L

Drugs with Important Interactions in mg FIGURE 42-3

Abbreviated interval assessment form for use in evaluating
Cyclosporine treatment for myasthenia gravis.
Broad range of drug interactions, which may raise or
lower cyclosporine levels.
Azathioprine
Avoid allopurinolcombination may result in myelo reliable quantitative measurement of AChR antibody lev-
suppression. els, it is best to compare antibody levels from prior frozen
serum aliquots with current serum samples in simultane-
ously run assays.

on repeated interval examinations. Because of the vari-

FURTHER READINGS
ability of symptoms of MG, the interval history and phys-
ical ndings on examination must be taken into account. HART IK et al: Immunosuppressant drugs for myasthenia gravis. J
The most useful clinical tests include forward arm abduc- Neurol Neurosurg Psychiatry 80:5, 2009
MERIGGIOLI MN, SANDERS DB: Autoimmune myasthenia gravis:
tion time (up to a full 5 min), forced vital capacity, range
emerging clinical and biological heterogeneity. Lancet Neurol
of eye movements, and time to development of ptosis on 8:475, 2009
upward gaze. Manual muscle testing or, preferably, quanti- SANDERS DB et al: An international, phase III, randomized trial of
tative dynamometry of limb muscles, especially proximal mycophenolate mofetil in myasthenia gravis. Neurology 71:400,
muscles, is also important. An interval form can provide a 2008
succinct summary of the patients status and a guide to SCHNEIDER-GOLD C et al: Mycophenolate mofetil and tacrolimus:
treatment results; an abbreviated form is shown in New therapeutic options in neuroimmunological diseases. Mus-
cle Nerve 34:284, 2006
Fig. 42-3. A progressive reduction in the patients AChR
THE MUSCLE STUDY GROUP: A trial of mycophenolate mofetil with
antibody level also provides clinically valuable conrma- prednisone as initial immunotherapy in myasthenia gravis. Neu-
tion of the effectiveness of treatment; conversely, a rise in rology 71:394, 2008
AChR antibody levels during tapering of immunosup- ZINMAN L et al: IV immunoglobulin in patients with myasthenia
pressive medication may predict clinical exacerbation. For gravis:A randomized controlled trial. Neurology 68:837, 2007
 CHAPTER 43
MUSCULAR DYSTROPHIES
AND OTHER MUSCLE DISEASES
Robert H. Brown, Jr. Anthony A. Amato Jerry R. Mendell

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 MTDNA Skeletal MuscleCentral Nervous

Laboratory Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573 System Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Hereditary Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574 Pure Myopathy Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Duchenne Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . 574 Disorders of Muscle Membrane Excitability . . . . . . . . . . . . . . 589
Becker Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . 577 Calcium Channel Disorders Of Muscle . . . . . . . . . . . . . . . . . 589
Limb-Girdle Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . 578 Sodium Channel Disorders of Muscle . . . . . . . . . . . . . . . . . . 591
Emery-Dreifuss Muscular Dystrophy . . . . . . . . . . . . . . . . . . . 578 Potassium Channel Disorders . . . . . . . . . . . . . . . . . . . . . . . . 592
Congenital Muscular Dystrophy (CMD) . . . . . . . . . . . . . . . . . 579 Chloride Channel Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 592
Myotonic Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 579 Endocrine and Metabolic Myopathies . . . . . . . . . . . . . . . . . . 592
Facioscapulohumeral (FSH) Muscular Dystrophy . . . . . . . . . . 581 Thyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Oculopharyngeal Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . 582 Parathyroid Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Distal Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 582 Adrenal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Congenital Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Pituitary Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Central Core Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Nemaline Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584 Vitamin Deciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Centronuclear (Myotubular) Myopathy . . . . . . . . . . . . . . . . . . 585 Myopathies of Systemic Illness . . . . . . . . . . . . . . . . . . . . . . . 593
Disorders of Muscle Energy Metabolism . . . . . . . . . . . . . . . . 585 Drug-Induced Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Glycogen Storage and Glycolytic Defects . . . . . . . . . . . . . . . 585 Myopathy from Lipid-Lowering Agents . . . . . . . . . . . . . . . . . 594
Lipid as an Energy Source and Associated Defects . . . . . . . 586 Glucocorticoid-Related Myopathies . . . . . . . . . . . . . . . . . . . 594
Mitochondrial Myopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 Myopathy of Nondepolarizing Neuromuscular
Progressive External Ophthalmoplegia Syndromes Blocking Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
with Ragged Red Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . 587 Drug-Induced Mitochondrial Myopathy . . . . . . . . . . . . . . . . . 595
Kearns-Sayre Syndrome (KSS) . . . . . . . . . . . . . . . . . . . . . . . 587 Drugs of Abuse and Related Myopathies . . . . . . . . . . . . . . . 595
Progressive External Ophthalmoplegia (PEO) . . . . . . . . . . . . 588 Drug-Induced Autoimmune Myopathies . . . . . . . . . . . . . . . . 595
Autosomal Recessive Cardiomyopathy Other Drug-Induced Myopathies . . . . . . . . . . . . . . . . . . . . . . 596
and Ophthalmoplegia (ARCO) . . . . . . . . . . . . . . . . . . . . . . . 588 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596

Skeletal muscle diseases, or myopathies, are disorders with preserved reexes and sensation. An associated sensory loss
structural changes or functional impairment of muscle. suggests injury to peripheral nerve or the central nervous
These conditions can be differentiated from other dis- system (CNS) rather than myopathy. On occasion, disorders
eases of the motor unit (e.g., lower motor neuron or affecting the motor nerve cell bodies in the spinal cord
neuromuscular junction pathologies) by characteristic (anterior horn cell disease), the neuromuscular junction,
clinical and laboratory ndings. Myasthenia gravis and or peripheral nerves can mimic ndings of myopathy.
related disorders are discussed in Chap. 42; dermato-
myositis, polymyositis, and inclusion body myositis are Muscle Weakness
discussed in Chap. 44.
Symptoms of muscle weakness can be either intermit-
tent or persistent. Disorders causing intermittent weakness
CLINICAL FEATURES
(Fig. 43-1) include myasthenia gravis, periodic paralyses
The most common clinical ndings of a myopathy are (hypokalemic, hyperkalemic, and paramyotonia congenita),
proximal, symmetric limb weakness (arms or legs) with and metabolic energy deciencies of glycolysis (especially
568
 Intermittent weakness 569

Myoglobinuria

No Yes

Variable weakness includes Exam normal between attacks Exam usually normal between attacks
EOMs, ptosis, bulbar and limb muscles Proximal > distal weakness during attacks Proximal > distal weakness during attacks

Repetitive nerve Paradoxical myotonia on exam

stimulation decrement
Forearm exercise

Low potassium level Normal or elevated

potassium level
Reduced lactic acid: Normal lactic acid:
Consider glycolytic defect Consider CPT deficiency
Hypokalemic PP Hyperkalemic PP
(myotonia confined Paramyotonia congenita
to eyelids)

AChR AB positive AChR AB negative

CHAPTER 43
Acquired MG Congenital MG Muscle biopsy
Acquired MG DNA test confirms diagnosis defines specific defect

FIGURE 43-1
Diagnostic evaluation of intermittent weakness. EOMs, antibody; PP, periodic paralysis; CPT, carnitine palmitoyl-
extraocular muscles; AChR AB, acetylcholine receptor transferase; MG, myasthenia gravis.

Muscular Dystrophies and Other Muscle Diseases

myophosphorylase deciency) and fatty acid utilization pattern of weakness include myasthenia gravis, amy-
(carnitine palmitoyltransferase deciency and some mito- otrophic lateral sclerosis, late-onset nemaline myopathy,
chondrial myopathies). The states of energy deciency hyperparathyroidism, focal myositis, and some forms of
cause activity-related muscle breakdown accompanied by inclusion body myopathy. A nal pattern, recognized
myoglobinuria, appearing as light-brown- to dark-brown- because of preferential distal extremity weakness, is typi-
colored urine. cal of a unique category of muscular dystrophy, the distal
Most muscle disorders cause persistent weakness myopathies.
(Fig. 43-2). In the majority of these, including most types It is important to examine functional capabilities to help
of muscular dystrophy, polymyositis, and dermatomyositis, disclose certain patterns of weakness (Table 43-2). The
the proximal muscles are weaker than the distal and are Gowers sign (Fig. 43-4) is particularly useful. Observing
symmetrically affected, and the facial muscles are spared, the gait of an individual may disclose a lordotic posture
a pattern referred to as limb-girdle. The differential diag- caused by combined trunk and hip weakness, frequently
nosis is more restricted for other patterns of weakness. exaggerated by toe walking (Fig. 43-5). A waddling gait
Facial weakness (difculty with eye closure and impaired is caused by the inability of weak hip muscles to prevent
smile) and scapular winging (Fig. 43-3) are characteristic hip drop or hip dip. Hyperextension of the knee (genu
of facioscapulohumeral dystrophy. Facial and distal limb recurvatum or backkneeing) is characteristic of quadriceps
weakness associated with hand grip myotonia is virtually muscle weakness; and a steppage gait, due to footdrop,
diagnostic of myotonic dystrophy. When other cranial accompanies distal weakness.
nerve muscles are weak, causing ptosis or extraocular Any disorder causing muscle weakness may be accom-
muscle weakness, the most important disorders to consider panied by fatigue, referring to an inability to maintain or
include neuromuscular junction disorders, oculopharyngeal sustain a force (pathologic fatigability).This condition must
muscular dystrophy, mitochondrial myopathies, or some be differentiated from asthenia, a type of fatigue caused by
of the congenital myopathies (Table 43-1). A pathogno- excess tiredness or lack of energy. Associated symptoms
monic pattern characteristic of inclusion body myositis may help differentiate asthenia and pathologic fatigability.
is atrophy and weakness of the exor forearm (e.g., wrist Asthenia is often accompanied by a tendency to avoid
and nger exors) and quadriceps muscles that is often physical activities, complaints of daytime sleepiness, neces-
asymmetric. Less frequently, but important diagnostically, sity for frequent naps, and difculty concentrating on
is the presence of a dropped head syndrome indicative activities such as reading.There may be feelings of over-
of selective neck extensor muscle weakness. The most whelming stress and depression. Thus, asthenia is not a
important neuromuscular diseases associated with this myopathy. In contrast, pathologic fatigability occurs in
 570
Persistent Weakness

Patterns of Weakness on Neurologic Exam

Proximal > distal Ptosis, EOMs Facial and Facial, distal, Proximal & distal Distal Dropped head
PM; DM; muscular OPMD; scapular winging quadriceps; (hand grip), & Distal myopathy MG; PM; ALS
dystrophies mitochondrial FSHD handgrip myotonia quadriceps
myopathy; Myotonic muscular IBM
myotubular dystrophy
myopathy

Myopathic EMG confirms muscle disease and excludes ALS

Repetitive nerve stimulation indicates MG
CK elevation supports myopathy

May need DNA testing for further distinction of inherited myopathies

SECTION III

Muscle biopsy will help distinguish many disorders

FIGURE 43-2
Diagnostic evaluation of persistent weakness. Examina- oculopharyngeal muscular dystrophy; FSHD, facioscapulo-
tion reveals one of seven patterns of weakness. The pattern humeral dystrophy; IBM, inclusion body myositis; DM, der-
of weakness in combination with the laboratory evaluation matomyositis; PM, polymyositis; MG, myasthenia gravis; ALS,
Diseases of the Central Nervous System

leads to a diagnosis. EOM, extraocular muscles; OPMD, amyotrophic lateral sclerosis; CK, creatine kinase.

disorders of neuromuscular transmission and in disor- Muscle Pain (Myalgias), Cramps, and Stiffness
ders altering energy production, including defects in
Muscle pain can be associated with cramps, spasms,
glycolysis, lipid metabolism, or mitochondrial energy
contractures, and stiff or rigid muscles. In distinction,
production. Pathologic fatigability also occurs in chronic
true myalgia (muscle aching), which can be localized or
myopathies because of difficulty accomplishing a task
with less muscle. Pathologic fatigability is accompanied
by abnormal clinical or laboratory findings. Fatigue
without those supportive features almost never indi- TABLE 43-1
cates a primary muscle disease. NEUROMUSCULAR CAUSES OF PTOSIS
OR OPHTHALMOPLEGIA
Peripheral neuropathy
Guillain-Barr syndrome
Miller-Fisher syndrome
Neuromuscular junction
Botulism
Lambert-Eaton syndrome
Myasthenia gravis
Congenital myasthenia
Myopathy
Mitochondrial myopathies
Kearns-Sayre syndrome
Progressive external ophthalmoplegia
Oculopharyngeal and oculopharyngodistal
muscular dystrophy
Myotonic dystrophy (ptosis only)
Congenital myopathy
Myotubular
Nemaline (ptosis only)
FIGURE 43-3 Hyperthyroidism/Graves disease (ophthalmoplegia
Facioscapulohumeral dystrophy with prominent scapular without ptosis)
winging.
 TABLE 43-2 571
OBSERVATIONS ON EXAMINATION THAT DISCLOSE MUSCLE WEAKNESS

FUNCTIONAL IMPAIRMENT MUSCLE WEAKNESS

Inability to forcibly close eyes Upper facial muscles

Impaired pucker Lower facial muscles
Inability to raise head from prone position Neck extensor muscles
Inability to raise head from supine position Neck exor muscles
Inability to raise arms above head Proximal arm muscles (may be only
scapular stabilizing muscles)
Inability to walk without hyperextending knee (backkneeing Knee extensor muscles
or genu recurvatum)
Inability to walk with heels touching the oor (toe walking) Shortening of the Achilles tendon
Inability to lift foot while walking (steppage gait or footdrop) Anterior compartment of leg
Inability to walk without a waddling gait Hip muscles
Inability to get up from the oor without climbing up the Hip muscles
extremities (Gowers sign)
Inability to get up from a chair without using arms Hip muscles

CHAPTER 43
generalized, may be accompanied by weakness, tender-
ness to palpation, or swelling. Certain drugs cause true
myalgia (Table 43-3).
There are two painful muscle conditions of particu-

Muscular Dystrophies and Other Muscle Diseases

lar importance, neither of which is associated with
muscle weakness. Fibromyalgia is a common, yet poorly
understood type of myofascial pain syndrome. Patients
complain of severe muscle pain and tenderness and
have specic painful trigger points, sleep disturbances,

FIGURE 43-4 FIGURE 43-5

Gowers sign showing a patient using arms to climb up the Lordotic posture, exaggerated by standing on toes, associ-
legs in attempting to get up from the oor. ated with trunk and hip weakness.
 572 TABLE 43-3 disorders. The muscle is unable to relax after an active
DRUGS THAT CAUSE TRUE MYALGIA muscle contraction. The EMG shows electrical silence.
Confusion is created because contracture also refers to
Cimetidine
Cocaine
a muscle that cannot be passively stretched to its
Cyclosporine proper length (fixed contracture) because of fibrosis. In
Danazol some muscle disorders, especially in Emery-Dreifuss
Emetine muscular dystrophy and Bethlem myopathy, fixed con-
Epsilon aminocaproic acid tractures occur early and represent distinctive features
Gold of the disease.
Heroin Muscle stiffness can refer to different phenomena. Some
Labetalol
patients with inammation of joints and periarticular sur-
Methadone
D-Penicillamine
faces feel stiff.This condition is different from the disorders
Statins and other cholesterol-lowering agents of hyperexcitable motor nerves causing stiff or rigid
L-Tryptophan muscles. In stiff-person syndrome spontaneous discharges of
Zidovudine the motor neurons of the spinal cord cause involuntary
muscle contractions mainly involving the axial (trunk) and
proximal lower extremity muscles.The gait becomes stiff
SECTION III

and labored, with hyperlordosis of the lumbar spine.

Superimposed episodic muscle spasms are precipitated by
and easy fatigability. Serum creatine kinase (CK), erythro- sudden movements, unexpected noises, and emotional
cyte sedimentation rate (ESR), electromyography (EMG), upset. The muscles relax during sleep. Serum antibodies
and muscle biopsy are normal. Polymyalgia rheumatica against glutamic acid decarboxylase are present in approx-
occurs mainly in patients >50 years and is characterized imately two-thirds of cases. In neuromyotonia (Isaacs
Diseases of the Central Nervous System

by stiffness and pain in the shoulders, lower back, hips, syndrome) there is hyperexcitability of the peripheral
and thighs. The ESR is elevated, while serum CK, nerves manifesting as continuous muscle ber activity.
EMG, and muscle biopsy are normal. Temporal arteritis, Myokymia (groups of fasciculations associated with con-
an inammatory disorder of medium- and large-sized tinuous undulations of muscle) and impaired muscle
arteries, usually involving one or more branches of the relaxation are the result. Muscles of the leg are stiff, and
carotid artery, may accompany polymyalgia rheumatica. the constant contractions of the muscle cause increased
Vision is threatened by ischemic optic neuritis. Gluco- sweating of the extremities. This peripheral nerve
corticoids can relieve the myalgias and protect against hyperexcitability is antibody-mediated, targeted against
visual loss. voltage-gated potassium channels. The site of origin of
Localized muscle pain is most often traumatic. A the spontaneous nerve discharges is principally in the
common cause of sudden abrupt-onset pain is a rup- distal portion of the motor nerves.
tured tendon, which leaves the muscle belly appearing Myotonia is a condition of prolonged muscle contrac-
rounded and shorter in appearance compared to the tion followed by slow muscle relaxation. It always follows
normal side.The biceps brachii and Achilles tendons are muscle activation (action myotonia), usually voluntary,
particularly vulnerable to rupture. Infection or neoplas- but may be elicited by mechanical stimulation (percus-
tic inltration of the muscle is a rare cause of localized sion myotonia) of the muscle. Myotonia typically causes
muscle pain. difculty in releasing objects after a rm grasp. In
A muscle cramp or spasm is a painful, involuntary, local- myotonic muscular dystrophy type 1 (DM1), distal weak-
ized, muscle contraction with a visible or palpable hard- ness usually accompanies myotonia, whereas in DM2
ening of the muscle. Cramps are abrupt in onset, short proximal muscles are more affected; thus the related
in duration, and may cause abnormal posturing of the term proximal myotonic myopathy (PROMM) is used to
joint. The EMG shows ring of motor units, reecting describe this condition. Myotonia also occurs with
an origin from spontaneous neural discharge. Muscle myotonia congenita (a chloride channel disorder), but in
cramps often occur in neurogenic disorders, especially this condition muscle weakness is not prominent. Myoto-
motor neuron disease (Chap. 27), radiculopathies, and nia may also be seen in individuals with sodium channel
polyneuropathies (Chap. 40), but are not a feature of mutations (hyperkalemic periodic paralysis or potassium-
most primary muscle diseases. Duchenne muscular dys- sensitive myotonia). Another sodium channelopathy,
trophy is an exception since calf muscle complaints are a paramyotonia congenita, also is associated with muscle
common complaint. Muscle cramps are also common stiffness. In contrast to other disorders associated with
during pregnancy. myotonia in which the myotonia is eased by repetitive
A muscle contracture is different from a muscle cramp. activity, paramyotonia congenita is named for a para-
In both conditions, the muscle becomes hard, but a con- doxical phenomenon whereby the myotonia worsens
tracture is associated with energy failure in glycolytic with repetitive activity.
Muscle Enlargement and Atrophy TABLE 43-4 573
MYOTONIC DISORDERS
In most myopathies muscle tissue is replaced by fat and
connective tissue, but the size of the muscle is usually Myotonic dystrophy type 1
not affected. However, in many limb-girdle muscular Myotonic dystrophy type 2/Proximal myotonic myopathy
dystrophies (and particularly the dystrophinopathies) Myotonia congenita
Paramyotonia congenita
enlarged calf muscles are typical.The enlargement repre-
Hyperkalemic periodic paralysis
sents true muscle hypertrophy, thus the term pseudohy- Chondrodystrophic myotonia (Schwartz-Jampel
pertrophy should be avoided when referring to these syndrome)
patients.The calf muscles remain very strong even late in Centronuclear/myotubular myopathya
the course of these disorders. Muscle enlargement can Drug-induced
also result from inltration by sarcoid granulomas, amy- Cholesterol-lowering agents (statin
loid deposits, bacterial and parasitic infections, and focal medications, brates)
myositis. In contrast, muscle atrophy is characteristic of Cyclosporine
Chloroquine
other myopathies. In dysferlinopathies (LGMD2B) there Glycogen storage disordersa (Pompe disease, debrancher
is a predilection for early atrophy of the gastrocnemius deciency, branching enzyme deciency)
muscles. Atrophy of the humeral muscles is characteristic Myobrillar myopathiesa

CHAPTER 43
of facioscapulohumeral muscular dystrophy.
a
Associated with myotonic discharges on EMG but no clinical
myotonia.
LABORATORY EVALUATION
A limited battery of tests can be used to evaluate a sus-
pected myopathy. Nearly all patients require serum enzyme junction diseases. Routine nerve conduction studies are
level measurements and electrodiagnostic studies as screen- typically normal in myopathies but reduced amplitudes

Muscular Dystrophies and Other Muscle Diseases

ing tools to differentiate muscle disorders from other motor of compound muscle action potentials may be seen in
unit diseases.The other tests describedDNA studies, the atrophied muscles.The needle EMG may reveal irritability
forearm exercise test, and muscle biopsyare used to diag- on needle placement suggestive of a necrotizing myopathy
nose specic types of myopathies. (inammatory myopathies, dystrophies, toxic myopathies,
myotonic myopathies), whereas a lack of irritability is char-
acteristic of long-standing myopathic disorders (muscular
Serum Enzymes dystrophies, endocrine myopathies, disuse atrophy, and
CK is the preferred muscle enzyme to measure in the many of the metabolic myopathies). In addition, the EMG
evaluation of myopathies. Damage to muscle causes the may demonstrate myotonic discharges that will narrow the
CK to leak from the muscle ber to the serum.The MM differential diagnosis (Table 43-4). Another important
isoenzyme predominates in skeletal muscle, while CK-MB EMG nding is the presence of short-duration, small-
is the marker for cardiac muscle. Serum CK can be ele- amplitude, polyphasic motor unit action potentials
vated in normal individuals without provocation, presum- (MUAPs). Such MUAPs can be seen in both myopathic
ably on a genetic basis or after strenuous activity, minor and neuropathic disorders; however, the recruitment or
trauma (including the EMG needle), a prolonged muscle ring pattern is different. In myopathies, the MUAPs re
cramp, or a generalized seizure. Aspartate aminotrans- early but at a normal rate to compensate for the loss of
ferase (AST), alanine aminotransferase (ALT), aldolase, individual muscle bers, whereas in neurogenic disorders
and lactic dehydrogenase (LDH) are enzymes sharing an the MUAPs re faster. The EMG is usually normal in
origin in both muscle and liver. Problems arise when the steroid or disuse myopathy, both of which are associated
levels of these enzymes are found to be elevated in a with type 2 ber atrophy; this is because the EMG prefer-
routine screening battery, leading to the erroneous assump- entially assesses the physiologic function of type 1 bers.
tion that liver disease is present when in fact muscle could The EMG can also be invaluable in helping to choose an
be the cause. An elevated -glutamyl transferase (GGT) appropriately affected muscle to sample for biopsy.
helps to establish a liver origin since this enzyme is not
found in muscle. DNA Analysis
This now serves as an important tool for the denitive
Electrodiagnostic Studies
diagnosis of many muscle disorders. Nevertheless, there are
EMG, repetitive nerve stimulation, and nerve conduction a number of limitations in currently available molecular
studies (Chap. 3) are essential methods for evaluation of diagnostics. For example, in Duchenne and Becker dystro-
the patient with suspected muscle disease. In combina- phies, two-thirds of patients have deletion or duplication
tion they provide the information necessary to differenti- mutations that are easy to detect, while the remainder
ate myopathies from neuropathies and neuromuscular have point mutations that are much more difcult to nd.
 574 For patients without identiable gene defects, the muscle HEREDITARY MYOPATHIES
biopsy remains the main diagnostic tool.
Muscular dystrophy refers to a group of hereditary pro-
Forearm Exercise Test gressive diseases each with unique phenotypic and
genetic features (Tables 43-5, 43-6, and 43-7).
In myopathies with intermittent symptoms, and especially
those associated with myoglobinuria, there may be a defect
in glycolysis. Many variations of the forearm exercise test DUCHENNE MUSCULAR DYSTROPHY
exist. For safety, the test should not be performed under This X-linked recessive disorder, sometimes also called
ischemic conditions to avoid an unnecessary insult to the pseudohypertrophic muscular dystrophy, has an incidence of
muscle, causing rhabdomyolysis. The test is performed by ~30 per 100,000 live-born males.
placing a small indwelling catheter into an antecubital vein.A
baseline blood sample is obtained for lactic acid and ammo-
nia.The forearm muscles are exercised by asking the patient Clinical Features
to vigorously open and close the hand for 1 min. Blood is Duchenne dystrophy is present at birth, but the disorder
then obtained at intervals of 1, 2, 4, 6, and 10 min for com- usually becomes apparent between 3 and 5 years of age.
parison with the baseline sample.A three- to fourfold rise of The boys fall frequently and have difculty keeping up
SECTION III

lactic acid is typical. The simultaneous measurement of with friends when playing. Running, jumping, and hop-
ammonia serves as a control, since it should also rise with ping are invariably abnormal. By 5 years, muscle weakness
exercise. In patients with myophosphorylase deciency or is obvious by muscle testing. On getting up from the oor,
other glycolytic defects, the lactic acid rise will be absent or the patient uses his hands to climb up himself [Gowers
below normal, while the rise in ammonia will reach con- maneuver (Fig. 43-4)]. Contractures of the heel cords and
trol values. If there is lack of effort, neither lactic acid nor iliotibial bands become apparent by 6 years, when toe
Diseases of the Central Nervous System

ammonia will rise. Patients with selective failure to increase walking is associated with a lordotic posture. Loss of muscle
ammonia may have myoadenylate deaminase deciency. strength is progressive, with predilection for proximal limb
This condition has been reported to be a cause of myoglo- muscles and the neck exors; leg involvement is more
binuria, but deciency of this enzyme in asymptomatic severe than arm involvement. Between 8 and 10 years,
individuals makes interpretation controversial. walking may require the use of braces; joint contractures
and limitations of hip exion, knee, elbow, and wrist exten-
Muscle Biopsy sion are made worse by prolonged sitting. By 12 years,
most patients are wheelchair dependent. Contractures
Muscle biopsy is an important step in establishing the become xed, and a progressive scoliosis often develops
diagnosis of a suspected myopathy. The biopsy is usually that may be associated with pain.The chest deformity with
obtained from a quadriceps or biceps brachii muscle, less scoliosis impairs pulmonary function, which is already
commonly from a deltoid muscle. Evaluation includes a diminished by muscle weakness. By 16 to 18 years, patients
combination of techniqueslight microscopy, histochem- are predisposed to serious, sometimes fatal pulmonary
istry, immunocytochemistry with a battery of antibodies, infections. Other causes of death include aspiration of
and electron microscopy. Not all techniques are needed food and acute gastric dilation.
for every case. A specic diagnosis can be established in A cardiac cause of death is uncommon despite the
many disorders. A combination of stains to identify presence of a cardiomyopathy in almost all patients.
mononuclear cells (polymyositis), complement (dermato- Congestive heart failure seldom occurs except with
myositis), and amyloid (inclusion body myositis) helps to severe stress such as pneumonia. Cardiac arrhythmias are
distinguish the inammatory myopathies. In addition, the rare. The typical electrocardiogram (ECG) shows an
congenital myopathies have distinctive light and electron increase net RS in lead V1; deep, narrow Q waves in the
microscopy features essential for diagnosis. Mitochondrial precordial leads; and tall right precordial R waves in V1.
and metabolic (e.g., myophosphorylase and acid maltase Intellectual impairment in Duchenne dystrophy is com-
deciencies) myopathies also demonstrate distinctive his- mon; the average intelligence quotient (IQ) is ~1 SD
tochemical and electron-microscopic proles. Biopsied below the mean. Impairment of intellectual function
muscle tissue can be sent for metabolic enzyme or mito- appears to be nonprogressive and affects verbal ability
chondrial DNA analyses. A battery of antibodies is avail- more than performance.
able for the identication of missing components of the
dystrophin-glycoprotein complex and related proteins to
Laboratory Features
help diagnose specic types of muscular dystrophies.
Western blot analysis on muscle specimens can be per- Serum CK levels are invariably elevated to between 20
formed to determine whether specic muscle proteins are and 100 times normal. The levels are abnormal at birth
reduced in quantity or are of abnormal size. but decline late in the disease because of inactivity and
TABLE 43-5 575
PROGRESSIVE MUSCULAR DYSTROPHIES

DEFECTIVE OTHER ORGAN

TYPE INHERITANCE GENE/PROTEIN ONSET AGE CLINICAL FEATURES SYSTEMS INVOLVED

Duchenne XR Dystrophin <5 years Progressive weakness Cardiomyopathy

of girdle muscles Mental impairment
Unable to walk >12 years
Progressive kyphoscoliosis
Respiratory failure in 2d or
3d decade
Becker XR Dystrophin Early childhood Progressive weakness Cardiomyopathy
to adult of girdle muscles
Able to walk >15 years
Respiratory failure may
develop by 4th decade
Limb-girdle AD/AR Several (Tables 43-6, Early childhood Slow progressive weakness Cardiomyopathy
43-7) to early adult of shoulder and hip girdle

CHAPTER 43
muscles
Emery- XR/AD Emerin/Lamins A/C Childhood to Elbow contractures, humeral Cardiomyopathy
Dreifuss adult and peroneal weakness
Congenital AR Several At birth or Hypotonia, contractures, CNS abnormalities
within rst few delayed milestones (hypomyelination,
months Progression to respiratory malformation)
failure in some; static course Eye abnormalities
in others

Muscular Dystrophies and Other Muscle Diseases

Myotonica AD DM1: Expansion CTG Usually 2d Slowly progressive weakness Cardiac conduction
(DM1, DM2) repeat decade of face, shoulder girdle, and defects
DM2: Expansion May be infancy if foot dorsiexion Mental impairment
CCTG repeat mother affected Preferential proximal weak- Cataracts
(DM1 only) ness in DM2 Frontal baldness
Gonadal atrophy
Facioscapulo- AD Deletion, distal 4q <20 years Slowly progressive weakness Deafness
humeral of face, shoulder girdle, and Coats (eye)
foot dorsiexion disease
Oculopharyn- AD Expansion, poly-A 5th to 6th Slowly progressive weakness
geal RNA binding decade of extraocular, pharyngeal,
protein and limb muscles

a
Two forms of myotonic dystrophy, DM1 and DM2, have been identied. Many features overlap (see text).
Note: XR, X-linked recessive; AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system.

loss of muscle mass. EMG demonstrates features typical not uniformly distributed over the gene but rather are
of myopathy. The muscle biopsy shows muscle bers of most common near the beginning (5 end) and middle of
varying size as well as small groups of necrotic and the gene. Less often, Duchenne dystrophy is caused by a
regenerating bers. Connective tissue and fat replace lost gene duplication or point mutation. Identication of a
muscle bers. A denitive diagnosis of Duchenne dystro- specic mutation allows for an unequivocal diagnosis,
phy can be established on the basis of dystrophin de- makes possible accurate testing of potential carriers, and is
ciency in a biopsy of muscle tissue or mutation analysis useful for prenatal diagnosis.
on peripheral blood leukocytes, as discussed below. A diagnosis of Duchenne dystrophy can also be made by
Duchenne dystrophy is caused by a mutation of the Western blot analysis of muscle biopsy specimens, revealing
gene that encodes dystrophin, a 427-kDa protein local- abnormalities on the quantity and molecular weight of dys-
ized to the inner surface of the sarcolemma of the muscle trophin protein. In addition, immunocytochemical staining
ber.The dystrophin gene is >2000 kb in size and thus is of muscle with dystrophin antibodies can be used to
one of the largest identied human genes. It is localized demonstrate absence or deciency of dystrophin localizing
to the short arm of the X chromosome at Xp21. The to the sarcolemmal membrane. Carriers of the disease may
most common gene mutation is a deletion.The size varies demonstrate a mosaic pattern, but dystrophin analysis of
but does not correlate with disease severity. Deletions are muscle biopsy specimens for carrier detection is not reliable.
 576 TABLE 43-6
AUTOSOMAL DOMINANT LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS)

DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE

LGMD1A Onset 3d to 4th decade Serum CK 2 normal Myotilin

Muscle weakness affects distal limb muscles, EMG mixed myopathy/neuropathy
vocal cords, and pharyngeal muscles NCS normal
LGMD1B Onset 1st or 2d decade Serum CK 35 normal Lamin A/C
Proximal lower limb weakness and NCS normal
cardiomyopathy with conduction defects EMG myopathic
Some cases indistinguishable from Emery-Dreifuss
muscular dystrophy with joint contractures
LGMD1C Onset in early childhood Serum CK 425 normal Caveolin-3
Proximal weakness NCS normal
Gowers sign, calf hypertrophy EMG myopathic
Exercise-related muscle cramps
LGMD1D Onset 3d to 5th decade Serum CK 24 normal Linked to chromosome 7q
Proximal muscle weakness NCS normal Gene unidentied
Cardiomyopathy and arrhythmias EMG myopathic
SECTION III

LGMD1E Childhood onset Serum CK usually normal Linked to chromosome 6q23

Proximal muscle weakness NCS normal Gene unidentied
EMG myopathic

Note: CK, creatine kinase; NCS, nerve conduction studies; EMG, electromyography.
Diseases of the Central Nervous System

TABLE 43-7
AUTOSOMAL RECESSIVE LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMDS)

DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE

LGMD2A Onset 1st or 2d decade Serum CK 315 normal Calpain-3

Tight heel cords NCS normal
Contractures at elbows, wrists, and EMG myopathic
ngers; rigid spine in some
Proximal and distal weakness
LGMD2B Onset 2d or 3d decade Serum CK 3100 normal Dysferlin
Proximal muscle weakness at onset, NCS normal
later distal (calf) muscles affected EMG myopathic
Miyoshi myopathy is variant of LGMD2B Inammation on muscle biopsy
with calf muscles affected at onset may simulate polymyositis
LGMD2CF Onset in childhood to teenage yrs Serum CK 5100 normal , , , sarcoglycans
Clinical condition similar to Duchenne NCS normal
and Becker muscular dystrophies EMG myopathic
Cardiomyopathy uncommon
Cognitive function normal
LGMD2G Onset age 10 to 15 Serum CK 317 normal Telethonin
Proximal and distal muscle weakness NCS normal
EMG myopathic
LGMD2H Onset 1st to 3d decade Serum CK 225 normal TRIM32 gene
Proximal muscle weakness NCS normal
EMG myopathic
LGMD2I Onset 1st to 3d decade Serum CK 1030 normal Fukutin-related protein
Clinical condition similar to Duchenne NCS normal
or Becker dystrophies EMG myopathic
Cardiomyopathy (some not all)
Cognitive function normal
LGMD2Ja Onset 1st to 3d decade Serum CK 1.52 normal Titin
Proximal lower limb weakness NCS normal
Mild distal weakness EMG myopathic
Progressive weakness causes loss of ambulation

a
Tibial muscular dystrophy is a form of titin deciency with only distal muscle weakness (see Table 43-9).
Note: CK, creatine kinase; NCS, nerve conduction studies; EMG, electromyography.
 Extracellular The dystrophin-glycoprotein complex appears to con- 577
Collagen VI
fer stability to the sarcolemma, although the function of
Merosin each individual component of the complex is incompletely
Dystoglycan
understood. Deciency of one member of the complex
complex Sarcoglycan may cause abnormalities in other components. For example,
complex a primary deciency of dystrophin (Duchenne dystrophy)


may lead to secondary loss of the sarcoglycans and dys-

1 7 troglycan. The primary loss of a single sarcoglycan (see
nNOS
Limb-Girdle Muscular Dystrophy, below) results in a
Caveolin-3 Integrin
secondary loss of other sarcoglycans in the membrane
Dystrophin Calpain Dysferlin complex without uniformly affecting dystrophin. In either instance,
F-Actin disruption of the dystrophin-glycoprotein complexes
Golgi
weakens the sarcolemma, causing membrane tears and a
cascade of events leading to muscle ber necrosis. This
POMT1 sequence of events occurs repeatedly during the life of a
Intracelluar patient with muscular dystrophy.
POMGnT1

CHAPTER 43
Fukutin

Fukutin-related
protein
Treatment:
DUCHENNE MUSCULAR DYSTROPHY
FIGURE 43-6
Glucocorticoids, administered as prednisone in a dose of
Selected muscular dystrophyassociated proteins in the
cell membrane and Golgi complex.
0.75 mg/kg per day, signicantly slow progression of

Muscular Dystrophies and Other Muscle Diseases

Duchenne dystrophy for up to 3 years. Some patients
cannot tolerate glucocorticoid therapy; weight gain and
increased risk of fractures in particular represent a sig-
Pathogenesis
nicant deterrent for some boys. As in other recessively
Dystrophin is part of a large complex of sarcolemmal inherited dystrophies presumed to arise from loss of
proteins and glycoproteins (Fig. 43-6). Dystrophin binds function of a critical muscle gene, there is optimism that
to F-actin at its amino terminus and to -dystroglycan Duchenne disease may benet from novel therapies
at the carboxyl terminus. -dystroglycan complexes to that either replace the defective gene or missing protein
-dystroglycan, which binds to laminin in the extracellular or implement downstream corrections (e.g., skipping
matrix (ECM). Laminin has a heterotrimeric molecular mutated exons or reading through mutations that intro-
structure arranged in the shape of a cross with one heavy duce stop codons).
chain and two light chains, 1 and 1.The laminin heavy
chain of skeletal muscle is designated laminin 2. Colla-
gen proteins IV and VI are also found in the ECM. Like
-dystroglycan, the transmembrane sarcoglycan proteins BECKER MUSCULAR DYSTROPHY
also bind to dystrophin; these ve proteins (designated This less severe form of X-linked recessive muscular dys-
- through -sarcoglycan) complex tightly with each other. trophy results from allelic defects of the same gene
More recently, other membrane proteins implicated in responsible for Duchenne dystrophy. Becker muscular
muscular dystrophy have been found to be loosely afli- dystrophy is ~10 times less frequent than Duchenne, with
ated with constituents of the dystrophin complex. These an incidence of about 3 per 100,000 live-born males.
include caveolin-3, 7 integrin, and collagen VI.
Dystrophin localizes to the cytoplasmic face of the
Clinical Features
muscle cell membrane. It complexes with two transmem-
brane protein complexes, the dystroglycans and the sarco- The pattern of muscle wasting in Becker muscular dystro-
glycans.The dystroglycans bind to the extracellular matrix phy closely resembles that seen in Duchenne. Proximal
protein merosin, which is also complexed with 1 and 7 muscles, especially of the lower extremities, are prominently
integrins (Tables 43-5, 43-6, and 43-7). Dysferlin com- involved.As the disease progresses, weakness becomes more
plexes with caveolin-3 (which binds to neuronal nitric generalized. Signicant facial muscle weakness is not a
oxide synthase, or nNOS) but not with the dystrophin- feature. Hypertrophy of muscles, particularly in the calves,
associated proteins or the integrins. In each of four con- is an early and prominent nding.
genital dystrophies, there is loss of function of different Most patients with Becker dystrophy rst experience
Golgi-associated proteins: POMT1, POMGnT1, Fukutin, difculties between ages 5 and 15 years, although onset
and Fukutin-related protein. in the third or fourth decade or even later can occur.
 578 By denition, patients with Becker dystrophy walk beyond LGMD2A, etc.). Disorders receive letters in the order
15 years of age, whereas patients with Duchenne dystrophy in which they are found to have chromosomal linkage.
are typically in a wheelchair by 12 years. Patients with This results in an ever-expanding list of conditions.
Becker dystrophy have a reduced life expectancy, but most Presently there are 5 autosomal dominant and 10 auto-
survive into the fourth or fth decade. somal recessive disorders, summarized in Tables 43-6 and
Mental retardation may occur in Becker dystrophy, 43-7. None of the conditions is as common as the dys-
but it is not as common as in Duchenne. Cardiac trophinopathies; however, prevalence data for the LGMDs
involvement occurs in Becker dystrophy and may result have not been systematically gathered for any large hetero-
in heart failure; some patients manifest with only heart geneous population. In referral-based clinical populations,
failure. Other less common presentations are asympto- Fukutin-related protein (FKRP) deciency (LGMD2I),
matic hyper-CK-emia, myalgias without weakness, and calpainopathies (LGMD2A), and to a lesser extent dys-
myoglobinuria. ferlinopathies (LGMD2B) have emerged as the most
common disorders.
Laboratory Features
Serum CK levels, results of EMG, and muscle biopsy nd- EMERY-DREIFUSS MUSCULAR
ings closely resemble those in Duchenne dystrophy. The DYSTROPHY
SECTION III

diagnosis of Becker muscular dystrophy requires Western There are two genetically distinct forms of Emery-
blot analysis of muscle biopsy samples demonstrating a Dreifuss muscular dystrophy (EDMD). One is inherited as
reduced amount or abnormal size of dystrophin or muta- an X-linked disorder, while the other is autosomal domi-
tion analysis of DNA from peripheral blood leukocytes. nant.The latter is classied under the rubric of LGMD1B,
Genetic testing reveals deletions or duplications of the but clinically the conditions are closely related.
dystrophin gene in 65% of patients with Becker dystrophy,
Diseases of the Central Nervous System

approximately the same percentage as in Duchenne dys-

trophy. In both Becker and Duchenne dystrophies, the size Clinical Features
of the DNA deletion does not predict clinical severity; Prominent contractures can be recognized in early child-
however, in ~95% of patients with Becker dystrophy, the hood and teenage years, often preceding muscle weak-
DNA deletion does not alter the translational reading ness. The contractures persist throughout the course of
frame of messenger RNA. These in-frame mutations the disease and are present at the elbows, ankles, and neck.
allow for production of some dystrophin, which accounts Muscle weakness affects humeral and peroneal muscles at
for the presence of altered rather than absent dystrophin rst and later spreads to a limb-girdle distribution. The
on western blot analysis. cardiomyopathy is potentially life threatening and may
result in sudden death. A spectrum of atrial rhythm and
conduction defects includes atrial brillation and paralysis
and atrioventricular heart block. Some patients have a
Treatment: dilated cardiomyopathy. Female carriers of the X-linked
BECKER MUSCULAR DYSTROPHY variant may have cardiac manifestations that become clin-
The use of glucocorticoids has not been adequately ically signicant.
studied in Becker dystrophy.
Laboratory Features
Serum CK may be elevated two- to tenfold. EMG is
myopathic. Muscle biopsy shows nonspecic dystrophic
LIMB-GIRDLE MUSCULAR DYSTROPHY
features. Immunohistochemistry reveals absent emerin
The syndrome of limb-girdle muscular dystrophy (LGMD) staining of myonuclei in X-lined EDMD. ECGs demon-
represents more than one disorder. Both males and females strate atrial and atrioventricular rhythm disturbances.
are affected, with onset ranging from late in the rst X-linked EDMD arises from defects in the emerin
decade to the fourth decade.The LGMDs typically mani- gene encoding a nuclear envelope protein.The autosomal
fest with progressive weakness of pelvic and shoulder girdle dominant disease is caused by mutations of the LMNA
musculature. Respiratory insufciency from weakness of gene on chromosome 1q21.2 encoding the lamin proteins
the diaphragm may occur, as may cardiomyopathy. A and C. These proteins are alternatively spliced products
A systematic classication of LGMD is based on auto- of the LMNA gene that are essential components of the
somal dominant (LGMD1) and autosomal recessive lamentous network underlying the inner nuclear mem-
(LGMD2) inheritance. Superimposed on the backbone brane. Loss of structural integrity of the nuclear envelope
of LGMD1 and LGMD2, the classication employs a from defects in emerin or lamin A/C accounts for over-
sequential alphabetical lettering system (LGMD1A, lapping phenotypes (Fig. 43-7).
 muscles are normal). Most patients have joint contractures 579
Dystroglycans Extracellular

of varying degrees at elbows, hips, knees, and ankles. Con-
tractures present at birth are referred to as arthrogryposis.
Respiratory failure may be seen in some cases.
Intracellular The CNS is affected in some forms of CMD. In
Dystrophin
merosin and FKRP deciency, cerebral hypomyelination
Myotilin Nebulin
Nucleus Actin may be seen by MRI, though only a small number of
patients have mental retardation and seizures.Three forms
-Actinin of congenital muscular dystrophy have severe brain impair-
Telothonin ment.These include Fukuyama congenital muscular dys-
trophy (FCMD), muscle-eye-brain (MEB) disease, and
Walker-Warburg syndrome (WWS). Patients are severely
Myosin
Titin
disabled in all three of these conditions. In MEB disease
and WWS, but not in FCMD, ocular abnormalities impair
Emerin
Z-band vision.WWS is the most severe congenital muscular dys-
Nuclear trophy, causing death by 1 year of age.
pore Contractile proteins
in sarcomere

CHAPTER 43
Lamin A/C
Laboratory Features
Serum CK is markedly elevated in all of these conditions.
FIGURE 43-7 The EMG is myopathic and muscle biopsies show non-
Selected muscular dystrophyassociated proteins in the specic dystrophic features. Merosin, or laminin 2 chain
nuclear membrane and sarcomere. As shown in the exploded (a basal lamina protein), is decient surrounding muscle
view, emerin and lamin A/C are constituents of the inner

Muscular Dystrophies and Other Muscle Diseases

bers in merosin deciency. Skin biopsies can also demon-
nuclear membrane. Several dystrophy-associated proteins are
strate defects in laminin 2 chain. In the other disorders
represented in the sarcomere including titin, nebulin, calpain,
(FKRP deficiency, FCMD, MEB disease, WWS) there
telethonin, actinin, and myotilin. The position of the dystrophin-
is abnormal alpha-dystroglycan staining in muscle. In
dystroglycan complex is also illustrated.
merosin deciency, cerebral hypomyelination is common,
and a host of brain malformations are seen in FCMD,
MEB disease, and WWS.
All forms of CMD are inherited as autosomal recessive
Treatment: disorders. Chromosomal linkage and specic gene defects
EMERY-DREIFUSS MUSCULAR are presented in Table 43-8.With the exception of merosin,
DYSTROPHY the other gene defects affect posttranslational glycosylation
Supportive care should be offered for neuromuscular of alpha-dystroglycan. This abnormality is thought to
disability, including ambulatory aids, if necessary. impair binding with merosin and leads to weakening of the
Stretching of contractures is difficult. Management of dystrophin-glycoprotein complex, instability of the muscle
cardiomyopathy and arrhythmias (e.g., early use of a membrane, and/or abnormalities in muscle contraction.
cardiac pacemaker) may be life saving. CMDs with brain and eye phenotypes probably involve
defective glycosylation of additional proteins, accounting
for the more extensive phenotypes.

CONGENITAL MUSCULAR
DYSTROPHY (CMD) Treatment:
CONGENITAL MUSCULAR DYSTROPHY
This is not one entity but rather a group of disorders with
There is no specic treatment for CMD. Proper wheel-
varying degrees of muscle weakness, central nervous sys-
chair seating is important. Management of epilepsy and
tem impairment, and eye abnormalities (Table 43-8).
cardiac manifestations is necessary for some patients.

Clinical Features
As a group, CMDs present at birth or in the rst few
MYOTONIC DYSTROPHY
months of life with hypotonia and proximal or general-
ized muscle weakness. Calf muscle hypertrophy is seen in Myotonic dystrophy is also known as dystrophia myotonica
some patients. Facial muscles may be weak, but other cra- (DM).The condition is composed of at least two clinical dis-
nial nerveinnervated muscles are spared (e.g., extraocular orders with overlapping phenotypes and distinct molecular
 580 TABLE 43-8
CONGENITAL MUSCULAR DYSTROPHIESa

DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE

Merosin Onset at birth with hypotonia, joint contractures, Serum CK 535 normal Laminin 2 chain
deciency delayed milestones, generalized muscle weakness EMG myopathic
Cerebral hypomyelination, less often cortical dysplasia NCS abnormal in some cases
Normal intelligence usually, some with MR (~6%)
and seizures (~8%)
Partial deciency leads to milder phenotype
(LGMD picture)
Fukitin-related Onset at birth or shortly after Serum CK 1050 normal Fukutin-related protein
protein Hypotonia and feeding problems EMG myopathic
deciencyb Weakness of proximal muscles, especially NCS normal
shoulder girdles
Hypertrophy of leg muscles
Joint contractures
Cognition normal
Fukuyama Onset at birth Serum CK 1050 normal Fukutin
SECTION III

congenital Hypotonia, joint contractures EMG myopathic

muscular Generalized muscle weakness NCS normal
dystrophyb Hypertrophy of calf muscles MRI shows hydrocephalus
Seizures, mental retardation and periventricular and
Cardiomyopathy frontal hypomyelination
Muscle-eye- Onset at birth, hypotonia Serum CK 520 normal N-acetyl-glucosaminyl
brain disease Eye abnormalities include: progressive myopia, MRI shows hydrocephalus, transferase
cataracts, and optic nerve, glaucoma, retinal cobblestone lissencephaly, (POMGnT1)
Diseases of the Central Nervous System

pigmentary changes corpus callosum and

Progressive muscle weakness cerebellar hypoplasia, cerebral
Joint contractures hypomyelination
Seizures, mental retardation
Walker-Warburg Onset at birth, hypotonia Serum CK 520 normal O-mannoxyl-
syndromeb Generalized muscle weakness MRI shows cobblestone transferase-1
Joint contractures lissencephaly, hydrocephalus, (POMT1)
Microphthalmos, retinal dysplasia, buphthalmos, encephalocele, absent corpus
glaucoma, cataracts callosum
Seizures, MR

a
All are inherited as recessive traits.
b
There is phenotypic overlap between disorders related to defective glycosylation. In muscle this is a consequence of altered glycosylation
of dystroglycans; in brain/eye, other glycosylated proteins are involved. Clinically, Walker-Warburg syndrome is more severe, with death by 1 year.
Note: CK, creatine kinase; EMG, electromyography; NCS, nerve conduction studies; MR, mental retardation; LGMD, limb-girdle muscular
dystrophy.

genetic defects: myotonic dystrophy type 1 (DM1), the the course, although preferential atrophy and weakness
classic disease originally described by Steinert, and myotonic of quadriceps muscles occur in many patients. Palatal,
dystrophy type 2 (DM2), also called proximal myotonic pharyngeal, and tongue involvement produce a dysarthric
myopathy (PROMM). speech, nasal voice, and swallowing problems. Some patients
have diaphragm and intercostal muscle weakness, resulting
in respiratory insufciency.
Clinical Features
Myotonia, which usually appears by age 5 years, is
The clinical expression of myotonic dystrophy varies widely demonstrable by percussion of the thenar eminence, the
and involves many systems other than muscle. Affected tongue, and wrist extensor muscles. Myotonia causes a slow
patients have a typical hatchet-faced appearance due to relaxation of hand grip after a forced voluntary closure.
temporalis, masseter, and facial muscle atrophy and weak- Advanced muscle wasting makes myotonia more dif-
ness. Frontal baldness is also characteristic of the disease. cult to detect.
Neck muscles, including exors and sternocleidomastoids, Cardiac disturbances occur commonly in patients with
and distal limb muscles are involved early.Weakness of wrist DM1. ECG abnormalities include rst-degree heart block
extensors, nger extensors, and intrinsic hand muscles and more extensive conduction system involvement. Com-
impairs function. Ankle dorsiexor weakness may cause plete heart block and sudden death can occur; recently,
footdrop. Proximal muscles remain stronger throughout risk factors for sudden death in these patients have been
identied, but whether pacemaker or debrillator implan- The DNA expansions in DM1 and DM2 almost cer- 581
tation can mitigate this risk remains to be determined. tainly impair muscle function by a toxic gain of function
Congestive heart failure occurs infrequently but may result of the mutant mRNA. In both DM1 and DM2, the
from cor pulmonale secondary to respiratory failure. Mitral mutant RNA appears to form intranuclear inclusions
valve prolapse also occurs commonly. Other associated composed of aberrant RNA. These RNA inclusions
features include intellectual impairment, hypersomnia, sequester RNA binding proteins essential for proper
posterior subcapsular cataracts, gonadal atrophy, insulin splicing of a variety of other mRNAs. This leads to
resistance, and decreased esophageal and colonic motility. abnormal transcription of multiple proteins in a variety
Congenital myotonic dystrophy is a more severe form of of tissues/organ systems, in turn causing the systemic
DM1 and occurs in ~25% of infants of affected mothers. manifestations of DM1 and DM2.
It is characterized by severe facial and bulbar weakness,
transient neonatal respiratory insufciency, and mental
retardation. Treatment:
DM2, or PROMM, has a distinct pattern of muscle MYOTONIC DYSTROPHY
weakness affecting mainly proximal muscles. Other features The myotonia in DM1 rarely warrants treatment, though
of the disease overlap with DM1, including cataracts, testic- some patients with DM2 are signicantly bothered by the
ular atrophy, insulin resistance, constipation, hypersomnia, discomfort related to the associated muscle stiffness.

CHAPTER 43
and cognitive defects. Cardiac conduction defects occur Phenytoin and mexiletine are the preferred agents for the
but are less common, and the hatchet face and frontal bald- occasional patient who requires an antimyotonia drug;
ness are less consistent features.A very striking difference is other agents, particularly quinine and procainamide, may
the failure to clearly identify a congenital form of DM2. worsen cardiac conduction. A cardiac pacemaker should
be considered for patients with unexplained syncope,
Laboratory Features advanced conduction system abnormalities with evi-

Muscular Dystrophies and Other Muscle Diseases

dence of second-degree heart block, or trifascicular con-
The diagnosis of myotonic dystrophy can usually be made duction disturbances with marked prolongation of the PR
on the basis of clinical ndings. Serum CK levels may be interval. Molded ankle-foot orthoses help prevent foot-
normal or mildly elevated. EMG evidence of myotonia is drop in patients with distal lower extremity weakness.
present in most cases of DM1 but may be more patchy in Excessive daytime somnolence with or without sleep
DM2. Muscle biopsy shows muscle atrophy, which selec- apnea is not uncommon. Sleep studies, noninvasive respi-
tively involves type 1 bers in 50% of cases, and ringed ratory support (BiPAP), and treatment with modanil may
bers in DM1 but not in DM2. Typically, numerous be benecial.
internalized nuclei can be seen in individual muscle bers
as well as atrophic bers with pyknotic nuclear clumps in
both DM1 and DM2. Necrosis of muscle bers and
increased connective tissue, common in other muscular FACIOSCAPULOHUMERAL (FSH)
dystrophies, are less apparent in myotonic dystrophy. MUSCULAR DYSTROPHY
DM1 and DM2 are both autosomal dominant disor- This form of muscular dystrophy has a prevalence of ~1
ders. New mutations do not appear to contribute to the in 20,000. It is distinct from a similar disorder known as
pool of affected individuals. DM1 is transmitted by an scapuloperoneal dystrophy.
intronic mutation consisting of an unstable expansion of
a CTG trinucleotide repeat in a serine-threonine protein
Clinical Features
kinase gene (named DMPK) on chromosome 19q13.3.
An increase in the severity of the disease phenotype in The condition typically has an onset in childhood or
successive generations (genetic anticipation) is accompa- young adulthood. In most cases, facial weakness is the
nied by an increase in the number of trinucleotide repeats. initial manifestation, appearing as an inability to smile,
A similar type of mutation has been identied in fragile whistle, or fully close the eyes.Weakness of the shoulder
X syndrome.The unstable triplet repeat in myotonic dys- girdles, rather than the facial muscles, usually brings the
trophy can be used for prenatal diagnosis. Congenital dis- patient to medical attention. Loss of scapular stabilizer
ease occurs almost exclusively in infants born to affected muscles makes arm elevation difcult. Scapular winging
mothers; it is possible that sperm with greatly expanded (Fig. 43-3) becomes apparent with attempts at abduction
triplet repeats do not function well. and forward movement of the arms. Biceps and triceps
DM2 is caused by a DNA expansion mutation con- muscles may be severely affected, with relative sparing of
sisting of a CCTG repeat in intron 1 of the ZNF9 gene the deltoid muscles. Weakness is invariably worse for
located at chromosome 3q13.3-q24.The gene is believed wrist extension than for wrist exion, and weakness of
to encode an RNA binding protein expressed in many the anterior compartment muscles of the legs may lead
different tissues, including skeletal and cardiac muscle. to footdrop.
 582 In most patients, the weakness remains restricted to Clinical Features
facial, upper extremity, and distal lower extremity muscles.
Oculopharyngeal muscular dystrophy has a late onset; it
In 20% of patients, weakness progresses to involve the
usually presents in the fourth to sixth decade with ptosis
pelvic girdle muscles, and severe functional impairment
and/or dysphagia.The extraocular muscle impairment is
and possible wheelchair dependency result.
less prominent in the early phase but may be severe
Characteristically, patients with FSH dystrophy do not
later. The swallowing problem may become debilitating
have involvement of other organ systems, although labile
and result in pooling of secretions and repeated episodes
hypertension is common, and there is an increased inci-
of aspiration. Mild weakness of the neck and extremities
dence of nerve deafness. Coats disease, a disorder consist-
also occurs.
ing of telangiectasia, exudation, and retinal detachment,
also occurs.
Laboratory Features
Laboratory Features The serum CK level may be two to three times normal.
Myopathic EMG ndings are typical. On biopsy, muscle
The serum CK level may be normal or mildly elevated.
bers are found to contain rimmed vacuoles, which by
EMG usually indicates a myopathic pattern. The muscle
electron microscopy are shown to contain membranous
biopsy shows nonspecic features of a myopathy.A promi-
whorls, accumulation of glycogen, and other nonspecic
SECTION III

nent inammatory inltrate, which is often multifocal in

debris related to lysosomes. A distinct feature of ocu-
distribution, is present in some biopsy samples.The cause
lopharyngeal dystrophy is the presence of tubular la-
or signicance of this nding is unknown.
ments, 8.5 nm in diameter, in muscle cell nuclei.
An autosomal dominant inheritance pattern with
Oculopharyngeal dystrophy has an autosomal domi-
almost complete penetrance has been established, but
nant inheritance pattern with complete penetrance. The
each family member should be examined for the pres-
incidence is high in French-Canadians and in Spanish-
Diseases of the Central Nervous System

ence of the disease, since ~30% of those affected are

American families of the southwestern United States.
unaware of involvement. FSH dystrophy is caused by
Large kindreds of Italian and of eastern European Jewish
deletions of tandem 3.3-kb repeats at 4q35.The deletion
descent have been reported. The molecular defect in
reduces the number of repeats to a fragment of <35 kb
oculopharyngeal muscular dystrophy is a subtle expan-
in most patients.This mutation may result in an overex-
sion of a modest polyalanine repeat tract in a poly-RNA
pression of upstream genes and a loss of DNA binding
binding protein (PABP2) in muscle.
of a multiprotein complex mediating transcriptional
repression of 4q35 genes. The mutation permits carrier
detection and prenatal diagnosis. Most sporadic cases
represent new mutations.
Treatment:
OCULOPHARYNGEAL DYSTROPHY
Dysphagia can cause inanition, making oculopharyngeal
Treatment:
muscular dystrophy a potentially life-threatening disease.
FACIOSCAPULOHUMERAL Cricopharyngeal myotomy may improve swallowing,
MUSCULAR DYSTROPHY although it does not prevent aspiration. Eyelid crutches
can improve vision when ptosis obstructs vision; candi-
No specic treatment is available; ankle-foot orthoses
dates for ptosis surgery must be carefully selectedthose
are helpful for footdrop. Scapular stabilization proce-
with severe facial weakness are not suitable.
dures improve scapular winging but may not improve
function.

DISTAL MYOPATHIES
OCULOPHARYNGEAL DYSTROPHY A group of muscle diseases, the distal myopathies, are
notable for their preferential distal distribution of
This form of muscular dystrophy represents one of several muscle weakness in contrast to most muscle conditions
disorders characterized by progressive external ophthal- associated with proximal weakness. The major distal
moplegia, which consists of slowly progressive ptosis and myopathies are summarized in Table 43-9.
limitation of eye movements with sparing of pupillary
reactions for light and accommodation. Patients usually
Clinical Features
do not complain of diplopia, in contrast to patients having
conditions with a more acute onset of ocular muscle Welander, Udd, and Markesbery-Griggs distal myopathies are
weakness (e.g., myasthenia gravis). all late-onset, dominantly inherited disorders of distal limb
TABLE 43-9 583
DISTAL MYOPATHIES

INHERITANCE/
DISEASE CLINICAL FEATURES LABORATORY FEATURES LOCUS OR GENE

Welander distal Onset in fth decade Serum CK 23 normal AD

myopathy Weakness begins in hands EMG myopathic Chromosome 2p13
Slow progression with spread to NCS normal
distal lower extremities Muscle biopsy shows dystrophic features
Lifespan normal
Tibial muscular Onset 4th to 8th decade Serum CK 24 normal AD
dystrophy (Udd) Distal lower extremity weakness EMG myopathic Titin
(tibial distribution) NCS normal
Upper extremities usually normal Muscle biopsy shows dystrophic features
Lifespan normal Titin absent in M-line of muscle
Markesbery- Onset 4th to 8th decade Serum CK is usually mildly elevated AD
Griggs distal Distal lower extremity weakness EMG reveals irritative myopathy Z-band alternatively spliced
myopathy (tibial distribution) with progression Muscle biopsies demonstrate rimmed vac- PDX motif-containing
to distal arms and proximal muscles uoles and features of myobrillar myopathy protein (ZASP)

CHAPTER 43
Laing distal Onset childhood to 3d decade Serum CK is normal or slightly elevated AD
myopathy Distal lower extremity weakness Muscle biopsies do not show rimmed Myosin heavy chain 7
(tibial distribution) and neck exors vacuoles
affected early Large deposits of myosin heavy chain
are seen in type 1 muscle bers
Nonaka distal Onset 2d to 3d decade Serum CK 310 normal ARGNE gene: UDP-
myopathy (auto- Lower extremity distal weakness EMG myopathic N-acetylglucosamine
somal recessive Mild distal upper limb weakness NCS normal 2-epimerase/

Muscular Dystrophies and Other Muscle Diseases

hereditary inclu- may be present early Dystrophic features on muscle biopsy N-acetylmannosamine
sion body Progression to other muscles sparing plus rimmed vacuoles and 15- to 19-nm kinase
myopathy) quadriceps laments within vacuoles Allelic to hereditary inclu-
Ambulation may be lost in 1015 years sion body myopathy
Miyoshi Onset 2d to 3d decade Serum CK 20100 normal AR
myopathy Lower extremity weakness in posterior EMG myopathic Allelic to LGMD2B (see
compartment muscles NCS normal Table 43-7)
Progression leads to weakness in Muscle biopsy shows nonspecic Dysferlin
other muscle groups dystrophic features often with prominent
Ambulation lost after 1015 years in inammatory cell inltration; no rimmed
about one-third of cases vacuoles
Myobrillar Onset from early childhood to late Serum CKs can be normal or moderately Genetically heterogeneous
myopathies adult life elevated AD:
Weakness may be distal, proximal, EMG is myopathic and often associated Myotilin (also known as
or generalized with myopathic discharges LGMD 1A)
Cardiomyopathy and respiratory Muscle biopsy demonstrates abnormal ZASP (see Markesbery-
involvement is not uncommon accumulation of desmin and other pro- Griggs distal myopathy)
teins, rimmed vacuoles, and myobrillar Filamin-C
degeneration Desmin
Alpha B crystallin
AR:
Desmin
Selenoprotein N1

Note: CK, creatine kinase; AD, autosomal dominant; AR, autosomal recessive; EMG, electromyography; NCS, nerve conduction studies.

muscles, usually beginning after 40 years of age.Welander or twenties. Nonaka myopathy entails anterior tibial weak-
distal myopathy preferentially involves the wrist and n- ness, whereas Miyoshi myopathy is unique in that gastroc-
ger extensors, whereas the others are associated with nemius muscles are preferentially affected at onset. Finally,
anterior tibial weakness leading to progressive footdrop. the myobrillar myopathies (MFM) are a clinically and genet-
Laing distal myopathy is also a dominantly inherited dis- ically heterogeneous group of disorders that can be associ-
order heralded by tibial weakness; however, it is distin- ated with prominent distal weakness; they can be inherited
guished by onset in childhood or early adult life. Nonaka in an autosomal dominant or recessive pattern.
distal myopathy and Miyoshi myopathy are distinguished by Confounding these clinical features is the observation
autosomal recessive inheritance and onset in the late teens that proximal muscles can be affected as each of these
 584 disorders progresses (less so for Welander disease than the with stair climbing, running, and getting up from the
others). In contrast to many other inherited muscle dis- oor. On examination, there is mild facial, neck-exor,
eases, the distal myopathies are for the most part limited and proximal-extremity muscle weakness. Legs are more
to skeletal muscle. affected than arms. Skeletal abnormalities include con-
genital hip dislocation, scoliosis, and pes cavus; clubbed
Laboratory Features feet also occur. Most cases are nonprogressive, but excep-
tions are well documented. Susceptibility to malignant
Serum CK level is particularly helpful in diagnosing hyperthermia must be considered as a potential risk
Miyoshi myopathy since it is very elevated. In the other factor for patients with central core disease.
conditions serum CK is only slightly increased. EMGs The serum CK level is usually normal. Needle EMG
are myopathic. In the myobrillar myopathies (MFM), demonstrates a myopathic pattern. Muscle biopsy shows
myotonic or pseudomyotonic discharges are common. bers with single or multiple central or eccentric discrete
Muscle biopsy shows nonspecic dystrophic features and, zones (cores) devoid of oxidative enzymes. Cores occur
with the exception of Laing and Nonaka distal myopathies, preferentially in type 1 bers and represent poorly aligned
often shows rimmed vacuoles. MFM is associated with sarcomeres associated with Z disk streaming.
the accumulation of dense inclusions, as well as amorphous Autosomal dominant inheritance is characteristic;
material best seen on Gomori trichrome and myobrillar sporadic cases also occur. The disease is caused by point
SECTION III

disruption on electron microscopy. Immune staining some- mutations of the ryanodine receptor gene on chromo-
times demonstrates accumulation of desmin and other some 19q, encoding the calcium-release channel of the
proteins in MFM, large deposits of myosin heavy chain in sarcoplasmic reticulum of skeletal muscle; mutations of
the subsarcolemmal region of type 1 muscle bers in Laing this gene also account for some cases of inherited malig-
myopathy, and reduced or absent dysferlin in Miyoshi nant hyperthermia. Malignant hyperthermia is an allelic
myopathy. condition; C-terminal mutations of the RYR1 gene pre-
The affected genes and their gene products are listed
Diseases of the Central Nervous System

dispose to this complication.

in Table 43-9. The gene for Welander disease awaits Specic treatment is not required, but establishing a
identication. diagnosis of central core disease is extremely important
because these patients have a known predisposition to
malignant hyperthermia during anesthesia.
Treatment:
DISTAL MYOPATHIES NEMALINE MYOPATHY
Occupational therapy is offered for loss of hand function;
ankle-foot orthoses can support distal lower limb mus-
The term nemaline refers to the distinctive presence in
cles. The MFMs can be associated with cardiomyopathy
muscle bers of rods or threadlike structures (Greek
(congestive heart failure or arrhythmias) and respiratory
nema, thread). Nemaline myopathy is clinically hetero-
failure that may require medical management.
geneous. A severe neonatal form presents with hypotonia
and feeding and respiratory difculties, leading to early
death. Nemaline myopathy usually presents in infancy or
childhood with delayed motor milestones.The course is
nonprogressive or slowly progressive.The physical appear-
CONGENITAL MYOPATHIES ance is striking because of the long, narrow facies, high-
These rare disorders are distinguished from muscular dys- arched palate, and open-mouthed appearance due to a
trophies by the presence of specic histochemical and struc- prognathous jaw. Other skeletal abnormalities include
tural abnormalities in muscle.Although primarily disorders pectus excavatum, kyphoscoliosis, pes cavus, and clubfoot
of infancy or childhood, three forms that may present in deformities. Facial and generalized muscle weakness,
adulthood are described here: central core disease, nemaline including respiratory muscle weakness, is common. An
(rod) myopathy, and centronuclear (myotubular) myopathy. adult-onset disorder with progressive proximal weakness
Other types, such as minicore myopathy (multi-minicore may be seen. Myocardial involvement is occasionally pre-
disease), ngerprint body myopathy, and sarcotubular sent in both the childhood and adult-onset forms. The
myopathy, are not discussed. serum CK level is usually normal or slightly elevated.The
EMG demonstrates a myopathic pattern. Muscle biopsy
shows clusters of small rods (nemaline bodies), which occur
CENTRAL CORE DISEASE
preferentially, but not exclusively, in the sarcoplasm of
Patients with central core disease may have decreased type 1 muscle bers. Occasionally, the rods are also appar-
fetal movements and breech presentation. Hypotonia ent in myonuclei.The muscle often shows type 1 muscle
and delay in motor milestones, particularly in walking, ber predominance. Rods originate from the Z disk mate-
are common. Later in childhood, patients develop problems rial of the muscle ber.
 Five genes have been associated with nemaline myopa- late infancyearly childhood disorder is probably autosomal 585
thy. All code for thin lamentassociated proteins, suggest- recessive, and for the late childhoodadult form is probably
ing disturbed assembly or interplay of these structures as a autosomal dominant. No specic treatment is available.
pivotal mechanism. Mutations of the nebulin (NEB) gene Some of the autosomal dominant late-onset cases, which
account for most cases, including both severe neonatal and are allelic to a form of CMT2, are associated with muta-
early childhood forms, inherited as autosomal recessive tions in the gene that encodes dynamin-2.
disorders. Neonatal and childhood cases, inherited as pre-
dominantly autosomal dominant disorders, are caused by
mutations of the skeletal muscle -actinin (ACTA1) gene. DISORDERS OF MUSCLE
In milder forms of the disease with autosomal dominant ENERGY METABOLISM
inheritance, mutations have been identied in both the
slow -tropomyosin (TPM3) and -tropomyosin (TPM2) There are two principal sources of energy for skeletal
genes accounting for <3% of cases. Muscle troponin T musclefatty acids and glucose. Abnormalities in either
(TNNT1) gene mutations appear to be limited to the glucose or lipid utilization can be associated with dis-
Amish population in North America. No specic treat- tinct clinical presentations that can range from an acute,
ment is available. painful syndrome with rhabdomyolysis and myoglobinuria
to a chronic, progressive muscle weakness simulating mus-

CHAPTER 43
cular dystrophy.
CENTRONUCLEAR (MYOTUBULAR)
MYOPATHY
GLYCOGEN STORAGE AND
Three distinct variants of centronuclear myopathy occur.A GLYCOLYTIC DEFECTS
neonatal form, also known as myotubular myopathy, presents
with severe hypotonia and weakness at birth. The late Disorders of Glycogen Storage Causing
Progressive Weakness

Muscular Dystrophies and Other Muscle Diseases

infancyearly childhood form presents with delayed motor
milestones. Later, difculty with running and stair climb- -Glucosidase, or Acid Maltase, Deciency
ing becomes apparent. A marfanoid, slender body habitus, (Pompes Disease)
long narrow face, and high-arched palate are typical. Sco- Three clinical forms of -glucosidase, or acid maltase,
liosis and clubbed feet may be present. Most patients deciency (type II glycogenosis) can be distinguished. The
exhibit progressive weakness, some requiring wheelchairs. infantile form is the most common, with onset of symp-
Progressive external ophthalmoplegia with ptosis and toms in the rst 3 months of life. Infants develop severe
varying degrees of extraocular muscle impairment are muscle weakness, cardiomegaly, hepatomegaly, and respi-
characteristic of both the neonatal and the late-infantile ratory insufciency. Glycogen accumulation in motor
forms. A third variant, the late childhoodadult form, has neurons of the spinal cord and brainstem contributes to
an onset in the second or third decade. Patients have full muscle weakness. Death usually occurs by 1 year of age.
extraocular muscle movements and rarely exhibit ptosis. In the childhood form, the picture resembles muscular
There is mild, slowly progressive limb weakness that may dystrophy. Delayed motor milestones result from proximal
be distally predominant [some of these patients have been limb muscle weakness and involvement of respiratory
classied as having Charcot-Marie-Tooth disease type 2 muscles. The heart may be involved, but the liver and
(CMT2); Chap. 40]. brain are unaffected. The adult form usually begins in
Normal or slightly elevated CK levels occur in each of the third or fourth decade but can present as late as the
the forms. Nerve conduction studies may reveal reduced seventh decade. Respiratory failure and diaphragmatic
amplitudes of distal compound muscle action potentials, weakness are often initial manifestations, heralding pro-
in particular in adult-onset cases that resemble CMT2. gressive proximal muscle weakness. The heart and liver
EMG studies often give distinctive results, showing posi- are not involved.
tive sharp waves and brillation potentials, complex and The serum CK level is 2 to 10 times normal in infantile
repetitive discharges, and rarely myotonic discharges. or childhood-onset Pompe disease but can be normal in
Muscle biopsy specimens in longitudinal section demon- adult-onset cases. EMG examination demonstrates a
strate rows of central nuclei, often surrounded by a halo. myopathic pattern, but other features are especially dis-
In transverse sections, central nuclei are found in 2580% tinctive, including myotonic discharges, trains of brilla-
of muscle bers. tion and positive waves, and complex repetitive discharges.
A gene for the neonatal form of centronuclear myopathy EMG discharges are very prominent in the lumbosacral
has been localized to Xq28; this gene encodes myotubu- paraspinal muscles.The muscle biopsy in infants typically
larin, a protein tyrosine phosphatase. Missense, frameshift, reveals vacuoles containing glycogen and the lysosomal
and splice-site mutations predict loss of myotubularin func- enzyme acid phosphatase. Electron microscopy reveals
tion in affected individuals. Carrier identication and pre- membrane-bound and free tissue glycogen. However, mus-
natal diagnosis are possible.The inheritance pattern for the cle biopsies in late-onset Pompes disease may demonstrate
 586 only nonspecic abnormalities. Enzyme analysis of dried (switching to utilization of fatty acids). Varying degrees
blood spots is a new and sensitive technique to screen of hemolytic anemia accompany deciencies of both
for Pompes disease. A denitive diagnosis is established phosphofructokinase (mild) and phosphoglycerate kinase
by enzyme assay in muscle or cultured broblasts or by (severe). In phosphoglycerate kinase deciency, the usual
genetic testing. clinical presentation is a seizure disorder associated with
Acid maltase deciency is inherited as an autosomal mental retardation; exercise intolerance is an infrequent
recessive disorder caused by mutations of the -glucosidase manifestation.
gene. Recently, replacement therapy with IV recombinant In all of these conditions, the serum CK levels uctu-
human -glucosidase has been shown to be benecial in ate widely and may be elevated even during symptom-
infantile-onset Pompe disease and was approved by the free periods. CK levels >100 times normal are expected,
U.S. Food and Drug Administration (FDA).The efcacy accompanying myoglobinuria. All patients with suspected
in later-onset cases is under study. Clinical benets in glycolytic defects leading to exercise intolerance should
the infantile disease include reduced heart size, improved undergo a forearm exercise test. An impaired rise in
muscle function, reduced need for ventilatory support, venous lactate is highly indicative of a glycolytic defect. In
and longer life. lactate dehydrogenase deciency, venous levels of lactate
do not increase, but pyruvate rises to normal. A denitive
Other Glycogen Storage Diseases diagnosis of glycolytic disease is made by muscle biopsy
SECTION III

with Progressive Weakness and subsequent enzyme analysis or by genetic testing.

In debranching enzyme deciency (type III glycogenosis), a slowly Myophosphorylase deciency, phosphofructokinase de-
progressive form of muscle weakness can develop after ciency, and phosphoglycerate mutase deciency are inher-
puberty. Rarely, myoglobinuria may be seen. Patients are ited as autosomal recessive disorders. Phosphoglycerate
usually diagnosed in infancy, however, because of hypo- kinase deciency is X-linked recessive. Mutations can be
tonia and delayed motor milestones, hepatomegaly, growth found in the respective genes encoding the abnormal
Diseases of the Central Nervous System

retardation, and hypoglycemia. Branching enzyme deciency proteins in each of these disorders.
(type IV glycogenosis) is a rare and fatal glycogen storage Training may enhance exercise tolerance, perhaps by
disease characterized by failure to thrive and hepatomegaly. increasing perfusion to muscle. Dietary intake of free
Hypotonia and muscle wasting may be present, but the glucose or fructose prior to activity may improve function
skeletal muscle manifestations are minor compared to but care must be taken to avoid obesity from ingesting
liver failure. too many calories.

Disorders of Glycolysis Causing LIPID AS AN ENERGY SOURCE

Exercise Intolerance AND ASSOCIATED DEFECTS
Several glycolytic defects are associated with recurrent Lipid is an important muscle energy source during rest and
myoglobinuria: myophosphorylase deciency (type V glycogeno- during prolonged, submaximal exercise. Fatty acids are
sis), phosphofructokinase deciency (type VII glycogenosis), derived from circulating very low density lipoprotein
phosphoglycerate kinase deciency (type IX glycogenosis), phos- (VLDL) in the blood or from triglycerides stored in muscle
phoglycerate mutase deciency (type X glycogenosis), lactate bers. Oxidation of fatty acids occurs in the mitochondria.
dehydrogenase deciency (glycogenosis type XI), and beta-enolase To enter the mitochondria, a fatty acid must rst be con-
deciency. Myophosphorylase deciency, also known as verted to an activated fatty acid, acyl-CoA.The acyl-CoA
McArdles disease, is by far the most common of the gly- must be linked with carnitine by the enzyme carnitine
colytic defects associated with exercise intolerance. These palmitoyltransferase (CPT) I for transport into the mito-
glycolytic defects result in a common failure to support chondria. CPT I is present on the inner side of the outer
energy production at the initiation of exercise, although mitochondrial membrane. Carnitine is removed by CPT
the exact site of energy failure remains controversial. II, an enzyme attached to the inside of the inner mito-
Clinical muscle manifestations in these conditions usu- chondrial membrane, allowing transport of acyl-CoA into
ally begin in adolescence. Symptoms are precipitated by the mitochondrial matrix for -oxidation.
brief bursts of high-intensity exercise, such as running or
lifting heavy objects.A history of myalgia and muscle stiff-
Carnitine Palmitoyltransferase Deciency
ness usually precedes the intensely painful muscle contrac-
tures, which may be followed by myoglobinuria. Acute CPT II deciency is the most common recognizable cause
renal failure accompanies signicant pigmenturia. of recurrent myoglobinuria, more common than the gly-
Certain features help distinguish some enzyme defects. colytic defects. Onset is usually in the teenage years or
In McArdles disease exercise tolerance can be enhanced by early twenties. Muscle pain and myoglobinuria typically
a slow induction phase (warm-up) or brief periods of rest, occur after prolonged exercise but can also be precipitated
allowing for the start of the second-wind phenomenon by fasting or infections; up to 20% of patients do not
exhibit myoglobinuria, however. Strength is normal equivalents.The latter are transported through the respi- 587
between attacks. In contrast to disorders caused by defects ratory chain in the process known as oxidative phosphory-
in glycolysis, in which muscle cramps follow short, intense lation. The energy generated by the oxidation-reduction
bursts of exercise, the muscle pain in CPT II deciency reactions of the respiratory chain is stored in an electro-
does not occur until the limits of utilization have been chemical gradient coupled to ATP synthesis.
exceeded and muscle breakdown has already begun. A novel feature of mitochondria is their genetic com-
Episodes of rhabdomyolysis may produce severe weak- position. Each mitochondrion possesses a DNA genome
ness. In young children and newborns, CPT II deciency that is distinct from that of the nuclear DNA. Human
can present with a very severe clinical picture including mitochondrial DNA (mtDNA) consists of a double-strand,
hypoketotic hypoglycemia, cardiomyopathy, liver failure, circular molecule comprising 16,569 base pairs. It codes for
and sudden death. 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypep-
Serum CK levels and EMG ndings are both usually tides of the respiratory chain enzymes. The genetics of
normal between episodes. A normal rise of venous lactate mitochondrial diseases differ from the genetics of chro-
during forearm exercise distinguishes this condition from mosomal disorders.The DNA of mitochondria is directly
glycolytic defects, especially myophosphorylase deciency. inherited from the cytoplasm of the gametes, mainly from
Muscle biopsy does not show lipid accumulation and is the oocyte. The sperm contributes very little of its mito-
usually normal between attacks. The diagnosis requires chondria to the offspring at the time of fertilization.Thus,

CHAPTER 43
direct measurement of muscle CPT or genetic testing. mitochondrial genes are derived almost exclusively from
CPT II deciency is much more common in men than the mother, accounting for maternal inheritance of some
women (5:1); nevertheless, all evidence indicates autoso- mitochondrial disorders.
mal recessive inheritance. A mutation in the gene for CPT Patients with mitochondrial disorders have clinical man-
II (chromosome 1p36) causes the disease in some individ- ifestations that fall into three groups: chronic progressive
uals.Attempts to improve exercise tolerance with frequent external ophthalmoplegia (CPEO), skeletal muscleCNS

Muscular Dystrophies and Other Muscle Diseases

meals and a low-fat, high-carbohydrate diet, or by substi- syndromes, and pure myopathy simulating muscular dystro-
tuting medium-chain triglycerides in the diet, have not phy or metabolic myopathy.
proven to be benecial.
PROGRESSIVE EXTERNAL
Myoadenylate Deaminase Deciency OPHTHALMOPLEGIA SYNDROMES
WITH RAGGED RED FIBERS
The muscle enzyme myoadenylate deaminase converts
adenosine 5-monophosphate (5-AMP) to inosine The single most common sign of a mitochondrial myopa-
monophosphate (IMP) with liberation of ammonia. thy is CPEO, occurring in >50% of all mitochondrial
Myoadenylate deaminase may play a role in regulating myopathies. Varying degrees of ptosis and weakness of
adenosine triphosphate (ATP) levels in muscles. Most extraocular muscles are seen, usually in the absence of
individuals with myoadenylate deaminase deciency have diplopia, a point of distinction from disorders with uc-
no symptoms. There have been a few reports of patients tuating eye weakness (e.g., myasthenia gravis).
with this disorder who have exercise-exacerbated myal-
gia and myoglobinuria. Many questions have been raised KEARNS-SAYRE SYNDROME (KSS)
about the clinical effects of myoadenylate deaminase
deciency, and, specically, its relationship to exertional KSS is a widespread multiorgan system disorder with a
myalgia and fatigability, but there is no consensus. dened triad of clinical ndings: onset <20 years, CPEO,
and pigmentary retinopathy plus one or more of the fol-
lowing features: complete heart block, cerebrospinal uid
MITOCHONDRIAL MYOPATHIES (CSF) protein >1.0 g/L (100 mg/dL), or cerebellar ataxia.
Some patients with CPEO and ragged red bers may
In 1972, Olson and colleagues recognized that muscle not fulll all of the criteria for KSS. The cardiac disease
bers with signicant numbers of abnormal mitochondria includes syncopal attacks and cardiac arrest related to the
could be highlighted with the modied trichrome stain; abnormalities in the cardiac conduction system: prolonged
the term ragged red bers was coined. By electron microscopy, intraventricular conduction time, bundle branch block,
the mitochondria in ragged red bers are enlarged and and complete atrioventricular block. Death attributed to
often bizarrely shaped and have crystalline inclusions. heart block occurs in ~20% of the patients.Varying degrees
Since that seminal observation, the understanding of these of progressive limb muscle weakness and easy fatigability
disorders of muscle and other tissues has expanded. affect activities of daily living. Endocrine abnormalities
Mitochondria play a key role in energy production. are common, including gonadal dysfunction in both sexes
Oxidation of the major nutrients derived from carbohy- with delayed puberty, short stature, and infertility. Diabetes
drate, fat, and protein leads to the generation of reducing mellitus is a cardinal sign of mitochondrial disorders and
 588 is estimated to occur in 13% of KSS patients. Other less inner mitochondrial channel through which ADP enters
common endocrine disorders include thyroid disease, and ATP leaves the mitochondrial matrix. In the chro-
hyperaldosteronism, Addisons disease, and hypoparathy- mosome 10qrelated disorder, mutations of the gene
roidism. Both mental retardation and dementia are com- C10orf2 are found. Its gene product, twinkle, co-localizes
mon accompaniments to this disorder. Serum CK levels with the mtDNA and is named for its punctate, starlike
are normal or slightly elevated. Serum lactate and pyru- staining properties. The function of twinkle is presumed
vate levels may be elevated. EMG is myopathic. Nerve to be critical for lifetime maintenance of mitochondrial
conduction studies may be abnormal related to an associ- integrity. In the cases mapped to chromosome 15q, a
ated neuropathy. Muscle biopsies reveal ragged red bers, mutation affects the gene encoding mtDNA polymerase
highlighted in oxidative enzyme stains, many showing (POLG), an enzyme important in mtDNA replication.
defects in cytochrome oxidase. By electron microscopy Autosomal recessive PEO has also been described with
there are increased numbers of mitochondria that often mutations in the POLG gene. Point mutations have been
appear enlarged and contain paracrystalline inclusions. identied within various mitochondrial tRNA (Leu,
KSS is a sporadic disorder.The disease is caused by sin- Ile, Asn, Trp) genes in families with maternal inheri-
gle mtDNA deletions presumed to arise spontaneously in tance of PEO.
the ovum or zygote. The most common deletion, occur- Exercise may improve function but will depend on
ring in about one-third of patients, removes 4977 bp of the patients ability to participate.
SECTION III

contiguous mtDNA. Monitoring for cardiac conduction

defects is critical. Prophylactic pacemaker implantation is
indicated when ECGs demonstrate a bifascicular block. In AUTOSOMAL RECESSIVE CARDIOMYOPATHY
KSS no benet has been shown for supplementary thera- AND OPHTHALMOPLEGIA (ARCO)
pies, including multivitamins or coenzyme Q10. Of all ARCO is a rare mitochondrial disorder clinically impor-
the proposed options, exercise might be the most applica- tant because of an associated life-threatening cardiomy-
Diseases of the Central Nervous System

ble but must be approached cautiously because of defects opathy. CPEO is the initial manifestation, occurring
in the cardiac conduction system. between ages 8 and 10. Exercise intolerance and fatigue
follow the early symptoms, accompanied by palpitations
PROGRESSIVE EXTERNAL and chest pain. Examination reveals extraocular muscle
OPHTHALMOPLEGIA (PEO) weakness, ptosis, facial weakness, reduced muscle bulk,
and limb weakness, greater in proximal muscles. A dilated
This condition is caused by nuclear DNA mutations cardiomyopathy is typical, and some patients have con-
affecting mtDNA copy number and integrity and is thus duction system involvement. Death from congestive heart
inherited in a Mendelian fashion. Onset is usually after failure occurs as early as 13 years of age. Serum lactate is
puberty. Fatigue, exercise intolerance, and complaints of normal at rest but increases with mild exercise. Serum CK
muscle weakness are typical. Some patients notice swal- is increased two- to fourfold. EMG is normal or myo-
lowing problems. The neurologic examination conrms pathic. Muscle biopsy demonstrates typical ragged red
the ptosis and ophthalmoplegia, usually asymmetric in bers. Multiple mtDNA deletions are seen on Southern
distribution. A sensorineural hearing loss may be encoun- blots of muscle. Echocardiograms show reduced ejection
tered. Mild facial, neck exor, and proximal weakness are fraction. Conduction block is seen on ECGs. The disease
typical. Rarely, respiratory muscles may be progressively is inherited as an autosomal recessive disorder.The gene
affected and may be the direct cause of death. Serum has not been identied. Heart failure may require ortho-
CK is normal or mildly elevated. The resting lactate topic cardiac transplantation. Cardiac pacemakers are
level is normal or slightly elevated but may rise exces- appropriate for patients with heart block.
sively after exercise. CSF protein is normal.The EMG is
myopathic, and nerve conduction studies are usually
normal. Ragged red bers are prominently displayed in MTDNA SKELETAL MUSCLECENTRAL
the muscle biopsy. Southern blots of muscle reveal a NERVOUS SYSTEM SYNDROMES
normal mtDNA band at 16.6 kb and several additional
mtDNA deletion bands with genomes varying from 0.5 Myoclonic Epilepsy with Ragged
Red Fibers (MERRF)
to 10 kb.
This autosomal dominant form of CPEO has been The onset of MERRF is variable, ranging from late child-
linked to loci on three chromosomes: 4q35, 10q24, and hood to middle adult life. Characteristic features include
15q22-26. In the chromosome 4qrelated form of disease, myoclonic epilepsy, cerebellar ataxia, and progressive mus-
mutations of the gene encoding the heart and skeletal cle weakness.The seizure disorder is an integral part of the
musclespecic isoform of the adenine nucleotide disease and may be the initial symptom. Cerebellar ataxia
translocator 1 (ANT1) gene are found. This highly precedes or accompanies epilepsy. It is slowly progressive
abundant mitochondrial protein forms a homodimeric and generalized. The third major feature of the disease is
muscle weakness in a limb-girdle distribution. Other more reported in mtDNA polypeptide-coding genes. Two 589
variable features include dementia, peripheral neuropathy, mutations were found in the ND5 subunit of complex I
optic atrophy, hearing loss, and diabetes mellitus. of the respiratory chain. A missense mutation has been
Serum CK levels are normal or slightly increased.The reported at mtDNA position 9957 in the gene for sub-
serum lactate may be elevated. EMG is myopathic, and unit III of cytochrome C oxidase. No specic treatment
in some patients nerve conduction studies show a neu- is available. Supportive treatment is essential for the stroke-
ropathy. The electroencephalogram is abnormal, corrob- like episodes, seizures, and endocrinopathies.
orating clinical ndings of epilepsy. Typical ragged red
bers are seen on muscle biopsy. MERRF is caused by PURE MYOPATHY SYNDROMES
maternally inherited point mutations of mitochondrial
tRNA genes.The most common mutation found in 80% Muscle weakness and fatigue can be the predominant
of MERRF patients is an A to G substitution at nucleotide manifestations of mtDNA mutations.When the condition
8344 of tRNA lysine (A8344G tRNAlys). Other tRNAlys affects exclusively muscle (pure myopathy), the disorder
mutations include base-pair substitutions T8356C and becomes difcult to recognize. Occasionally, mitochondr-
G8363A. Only supportive treatment is possible, with ial myopathies can present with recurrent myoglobinuria
special attention to epilepsy. without xed weakness and thus resemble a glycogen
storage disorder or CPT deciency.

CHAPTER 43
Mitochondrial Myopathy, Encephalopathy, Mitochondrial DNA Depletion Myopathy
Lactic Acidosis, and Stroke-Like
Episodes (MELAS) This disorder, clinically indistinguishable from muscular
MELAS is the most common mitochondrial encephalomy- dystrophy, usually presents in the neonatal period with
opathy. The term stroke-like is appropriate because the weakness, hypotonia, and delayed motor milestones.
Some cases are rapidly fatal, with death <2 years of age.A

Muscular Dystrophies and Other Muscle Diseases

cerebral lesions do not conform to a strictly vascular dis-
tribution.The age of onset in the majority of patients is milder form affects patients at a slightly later age. These
<20 years. Seizures, usually partial motor or generalized, patients have slowly evolving proximal muscle weakness
are common and may represent the rst clearly recog- simulating Duchenne muscular dystrophy. In some, seizures
nizable sign of disease.The cerebral insults that resemble and cardiomyopathy may be present. Serum CK can reach
strokes cause hemiparesis, hemianopia, and cortical blind- levels of 20 to 30 times normal. Resting lactate varies from
ness. A presumptive stroke occurring <40 years should normal to mildly elevated. The EMG is myopathic, and
place this mitochondrial encephalomyopathy high in the ragged red bers are seen on muscle biopsy. The
differential diagnosis. Associated conditions include hearing mtDNA depletion syndrome is inherited as an autosomal
loss, diabetes mellitus, hypothalamic pituitary dysfunction recessive condition. Mutations have been identied in
causing growth hormone deciency, hypothyroidism, and the TK2 gene on chromosome 16q22 encoding thymi-
absence of secondary sexual characteristics. In its full dine kinase-2. The affected gene controls the supply of
expression MELAS leads to dementia, a bedridden state, deoxyribonucleotides used for the synthesis of mtDNA.
and a fatal outcome. Serum lactic acid is typically ele- No specic treatment is available. Supportive care fol-
vated. The CSF protein is also increased but is usually lows the approaches outlined for muscular dystrophy.
1.0 g/L (100 mg/dL). Muscle biopsies show ragged red
bers. Neuroimaging demonstrates basal ganglia calci- DISORDERS OF MUSCLE
cation in a high percentage of cases. Focal lesions that MEMBRANE EXCITABILITY
mimic infarction are present predominantly in the occipi-
tal and parietal lobes. Strict vascular territories are not Muscle membrane excitability is affected in a group of
respected, and cerebral angiography fails to demonstrate disorders referred to as channelopathies. The heart may
lesions of the major cerebral blood vessels. also be involved, resulting in life-threatening complica-
MELAS is caused by maternally inherited point muta- tions (Table 43-10).
tions of mitochondrial tRNA genes. Most of the tRNA
mutations are lethal, accounting for the paucity of multi- CALCIUM CHANNEL DISORDERS
generation families with this syndrome.The A3243G point OF MUSCLE
mutation in tRNALeu(UUR) is the most common, occur-
Hypokalemic Periodic Paralysis (HypoKPP)
ring in ~80% of MELAS cases. About 10% of MELAS
patients have other mutations of the tRNALeu(UUR) gene Onset occurs at adolescence. Men are more often affected
including 3252G, 3256T, 3271C, and 3291C. Other tRNA because of decreased penetrance in women. Episodic
gene mutations have also been reported in MELAS weakness with onset >25 years of age is almost never due
including G583A tRNAPhe, G1642A tRNAVal, G4332A to periodic paralyses with the exception of thyrotoxic
tRNAGlu, and T8316C tRNALys. Mutations have also been periodic paralysis (see later). Attacks are often provoked
 590 TABLE 43-10
CLINICAL FEATURES OF PERIODIC PARALYSIS AND NONDYSTROPHIC MYOTONIAS

CALCIUM CHANNEL SODIUM CHANNEL POTASSIUM CHANNEL

FEATURE HYPOKALEMIC PP HYPERKALEMIC PP PARAMYOTONIA CONGENITA ANDERSONS SYNDROMEb

Mode of inheritance AD AD AD AD
Age of onset Adolescence Early childhood Early childhood Early childhood
Myotoniaa No Yes Yes No
Episodic weakness Yes Yes Yes Yes
Frequency of attacks Daily to yearly May be 23/d With cold, usually rare Daily to yearly
of weakness
Duration of attacks 212 h From 12 h to >1 d 224 h 224 h
of weakness
Serum K+ level during Decreased Increased or normal Usually normal Variable
attacks of weakness
Effect of K+ loading No change Increased myotonia, Increased myotonia No change
then weakness
Effect of muscle No change Increased myotonia Increased myotonia, No change
SECTION III

cooling then weakness

Fixed weakness Yes Yes Yes Yes

a
May be paradoxical in paramyotonia congenita.
b
Dysmorphic features and cardiac arrhythmias are distinguishing features (see text).
Note: AD, autosomal dominant; PP, periodic paralysis.
Diseases of the Central Nervous System

by meals high in carbohydrates or sodium and may voltage-sensitive, skeletal muscle calcium channel gene,
accompany rest following prolonged exercise. Weakness CALCL1A3 (Fig. 43-8). Approximately 10% of cases
usually affects proximal limb muscles more than distal. are HypoKPP type 2, arising from mutations in the
Ocular and bulbar muscles are less likely to be affected. voltage-sensitive sodium channel gene (SCN4A).
Respiratory muscles are usually spared but when they are
involved, the condition may prove fatal.Weakness may take
as long as 24 h to resolve. Life-threatening cardiac arrhyth-
mias related to hypokalemia may occur during attacks. As Treatment:
a late complication, patients commonly develop severe, HYPOKALEMIC PERIODIC PARALYSIS
disabling proximal lower extremity weakness.
The acute paralysis improves after the administration of
Attacks of thyrotoxic periodic paralysis resemble those of
potassium. Muscle strength and ECG should be moni-
primary HypoKPP. Despite a higher incidence of thyrotoxi-
tored. Oral KCl (0.20.4 mmol/kg) should be given every
cosis in women, men, particularly those of Asian descent,
30 min. Only rarely is IV therapy necessary (e.g., when
are more likely to manifest this complication.Attacks abate
swallowing problems or vomiting is present). Adminis-
with treatment of the underlying thyroid condition.
tration of potassium in a glucose solution should be
A low serum potassium level during an attack, exclud-
avoided because it may further reduce serum potassium
ing secondary causes, establishes the diagnosis. Interattack
levels. Mannitol is the preferred vehicle for administra-
muscle biopsies show the presence of single or multiple
tion of IV potassium. The long-term goal of therapy is to
centrally placed vacuoles or tubular aggregates. Provoca-
avoid attacks. This may reduce late-onset, xed weak-
tive tests with glucose and insulin to establish a diagnosis
ness. Patients should be made aware of the importance
are usually not necessary and are potentially hazardous.
of a low-carbohydrate, low-sodium diet and conse-
In the midst of an attack of weakness, motor conduc-
quences of intense exercise. Prophylactic administration
tion studies may demonstrate reduced amplitudes, whereas
of acetazolamide (1251000 mg/d in divided doses)
EMG may show electrical silence in severely weak mus-
reduces or may abolish attacks in HypoKPP type 1. Para-
cles. In between attacks, the EMG and nerve conduction
doxically the potassium is lowered, but this is offset by
studies are normal, with the exception that myopathic
the benecial effect of metabolic acidosis. If attacks per-
motor unit action potentials may be seen in patients with
sist on acetazolamide, oral KCl should be added. Some
xed weakness.
patients require treatment with triamterine (25100 mg/d)
HypoKPP is caused by mutations in either of two
or spironolactone (25100 mg/d). However, in patients
genes. HypoKPP type 1, the most common form, is
with HypoKPP type 2, attacks of weakness can be exac-
inherited as an autosomal dominant disorder with incom-
erbated with acetazolamide.
plete penetrance. These patients have mutations in the
Sodium channel subunit variant of this disorder, the predominant symptom is 591
I II III IV myotonia without weakness (potassium-aggravated myoto-
Outside nia). The symptoms are aggravated by cold, and myoto-
nia makes the muscles stiff and painful.This disorder can
1 234 5 6
be confused with paramyotonia congenita, myotonia
Inside congenita, and proximal myotonic myopathy (DM2).
1
NH3 COO2
Potassium may be slightly elevated but may also be nor-
mal during an attack. As in HypoKPP, nerve conduction
HyperKPP PC PAM
studies in HyperKPP muscle may demonstrate reduced
Calcium channel subunit motor amplitudes and the EMG may be silent in very
I II III IV weak muscles. In between attacks of weakness, the con-
H H G
Outside
duction studies are normal. The EMG will often demon-
R R strate myotonic discharges during and between attacks.
The muscle biopsy shows vacuoles that are smaller,
Inside less numerous, and more peripheral compared to the
1 hypokalemic form or tubular aggregates. Provocative tests
NH3
COO2 by administration of potassium can induce weakness but

CHAPTER 43
Chloride channel are usually not necessary to establish the diagnosis. Hyper-
2 KPP and potassium-aggravated myotonia are inherited as
Outside
autosomal dominant disorders. Mutations of the voltage-
1 3 4 5 6 7 8 9 1112 gated sodium channel SCN4A gene (Fig. 43-8) cause these
conditions. For patients with frequent attacks, acetazo-
13 Inside
10 lamide (1251000 mg/d) is helpful.We have found mexile-

Muscular Dystrophies and Other Muscle Diseases

1
NH3 COO2 tine to be helpful in patients with signicant myotonia.
Myotonia Congenita Myotonia Congenita ADR (murine)
Dominant Recessive insertion Paramyotonia Congenita
Myotonic goat adrmto (murine)
Ala Pro stop In paramyotonia congenita (PC) the attacks of weakness
FIGURE 43-8 are cold-induced or occur spontaneously and are mild.
The sodium and calcium channels are depicted here as con- Myotonia is a prominent feature but worsens with muscle
taining four homologous domains, each with six membrane- activity (paradoxical myotonia).This is in contrast to clas-
spanning segments. The fourth segment of each domain bears sic myotonia in which exercise alleviates the condition.
positive charges and acts as the voltage sensor for the chan- Attacks of weakness are seldom severe enough to require
nel. The association of the four domains is thought to form a emergency room treatment. Over time patients develop
pore through which ions pass. Sodium channel mutations are interattack weakness as they do in other forms of periodic
shown along with the phenotype that they confer. HyperKPP, paralysis. PC is usually associated with normokalemia or
hyperkalemic periodic paralysis; PC, paramyotonia congenita; hyperkalemia.
PAM, potassium-aggravated myotonia. See text for details. Serum CK is usually mildly elevated. Routine sensory
The chloride channel is envisioned to have ten membrane- and motor nerve conduction studies are normal. Cooling
spanning domains. The positions of mutations causing of the muscle often dramatically reduces the amplitude of
dominantly and recessively inherited myotonia congenita are
the compound muscle action potentials. EMG reveals dif-
indicated, along with mutations that cause this disease in
fuse myotonic potentials in PC. Upon local cooling of the
mice and goats.
muscle the myotonic discharges disappear as the patient
becomes unable to activate motor unit action potentials.
PC is inherited as an autosomal dominant condition;
SODIUM CHANNEL DISORDERS voltage-gated sodium channel mutations (Fig. 43-8) are
OF MUSCLE responsible and thus this disorder is allelic with Hyper-
KPP and potassium-aggravated myotonia. Patients with
Hyperkalemic Periodic Paralysis (HyperKPP)
PC seldom seek treatment during attacks. Oral adminis-
The term hyperkalemic is misleading since patients are tration of glucose or other carbohydrates hastens recovery.
often normokalemic during attacks. The fact that attacks Since interattack weakness may develop after repeated
are precipitated by potassium administration best denes episodes, prophylactic treatment is usually indicated.
the disease. The onset is in the rst decade. Attacks are Thiazide diuretics (e.g., chlorothiazide, 2501000 mg/d)
brief and mild, usually lasting 30 min to 4 h. Weakness and mexiletine (slowly increase dose from 450 mg/d)
affects proximal muscles, sparing bulbar muscles. Attacks are reported to be helpful. Patients should be advised to
are precipitated by rest following exercise and fasting. In a increase carbohydrates in their diet.
 592 POTASSIUM CHANNEL DISORDERS atrophy rather than destruction of muscle bers. Nearly
all endocrine myopathies respond to treatment.
Andersen-Tawil Syndrome
This rare disease is characterized by episodic weakness, THYROID DISORDERS
cardiac arrhythmias, and dysmorphic features (short stature,
scoliosis, clinodactyly, hypertelorism, small or prominent Abnormalities of thyroid function can cause a wide array
low set ears, micrognathia, and broad forehead). The of muscle disorders. These conditions relate to the impor-
cardiac arrhythmias are potentially serious and life threat- tant role of thyroid hormones in regulating the metabolism
ening.They include long QT, ventricular ectopy, bidirec- of carbohydrates and lipids as well as the rate of protein
tional ventricular arrhythmias, and tachycardia. For many synthesis and enzyme production. Thyroid hormones also
years the classication of this disorder was uncertain because stimulate calorigenesis in muscle, increase muscle demand
episodes of weakness are associated with elevated, nor- for vitamins, and enhance muscle sensitivity to circulating
mal, or reduced levels of potassium during an attack. catecholamines.
In addition, the potassium levels differ among kindreds
but are consistent within a family. Inheritance is autoso- Hypothyroidism
mal dominant, with incomplete penetrance and variable Patients with hypothyroidism have frequent muscle com-
expressivity. The disease is caused by mutations of the plaints, and proximal muscle weakness occurs in about
SECTION III

inwardly rectifying potassium channel (Kir 2.1) gene. one-third of them. Muscle cramps, pain, and stiffness are
The treatment is similar to that for other forms of peri- common. Some patients have enlarged muscles. Features
odic paralysis and must include cardiac monitoring. The of slow muscle contraction and relaxation occur in 25%
episodes of weakness may differ between patients because of patients; the relaxation phase of muscle stretch reexes
of potassium variability.Acetazolamide decreases the attack is characteristically prolonged and best observed at the
frequency and severity. ankle or biceps brachii reexes. The serum CK level is
Diseases of the Central Nervous System

often elevated (up to 10 times normal), even when there

CHLORIDE CHANNEL DISORDERS is minimal clinical evidence of muscle disease. EMG is
typically normal. The cause of muscle enlargement has
Two forms of this disorder, autosomal dominant (Thomsens not been determined, and muscle biopsy shows no dis-
disease) and autosomal recessive (Beckers disease) are related tinctive morphologic abnormalities.
to the same gene abnormality. Symptoms are noted in
infancy and early childhood. The severity lessens in the Hyperthyroidism
third to fourth decade. Myotonia is worsened by cold and
improved by activity. The gait may appear slow and Patients who are thyrotoxic commonly have proximal mus-
labored at rst but improves with walking. In Thomsens cle weakness and atrophy on examination, but they rarely
disease muscle strength is normal, but in Beckers, which is complain of myopathic symptoms. Activity of deep tendon
usually more severe, there may be muscle weakness. Mus- reexes may be enhanced. Bulbar, respiratory, and even
cle hypertrophy is usually present. Myotonic discharges are esophageal muscles may occasionally be affected, causing
prominently displayed by EMG recordings. dysphagia, dysphonia, and aspiration.When bulbar involve-
Serum CK is normal or mildly elevated. The muscle ment occurs, it is usually accompanied by chronic proximal
biopsy shows hypertrophied bers.The disease is inherited limb weakness, but occasionally it presents in the absence
as dominant or recessive and is caused by mutations of the of generalized thyrotoxic myopathy. Fasciculations may be
chloride channel gene (Fig. 43-8). Many patients will not apparent and, when coupled with increased muscle stretch
require treatment and learn that the symptoms improve reexes, may lead to an erroneous diagnosis of amyotrophic
with activity. Medications that can be used to decrease lateral sclerosis. Other neuromuscular disorders occur
myotonia include quinine, phenytoin, and mexiletine. in association with hyperthyroidism, including acquired
hypokalemic periodic paralysis, myasthenia gravis, and a
progressive ocular myopathy associated with proptosis
ENDOCRINE AND METABOLIC (Graves ophthalmopathy). Serum CK levels are not elevated
MYOPATHIES in thyrotoxic myopathy, the EMG is normal, and muscle
histology usually shows only atrophy of muscle bers.
Many endocrine disorders cause weakness. Muscle fatigue
is more common than true weakness. The cause of PARATHYROID DISORDERS
weakness in these disorders is not well dened. It is not
Hyperparathyroidism
even clear that weakness results from disease of muscle
as opposed to another part of the motor unit, since the Muscle weakness is an integral part of primary and sec-
serum CK level is often normal (except in hypothy- ondary hyperparathyroidism. Proximal muscle weakness,
roidism) and the muscle histology is characterized by muscle wasting, and brisk muscle stretch reexes are the
main features of this endocrinopathy. Some patients a neuropathy affecting the proximal major nerve trunks 593
develop neck extensor weakness (part of the dropped head and lumbosacral plexus. More appropriate terms for this
syndrome). Serum CK levels are usually normal or slightly disorder include diabetic proximal neuropathy and lum-
elevated. Serum parathyroid hormone levels are elevated. bosacral radiculoplexus neuropathy.
Serum calcium and phosphorus levels show no correlation The only notable myopathy of diabetes mellitus is
with the clinical neuromuscular manifestations. Muscle ischemic infarction of leg muscles, usually involving one
biopsies show only varying degrees of atrophy without of the thigh muscles but on occasion affecting the distal
muscle ber degeneration. leg. This condition occurs in patients with poorly con-
trolled diabetes and presents with abrupt onset of pain,
Hypoparathyroidism tenderness, and edema of one thigh. The area of muscle
infarction is hard and indurated.The muscles most often
An overt myopathy due to hypocalcemia rarely occurs. affected include the vastus lateralis, thigh adductors,
Neuromuscular symptoms are usually related to localized and biceps femoris. CT or MRI can demonstrate focal
or generalized tetany. Serum CK levels may be increased abnormalities in the affected muscle. Diagnosis by imaging
secondary to muscle damage from sustained tetany. is preferable to muscle biopsy, if possible, as hemorrhage
Hyporeexia or areexia is usually present and contrasts into the biopsy site can occur.
with the hyperreexia in hyperparathyroidism.

CHAPTER 43
VITAMIN DEFICIENCY
ADRENAL DISORDERS
Vitamin D deciency due to either decreased intake,
Conditions associated with glucocorticoid excess cause a decreased absorption, or impaired vitamin D metabolism
myopathy; in fact, steroid myopathy is the most commonly (as occurs in renal disease) may lead to chronic muscle
diagnosed endocrine muscle disease. Glucocorticoid excess, weakness. Pain reects the underlying bone disease (osteo-

Muscular Dystrophies and Other Muscle Diseases

either endogenous or exogenous (see Drug-Induced malacia).Vitamin E deciency may result from malabsorp-
Myopathies, below), produces various degrees of proxi- tion. Clinical manifestations include ataxic neuropathy
mal limb weakness. Muscle wasting may be striking. A due to loss of proprioception and myopathy with proxi-
cushingoid appearance usually accompanies clinical signs mal weakness. Progressive external ophthalmoplegia is a
of myopathy. Histologic sections demonstrate muscle ber distinctive nding. It has not been established that de-
atrophy, preferentially affecting type 2b bers, rather than ciency of other vitamins causes a myopathy.
degeneration or necrosis of muscle bers. Adrenal insuf-
ciency commonly causes muscle fatigue.The degree of
weakness may be difcult to assess but is typically mild. MYOPATHIES OF SYSTEMIC ILLNESS
In primary hyperaldosteronism (Conns syndrome), neuro-
muscular complications are due to potassium depletion. Systemic illnesses such as chronic respiratory, cardiac, or
The clinical picture is one of persistent muscle weakness. hepatic failure are frequently associated with severe
Long-standing hyperaldosteronism may lead to proximal muscle wasting and complaints of weakness. Fatigue is
limb weakness and wasting. Serum CK levels may be usually a more signicant problem than weakness, which
elevated, and a muscle biopsy may demonstrate degener- is typically mild.
ating bers, some with vacuoles.These changes relate to Myopathy may be a manifestation of chronic renal
hypokalemia and are not a direct effect of aldosterone failure, independent of the better known uremic polyneu-
on skeletal muscle. ropathy.Abnormalities of calcium and phosphorus home-
ostasis and bone metabolism in chronic renal failure
result from a reduction in 1,25-dihydroxyvitamin D,
PITUITARY DISORDERS
leading to decreased intestinal absorption of calcium.
Patients with acromegaly usually have mild proximal weak- Hypocalcemia, further accentuated by hyperphosphatemia
ness without muscle atrophy. Muscles often appear enlarged due to decreased renal phosphate clearance, leads to sec-
but exhibit decreased force generation. The duration of ondary hyperparathyroidism. Renal osteodystrophy results
acromegaly, rather than the serum growth hormone levels, from the compensatory hyperparathyroidism, which
correlates with the degree of myopathy. leads to osteomalacia from reduced calcium availability
and to osteitis brosa from the parathyroid hormone
excess. The clinical picture of the myopathy of chronic
DIABETES MELLITUS
renal failure is identical to that of primary hyperparathy-
Neuromuscular complications of diabetes mellitus are most roidism and osteomalacia.There is proximal limb weakness
often related to neuropathy, with cranial and peripheral with bone pain.
nerve palsies or distal sensorimotor polyneuropathy. Diabetic Gangrenous calcication represents a separate, rare, and
amyotrophy is a clumsy term since the condition represents sometimes fatal complication of chronic renal failure. In
 594 this condition, widespread arterial calcication occurs and of muscle necrosis are seen, and in severe reactions rhab-
results in ischemia. Extensive skin necrosis may occur, domyolysis and myoglobinuria occur. Concomitant use
along with painful myopathy and even myoglobinuria. of statins with brates and cyclosporine is more likely to
cause adverse reactions than use of one agent alone. A
polymorphism has been identied which increases the
DRUG-INDUCED MYOPATHIES
risk of statin-induced myopathy. Elevated serum CK is an
Drug-induced myopathies are relatively uncommon in important indication of toxicity. Muscle weakness is
clinical practice with the exception of those caused by the accompanied by a myopathic EMG, and muscle necrosis
cholesterol-lowering agents and glucocorticoids. Others is observed by muscle biopsy. Severe myalgias, muscle
impact practice to a lesser degree but are important to weakness, signicant elevations in serum CK (> three
consider in specic situations. Table 43-11 provides a times baseline), and myoglobinuria are indications for
comprehensive list of drug-induced myopathies with their stopping the drug. Patients usually improve with drug
distinguishing features. cessation, although this may take several weeks. Rare
cases continue to progress after the offending agent is
discontinued. It is possible that in such cases the statin
MYOPATHY FROM LIPID-LOWERING may have triggered an immune-mediated necrotizing
AGENTS myopathy, as these individuals may respond to glucocor-
SECTION III

All classes of lipid-lowering agents have been implicated ticoid therapy.

in muscle toxicity including brates (clobrate, gem-
brozil), HMG-CoA reductase inhibitors (referred to as
GLUCOCORTICOID-RELATED MYOPATHIES
statins), niacin (nicotinic acid), and ezetimibe. Myalgia,
malaise, and muscle tenderness are the most common Glucocorticoid myopathy occurs with chronic treatment
manifestations. Muscle pain may be related to exercise. or as acute quadriplegic myopathy secondary to high-
Diseases of the Central Nervous System

Patients may exhibit proximal weakness.Varying degrees dose, IV glucocorticoids. Chronic administration produces

TABLE 43-11
DRUG-INDUCED MYOPATHIES

DRUGS MAJOR TOXIC REACTION

Lipid-lowering agents Drugs belonging to all three of the major classes of lipid-
Fibric acid derivatives lowering agents can produce a spectrum of toxicity: asymp-
HMG-CoA reductase inhibitors tomatic serum creatine kinase elevation, myalgias, exercised-
Niacin (nicotinic acid) induced pain, rhabdomyolysis, and myoglobinuria.
Glucocorticoids Acute, high-dose glucocorticoid treatment can cause acute
quadriplegic myopathy. These high doses of steroids are often
combined with nondepolarizing neuromuscular blocking agents
but the weakness can occur without their use. Chronic steroid
administration produces predominantly proximal weakness.
Nondepolarizing neuromuscular Acute quadriplegic myopathy can occur with or without
blocking agents concomitant glucocorticoids.
Zidovudine Mitochondrial myopathy with ragged red bers.
Drugs of abuse All drugs in this group can lead to widespread muscle
Alcohol breakdown, rhabdomyolysis, and myoglobinuria.
Amphetamines Local injections cause muscle necrosis, skin induration,
Cocaine and limb contractures.
Heroin
Phencyclidine
Meperidine
Autoimmune toxic myopathy Use of this drug may cause polymyositis and myasthenia gravis.
D-Penicillamine
Amphophilic cationic drugs All amphophilic drugs have the potential to produce painless,
Amiodarone proximal weakness associated with autophagic vacuoles in
Chloroquine the muscle biopsy.
Hydroxychloroquine
Antimicrotubular drugs This drug produces painless, proximal weakness especially
Colchicine in the setting of renal failure. Muscle biopsy shows autophagic
vacuoles.
proximal weakness accompanied by cushingoid manifes- to be drug-related, the medication should be stopped or 595
tations, which can be quite debilitating; the chronic use the dosage reduced.
of prednisone at a daily dose of 30 mg/d is most often
associated with toxicity. Patients taking uorinated gluco-
DRUGS OF ABUSE AND
corticoids (triamcinolone, betamethasone, dexamethasone)
RELATED MYOPATHIES
appear to be at especially high risk for myopathy. Patients
receiving high-dose, IV glucocorticoids for status asth- Myotoxicity is a potential consequence of addiction to
maticus, chronic obstructive pulmonary disease, or other alcohol and illicit drugs. Ethanol is one of the most
indications may develop severe generalized weakness. commonly abused substances with potential to damage
Involvement of the diaphragm and intercostal muscles muscle. Other potential toxins include cocaine, heroin,
causes respiratory failure and requires ventilatory support. and amphetamines.The most deleterious reactions occur
In this setting, the use of glucocorticoids in combination from overdosing leading to coma and seizures, causing
with nondepolarizing neuromuscular blocking agents to rhabdomyolysis, myoglobinuria, and renal failure. Direct
further decrease airway resistance is particularly likely to toxicity can occur from cocaine, heroin, and ampheta-
lead to this complication. In chronic steroid myopathy mines causing muscle breakdown and varying degrees of
the serum CK is usually normal. Serum potassium may weakness. The effects of alcohol are more controversial.
be low. The muscle biopsy in chronic cases shows pref- Direct muscle damage is less certain, since toxicity usu-

CHAPTER 43
erential type 2 muscle ber atrophy; this is not reected ally occurs in the setting of poor nutrition and possible
in the EMG, which is usually normal. In acute cases contributing factors such as hypokalemia and hypophos-
with quadriplegic myopathy the muscle biopsy is abnormal, phatemia. Alcoholics are also prone to neuropathy and a
showing a distinctive loss of thick laments (myosin) by variety of CNS disorders (Chap. 50).
electron microscopy. By light microscopy there is focal Focal myopathies from self-administration of meperi-
loss of ATPase staining in central or paracentral areas of dine, heroin, and pentazocine can cause pain, swelling,

Muscular Dystrophies and Other Muscle Diseases

the muscle ber. Calpain stains show diffusely reactive muscle necrosis, and hemorrhage.The cause is multifactor-
atrophic bers.Withdrawal of glucocorticoids will improve ial; needle trauma, direct toxicity of the drug or vehicle,
the chronic myopathy. In acute quadriplegic myopathy, and infection may all play a role.When severe, there may
recovery is slow. Patients require supportive care and be overlying skin induration and contractures with
rehabilitation. replacement of muscle by connective tissue. Elevated serum
CK and myopathic EMG are characteristic of these reac-
tions.The muscle biopsy shows widespread or focal areas
MYOPATHY OF NONDEPOLARIZING
of necrosis. In conditions leading to rhabdomyolysis,
NEUROMUSCULAR BLOCKING AGENTS
patients need adequate hydration to reduce serum myo-
Patients may receive nondepolarizing neuromuscular globin and protect renal function. In all of these condi-
blocking agents because of life-threatening airway resis- tions, counseling is essential to limit drug abuse.
tance. Acute quadriplegic myopathy may result, with or
without glucocorticoid use. The clinical features are
DRUG-INDUCED AUTOIMMUNE
identical to acute quadriplegic myopathy secondary to
MYOPATHIES
glucocorticoids.
The most consistent drug-related inflammatory or
antibody-mediated myopathy is caused by D-penicillamine.
DRUG-INDUCED MITOCHONDRIAL
This drug chelates copper and is used in the treatment of
MYOPATHY
Wilsons disease. It is also used to treat other disorders
Zidovudine, used in the treatment of HIV infection, is a including scleroderma, rheumatoid arthritis, and primary
thymidine analogue that inhibits viral replication by inter- biliary cirrhosis. Adverse events include drug-induced
rupting reverse transcriptase. Myopathy is a well-established polymyositis, indistinguishable from the spontaneous
complication of this agent. Patients present with myalgias, disease. The incidence of this inammatory muscle dis-
muscle weakness, and atrophy affecting the thigh and calf ease is about 1%. Myasthenia gravis is also induced by
muscles.The complication occurs in about 17% of patients d-penicillamine, with a higher incidence estimated at
treated with doses of 1200 mg/d for 6 months. The 7%. These disorders resolve with drug withdrawal,
introduction of protease inhibitors for treatment of HIV although immunosuppressive therapy may be warranted
infection has led to lower doses of zidovudine therapy in severe cases.
and a decreased incidence of myopathy. Serum CK is Scattered reports of other drugs causing an inamma-
elevated and EMG is myopathic. Muscle biopsy shows tory myopathy are rare and include a heterogeneous group
ragged red bers with minimal inammation; the lack of of agents: cimetidine, phenytoin, procainamide, and
inammation serves to distinguish zidovudine toxicity propylthiouracil. In most cases, a cause-and-effect relation-
from HIV-related myopathy. If the myopathy is thought ship is uncertain. A complication of interest was related
 596 to L-tryptophan. In 1989 an epidemic of eosinophilia- GLOVER L, BROWN RH Jr: Dysferlin in membrane trafcking and
myalgia syndrome (EMS) in the United States was caused patch repair.Trafc 8:785, 2007
by a contaminant in the product from one manufacturer. GODFREY C et al: Fukutin mutations in steroid-responsive limb girdle
muscular dystrophy.Ann Neurol 60:603, 2006
The product was withdrawn, and incidence of EMS GROH WJ et al: Electrocardiographic abnormalities and sudden death
diminished abruptly following this action. in myotonic dystrophy type 1. N Engl J Med 358:2688, 2008
GUGLIERI M et al: Limb-girdle muscular dystrophies. Curr Opin Neurol
21:576, 2008
OTHER DRUG-INDUCED MYOPATHIES LUECK JD et al: Chloride channelopathy in myotonic dystrophy
resulting from loss of post-transcriptional regulation for CLCN1.
Certain drugs produce painless, largely proximal, muscle Am J Physiol Cell Physiol 292:C1291, 2007
weakness. These drugs include the amphophilic cationic MENDELL JR et al:The congenital muscular dystrophies: Recent advances
drugs (amiodarone, chloroquine, hydroxychloroquine) and and molecular insights. Pediatr Devel Path 9:427, 2006
antimicrotubular drugs (colchicine) (Table 43-11). Muscle MEOLA G et al: Diagnosis and new treatment in muscle channelopathies.
biopsy can be useful in the identication of toxicity since J Neurol Neurosurg Psychiatry 80:360, 2009
autophagic vacuoles are prominent pathologic features of RANUM LPW, COOPER TA: RNA-mediated neuromuscular disorders.
Ann Rev Neurosci 29:259, 2006
these toxins.
RODINO-KLAPAC LR et al: Gene therapy for Duchenne muscular
dystrophy: Expectations and challenges. Arch Neurol 64:1236,
SECTION III

2007
FURTHER READINGS SAMPAOLESI M et al: Mesangioblast stem cells ameliorate muscle function
BRAIS B: Oculopharyngeal muscular dystrophy: a polyalanine myopathy. in dystrophic dogs. Nature 444:574, 2006
Curr Neurol Neurosci Rep 9:76, 2009 THE SEARCH COLLABORATIVE GROUP: SLCO1B1 variants and
DALAKAS MC:Toxic and drug-induced myopathies. J Neurol Neurosurg statin-induced myopathyA genomewide study. N Engl J Med
Psychiatry 80:832, 2009 359:789, 2008
DAVIES KE, NOWAK KJ: Molecular mechanisms of muscular dystrophies: VAN DE MAAREL SM et al: Facioscapuloperoneal muscular dystrophy.
Diseases of the Central Nervous System

Old and new players. Nat Rev Mol Cell Biol 7:762, 2006 Biochim Biophys Acta 189:697, 2007
DIMAURO S, DAVIDZON G: Mitochondrial DNA and disease. Ann WELCH E et al: PTC124 targets genetic disorders caused by nonsense
Med 37:222, 2005 mutations. Nature 447:87, 2007
 CHAPTER 44
POLYMYOSITIS, DERMATOMYOSITIS,
AND INCLUSION BODY MYOSITIS
Marinos C. Dalakas

Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597

Specic Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Associated Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . 599
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608

The inammatory myopathies represent the largest muscles are spared, even in advanced, untreated cases; if
group of acquired and potentially treatable causes of these muscles are affected, the diagnosis of inammatory
skeletal muscle weakness. They are classied into three myopathy should be questioned. Facial muscles are unaf-
major groups: polymyositis (PM), dermatomyositis fected in PM and DM, but mild facial muscle weakness
(DM), and inclusion body myositis (IBM). is common in patients with IBM. In all forms of inam-
matory myopathy, pharyngeal and neck-exor muscles
are often involved, causing dysphagia or difculty in
CLINICAL FEATURES
holding up the head (head drop). In advanced and rarely
The prevalence of the inammatory myopathies is esti- in acute cases, respiratory muscles may also be affected.
mated at 1 in 100,000. PM as a stand-alone entity is a Severe weakness, if untreated, is almost always associated
rare disease affecting adults. DM affects both children with muscle wasting. Sensation remains normal. The
and adults and women more often than men. IBM is tendon reexes are preserved but may be absent in
three times more frequent in men than in women, more severely weakened or atrophied muscles, especially in
common in whites than blacks, and is most likely to IBM where atrophy of the quadriceps and the distal
affect persons >50 years of age. muscles is common. Myalgia and muscle tenderness
These disorders present as progressive and symmetric may occur in a small number of patients, usually early
muscle weakness except for IBM, which can have an in the disease, and particularly in DM associated with
asymmetric pattern. Patients usually report increasing connective tissue disorders. Weakness in PM and DM
difculty with everyday tasks requiring the use of proxi- progresses subacutely over a period of weeks or months
mal muscles, such as getting up from a chair, climbing and rarely acutely; by contrast, IBM progresses very
steps, stepping onto a curb, lifting objects, or combing slowly, over years, simulating a late-life muscular dystro-
hair. Fine-motor movements that depend on the phy (Chap. 43) or slowly progressive motor neuron dis-
strength of distal muscles, such as buttoning a shirt, order (Chap. 27).
sewing, knitting, or writing, are affected only late in the
course of PM and DM, but fairly early in IBM. Falling is
SPECIFIC FEATURES
common in IBM because of early involvement of the
quadriceps muscle with buckling of the knees. Ocular (Table 44-1)

597
 598 TABLE 44-1
FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES

CHARACTERISTIC POLYMYOSITIS DERMATOMYOSITIS INCLUSION BODY MYOSITIS

Age at onset >18 years Adulthood and childhood >50 years

Familial association No No Yes, in some cases
Extramuscular manifestations Yes Yes Yes
Associated conditions
Connective tissue diseases Yesa Scleroderma and mixed Yes, in up to 20% of casesa
connective tissue disease
(overlap syndromes)
Systemic autoimmune Frequent Infrequent Infrequent
diseasesb
Malignancy No Yes, in up to 15% of cases No
Viruses Yesc Unproven Yesc
Drugsd Yes Yes, rarely No
Parasites and bacteriae Yes No No
SECTION III

a
Systemic lupus erythematosus, rheumatoid arthritis, Sjgrens syndrome, systemic sclerosis, mixed connective tissue disease.
b
Crohns disease, vasculitis, sarcoidosis, primary biliary cirrhosis, adult celiac disease, chronic graft-versus-host disease, discoid lupus, ankylos-
ing spondylitis, Behets syndrome, myasthenia gravis, acne fulminans, dermatitis herpetiformis, psoriasis, Hashimotos disease, granulomatous
diseases, agammaglobulinemia, monoclonal gammopathy, hypereosinophilic syndrome, Lyme disease, Kawasaki disease, autoimmune throm-
bocytopenia, hypergammaglobulinemic purpura, hereditary complement deciency, IgA deciency.
c
HIV (human immunodeciency virus) and HTLV-I (human T cell lymphotropic virus type I).
d
Drugs include penicillamine (dermatomyositis and polymyositis), zidovudine (polymyositis), and contaminated tryptophan (dermatomyositis-like
illness). Other myotoxic drugs may cause myopathy but not an inammatory myopathy (see text for details).
Diseases of the Central Nervous System

e
Parasites (protozoa, cestodes, nematodes), tropical and bacterial myositis (pyomyositis).

Polymyositis violaceous scaly eruption (Gottrons sign). The erythema-

tous rash can also occur on other body surfaces, including
The actual onset of PM is often not easily determined,
the knees, elbows, malleoli, neck and anterior chest (often
and patients typically delay seeking medical advice for
in a V sign), or back and shoulders (shawl sign), and may
several months. This is in contrast to DM, in which the
worsen after sun exposure. In some patients the rash is
rash facilitates early recognition (see later). PM mimics
pruritic, especially on the scalp, chest, and back. Dilated
many other myopathies and is a diagnosis of exclusion.
capillary loops at the base of the ngernails are also char-
It is a subacute inammatory myopathy affecting adults,
acteristic. The cuticles may be irregular, thickened, and dis-
and rarely children, who do not have any of the follow-
torted, and the lateral and palmar areas of the ngers may
ing: rash, involvement of the extraocular and facial mus-
become rough and cracked, with irregular, dirty hori-
cles, family history of a neuromuscular disease, history of
zontal lines, resembling mechanics hands.The weakness can
exposure to myotoxic drugs or toxins, endocrinopathy,
be mild, moderate, or severe enough to lead to quadri-
neurogenic disease, muscular dystrophy, biochemical
paresis. At times, the muscle strength appears normal,
muscle disorder (deciency of a muscle enzyme), or
hence the term dermatomyositis sine myositis. When muscle
IBM as excluded by muscle biopsy analysis (see later). As
biopsy is performed in such cases, however, signicant
an isolated entity, PM is a rare (and overdiagnosed) dis-
perivascular and perimysial inammation is often seen.
order; more commonly, PM occurs in association with a
DM usually occurs alone but may overlap with scle-
systemic autoimmune or connective tissue disease, or
roderma and mixed connective tissue disease. Fasciitis
with a known viral or bacterial infection. Drugs, espe-
and thickening of the skin, similar to that seen in
cially d-penicillamine or zidovudine (AZT), may also
chronic cases of DM, have occurred in patients with the
produce an inammatory myopathy similar to PM.
eosinophilia-myalgia syndrome associated with the inges-
tion of contaminated l-tryptophan.
Dermatomyositis
Inclusion Body Myositis
DM is a distinctive entity identied by a characteristic rash
accompanying, or more often preceding, muscle weakness. In patients 50 years, IBM is the most common of the
The rash may consist of a blue-purple discoloration on the inammatory myopathies. It is often misdiagnosed as PM
upper eyelids with edema, a at red rash on the face and and is suspected only later when a patient with presumed
upper trunk, and erythema of the knuckles with a raised PM does not respond to therapy. Weakness and atrophy
of the distal muscles, especially foot extensors and deep itself or from hypertension associated with long- 599
nger exors, occur in almost all cases of IBM and may term use of glucocorticoids.
be a clue to early diagnosis. Some patients present with 5. Pulmonary dysfunction, due to weakness of the tho-
falls because their knees collapse due to early quadriceps racic muscles, interstitial lung disease, or drug-
weakness. Others present with weakness in the small induced pneumonitis (e.g., from methotrexate),
muscles of the hands, especially nger exors, and com- which may cause dyspnea, nonproductive cough,
plain of inability to hold objects such as golf clubs or and aspiration pneumonia. Interstitial lung disease
perform tasks such as turning keys or tying knots. On may precede myopathy or occur early in the disease
occasion, the weakness and accompanying atrophy can and develops in up to 10% of patients with PM or
be asymmetric and selectively involve the quadriceps, DM, most of whom have antibodies to t-RNA syn-
iliopsoas, triceps, biceps, and nger exors, resembling a thetases, as described below.
lower motor neuron disease. Dysphagia is common, 6. Subcutaneous calcications, in DM, sometimes extrud-
occurring in up to 60% of IBM patients, and may lead to ing on the skin and causing ulcerations and
episodes of choking. Sensory examination is generally infections.
normal; some patients have mildly diminished vibratory 7. Arthralgias, synovitis, or deforming arthropathy with
sensation at the ankles that presumably is age-related.The subluxation in the interphalangeal joints can occur
pattern of distal weakness, which supercially resembles in some patients with DM and PM who have Jo-1

CHAPTER 44
motor neuron or peripheral nerve disease, results from antibodies (see later).
the myopathic process affecting distal muscles selectively.
Disease progression is slow but steady, and most patients Association with Malignancies
require an assistive device such as cane, walker, or wheel-
chair within several years of onset. Although all the inammatory myopathies can have a
In at least 20% of cases, IBM is associated with systemic chance association with malignant lesions, especially in

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

autoimmune or connective tissue diseases. Familial aggre- older age groups, the incidence of malignant conditions
gation of typical IBM may occur; such cases have been appears to be specically increased only in patients with
designated as familial inammatory IBM.This disorder is dis- DM and not in those with PM or IBM.The most com-
tinct from hereditary inclusion body myopathy (h-IBM), mon tumors associated with DM are ovarian cancer,
which describes a heterogeneous group of recessive, and breast cancer, melanoma, colon cancer, and non-
less frequently dominant, inherited syndromes; the h-IBMs Hodgkin lymphoma. The extent of the search that
are noninammatory myopathies. A subset of h-IBM that should be conducted for an occult neoplasm in adults
spares the quadriceps muscles has emerged as a distinct with DM depends on the clinical circumstances.Tumors
entity. This disorder, originally described in Iranian Jews in these patients are usually uncovered by abnormal
and now seen in many ethnic groups, is linked to chromo- ndings in the medical history and physical examination
some 9p1 and results from mutations in the UDP- and not through an extensive blind search. The weight
N-acetylglucosamine 2-epimerase/N-acetylmannosamine of evidence argues against performing expensive, inva-
kinase (GNE) gene. sive, and nondirected tumor searches. A complete annual
physical examination with pelvic, breast (mammogram,
if indicated), and rectal examinations (with colonoscopy
ASSOCIATED CLINICAL FINDINGS
according to age and family history); urinalysis; com-
Extramuscular Manifestations plete blood count; blood chemistry tests; and a chest
These may be present to a varying degree in patients lm should sufce in most cases. In Asians, nasopharyn-
with PM or DM, and include: geal cancer is common, and a careful examination of
ears, nose, and throat is indicated.
1. Systemic symptoms, such as fever, malaise, weight loss,
arthralgia, and Raynauds phenomenon, especially
Overlap Syndromes
when inammatory myopathy is associated with a
connective tissue disorder. These describe the association of inammatory myopathies
2. Joint contractures, mostly in DM and especially in with connective tissue diseases. A well-characterized over-
children. lap syndrome occurs in patients with DM who also have
3. Dysphagia and gastrointestinal symptoms, due to manifestations of systemic sclerosis or mixed connective tis-
involvement of oropharyngeal striated muscles and sue disease, such as sclerotic thickening of the dermis, con-
upper esophagus, especially in DM and IBM. tractures, esophageal hypomotility, microangiopathy, and
4. Cardiac disturbances, including atrioventricular con- calcium deposits (Table 44-1). By contrast, signs of rheuma-
duction defects, tachyarrhythmias, dilated cardiomy- toid arthritis, systemic lupus erythematosus, or Sjgrens
opathy, a low ejection fraction, and congestive heart syndrome are very rare in patients with DM. Patients with
failure, may rarely occur, either from the disease the overlap syndrome of DM and systemic sclerosis may
 600 have a specic antinuclear antibody, the anti-PM/Scl, hypoperfusion that is prominent in the periphery of the
directed against a nucleolar-protein complex. muscle fascicles.
By contrast, in PM and IBM a mechanism of T
cellmediated cytotoxicity is likely. CD8 T cells, along
PATHOGENESIS
with macrophages, initially surround and eventually
An autoimmune etiology of the inammatory myopathies invade and destroy healthy, nonnecrotic muscle bers
is indirectly supported by an association with other auto- that aberrantly express class I MHC molecules. MHC-I
immune or connective tissue diseases; the presence of various expression, absent from the sarcolemma of normal mus-
autoantibodies; an association with specic major histo- cle bers, is probably induced by cytokines secreted by
compatibility complex (MHC) genes; demonstration of T activated T cells and macrophages. The CD8/MHC-I
cellmediated myocytotoxicity or complement-mediated complex is characteristic of PM and IBM; its detection
microangiopathy; and a response to immunotherapy. can aid in conrming the histologic diagnosis of PM, as
discussed below.The cytotoxic CD8 T cells contain per-
Autoantibodies and Immunogenetics forin and granzyme granules directed towards the sur-
face of the muscle bers and capable of inducing
Various autoantibodies against nuclear antigens (antinu- myonecrosis. Analysis of T cell receptor molecules
clear antibodies) and cytoplasmic antigens are found in expressed by the inltrating CD8 cells have revealed
SECTION III

up to 20% of patients with inammatory myopathies. clonal expansion and conserved sequences in the anti-
The antibodies to cytoplasmic antigens are directed gen-binding region, both suggesting an antigen-driven
against ribonucleoproteins involved in protein synthesis T cell response. Whether the putative antigens are
(anti-synthetases) or translational transport (anti-signal- endogenous (e.g., muscle) or exogenous (e.g., viral)
recognition particles). The antibody directed against sequences is unknown.Viruses have not been identied
the histidyl-transfer RNA synthetase, called anti-Jo-1, within the muscle bers. Co-stimulatory molecules and
accounts for 75% of all the anti-synthetases and is clini-
Diseases of the Central Nervous System

their counterreceptors, which are fundamental for T cell

cally useful because up to 80% of patients with anti-Jo-1 activation and antigen recognition, are strongly upregu-
antibodies have interstitial lung disease. Some patients lated in PM and IBM. Key molecules involved in T
with the anti-Jo-1 antibody also have Raynauds phe- cellmediated cytotoxicity are depicted in Fig. 44-2.
nomenon, nonerosive arthritis, and the MHC molecules
DR3 and DRw52. DR3 haplotypes (molecular designa-
tion DRB10301, DQB10201) occur in up to 75% of The Role of Nonimmune Factors in IBM
patients with PM and IBM, whereas in juvenile DM In IBM, the presence of -amyloid deposits within vac-
there is an increased frequency of DQA10501. uolated muscle bers and abnormal mitochondria with
cytochrome oxidasenegative bers suggest that, in
Immunopathologic Mechanisms addition to the autoimmune component, there is also a
degenerative process. Similar to Alzheimers disease, the
In DM, humoral immune mechanisms are implicated, amyloid deposits in IBM are immunoreactive against
resulting in a microangiopathy and muscle ischemia amyloid precursor protein (APP), chymotrypsin,
(Fig. 44-1). Endomysial inammatory inltrates are apolipoprotein E, and phosphorylated tau, but it is
composed of B cells located in proximity to CD4 T cells, unclear whether these deposits are directly pathogenic
dendritic cells, and macrophages; there is a relative or represent secondary phenomena.The same is true for
absence of lymphocytic invasion of nonnecrotic muscle the mitochondrial abnormalities, which may also be sec-
bers. Activation of the complement C5b-9 membra- ondary to the effects of aging or a bystander effect of
nolytic attack complex is thought to be a critical early upregulated cytokines. Expression of cytokines and
event that triggers release of proinammatory cytokines upregulation of MHC class I by the muscle bers may
and chemokines, induces expression of vascular cell cause an endoplasmic reticulum stress response resulting
adhesion molecule (VCAM) 1 and intracellular adhesion in intracellular accumulation of misfolded glycoproteins
molecule (ICAM) 1 on endothelial cells, and facilitates and activation of nuclear factor B (NFB), leading to
migration of activated lymphoid cells to the perimysial further cytokine activation.
and endomysial spaces. Necrosis of the endothelial cells,
reduced numbers of endomysial capillaries, ischemia, and
muscle-ber destruction resembling microinfarcts occur. Association with Viral Infections and the Role
of Retroviruses
The remaining capillaries often have dilated lumens in
response to the ischemic process. Larger intramuscular Several viruses, including coxsackieviruses, inuenza,
blood vessels may also be affected in the same pattern. paramyxoviruses, mumps, cytomegalovirus, and Epstein-
Residual perifascicular atrophy reects the endofascicular Barr virus, have been indirectly associated with myositis.
 Molecular mimicry, 601
tumors, viruses?

C1 C3a
C4
C2 Cytokines Macrophage
C3 C3b
B
C3 B cell T cell T cell Chemokines
D MAC
LFA-1 VLA-4 Mac-1

ICAM-1 VCAM-1 ICAM-1

MAC

C3bNEO
B cell
T cell

Cytokines
NO, TNF-

CHAPTER 44
STAT-1, Chemokines,
Cathepsin, TGF-

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

FIGURE 44-1
Immunopathogenesis of dermatomyositis. Activation of B cells, CD4 T cells, and macrophages trafc from the circu-
complement, possibly by autoantibodies (Y), against lation to the muscle. Endothelial expression of vascular cell
endothelial cells and formation of C3 via the classic or alter- adhesion molecule (VCAM) and intercellular adhesion mole-
native pathway. Activated C3 leads to formation of C3b, cule (ICAM) is induced by cytokines released by the
C3bNEO, and membrane attack complexes (MAC), which mononuclear cells. Integrins, specically very late activation
are deposited in and around the endothelial cell wall of the antigen (VLA)-4 and leukocyte function-associated antigen
endomysial capillaries. Deposition of MAC leads to destruc- (LFA)-1, bind VCAM and ICAM and promote T cell and
tion of capillaries, ischemia, or microinfarcts most prominent macrophage inltration of muscle through the endothelial
in the periphery of the fascicles, and perifascicular atrophy. cell wall.

For the coxsackieviruses, an autoimmune myositis trig- disease course. Retroviral antigens have been detected
gered by molecular mimicry has been proposed because only in occasional endomysial macrophages and not
of structural homology between histidyl-transfer RNA within the muscle bers themselves, suggesting that per-
synthetase that is the target of the Jo-1 antibody (see ear- sistent infection and viral replication within the muscle
lier) and genomic RNA of an animal picornavirus, the does not occur. Histologic ndings are identical to
encephalomyocarditis virus. Sensitive polymerase chain retroviral-negative PM or IBM. The inltrating T cells
reaction (PCR) studies, however, have repeatedly failed to in the muscle are clonally driven and a number of them
conrm the presence of such viruses in muscle biopsies. are retroviral-specic. This disorder should be distin-
The best evidence of a viral connection in PM and guished from a toxic myopathy related to long-term
IBM is with the retroviruses. Some individuals infected therapy with AZT, characterized by fatigue, myalgia,
with HIV or with human T cell lymphotropic virus I mild muscle weakness, and mild elevation of creatine
(HTLV-I) develop PM or IBM; a similar disorder has kinase (CK). AZT-induced myopathy, which generally
been described in nonhuman primates infected with the improves when the drug is discontinued, is a mitochon-
simian immunodeciency virus. The inammatory drial disorder characterized histologically by ragged-
myopathy may occur as the initial manifestation of a red bers. AZT inhibits -DNA polymerase, an enzyme
retroviral infection, or myositis may develop later in the found solely in the mitochondrial matrix.
 602 Antigen
Macrophage
Systemic immune compartment

Co-stimulation MHC
TCR Clonal expansion
CD8
Infection?
CD8

Integrins
Chemokines VCAM-1
LFA-4
(MCP-1, Mig, IP-10) MMPs
CD8 CD8
Cytokines
IFN- TNF-
IL-1, 2
MMP-9
CD28 CTLA-4 LFA-1
TCR IFN-
BB1 ICAM-1 MMP-9
MMP-2 TFN-
SECTION III

MHC-I Perforin IL-1, 2

Calnexin
MHC-I
Ag Necrosis
(virus, muscle
peptide) TAP 2m
Diseases of the Central Nervous System

Endoplasmic reticulum

FIGURE 44-2
Cell-mediated mechanisms of muscle damage in of T cells and their attachment to the muscle surface. Muscle
polymyositis (PM) and inclusion body myositis (IBM). ber necrosis occurs via perforin granules released by the
Antigen-specic CD8 cells are expanded in the periphery, autoaggressive T cells. A direct myocytotoxic effect exerted
cross the endothelial barrier, and bind directly to muscle bers by the cytokines interferon (IFN) , interleukin (IL) 1, or tumor
via T cell receptor (TCR) molecules that recognize aberrantly necrosis factor (TNF) may also play a role. Death of the mus-
expressed MHC-I. Engagement of co-stimulatory molecules cle ber is mediated by necrosis. MHC class I molecules con-
(BB1 and ICOSL) with their ligands (CD28, CTLA-4, and ICOS) sist of a heavy chain and a light chain [2 microglobulin (2m)]
along with ICAM-1/LFA-1, stabilize the CD8muscle ber complexed with an antigenic peptide that is transported into
interaction. Metalloproteinases (MMP) facilitate the migration the endoplasmic reticulum by TAP proteins.

DIFFERENTIAL DIAGNOSIS rarely present after the age of 30. It may be difcult,
even with a muscle biopsy, to distinguish chronic PM
The clinical picture of the typical skin rash and proximal
from a rapidly advancing muscular dystrophy. This is
or diffuse muscle weakness has few causes other than
particularly true of facioscapulohumeral muscular dys-
DM. However, proximal muscle weakness without skin
trophy, dysferlin myopathy, and the dystrophinopathies
involvement can be due to many conditions other than
where inammatory cell inltration is often found early
PM or IBM.
in the disease. Such doubtful cases should always be
given an adequate trial of glucocorticoid therapy and
Subacute or Chronic Progressive undergo genetic testing to exclude muscular dystrophy.
Muscle Weakness
Identication of the MHC/CD8 lesion by muscle
This may be due to denervating conditions such as the biopsy is helpful to identify cases of PM. Some meta-
spinal muscular atrophies or amyotrophic lateral sclerosis bolic myopathies, including glycogen storage disease due
(Chap. 27). In addition to the muscle weakness, upper to myophosphorylase or acid maltase deciency, lipid
motor neuron signs in the latter and signs of denerva- storage myopathies due to carnitine deciency, and
tion detected by electromyography (EMG) aid in the mitochondrial diseases produce weakness that is often
diagnosis. The muscular dystrophies (Chap. 43) may be associated with other characteristic clinical signs; diag-
additional considerations; however, these disorders usu- nosis rests upon histochemical and biochemical studies
ally develop over years rather than weeks or months and of the muscle biopsy. The endocrine myopathies such as
those due to hypercorticosteroidism, hyper- and syndrome, contaminated l-tryptophan) or with muta- 603
hypothyroidism, and hyper- and hypoparathyroidism tions in the calpain gene. A distinct subset of myofasciitis
require the appropriate laboratory investigations for is characterized by pronounced inltration of the con-
diagnosis. Muscle wasting in patients with an underlying nective tissue around the muscle by sheets of periodic
neoplasm may be due to disuse, cachexia, or rarely to a acidSchiff-positive macrophages and occasional CD8 T
paraneoplastic neuromyopathy (Chap. 39). cells (macrophagic myofasciitis). Such histologic involve-
Diseases of the neuromuscular junction, including ment is focal and limited to sites of previous vaccina-
myasthenia gravis or the Lambert-Eaton myasthenic tions, which may have been administered months or
syndrome, cause fatiguing weakness that also affects ocu- years earlier. This disorder, which to date has not been
lar and other cranial muscles (Chap. 42). Repetitive observed outside of France, has been linked to an alu-
nerve stimulation and single-ber EMG studies aid in minum-containing substrate in vaccines. Most patients
diagnosis. respond to glucocorticoid therapy, and the overall prog-
nosis seems favorable.
Acute Muscle Weakness
Necrotizing Myositis
This may be caused by an acute neuropathy such as
Guillain-Barr syndrome (Chap. 41), transverse myelitis This is an increasingly recognized entity that has distinct

CHAPTER 44
(Chap. 30), a neurotoxin, or a neurotropic viral infection features, even though it is often labeled as PM. It pre-
such as poliomyelitis or West Nile virus (Chap. 35).When sents often in the fall or winter as an acute or subacute
acute weakness is associated with painful muscle cramps, onset of symmetric muscle weakness; CK is typically
rhabdomyolysis, and myoglobinuria, it may be due to a extremely high. The weakness can be severe. Coexisting
viral infection or a metabolic disorder such as myophos- interstitial lung disease and cardiomyopathy may be pre-
phorylase deciency or carnitine palmitoyltransferase sent. The disorder may develop after a viral infection or

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

deciency (Chap. 43). Several animal parasites, including in association with cancer. Some patients have antibod-
protozoa (toxoplasma, trypanosoma), cestodes (cysticerci), ies against signal recognition particle (SRP).The muscle
and nematodes (trichinae), may produce a focal or diffuse biopsy demonstrates necrotic bers inltrated by
inammatory myopathy known as parasitic polymyositis. macrophages but only rare, if any,T cell inltrates. Muscle
Staphylococcus aureus, Yersinia, Streptococcus, or anaerobic MHC-I expression is only slightly and focally upregu-
bacteria may produce a suppurative myositis, known as lated. The capillaries may be swollen with hyalinization,
tropical polymyositis, or pyomyositis. Pyomyositis, previously thickening of the capillary wall, and deposition of com-
rare in the west, is now occasionally seen in AIDS plement. Some patients respond to immunotherapy, but
patients. Other bacteria, such as Borrelia burgdorferi (Lyme others are resistant.
disease) and Legionella pneumophila (Legionnaires disease)
may infrequently cause myositis. Drug-Induced Myopathies
Patients with periodic paralysis experience recurrent
episodes of acute muscle weakness without pain, always D-Penicillamine and procainamide may produce a true
beginning in childhood. Chronic alcoholics may develop myositis resembling PM, and a DM-like illness had
painful myopathy with myoglobinuria after a bout of been associated with the contaminated preparations of
heavy drinking. Acute painless muscle weakness with l-tryptophan. As noted above, AZT causes a mitochon-
myoglobinuria may occur with prolonged hypokalemia, drial myopathy. Other drugs may elicit a toxic nonin-
or hypophosphatemia and hypomagnesemia, usually in ammatory myopathy that is histologically different
chronic alcoholics or in patients on nasogastric suction from DM, PM, or IBM. These include cholesterol-
receiving parenteral hyperalimentation. lowering agents such as clobrate, lovastatin, simvas-
tatin, or pravastatin, especially when combined with
cyclosporine or gembrozil. Rhabdomyolysis and myo-
Myofasciitis
globinuria have been rarely associated with ampho-
This distinctive inammatory disorder affecting muscle tericin B, -aminocaproic acid, fenuramine, heroin,
and fascia presents as diffuse myalgias, skin induration, and phencyclidine.The use of amiodarone, chloroquine,
fatigue, and mild muscle weakness; mild elevations of colchicine, carbimazole, emetine, etretinate, ipecac
serum CK are usually present. The most common form syrup, chronic laxative or licorice use resulting in
is eosinophilic myofasciitis characterized by peripheral hypokalemia, and glucocorticoids or growth hormone
blood eosinophilia and eosinophilic inltrates in the administration have also been associated with myo-
endomysial tissue. In some patients, the eosinophilic pathic muscle weakness. Some neuromuscular blocking
myositis/fasciitis occurs in the context of parasitic infec- agents such as pancuronium, in combination with gluco-
tions, vasculitis, mixed connective tissue disease, hypere- corticoids, may cause an acute critical illness myopathy. A
osinophilic syndrome, or toxic exposures (e.g., toxic oil careful drug history is essential for diagnosis of these
 604 drug-induced myopathies, which do not require biopsy is usually normal or nonspecic. Many such
immunosuppressive therapy. patients show some response to nonsteroidal anti-
inammatory agents or glucocorticoids, though most
Weakness Due to Muscle Pain continue to have indolent complaints. An indolent fasci-
and Muscle Tenderness itis in the setting of an ill-dened connective tissue dis-
order may be present, and these patients should not be
A number of conditions including polymyalgia rheumatica labeled as having a psychosomatic disorder. Chronic
and arthritic disorders of adjacent joints may enter into fatigue syndrome, which may follow a viral infection, can
the differential diagnosis of inammatory myopathy, present with debilitating fatigue, fever, sore throat,
even though they do not cause myositis. The muscle painful lymphadenopathy, myalgia, arthralgia, sleep dis-
biopsy is either normal or discloses type II muscle ber order, and headache (Chap. 47). These patients do not
atrophy. Patients with brositis and bromyalgia complain have muscle weakness, and the muscle biopsy is normal.
of focal or diffuse muscle tenderness, fatigue, and aching,
which is sometimes poorly differentiated from joint
pain. Some patients, however, have muscle tenderness, DIAGNOSIS
painful muscles on movement, and signs suggestive of a The clinically suspected diagnosis of PM, DM, or IBM
collagen vascular disorder, such as an increased erythro- is conrmed by examining the serum muscle enzymes,
SECTION III

cyte sedimentation rate, C-reactive protein, antinuclear EMG ndings, and muscle biopsy (Table 44-2).
antibody, or rheumatoid factor, along with modest ele- The most sensitive enzyme is CK, which in active
vation of the serum CK and aldolase. They demonstrate disease can be elevated as much as 50-fold. Although the
a give-way pattern of weakness with difculty sustain- CK level usually parallels disease activity, it can be nor-
ing effort but not true muscle weakness. The muscle mal in some patients with active IBM or DM, especially
Diseases of the Central Nervous System

TABLE 44-2
CRITERIA FOR DIAGNOSIS OF INFLAMMATORY MYOPATHIES

POLYMYOSITIS
INCLUSION BODY
CRITERION DEFINITE PROBABLE DERMATOMYOSITIS MYOSITIS

Myopathic muscle Yes Yes Yesb Yes; slow onset,

weaknessa early involvement
of distal muscles,
frequent falls
Electromyographic Myopathic Myopathic Myopathic Myopathic with
ndings mixed potentials
Muscle enzymes Elevated (up to Elevated (up to Elevated (up to Elevated (up to
50-fold) 50-fold) 50-fold) or normal 10-fold) or normal
Muscle biopsy Primary inammation Ubiquitous MCH-I Perifascicular, perimysial, Primary inammation
ndingsc with the CD8/MHC-I expression but or perivascular inltrates, with CD8/MHC-I
complex and no minimal inammation perifascicular atrophy complex; vacuolated
vacuoles and no vacuolesd bers with -amyloid
deposits; cytochrome
oxygenasenegative
bers; signs of
chronic myopathye
Rash or calcinosis Absent Absent Presentf Absent

a
Myopathic muscle weakness, affecting proximal muscles more than distal ones and sparing eye and facial muscles, is characterized by a suba-
cute onset (weeks to months) and rapid progression in patients who have no family history of neuromuscular disease, no endocrinopathy, no
exposure to myotoxic drugs or toxins, and no biochemical muscle disease (excluded on the basis of muscle-biopsy ndings).
b
In some cases with the typical rash, the muscle strength is seemingly normal (dermatomyositis sine myositis); these patients often have new
onset of easy fatigue and reduced endurance. Careful muscle testing may reveal mild muscle weakness.
c
See text for details.
d
An adequate trial of prednisone or other immunosuppressive drugs is warranted in probable cases. If, in retrospect, the disease is unresponsive
to therapy, another muscle biopsy should be considered to exclude other diseases or possible evolution in inclusion body myositis.
e
If the muscle biopsy does not contain vacuolated bers but shows chronic myopathy with hypertrophic bers, primary inammation with the
CD8/MHC-I complex and cytochrome oxygenasenegative bers, the diagnosis is probable inclusion body myositis.
f
If rash is absent but muscle biopsy ndings are characteristic of dermatomyositis, the diagnosis is probable DM.
 605

FIGURE 44-4
FIGURE 44-3 Cross section of a muscle biopsy from a patient with der-

CHAPTER 44
Cross section of a muscle biopsy from a patient with matomyositis demonstrates atrophy of the bers at the
polymyositis demonstrates scattered inammatory foci with periphery of the fascicle (perifascicular atrophy).
lymphocytes invading or surrounding muscle bers. Note
lack of chronic myopathic features (increased connective tis-
sue, atrophic or hypertrophic bers) as seen in inclusion
body myositis.
ubiquitously expressed on the sarcolemma, even in

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

bers not invaded by CD8+ cells. The CD8/MHC-I
lesion is now fundamental for conrming or establishing
when associated with a connective tissue disease. The the diagnosis and to exclude disorders with secondary,
CK is always elevated in patients with active PM. Along nonspecic, inammation. When the disease is chronic,
with the CK, the serum glutamic-oxaloacetic and gluta- connective tissue is increased and may react positively
mate pyruvate transaminases, lactate dehydrogenase, and with alkaline phosphatase.
aldolase may be elevated. In DM the endomysial inammation is predominantly
Needle EMG shows myopathic potentials character- perivascular or in the interfascicular septae and around,
ized by short-duration, low-amplitude polyphasic units rather than within, the muscle fascicles (Fig. 44-4). The
on voluntary activation and increased spontaneous activ- intramuscular blood vessels show endothelial hyperplasia
ity with brillations, complex repetitive discharges, and with tubuloreticular proles, brin thrombi, and oblitera-
positive sharp waves. Mixed potentials (polyphasic units tion of capillaries. The muscle bers undergo necrosis,
of short and long duration) indicating a chronic process degeneration, and phagocytosis, often in groups involv-
and muscle ber regeneration are often present in IBM. ing a portion of a muscle fasciculus in a wedge-like
These EMG ndings are not diagnostic of an inamma- shape or at the periphery of the fascicle, due to microin-
tory myopathy but are useful to identify the presence of farcts within the muscle. This results in perifascicular
active or chronic myopathy and to exclude neurogenic atrophy, characterized by 210 layers of atrophic bers at
disorders. the periphery of the fascicles.The presence of perifascic-
MRI is not routinely used for the diagnosis of PM, ular atrophy is diagnostic of DM, even in the absence of
DM, or IBM. However, it may guide the location of the inammation.
muscle biopsy in certain clinical settings. In IBM (Fig. 44-5), there is endomysial inammation
Muscle biopsy is the denitive test for establishing the with T cells invading MHC-I-expressing nonvacuolated
diagnosis of inammatory myopathy and for excluding muscle bers; basophilic granular deposits distributed
other neuromuscular diseases. Inammation is the histo- around the edge of slitlike vacuoles (rimmed vacuoles);
logic hallmark for these diseases; however, additional fea- loss of bers, replaced by fat and connective tissue,
tures are characteristic of each subtype (Figs. 44-3, 44-4, hypertrophic bers, and angulated or round bers;
and 44-5). eosinophilic cytoplasmic inclusions; abnormal mito-
In PM the inflammation is primary, a term used to chondria characterized by the presence of ragged-red
indicate that T cell infiltrates, located primarily within bers or cytochrome oxidasenegative bers; amyloid
the muscle fascicles (endomysially), surround individ- deposits within or next to the vacuoles; and lamentous
ual, healthy muscle fibers and result in phagocytosis inclusions seen by electron microscopy in the vicinity of
and necrosis (Fig. 44-3). The MHC-I molecule is the rimmed vacuoles.
 606
SECTION III
Diseases of the Central Nervous System

FIGURE 44-5
Cross sections of a muscle biopsy from a patient with amyloid visualized with crystal violet (B), cytochrome oxi-
inclusion body myositis demonstrate the typical features of dase-negative bers, indicative of mitochondrial dysfunction
vacuoles with lymphocytic inltrates surrounding nonvacuo- (C), and ubiquitous MHC-I expression at the periphery of all
lated or necrotic bers (A), tiny endomysial deposits of bers (D).

1. Glucocorticoids. Oral prednisone is the initial treat-

Treatment:
ment of choice; the effectiveness and side effects of
INFLAMMATORY MYOPATHIES
this therapy determine the future need for stronger
The goal of therapy is to improve muscle strength, immunosuppressive drugs. High-dose prednisone, at
thereby improving function in activities of daily living, least 1 mg/kg per day, is initiated as early in the
and ameliorate the extramuscular manifestations (rash, disease as possible. After 34 weeks, prednisone is
dysphagia, dyspnea, fever). When strength improves, the tapered slowly over a period of 10 weeks to 1 mg/kg
serum CK falls concurrently; however, the reverse is not every other day. If there is evidence of efcacy and no
always true. Unfortunately, there is a common tendency serious side effects, the dosage is then further
to chase or treat the CK level instead of the muscle reduced by 5 or 10 mg every 34 weeks until the low-
weakness, a practice that has led to prolonged and est possible dose that controls the disease is reached.
unnecessary use of immunosuppressive drugs and erro- The efcacy of prednisone is determined by an
neous assessment of their efcacy. It is prudent to dis- objective increase in muscle strength and activities
continue these drugs if, after an adequate trial, there is of daily living, which almost always occurs by the
no objective improvement in muscle strength whether third month of therapy. A feeling of increased energy
or not CK levels are reduced. Agents used in the treat- or a reduction of the CK level without a concomitant
ment of PM and DM include:
 increase in muscle strength is not a reliable sign of 3. Immunomodulation. In a controlled trial of patients 607
improvement. If prednisone provides no objective with refractory DM, intravenous immunoglobulin
benet after ~3 months of high-dose therapy, the (IVIg) improved not only strength and rash but also
disease is probably unresponsive to the drug and the underlying immunopathology. The benet is
tapering should be accelerated while the next-in-line often short-lived (8 weeks); repeated infusions every
immunosuppressive drug is started. Although con- 68 weeks are generally required to maintain
trolled trials have not been performed, almost all improvement. A dose of 2 g/kg divided over 25 days
patients with true PM or DM respond to glucocorti- per course is recommended. Uncontrolled observa-
coids to some degree and for some period of time; in tions suggest that IVIg may also be benecial for
general, DM responds better than PM. patients with PM. Neither plasmapheresis nor leuka-
The long-term use of prednisone may cause pheresis appears to be effective in PM and DM.
increased weakness associated with a normal or
The following sequential empirical approach to the
unchanged CK level; this effect is referred to as steroid
treatment of PM and DM is suggested: Step 1: high-dose
myopathy. In a patient who previously responded to prednisone; Step 2: azathioprine, mycophenolate, or
high doses of prednisone, the development of new methotrexate for steroid-sparing effect; Step 3: IVIg;
weakness may be related to steroid myopathy or to Step 4: a trial, with guarded optimism, of one of the fol-

CHAPTER 44
disease activity that either will respond to a higher lowing agents, chosen according to the patients age,
dose of glucocorticoids or has become glucocorti- degree of disability, tolerance, experience with the drug,
coid-resistant. In uncertain cases, the prednisone and general health: rituximab, cyclosporine, cyclophos-
dosage can be steadily increased or decreased as phamide, or tacrolimus. Patients with interstitial lung
desired: the cause of the weakness is usually evident disease may benet from aggressive treatment with
in 28 weeks. cyclophosphamide or tacrolimus.
2. Other immunosuppressive drugs. Approximately 75%

Polymyositis, Dermatomyositis, and Inclusion Body Myositis

of patients ultimately require additional treatment. A patient with presumed PM who has not responded
This occurs when a patient fails to respond ade- to any form of immunotherapy most likely has IBM
quately to glucocorticoids after a 3-month trial, the or another disease, usually a metabolic myopathy, a
patient becomes glucocorticoid-resistant, glucocorti- muscular dystrophy, a drug-induced myopathy, or an
coid-related side effects appear, attempts to lower endocrinopathy. In these cases, a repeat muscle biopsy
the prednisone dose repeatedly result in a new and a renewed search for another cause of the myopa-
relapse, or rapidly progressive disease with evolving thy is indicated.
severe weakness and respiratory failure develops. Calcinosis, a manifestation of DM, is difcult to treat;
The following drugs are commonly used but have however, new calcium deposits may be prevented if the
never been tested in controlled studies: (1) Azathio- primary disease responds to the available therapies.
prine is well tolerated, has few side effects, and Bisphosphonates, aluminum hydroxide, probenecid,
appears to be as effective for long-term therapy as colchicine, low doses of warfarin, calcium blockers, and
other drugs. The dose is up to 3 mg/kg daily. (2) surgical excision have all been tried without success.
Methotrexate has a faster onset of action than aza- IBM is generally resistant to immunosuppressive ther-
thioprine. It is given orally starting at 7.5 mg weekly apies. Prednisone together with azathioprine or
for the rst 3 weeks (2.5 mg every 12 h for 3 doses), methotrexate is often tried for a few months in newly
with gradual dose escalation by 2.5 mg per week to diagnosed patients, although results are generally disap-
a total of 25 mg weekly. A rare side effect is pointing. Because occasional patients may feel subjec-
methotrexate pneumonitis, which can be difcult to tively weaker after these drugs are discontinued, some
distinguish from the interstitial lung disease of the clinicians prefer to maintain some patients on low-dose,
primary myopathy associated with Jo-1 antibodies every-other-day prednisone or weekly methotrexate in
(described above). (3) Mycophenolate mofetil also has an effort to slow disease progression, even though there
a faster onset of action than azathioprine. At doses is no objective evidence or controlled study to support
up to 2.5 mg/d, it is well tolerated and appears this practice. In two controlled studies of IVIg in IBM, mini-
promising for long-term use. (4) Monoclonal anti- mal benet in up to 30% of patients was found; the
CD20 (rituximab) has been shown in a small uncon- strength gains, however, were not of sufcient magnitude
trolled series to benet patients with DM. (5) to justify its routine use. Another trial of IVIg combined
Cyclosporine has inconsistent and mild benet. (6) with prednisone was ineffective. Nonetheless, many
Cyclophosphamide (0.51 g IV monthly for 6 months) experts believe that a 2- to 3-month trial with IVIg may be
has limited success and signicant toxicity. (7) reasonable for selected patients with IBM who experi-
Tacrolimus (formerly known as FK506) has been ence rapid progression of muscle weakness or choking
effective in some difcult cases of PM. episodes due to worsening dysphagia.
 608 PROGNOSIS FURTHER READINGS
The 5-year survival rate for treated patients with PM AMATO AA, BAROHN RJ: Evaluation and treatment of inammatory
and DM is ~95% and the 10-year survival 84%; death is myopathies. J Neurol Neurosurg Psychiatry 80:1060, 2009
ASKANAS V et al: Inclusion-body myositis: Clinical and pathologic
usually due to pulmonary, cardiac, or other systemic aspects, and basic research potentially relevant to treatment.
complications. Patients severely affected at presentation Neurology 24:66(Suppl 1), 2006
or treated after long delays, those with severe dysphagia DALAKAS MC: Signaling pathways and immunobiology of inamma-
or respiratory difculties, older patients, and those with tory myopathies. Nat Clin Pract Rheumatol 2:219, 2006
associated cancer have a worse prognosis. DM responds ENGEL AG, HOHLFELD R: The polymyositis and dermatomyositis
more favorably to therapy than PM and thus has a better syndromes, in Myology, 3d ed, AG Engel, C Franzini-Armstrong
prognosis. Most patients improve with therapy, and (eds). New York, McGraw-Hill, 2004, pp 13211366
GREENBERG SA: Inammatory myopathies: Evaluation and manage-
many make a full functional recovery, which is often
ment. Semin Neurol 28:241, 2008
sustained with maintenance therapy. Up to 30% may be KARPATI G, OFERRALL EK: Sporadic inclusion body myositis: path-
left with some residual muscle weakness. Relapses may ogenic considerations.Ann Neurol 65:7, 2009
occur at any time. MIKOL J, ENGEL AG: Inclusion body myositis, in: Myology, 3d ed, AG
IBM has the least favorable prognosis of the inamma- Engel, C Franzini-Armstrong (eds). New York, McGraw-Hill,
tory myopathies. Most patients will require the use of an 2004, pp 13671388
SECTION III

assistive device such as a cane, walker, or wheelchair within

510 years of onset. In general, the older the age of onset
in IBM, the more rapidly progressive is the course.
Diseases of the Central Nervous System
 CHAPTER 45
SPECIAL ISSUES IN INPATIENT
NEUROLOGIC CONSULTATION
Scott Andrew Josephson I Martin A. Samuels

I Consultations Regarding Central Nervous Magnesium Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

System Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 I Consultations Regarding Peripheral Nervous
Hyperperfusion States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 System Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
Post-Cardiac Bypass Brain Injury . . . . . . . . . . . . . . . . . . . . . 611 Entrapment Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
Post-Solid Organ Transplant Brain Injury . . . . . . . . . . . . . . . . 612 I Radial Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
I Common Neurologic Complications of Electrolyte I Ulnar Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 I Peroneal Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
Hypernatremia and Hyperosmolality . . . . . . . . . . . . . . . . . . . 612 Proximal Femoral Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . 615
Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 I Lateral Femoral Cutaneous Nerve . . . . . . . . . . . . . . . . . . . . . 615
Hypokalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Obstetric Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
Hyperkalemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
Calcium Disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

Inpatient neurologic consultations usually involve ques- should allow for clinical recovery if superimposed hemor-
tions about specic disease processes or prognostication rhage or infarction has not occurred.
after various cerebral injuries. Common reasons for neu- The brains autoregulatory capability successfully
rologic consultation include stroke (Chap. 21), seizures maintains a fairly stable cerebral blood ow in adults
(Chap. 20), altered mental status (Chap. 13), headache despite alterations in systemic mean arterial pressure
(Chap. 6), and management of coma and other critical (MAP) ranging from 50150 mm Hg. In patients with
conditions (Chaps. 14 and 22). This chapter focuses on chronic hypertension, this cerebral autoregulation curve
additional common reasons for consultation that are not is shifted, resulting in autoregulation working over a
addressed elsewhere in the text. much higher range of pressures (e.g., 70175 mmHg).
In these hypertensive patients, cerebral blood ow is
kept steady at higher MAP, but a rapid lowering of
CONSULTATIONS REGARDING CENTRAL pressure can more easily lead to ischemia on the lower
NERVOUS SYSTEM DYSFUNCTION end of the autoregulatory curve. This autoregulatory
phenomenon is achieved through both myogenic and
HYPERPERFUSION STATES
neurogenic inuences causing small arterioles to con-
A group of neurologic disorders shares the common fea- tract and dilate. When the systemic blood pressure
ture of hyperperfusion playing a key role in pathogenesis. exceeds the limits of this mechanism, breakthrough of
These seemingly diverse syndromes include hypertensive autoregulation occurs, resulting in hyperperfusion via
encephalopathy, eclampsia, post-carotid endarterectomy increased cerebral blood ow, capillary leakage into the
syndrome, and toxicity from calcineurin-inhibitor med- interstitium, and resulting edema.The predilection of all
ications. Modern imaging techniques and experimental of the hyperperfusion disorders to affect the posterior
models suggest that vasogenic edema is usually the pri- rather than anterior portions of the brain may be due
mary process leading to neurologic dysfunction; therefore to a lower threshold for autoregulatory breakthrough in
prompt recognition and management of this condition the posterior circulation.

609
 610 TABLE 45-1
SOME COMMON ETIOLOGIES OF HYPERPERFUSION
SYNDROME
Disorders in which increased capillary pressure dominates
the pathophysiology
Hypertensive encephalopathy, including secondary
causes such as renovascular hypertension,
pheochromocytoma, cocaine use, etc.
Post-carotid endarterectomy syndrome
Preeclampsia/eclampsia
High-altitude cerebral edema
Disorders in which endothelial dysfunction dominates the
pathophysiology
Calcineurin-inhibitor toxicity FIGURE 45-1
Chemotherapeutic agent toxicity (e.g., cytarabine,
Axial uid-attenuated inversion recovery (FLAIR) MRI of
azathioprine, 5-uorouracil, cisplatin, methotrexate)
the brain in a patient taking cyclosporine after liver trans-
Glucocorticoids
Erythropoietin plantation who presented with seizures, headache, and corti-
cal blindness. Increased signal is seen bilaterally in the
SECTION III

HELLP syndrome (hemolysis, elevated liver enzyme

levels, low platelet count) occipital lobes predominantly involving the white matter, con-
Thrombotic thrombocytopenic purpura (TTP) sistent with a hyperperfusion state secondary to calcineurin-
Hemolytic uremic syndrome (HUS) inhibitor exposure.
Systemic lupus erythematosus (SLE)
Wegeners granulomatosis
Diseases of the Central Nervous System

reveal a systemic blood pressure that is increased above

baseline. It appears as if the rapidity of rise rather than
Although elevated or relatively elevated blood pressure the absolute value of pressure is the most important risk
is common in many of these disorders, some hyperperfu- factor.
sion states such as calcineurin-inhibitor toxicity occur The diagnosis in all of these conditions is clinical.
with no apparent pressure rise. In these cases, vasogenic The symptoms of these disorders are common and
edema is likely due primarily to dysfunction of the capil- nonspecic, so a long differential diagnosis should be
lary endothelium itself, leading to breakdown of the entertained, including consideration of other causes of
blood-brain barrier. It is useful to separate disorders of confusion, focal decits, headache, and seizures. MRI
hyperperfusion into those caused primarily by increased has improved the ability of clinicians to diagnose hyper-
pressure and those due mostly to endothelial dysfunction perfusion syndromes, although cases have been reported
from a toxic or autoimmune etiology (Table 45-1). In with normal imaging. Patients classically exhibit the
reality, both of these pathophysiologic processes are likely high T2 signal of edema primarily in the posterior
playing some role in each of these disorders. occipital lobes, not respecting any single vascular terri-
The clinical presentation of the hyperperfusion syn- tory (Fig. 45-1). Diffusion-weighted images are typically
dromes is similar, with prominent headaches, seizures, or normal, emphasizing the vasogenic rather than cytotoxic
focal decits. Headaches have no specic characteristics, nature of this edema. Imaging with CT is less sensitive
range from mild to severe, and may be accompanied by but may show a pattern of patchy hypodensity in the
alterations in consciousness ranging from confusion to involved territory. Previously this classic radiographic
coma. Seizures may be present, and these can be of mul- appearance had been termed reversible posterior leukoen-
tiple types depending on the severity and location of the cephalopathy (RPLE). However, this term has fallen out of
edema. Nonconvulsive seizures have been described in favor because none of its elements are completely accu-
hyperperfusion states; therefore a low threshold for rate: the radiographic and clinical changes are not always
obtaining an electroencephalogram (EEG) in these reversible, the territory involved is not uniquely poste-
patients should be maintained. The typical focal decit rior, and gray matter may be affected as well, rather than
in hyperperfusion states is cortical visual loss, given the purely white matter as the word leukoencephalopathy
tendency of the process to involve the occipital lobes. intimates. Other ancillary studies such as cerebrospinal
However, any focal decit can occur depending on the uid (CSF) analysis often yield nonspecic results. It
area affected, as evidenced by patients who, after carotid should be noted that many of the substances that have
endarterectomy, exhibit neurologic dysfunction in the been implicated, such as cyclosporine, can cause this
ipsilateral newly reperfused hemisphere. In conditions syndrome even at low doses or after years of treatment.
where increased cerebral blood ow plays a role, exami- Therefore, normal serum levels of these medications do
nation of the inpatient vital signs record will usually not exclude them as inciting agents.
 In cases of hyperperfusion syndromes, treatment should 611
commence urgently once the diagnosis is considered.
Hypertension plays a key role commonly, and judicious
lowering of the blood pressure with IV agents such as
labetolol or nicardipine is advised along with continuous
cardiac and blood pressure monitoring, often through an
arterial line. It is reasonable to lower mean arterial pres-
sure by ~20% initially, as further lowering of the pressure
may cause secondary ischemia as pressure drops below the
lower range of the patients autoregulatory capability. In
cases where there is an identied cause of the syndrome,
these etiologies should be treated promptly, including
discontinuation of offending substances such as calcineurin FIGURE 45-2
inhibitors in toxic processes, treatment of immune-mediated Coronal uid-attenuated inversion recovery (FLAIR) MRI
disorders such as thrombotic thrombocytopenic purpura of the brain in a patient presenting with altered mental
(TTP), and prompt delivery of the fetus in eclampsia. status after an episode of hypotension during coronary
Seizures must be identied and controlled, often neces- artery bypass grafting (CABG). Increased signal is seen in the

CHAPTER 45
sitating continuous EEG monitoring. Anticonvulsants are border zones bilaterally between the middle cerebral artery
effective, but in the special case of eclampsia, there is good and anterior cerebral artery territories. Diffusion-weighted
evidence to support the use of magnesium sulfate for MRI sequences demonstrated restricted diffusion in these
seizure control. same locations, suggesting acute infarction.

POST-CARDIAC BYPASS BRAIN INJURY

Special Issues in Inpatient Neurologic Consultation

cerebral circulation. Cross-clamping of the aorta, manipu-
Central nervous system (CNS) injuries following open lation of the heart, extracorporeal circulation techniques
heart or coronary artery bypass grafting (CABG) surgery (bypass), arrhythmias such as atrial fibrillation, and
are common and include acute encephalopathy, stroke, and introduction of air through suctioning have all been
a chronic syndrome of cognitive impairment, which is implicated as potential sources of emboli. Histologic stud-
now increasingly recognized. Hypoperfusion and embolic ies indicate that literally millions of tiny emboli may be
disease are frequently involved in the pathogenesis of released, even using modern surgical techniques.
these syndromes, although multiple mechanisms may be This shower of microemboli results in a number of
involved in these critically ill patients who are at risk for clinical syndromes. Occasionally, a single large embolus
various metabolic and polypharmaceutical complications. leads to an isolated large-vessel stroke that presents with
The frequency of hypoxic injury secondary to inade- obvious clinical focal decits. More commonly, the
quate blood ow intraoperatively has been markedly emboli released are multiple and smaller.When there is a
decreased by the use of modern surgical and anesthetic high burden of these small emboli, an acute encephalopa-
techniques. Despite these advances, some patients still thy can occur postoperatively, presenting as either a
experience neurologic complications from cerebral hyperactive or hypoactive confusional state, the latter of
hypoperfusion or may suffer focal ischemia from tight which is frequently and incorrectly ascribed to depres-
carotid or focal intracranial stenoses in the setting of sion.When the burden of microemboli is lower, no acute
regional hypoperfusion. Postoperative infarcts in the bor- syndrome is recognized, but the patient may suffer a
der zones between vascular territories commonly are chronic cognitive decit. Cardiac surgery can be viewed,
blamed on systemic hypotension although some have like delirium, as a stress test for the brain. Some patients
suggested that these infarcts can also result from embolic with a low cerebral reserve due to underlying cerebrovas-
disease (Fig. 45-2). cular disease or an early neurodegenerative process will
Embolic disease is likely the predominant mecha- develop a chronic, cognitive decit, whereas others with
nism of cerebral injury during cardiac surgery as evi- higher reserves may remain asymptomatic despite a simi-
denced by diffusion-weighted MRI and intraoperative lar dose of microemboli. In this manner, cardiac surgery
transcranial Doppler studies. It should be noted that may serve to unmask the early manifestations of disorders
some of the emboli that are found histologically in these such as vascular dementia and Alzheimers disease.
patients are too small to be detected by standard imaging Since modern techniques have successfully mini-
sequences; therefore, a negative MRI after surgery does mized hypoperfusion complications during these surg-
not exclude the diagnosis of emboli-related complica- eries, much attention is now focused on reducing this
tions.Thrombus in the heart itself as well as atheromas in inevitable shower of microemboli. Off-pump CABG
the aortic arch can become dislodged during cardiac surgeries have the advantages of reducing length of stay
surgeries, releasing a shower of particulate matter into the and perioperative complications; however, some recent
 612 data suggest that off-pump CABG does not preserve providing yet another mechanism for stroke. Imaging
cognitive function compared with on-pump CABG. Fil- with CT or MRI with diffusion is advised when cere-
ters placed in the aortic arch may have some promise in brovascular complications are suspected to conrm the
capturing these emboli, although convincing evidence is diagnosis and to exclude intracerebral hemorrhage, which
currently lacking. Development of successful endovascu- most often occurs in the setting of coagulopathy sec-
lar operative approaches may provide a reasonable alter- ondary to liver failure or after cardiac bypass procedures.
native to conventional CABG procedures, especially for Because patients with solid organ transplants are chron-
patients at high risk of developing cognitive dysfunction ically immunosuppressed, infections are a common con-
after surgery due to advanced age, previous stroke, or cern. In any transplant patient with new CNS signs or
severe atheromatous disease of the carotid arteries or symptoms such as seizure, confusion, or focal decit, the
aortic arch. diagnosis of a nervous system infection should be consid-
ered and evaluated through imaging (usually MRI) and
POST-SOLID ORGAN TRANSPLANT possibly lumbar puncture. The most common pathogens
BRAIN INJURY responsible for CNS infections in these patients vary based
on time since transplant. In the rst month posttransplant,
Patients who have undergone solid organ transplantation common pathogens include the usual bacterial organisms
are at risk for neurologic injury in the postoperative associated with surgical procedures and indwelling
SECTION III

period and for the months to years thereafter. Neuro- catheters. Starting in the second month posttransplant,
logic consultants should view these patients as a special opportunistic infections of the CNS become more com-
population at risk for both unique neurologic complica- mon, including Nocardia and Toxoplasma species as well as
tions as well as for the usual disorders found in any criti- fungal infections such as aspergillosis.Viral infections that
cally ill inpatient. can affect the brain of the immunosuppressed patient, such
Immunosuppressive medications are administered in as herpes simplex virus, cytomegalovirus, and varicella, also
Diseases of the Central Nervous System

high doses to patients after solid organ transplant, and become more common after the rst month posttrans-
many of these compounds have well-described neuro- plant. After 6 months posttransplant, immunosuppressed
logic complications. In patients with headache, seizures, patients still remain at risk for these opportunistic bacter-
or focal neurologic decits taking calcineurin inhibitors, ial, fungal, and viral infections but can also suffer late CNS
the diagnosis of hyperperfusion syndrome should be infectious complications such as progressive multifocal
considered, as discussed above.This neurotoxicity occurs leukoencephalopathy (PML) associated with JC virus and
mainly with cyclosporine and tacrolimus and can pre- Epstein-Barr virusdriven clonal expansions of B cells
sent even in the setting of normal serum drug levels. resulting in CNS lymphoma.
Treatment primarily involves lowering the drug dosage
or discontinuing the drug. A related newer agent,
sirolimus, has very few recorded cases of neurotoxicity COMMON NEUROLOGIC
and may be a reasonable alternative for some patients. COMPLICATIONS OF
Other examples of immunosuppressive medications and ELECTROLYTE DISTURBANCES
their neurologic complications include OKT3-associated
akinetic mutism and the leukoencephalopathy seen with A wide variety of neurologic conditions can result from
methotrexate, especially when it is administered intrathe- abnormalities in serum electrolytes, and consideration of
cally or with concurrent radiotherapy. In any solid organ electrolyte disturbances should be part of any inpatient
transplant patient with neurologic complaints, a careful neurologic consultation.
examination of the medication list is required to search
for these possible drug effects.
HYPERNATREMIA AND HYPEROSMOLALITY
Cerebrovascular complications of solid organ transplant
are often rst recognized in the immediate postoperative The normal range of serum osmolality is around
period. Border zone territory infarctions can occur, espe- 275295 mOsm/kg, but neurologic manifestations are
cially in the setting of systemic hypotension during car- usually seen only at levels >325 mOsm/kg. Hyperosmo-
diac transplant surgery. Embolic infarctions classically lality is usually due to hypernatremia, hyperglycemia,
complicate cardiac transplantation, but all solid organ azotemia, or the addition of extrinsic osmoles such as
transplant procedures place patients at risk for systemic mannitol, which is commonly used in critically ill neuro-
emboli. When cerebral embolization accompanies renal logic patients. Hyperosmolality itself can lead to a gener-
or liver transplantation surgery, a careful search for right- alized encephalopathy that is nonspecic and without
to-left shunting should include evaluation of the heart focal ndings; however, an underlying lesion such as a
with agitated saline echocardiography, as well as looking mass can become symptomatic under the metabolic stress
for intrapulmonary shunting. Renal and some cardiac of a hyperosmolar state, producing focal signs. Some
transplant patients often have advanced atherosclerosis, patients with hyperosmolality from severe hyperglycemia
can present, for unclear reasons, with generalized seizures or congestive heart failure. Finally, in hypovolemic hypotonic 613
unilateral movement disorders, which usually respond to hyponatremia, volume is replaced with isotonic saline
lowering of the serum glucose.The treatment of all forms of while underlying conditions of the kidneys, adrenals, and
hyperosmolality involves calculation of apparent water losses gastrointestinal tract are addressed.
and slow replacement so that the serum sodium declines no One neurologic cause of hypovolemic hypotonic
faster than 2 mmol/L (2 meq/L) per hour. hyponatremia is the cerebral salt-wasting syndrome that
Hypernatremia leads to the loss of intracellular water, accompanies subarachnoid hemorrhage and, less com-
leading to cell shrinkage. In the cells of the brain, solutes monly, other cerebral processes such as meningitis or
such as glutamine and urea are generated under these stroke. In these cases, the degree of renal sodium excre-
conditions in order to minimize this shrinkage. Despite tion can be remarkable, and large amounts of saline,
this corrective mechanism, when hypernatremia is hypertonic saline, or oral sodium may need to be given
severe [serum sodium >160 mmol/L (>160 meq/L)] or in a judicious fashion in order to avoid complications
occurs rapidly, cellular metabolic processes fail and from cerebral edema.
encephalopathy will result. There are many etiologies of
hypernatremia including, most commonly, renal and
HYPOKALEMIA
extrarenal losses of water. Causes of neurologic relevance
include central diabetes insipidus, where hyperosmolality Hypokalemia, defined as a serum potassium level

CHAPTER 45
is accompanied by submaximal urinary concentration <3.5 mmol/L (<3.5 meq/L), occurs either because of
due to inadequate release of antidiuretic hormone excessive potassium losses (from the kidneys or gut) or
(ADH) from the posterior pituitary, resulting often from due to an abnormal potassium distribution between the
pituitary injury in the setting of surgery, hemorrhage, intracellular and extracellular spaces. At very low levels
inltrative processes, or cerebral herniation. (<1.5 mmol/L), hypokalemia may be life threatening
due to the risk of cardiac arrhythmia and may present

Special Issues in Inpatient Neurologic Consultation

neurologically with severe muscle weakness and paraly-
HYPONATREMIA
sis. Hypokalemic periodic paralysis is a rare disorder
Hyponatremia is commonly dened as a serum sodium caused by excessive intracellular potassium uptake in the
<135 mmol/L (<135 meq/L). Neurologic symptoms setting of a calcium or sodium channel mutation. Treat-
occur at different levels of low sodium, depending not ment of hypokalemia is dependent on the etiology but
only on the absolute value but also on the rate of fall. In usually includes replacement of potassium through oral
patients with hyponatremia that develops over hours, or IV routes as well as correcting the cause of potassium
life-threatening seizures and cerebral edema may occur at balance problems (e.g., eliminating 2-adrenergic agonist
values as high as 125 mmol/L. In contrast, some patients medications).
with more chronic hyponatremia that has slowly devel-
oped over months to years may be asymptomatic even
HYPERKALEMIA
with serum levels <110 mmol/L. Correction of hypona-
tremia, especially when chronic, must take place slowly Hyperkalemia is dened as a serum potassium level
in order to avoid additional neurologic complications. >5.5 mmol/L (>5.5 meq/L) and can neurologically
Cells in the brain swell in hypotonic hyponatremic states present as muscle weakness with or without paresthesias.
but may compensate over time by excreting solute into Hyperkalemia becomes life threatening when it produces
the extracellular space, leading to restoration of cell vol- electrocardiographic abnormalities such as peaked T
ume when water follows the solute out of the cells. If waves or a widened QRS complex. In these cases, prompt
treatment of hyponatremia results in a rapid rise in serum treatment is essential and consists of strategies that protect
sodium, cells in the brain may quickly shrink, leading the heart against arrhythmias (calcium gluconate adminis-
to osmotic demyelination, a process that previously tration), promote potassium redistribution into cells (with
was thought to be limited exclusively to the brainstem glucose, insulin, and 2-agonist medications), and increase
(central pontine myelinolysis; see Fig. 22-6), but now has potassium removal (through sodium polystyrene sul-
been described elsewhere in the CNS. fonate, loop diuretics, or hemodialysis).
Treatment of hyponatremia is dependent on the cause.
Hypertonic hyponatremia treatment focuses on the
CALCIUM DISTURBANCES
underlying condition, such as hyperglycemia. Isovolemic
hyponatremia (syndrome of inappropriate antidiuretic Hypercalcemia usually occurs in the setting of either
hormone, SIADH) is managed with water restriction or hyperparathyroidism or systemic malignancy. Neurologic
administration of ADH antagonists. The management of manifestations include encephalopathy as well as muscle
choice for patients with hypervolemic hypotonic hypona- weakness due to reduced neuromuscular excitability.
tremia is free-water restriction and treatment of the under- Seizures can occur but are more common in states of
lying edematous disorder, such as nephrotic syndrome or low calcium.
 614 Hypocalcemia in adults often follows surgical treat- brachioradialis, and supinator muscles in addition to wrist
ment of the thyroid or parathyroid. Seizures and altered drop. A more common site of compression occurs in the
mental status dominate the neurologic picture and usu- spiral groove of the upper arm in the setting of a humerus
ally resolve with calcium repletion. Tetany is due to fracture or from sleeping with the arm draped over a
spontaneous, repetitive action potentials in peripheral bench or chair (Saturday night palsy). Sparing of the
nerves and remains the classic sign of symptomatic triceps is the rule when the nerve is injured in this loca-
hypocalcemia. tion. Because extensors of the upper extremity are injured
preferentially in radial nerve injury, these lesions may be
mistaken for the pyramidal distribution of weakness that
MAGNESIUM DISTURBANCES
accompanies upper motor neuron lesions from brain or
Disorders of magnesium are difcult to correlate with spinal cord processes.
serum levels because a very small amount of total-body
magnesium is located in the extracellular space. Hypo-
magnesemia presents neurologically with seizures, ULNAR NEUROPATHY
tremor, and myoclonus. When intractable seizures occur
Compression of the ulnar nerve is the second most
in the setting of hypomagnesemia, only administration
common entrapment neuropathy after carpal tunnel
of magnesium will lead to resolution. High levels of
syndrome. The most frequent site of compression is at
SECTION III

magnesium, in contrast, lead to CNS depression. Hyper-

the elbow where the nerve passes supercially in the
magnesemia usually occurs only in the setting of renal
ulnar groove. Symptoms usually begin with tingling in
failure and can lead to confusion and muscular paralysis
the ulnar distribution, including the fourth and fth
when severe.
digits of the hand (Fig. 45-3B). Sensory symptoms may
be worsened by elbow exion due to increased pressure
CONSULTATIONS REGARDING on the nerve, hence the tendency of patients to com-
Diseases of the Central Nervous System

PERIPHERAL NERVOUS SYSTEM plain of increasing paresthesias at night when the arm is
DYSFUNCTION exed at the elbow during sleep. Motor dysfunction can
be disabling and involves most of the intrinsic hand
ENTRAPMENT NEUROPATHIES muscles, limiting dexterity and strength of grasp and
Polyneuropathy is a common cause of outpatient neuro- pinch. Etiologies of ulnar entrapment include trauma to
logic consultation (Chap. 40). In the inpatient setting, the nerve (hitting the funny bone), malpositioning
however, mononeuropathies are more frequent, especially during anesthesia for surgical procedures, and chronic
the entrapment neuropathies that complicate many surgical arthritis of the elbow. When a perioperative ulnar nerve
procedures and medical conditions. Median neuropathy injury is considered, stretch injury or trauma to the
at the wrist (carpal tunnel syndrome) is the most frequent lower trunk of the brachial plexus should be entertained
entrapment neuropathy by far, but it is rarely a cause as well since its symptoms can mimic those of an ulnar
for inpatient consultation. Mechanisms for perioperative neuropathy. If the clinical examination is equivocal, elec-
mononeuropathy include traction, compression, and trodiagnostic studies can denitively distinguish between
ischemia of the nerve. Imaging with MR neurography plexus and ulnar nerve lesions a few weeks after the
may allow these causes to be distinguished denitively. In injury. Conservative methods of treatment are often the
all cases of mononeuropathy, the diagnosis can be made rst step, but a variety of surgical approaches may be
through the clinical examination and then conrmed effective, including anterior ulnar nerve transposition
with electrodiagnostic studies in the subacute period, if and release of the exor carpi ulnaris aponeurosis.
necessary. Treatment consists mainly of avoidance of
repetitive trauma but may also include surgical approaches
PERONEAL NEUROPATHY
to relieve pressure on the nerve.
The peroneal nerve winds around the head of the bula
RADIAL NEUROPATHY in the leg below the lateral aspect of the knee, and its
supercial location at this site makes it vulnerable to
Radial nerve injury classically presents with weakness of trauma. Patients present with weakness of foot dorsiex-
extension of the wrist and ngers (wrist drop) with ion (foot drop) as well as with weakness in eversion
or without more proximal weakness of extensor muscles but not inversion at the ankle. Sparing of inversion,
of the upper extremity, depending on the site of injury. which is a function of muscles innervated by the tibial
Sensory loss is in the distribution of the radial nerve, nerve, helps to distinguish peroneal neuropathies from L5
which includes the dorsum of the hand (Fig. 45-3A). radiculopathies. Sensory loss involves the lateral aspect of
Compression at the level of the axilla, e.g., resulting the leg as well as the dorsum of the foot (Fig. 45-3C).
from use of crutches, includes weakness of the triceps, Fractures of the bular head may be responsible for
 Radial nerve Ulnar nerve Peroneal nerve 615
Sensory distribution Sensory distribution of
of the radial nerve the peroneal nerve

Lateral cutaneous
nerve of arm

Posterior cutaneous
nerve of arm
Lateral cutaneous
Posterior cutaneous nerve of calf
nerve of forearm Sensory distribution of the ulnar nerve
Superficial peroneal nerve
Superficial branch

Deep peroneal
nerve
A B C

Sensory distribution
of the femoral nerve Anterior femoral
cutaneous nerve Lateral femoral

CHAPTER 45
cutaneous nerve
Medial femoral
cutaneous nerve

Saphenous nerve

Special Issues in Inpatient Neurologic Consultation

D E

FIGURE 45-3
Sensory distribution of peripheral nerves commonly B. Ulnar nerve. C. Peroneal nerve. D. Femoral nerve. E. Lat-
affected by entrapment neuropathies. A. Radial nerve. eral femoral cutaneous nerve.

peroneal neuropathies, but in the perioperative setting these conditions. Bleeding into the pelvis resulting in
poorly applied braces exerting pressure on the nerve hematoma can occur spontaneously, following trauma, or
while the patient is unconscious are more often responsi- after intrapelvic surgeries such as renal transplantation. In
ble. Tight-tting stockings or casts of the upper leg can intoxicated or comatose patients, stretch injuries to the
also cause a peroneal neuropathy, and thin individuals femoral nerve are seen following prolonged, extreme hip
and those with recent weight loss are at increased risk. exion or extension. Rarely, attempts at femoral vein or
arterial puncture can be complicated by injury to this
nerve.
PROXIMAL FEMORAL NEUROPATHY
Lesions of the proximal femoral nerve are relatively
uncommon but may present dramatically with weakness LATERAL FEMORAL CUTANEOUS
of hip exion, quadriceps atrophy, weakness of knee NERVE
extension (often manifesting with leg-buckling falls), and
an absent patellar reex. Adduction of the thigh is spared The symptoms of lateral femoral cutaneous nerve
as these muscles are supplied by the obturator nerve, entrapment, commonly known as meralgia paresthetica,
thereby distinguishing a femoral neuropathy from a more include sensory loss, pain, and dysesthesia in part of the
proximal lumbosacral plexus lesion. The sensory loss area supplied by the nerve (Fig. 45-3E). There is no
found is in the distribution of the femoral nerve sensory motor component to the nerve, and therefore weakness
branches on the anterior part of the thigh (Fig. 45-3D). is not a part of this syndrome. Symptoms often are
Compressive lesions from retroperitoneal hematomas or worsened by standing or walking. Compression of the
masses are common, and a CT of the pelvis should be nerve occurs where it enters the leg near the inguinal
obtained in all cases of femoral neuropathy to exclude ligament, usually in the setting of tight-tting belts,
 616 pants, corsets, or recent weight gain, including that of lithotomy positioning. The latter presents with medial
pregnancy. The differential diagnosis of these symptoms thigh pain that may be accompanied by weakness of thigh
includes hip problems such as trochanteric bursitis. adduction.There is also a clear association between preg-
nancy and an increased frequency of idiopathic facial
palsy (Bells palsy).
OBSTETRIC NEUROPATHIES
Pregnancy and delivery place women at special risk for a FURTHER READINGS
variety of nerve injuries. Radiculopathy due to a herni-
ated lumbar disc is not common during pregnancy, but BARYYNSKI WS: Posterior reversible encephalopathy syndrome, part 1:
fundamental imaging and clinical features. AJNR 29:1036, 2008
compressive injuries of the lumbosacral plexus do occur
JILLAPALLI D, SHEFNER JM: Electrodiagnosis in common mononeu-
secondary to either the fetal head passing through the ropathies and plexopathies. Semin Neurol 25:196, 2005
pelvis or the use of forceps during delivery. These plexus KARNAD DR, GUNTUPALLI KK: Neurologic disorders in pregnancy.
injuries are more frequent with cephalopelvic dispropor- Crit Care Med 33:S362, 2005
tion and often present with a painless unilateral foot drop KUMAR S et al: Central pontine myelinolysis, an update. Neurol Res
which must be distinguished from a peroneal neuropathy 28:360, 2006
caused by pressure on the nerve while in lithotomy SELNES OA et al: Cognition 6 years after surgical or medical therapy
for coronary artery disease.Ann Neurol 63:581, 2008
position during delivery. Other compressive mononeu-
SECTION III

SENZOLO M et al: Neurologic complications after solid organ trans-

ropathies of pregnancy include meralgia paresthetica, plantation.Transpl Int 22:269, 2009
carpal tunnel syndrome, femoral neuropathy when the VAN DIJK D et al: Cognitive and cardiac outcomes 5 years after off-
thigh is abducted severely in an effort to facilitate delivery pump vs. on-pump coronary artery bypass graft surgery. JAMA
of the fetal shoulder, and obturator neuropathy during 297;701, 2007
Diseases of the Central Nervous System
 CHAPTER 46

ATLAS OF NEUROIMAGING

Andre Furtado I William P. Dillon

FIGURE 46-1
Limbic encephalitis (Chap. 39) Coronal (A, B), axial FLAIR
(C, D), and axial T2-weighted (E ) MR images demonstrate
abnormal high signal involving the bilateral mesial temporal
lobes (arrowheads) including the hippocampi (left greater
than right) without signicant mass effect (arrows). There was
no enhancement on post-gadolinium images (not shown).
617
 618
SECTION III

FIGURE 46-1 (Continued)

Diseases of the Central Nervous System

FIGURE 46-2
CNS tuberculosis (Chap. 35) Axial T1-weighted MR images post-gadolinium (B, C) demon-
Axial T2-weighted MRI (A) demonstrates multiple lesions strate ring enhancement of the lesions (arrows) and additional
(arrows) with peripheral high signal and central low signal, lesions in the subarachnoid space (arrowheads).
located predominantly in the cortex and subcortical white
matter, as well as in the basal ganglia.
 619

CHAPTER 46
FIGURE 46-2 (Continued)
Sagittal T2-weighted MR image of the cervical spine (D) Sagittal T1-weighted MR image post-gadolinium of the cervi-
demonstrates a hypointense lesion in the subarachnoid space cal spine (E ) demonstrates enhancement of the lesion in the

Atlas of Neuroimaging
at the level of T5 (arrow). subarachnoid space at the level of T5 (arrow).

FIGURE 46-3
Neurosyphilis (Chap. 35) and in a wedge-shaped distribution in the right parietal lobe
Case I (arrows).
Axial T2-weighted MR images (A, B) demonstrate well-dened
areas of abnormal high signal in the basal ganglia bilaterally
 620
SECTION III
Diseases of the Central Nervous System

FIGURE 46-3 (Continued)

Axial (C, D) T1-weighted images post-gadiolinium. Coronal
(E, F ) T1-weighted images post-gadolinium demonstrate
irregular ring enhancement of the lesions (arrows).
 621

CHAPTER 46
Atlas of Neuroimaging
FIGURE 46-4
Neurosyphilis (Chap. 35)
Case II
Axial T2-weighted MRI (A) demonstrates a dural-based,
peripherally hyperintense and centrally hypointense lesion
located lateral to the left frontal lobe (arrows).
Axial (B) and coronal (C) T1-weighted MR images post-
gadolinium demonstrate peripheral enhancement of the lesion
(arrows).
 622
SECTION III
Diseases of the Central Nervous System

FIGURE 46-5
Histoplasmosis of the pons Axial FLAIR (A) and T2-
weighted (B) MR images demonstrate a low signal mass in
the right pons (arrows) with surrounding vasogenic edema.
Axial T1-weighted MR image post-gadolinium (C) demon-
strates ring enhancement of the lesion in the right pons
(arrows). Of note, there was no evidence of restricted diffusion
(not shown).
 623

CHAPTER 46
Atlas of Neuroimaging
FIGURE 46-6
Coccidiomycosis meningitis (Chap. 36)
Axial post-contrast CT (A) and axial (B) and coronal
(C) T1-weighted MR images post-gadolinium demonstrate
enhancement of the perimesencephalic cisterns (arrows), as
well as the sylvian and interhemispheric ssures.
 624
SECTION III
Diseases of the Central Nervous System

FIGURE 46-7
Candidiasis in a newborn Axial T2-weighted MR image (A) ADC map (D, E) demonstrates restricted diffusion of water
demonstrates multiple punctate foci of low signal diffusely molecules in the lesions (arrowheads).
distributed in the brain parenchyma (arrowheads).
Axial T1-weighted MR images post-gadolinium (B, C) demon-
strate marked enhancement of the lesions (arrowheads).
 625

CHAPTER 46
Atlas of Neuroimaging

FIGURE 46-8
CNS aspergillosis (Chap. 36) Axial T2-weighted MR images (C, D) demonstrate intrinsic low
Axial FLAIR MR images (A, B) demonstrate multiple areas of signal in the lesions (arrows), suggesting the presence of
abnormal high signal in the basal ganglia as well as cortex blood products. Some of the lesions also show vasogenic
and subcortical white matter (arrows). There is also abnormal edema.
high signal in the subarachnoid space adjacent to the lesions
(arrowhead) that can correspond to blood or high protein
content.
 626
SECTION III

FIGURE 46-8 (Continued)

Coronal (E ) and axial (F ) T1-weighted MR images post-
gadolinium demonstrate peripheral enhancement of the lesions
(arrows).
Diseases of the Central Nervous System

FIGURE 46-9
Invasive sinonasal aspergillosis Axial T2-weighted MR image B. T1-weighted image pre-gadolinium demonstrates enhance-
(A) demonstrates an irregularly shaped low signal lesion ment of lesion (arrow).
involving the left orbital apex (arrow).
 627

FIGURE 46-9 (Continued)

C. T1-weighted image post-gadolinium demonstrates enhance-

CHAPTER 46
ment of lesion (arrow).

Atlas of Neuroimaging
FIGURE 46-10
Behets disease Axial FLAIR MRI demonstrates abnormal
high signal involving the anterior pons (arrow); following
gadolinium administration, the lesion was nonenhancing (not
shown). Brainstem lesions are typical of Behets disease,
caused primarily by vasculitis and in some cases demyelinat-
ing lesions.
 628

FIGURE 46-11
Neurosarcoid
SECTION III

Case I
Axial (A) and coronal (B) T1-weighted images post-gadolinium
with fat suppression demonstrate a homogeneously enhancing
well circumscribed mass centered in the left Meckels cave
(arrows).
Diseases of the Central Nervous System

FIGURE 46-12
Neurosarcoid
Case II
Axial (A, B) and sagittal (C) T1-weighted images post-gadolinium
with fat suppression demonstrate a homogeneously enhanc-
ing mass involving the hypothalamus and the pituitary stalk
(arrows).
 629

CHAPTER 46
Atlas of Neuroimaging
FIGURE 46-13
Neurosarcoid
Case III
Axial FLAIR images (AE) demonstrate abnormal high signal
and slight expansion in the midbrain, dorsal pons, and pineal
region (arrows) without signicant mass effect.
 630
SECTION III

FIGURE 46-13 (Continued)

Sagittal T1-weighted images post-gadolinium (F) with fat
suppression demonstrate abnormal enhancement in the mid-
brain, dorsal pons, and pineal region (arrows).
Diseases of the Central Nervous System

FIGURE 46-14
Neurosarcoid internal capsule and globus pallidus, bilateral cerebral pedun-
Case IV cles, bilateral gyrus rectus, right frontal lobe periventricular
Axial T2-weighted images (AD) demonstrate numerous areas white matter, and patchy areas in bilateral temporal lobes.
of abnormal hyperintensity involving the corpus callosum, left
 631

CHAPTER 46
Atlas of Neuroimaging

FIGURE 46-14 (Continued)

T1-weighted images post-gadolinium (EH) demonstrate
abnormal enhancement of those areas with high T2 signal.
(Continued)
 632
SECTION III

FIGURE 46-14 (Continued)

Diseases of the Central Nervous System

FIGURE 46-15
Histiocytosis
Sagittal T1-weighted image (A) demonstrates enlargement of
the pituitary stalk (arrow) and absence of the posterior pitu-
itary intrinsic T1 hyperintensity (arrowhead).
Sagittal and coronal T1-weighted images post-gadolinium
(B, C) demonstrate enhancement of the pituitary stalk and
infundibulum (arrows).
 633

FIGURE 46-16
Middle cerebral artery stenosis (Chap. 21)

CHAPTER 46
Time-of-ight (TOF) MR angiography (MRA) (A, B) reveals
narrowing within the left M1 segment that is likely secondary
to atherosclerosis (arrows).

Atlas of Neuroimaging

FIGURE 46-17
Lacunar infarction (Chap. 21) Axial FLAIR MRI (B) demonstrates abnormal high signal
Axial noncontrast CT (A) demonstrates abnormal hypoden- involving the left anterior putamen and anterior limb of internal
sity involving the left anterior putamen and anterior limb of capsule with ex-vacuo dilatation of the adjacent frontal horn
internal capsule with ex-vacuo dilatation of the adjacent of the left lateral ventricle, suggestive of an old infarction
frontal horn of the left lateral ventricle, suggestive of an old (arrow). A small area of slight hyperintensity is also seen in the
infarction (arrow). A small area of slight hypodensity is also posterior limb of the right internal capsule that can corre-
seen in the posterior limb of the right internal capsule that spond to an acute lacunar infarct (arrowhead).
can correspond to an acute infarct (arrowhead).
 634
SECTION III

FIGURE 46-17 (Continued)

Diffusion-weighted image (C) and apparent diffusion coef- strongly suggestive for an acute lacunar infarct (arrowhead).
cient (ADC) map (D) demonstrate restricted water motion in There is no evidence of restricted diffusion in the old infarct
Diseases of the Central Nervous System

the lesion of the posterior limb of the right internal capsule, (arrow).

FIGURE 46-18
Cerebral autosomal dominant arteriopathy with subcortical Axial T2-weighted MR images (A, B) demonstrate multiple
infarcts and leukoencephalopathy (CADASIL) (Chap. 21) patchy areas of abnormal high signal in the periventricular
white matter (arrows).
 635

CHAPTER 46
FIGURE 46-18 (Continued)
Coronal FLAIR MRI (C, D) demonstrates multiple patchy some of these areas, there are small areas of tissue loss
areas of abnormal high signal in the periventricular white (encephalomalacia) (arrowheads).
matter bilaterally, including the temporal lobes (arrows). In

Atlas of Neuroimaging

FIGURE 46-19
CNS vasculitis Axial T2-weighted MRI (B) demonstrates a large hypointense
Axial noncontrast CT (A) demonstrates a large hyperdense intraparenchymal hematoma surrounded by hyperintense
intraparenchymal hematoma surrounded by hypodense vasogenic edema in the right parietal lobe.
vasogenic edema in the right parietal lobe.
 636

FIGURE 46-19 (Continued)

Conventional angiography (C) demonstrates multiple seg-
ments of intracranial arterial narrowing, some of which have
associated adjacent areas of focal arterial dilatation. These
abnormalities are suggestive of vasculitis.
SECTION III
Diseases of the Central Nervous System

FIGURE 46-20
Superior sagittal sinus thrombosis (Chap. 21) Axial T1-weighted MRI (B) demonstrates absence of ow
Noncontrast CT of the head (A) demonstrates increased den- void in the superior sagittal sinus, suggestive of thrombosis.
sity in the superior sagittal sinus, suggestive of thrombosis
(arrow), and small linear hyperdensities in some temporal lobe
sulci, suggestive of subarachnoid hemorrhage (arrowheads).
 637

CHAPTER 46
FIGURE 46-20 (Continued)
Coronal FLAIR images (C, D) demonstrate areas of abnormal adjacent sulci. These ndings are suggestive of vasogenic
high signal involving the gray and the subcortical white mat- edema with subarachnoid hemorrhage (arrowheads).

Atlas of Neuroimaging
ter of the right frontal and left parietal lobes, as well as the

FIGURE 46-20 (Continued)

 638
SECTION III

FIGURE 46-20 (Continued)

Diffusion-weighted images (E, F) and ADC maps (G, H)
demonstrate restricted diffusion of the abnormal areas on
Diseases of the Central Nervous System

FLAIR, suggestive of infarct.

FIGURE 46-20 (Continued)

Phase-contrast venography of the brain (I ) demonstrates
absence of signal in the superior sagittal sinus down to the
torcular herophili, and left transverse sinus and jugular vein.
 639

FIGURE 46-20 (Continued)

Axial (J) and coronal (K ) T1-weighted images post-gadolinium

CHAPTER 46
demonstrate a lling defect in the superior sagittal sinus,
suggestive of thrombosis.

Atlas of Neuroimaging

FIGURE 46-21
Multiple system atrophy (Chap. 26) Sagittal T1-weighted MR image (B) demonstrates pontine
Axial T2-weighted MR image ( A) reveals symmetric poorly atrophy and enlarged cerebellar ssures as a result of cere-
circumscribed abnormal high signal in the middle cerebellar bellar atrophy (arrows).
peduncles bilaterally (arrowheads).
 640
SECTION III
Diseases of the Central Nervous System

FIGURE 46-22
Huntingtons disease (Chap. 25) Axial (B) and coronal (C) FLAIR images demonstrate bilateral
Axial noncontrast CT (A) demonstrates symmetric bilateral symmetric abnormal high signal in the caudate and putamen.
severe atrophy involving the caudate nuclei, putamen, and Coronal T1-weighted image (D) demonstrates enlarged
globus pallidi bilaterally with consequent enlargement of the frontal horns with abnormal conguration. Also note diffusely
frontal horns of the lateral ventricles (arrows). There is also decreased marrow signal, which could represent anemia or
diffuse prominence of the sulci indicating generalized cortical myeloproliferative disease.
atrophy.
 641

CHAPTER 46
Atlas of Neuroimaging
FIGURE 46-23
Bells palsy (Chap. 29)
Axial T1-weighted images post-gadolinium with fat suppres-
sion (AC) demonstrate diffuse smooth linear enhancement
along the left facial nerve, involving the second and third
segments (genus, tympanic, and mastoid) within the tempo-
ral bone (arrows). Note that there is no evidence of a mass
lesion. A potential pitfall for facial nerve enhancement in the
stylomastoid foramen is the enhancement of the stylomas-
toid artery that enters the foramen and supplies the tympanic
cavity, the tympanic antrum, mastoid cells, and the semicir-
cular canals.
Coronal T1-weighted images post-gadolinium with fat sup-
pression (D, E) demonstrate the course of the enhancing facial
nerve (arrows). Although these ndings are highly suggestive
of Bells palsy, the diagnosis is established on clinical grounds.
 642
SECTION III

FIGURE 46-24
Spinal cord infarction (Chap. 30) T1-weighted MR image of the lumbar spine post-gadolinium
Sagittal T2-weighted MR image of the lumbar spine (A) (B) demonstrates mild enhancement (arrow).
Diseases of the Central Nervous System

demonstrates poorly dened areas of abnormal high signal in Sagittal diffusion-weighted MR image of the lumbar spine
the conus medullaris and mild cord expansion (arrow). (C) demonstrates restricted diffusion (arrow) in the areas of
abnormal high signal on the T2-weighted image (A).

FIGURE 46-25
Acute transverse myelitis (Chap. 30) Sagittal T1-weighted MR image post-gadolinium (B) demon-
Sagittal T2-weighted MR image (A) demonstrates abnormal strates abnormal enhancement in the posterior half of the
high signal in the cervical cord extending from C1 to T1 with cord from C2 to T1 (arrows).
associated cord expansion (arrows).
 643

CHAPTER 46
Atlas of Neuroimaging
FIGURE 46-26
Acute disseminated encephalomyelitis (ADEM) (Chap. 34) Following administration of gadolinium, corresponding axial
Axial T2-weighted (A) and coronal FLAIR (B) images demon- (C) and coronal (D) T1-weighted images demonstrate irregu-
strate abnormal areas of high signal involving predominantly lar enhancement consistent with blood-brain barrier break-
the subcortical white matter of the frontal lobe bilaterally, and down and inammation; some lesions show incomplete rim
left caudate head. enhancement, typical for demyelination.
 644
SECTION III
Diseases of the Central Nervous System

FIGURE 46-27
Balos concentric sclerosis (a variant of multiple sclerosis) Axial (B) and sagittal (CE) T2-weighted MR images demon-
(Chap. 34) strate multiple areas of abnormal high signal in the supratentorial
Coronal FLAIR MRI (A) demonstrates multiple areas of white matter bilaterally, as well as the involvement of the body
abnormal high signal in the supratentorial white matter bilat- and splenium of the corpus callosum and the callosal-septal
erally. The lesions are ovoid in shape, perpendicular to the interface (arrowhead). Some of the lesions reveal concentric lay-
orientation of the lateral ventricles, and with little mass effect. ers, typical of Balos concentric sclerosis (arrows).
 645

CHAPTER 46
Atlas of Neuroimaging

FIGURE 46-27 (Continued)

Sagittal (F) and axial (G, H) T1-weighted MR images post- with some of the lesions demonstrating concentric ring
gadolinium demonstrate abnormal enhancement of all lesions enhancement (arrows).
 646
SECTION III
Diseases of the Central Nervous System

FIGURE 46-28
Hashimotos encephalopathy
Axial FLAIR (A) demonstrates focal area of abnormal high
signal involving the gray and white matter in the left frontal
lobe. There is also a small area of abnormal high signal in the
precentral gyrus.
Axial T1-weighted images (B, C) pre- and post-gadolinium
demonstrate cortical/pial enhancement in the region of high
signal on FLAIR.
 647

CHAPTER 46
Atlas of Neuroimaging

FIGURE 46-29
Brachial plexopathy (Chap. 7) and C8 nerve roots, and the trunks and divisions that origi-
Axial (A), sagittal (B), and coronal (C, D) short tau inversion nate from these roots (arrows).
recovery (STIR) MR images demonstrate abnormal enlarge-
ment and abnormal high signal involving the right C6, C7,
 648

FIGURE 46-29 (Continued)

Diffusion-weighted MR imaging (E) demonstrates abnormal
reduced diffusion within the right C6, C7, C8 nerve roots and
SECTION III

their corresponding trunks and divisions (arrow). These ndings

are compatible with radiation-induced brachial plexopathy.
Diseases of the Central Nervous System
 SECTION IV

CHRONIC FATIGUE
SYNDROME
 CHAPTER 47

CHRONIC FATIGUE SYNDROME

Stephen E. Straus

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652

Chronic fatigue syndrome (CFS) is the current name for a Estimates of the prevalence of CFS have depended on
disorder characterized by debilitating fatigue and several the case denition used and the method of study. Chronic
associated physical, constitutional, and neuropsychological fatigue itself is a common symptom, occurring in as many
complaints (Table 47-1).This syndrome is not new; in the as 20% of patients attending general medical clinics; CFS
past, patients diagnosed with conditions such as the vapors, is far less common. Community-based studies nd that
neurasthenia, effort syndrome, chronic brucellosis, epi- 100300 individuals per 100,000 population in the
demic neuromyasthenia, myalgic encephalomyelitis, hypo- United States meet the current CDC case denition.
glycemia, multiple chemical sensitivity syndrome, chronic
candidiasis, chronic mononucleosis, chronic Epstein-Barr PATHOGENESIS
virus (EBV) infection, and postviral fatigue syndrome may The diverse names for the syndrome reect the many
have had what is now called CFS. A subset of ill veterans and controversial hypotheses about its etiology. Several
of military campaigns suffer from CFS. The U.S. Centers common themes underlie attempts to understand the
for Disease Control and Prevention (CDC) has developed disorder: (1) it is often postinfectious; (2) it is associated
diagnostic criteria for CFS based upon symptoms and the with mild immunologic disturbances and sedentary
exclusion of other illnesses (Table 47-2). behavior during childhood; and (3) it is commonly
accompanied by neuropsychological complaints, somatic
preoccupation, and/or depression.
EPIDEMIOLOGY
Many studies over the past quarter century sought to
Patients with CFS are twice as likely to be women as link CFS to acute and/or persisting infections with EBV,
men and are generally 2545 years of age, although cases cytomegalovirus, human herpesvirus type 6, retroviruses,
in childhood and in later life have been described. enteroviruses, Candida albicans, Mycoplasma spp., or
Cases are recognized in many developed countries. Coxiella burnetii, among other microbial pathogens.
Most arise sporadically, but many clusters have also Compared to ndings in age-matched control subjects,
been reported. Famous outbreaks of CFS occurred in the titers of antibodies to some microorganisms are ele-
Los Angeles County Hospital in 1934; in Akureyri, Ice- vated in CFS patients. Reports that viral antigens and
land, in 1948; in the Royal Free Hospital, London, in nucleic acids could be specically identied in patients
1955; and in Incline Village, Nevada, in 1985. While with CFS, however, have not been conrmed. One study
these clustered cases suggest a common environmental from the United Kingdom failed to detect any associa-
or infectious cause, none has been identied. tion between acute infections and subsequent prolonged

Deceased.
650
TABLE 47-1 Changes in numerous immune parameters of uncertain 651
SPECIFIC SYMPTOMS REPORTED BY PATIENTS functional signicance have been reported in CFS. Modest
WITH CHRONIC FATIGUE SYNDROME elevations in titers of antinuclear antibodies, reductions in
immunoglobulin subclasses, deciencies in mitogen-driven
SYMPTOM PERCENTAGE
lymphocyte proliferation, reductions in natural killer cell
Fatigue 100 activity, disturbances in cytokine production, and shifts in
Difculty concentrating 90 lymphocyte subsets have been described. None of these
Headache 90 immune ndings appears in most patients, nor do any cor-
Sore throat 85
Tender lymph nodes 80
relate with the severity of CFS. Comparison of monozy-
Muscle aches 80 gotic twin pairs discordant for CFS showed no substantive
Joint aches 75 immunologic differences between affected and unaffected
Feverishness 75 individuals. In theory, symptoms of CFS could result from
Difculty sleeping 70 excessive production of a cytokine, such as interleukin 1,
Psychiatric problems 65 which induces asthenia and other ulike symptoms; how-
Allergies 55 ever, compelling data in support of this hypothesis are
Abdominal cramps 40
lacking. A recently published population-based study from
Weight loss 20
Rash 10 Wichita, Kansas, reported differences in gene expression
Rapid pulse 10 patterns and in candidate gene polymorphisms between
Weight gain 5 CFS patients and controls; these results are controversial
Chest pain 5 and await conrmation.
Night sweats 5 In some but not the more recent studies, patients
with CFS commonly manifested sensitivity to sustained
Source: From SE Straus: J Infect Diseases 157:405, 1988; with upright posture or tilting, resulting in hypotension and
permission.
syncope, so as to suggest a form of dysautonomia.

CHAPTER 47
TABLE 47-2
Disturbances in hypothalamic-pituitary-adrenal func-
tion have been identied in several controlled studies of
CDC CRITERIA FOR DIAGNOSIS OF CHRONIC
CFS, with some evidence for normalization in patients
FATIGUE SYNDROME
whose fatigue abates. These neuroendocrine abnormali-
A case of chronic fatigue syndrome is dened by the ties could contribute to the impaired energy and
presence of: depressed mood of patients.
1. Clinically evaluated, unexplained, persistent or
Mild to moderate depression is present in one-half

Chronic Fatigue Syndrome

relapsing fatigue that is of new or denite onset; is not
the result of ongoing exertion; is not alleviated by rest;
to two-thirds of patients. Much of this depression may
and results in substantial reduction of previous levels be reactive, but its prevalence exceeds that seen in other
of occupational, educational, social, or personal chronic medical illnesses. Some propose that CFS is
activities; and fundamentally a psychiatric disorder and that the vari-
2. Four or more of the following symptoms that persist or ous neuroendocrine and immune disturbances arise
recur during six or more consecutive months of illness secondarily.
and that do not predate the fatigue:
Self-reported impairment in short-term memory or
concentration MANIFESTATIONS
Sore throat
Tender cervical or axillary nodes Typically, CFS arises suddenly in a previously active
Muscle pain individual. An otherwise unremarkable ulike illness or
Multijoint pain without redness or swelling some other acute stress leaves unbearable exhaustion in
Headaches of a new pattern or severity its wake. Other symptoms, such as headache, sore throat,
Unrefreshing sleep tender lymph nodes, muscle and joint aches, and fre-
Postexertional malaise lasting 24 h quent feverishness, lead to the belief that an infection
persists, and medical attention is sought. Over weeks to
Note: CDC, U.S. Centers for Disease Control and Prevention.
months, despite reassurances that nothing serious is
Source: Adapted from K Fukuda et al: Ann Intern Med 121:953,
1994; with permission. wrong, the symptoms persist and other features of the
syndrome become evidentdisturbed sleep, difculty in
concentration, and depression (Table 47-1).
fatigue. Another study found that chronic fatigue did not Depending on the dominant symptoms and the beliefs
develop after typical upper respiratory infections but did of the patient, additional consultations may be sought from
in some individuals after infectious mononucleosis.Thus, allergists, rheumatologists, infectious disease specialists, psy-
while antecedent infections are associated with CFS, a chiatrists, ecologic therapists, homeopaths, or other profes-
direct microbial causality is unproven and unlikely. sionals, frequently with unsatisfactory results. Once the
 652 pattern of illness is established, the symptoms may uctu- that should not be simply dismissed as additional sub-
ate somewhat. Many patients report that CFS symptoms, jective complaints.
including cognitive problems, are exacerbated by intensive Many symptoms of CFS respond to treatment. Nons-
physical or other stressors, yet recent prospective studies teroidal anti-inammatory drugs alleviate headache, dif-
have not conrmed this impression. fuse pain, and feverishness. Allergic rhinitis and sinusitis
Most patients remain capable of meeting family, work, are common; when present, antihistamines or decon-
or community obligations despite their symptoms; discre- gestants may be helpful. Although the patient may be
tionary activities are abandoned rst. Some feel unable to averse to psychiatric diagnoses, depression and anxiety
engage in any gainful employment. A minority of indi- are often prominent and should be treated. Expert psy-
viduals requires help with the activities of daily living. chiatric assessment is sometimes advisable. Nonsedat-
Econometric analyses conducted by the CDC have ing antidepressants improve mood and disordered
conrmed that CFS exacts a signicant toll on house- sleep and may attenuate the fatigue. Even modest
hold and workforce productivity. improvements in symptoms can make an important dif-
Ultimately, isolation, frustration, and pathetic resigna- ference in the patients degree of self-sufciency and
tion can mark the protracted course of illness. Patients ability to appreciate lifes pleasures.
may become angry at physicians for failing to acknowl- Practical advice should be given regarding life-style.
edge or resolve their plight. Fortunately, CFS does not Sleep disturbances are common; consumption of heavy
appear to progress. On the contrary, many patients experi- meals, alcohol, and caffeine at night can make sleep even
ence gradual improvement, and a minority recover fully. more elusive, compounding fatigue. Total rest leads to fur-
ther deconditioning and the self-image of being an invalid,
DIAGNOSIS whereas overexertion may worsen exhaustion and lead to
total avoidance of exercise. A carefully graded exercise reg-
A thorough history, physical examination, and judicious
imen should be encouraged and has been proven to
use of laboratory tests are required to exclude other causes
relieve symptoms and enhance exercise tolerance.
of the patients symptoms. Prominent abnormalities argue
SECTION IV

Controlled therapeutic trials have established that

strongly in favor of alternative diagnoses. No laboratory
acyclovir, udrocortisone, galantamine, modanil, and IV
test, however, can diagnose this condition or measure its
immunoglobulin, among other agents, offer no signi-
severity. In most cases, elaborate, expensive workups are not
cant benet in CFS. Low doses of hydrocortisone provide
helpful. Early claims that MRI or single photon emission
modest benet but may lead to adrenal suppression.
CT can identify abnormalities in the brain of CFS patients
Countless anecdotes circulate regarding other tradi-
have not withstood further study. The dilemma for patient
tional and nontraditional therapies. It is important to
Chronic Fatigue Syndrome

and clinician alike is that CFS has no pathognomonic fea-

guide patients away from those therapeutic modalities
tures and remains a constellation of symptoms and a diag-
that are toxic, expensive, or unreasonable.
nosis of exclusion. Often the patient presents with features
The physician should promote the patients efforts to
that also meet criteria for other subjective disorders such as
recover. Several controlled trials conducted in the United
bromyalgia and irritable bowel syndrome. Questions have
Kingdom, in Australia, and in the Netherlands showed
been raised as to the relative merits of rendering a diagno-
cognitive-behavioral therapy to be helpful in adolescents
sis of CFS. Being diagnosed can provide validation of a
and adults with CFS. This approach aims to dispel mis-
patients perceived symptoms but may also perpetuate or
guided beliefs and fears about CFS that can contribute to
exacerbate them. Refusal to label a patient as having CFS,
inactivity and despair. For CFS, as for many other condi-
however, can deny the patient the opportunity to under-
tions, a comprehensive approach to physical, psychologi-
take treatments that are of proven merit.
cal, and social aspects of well-being is in order.

Treatment:
CHRONIC FATIGUE SYNDROME
FURTHER READINGS
After other illnesses have been excluded, there are sev-
BAKER R, SHAW EJ: Diagnosis and management of chronic fatigue
eral points to address in the long-term care of a patient syndrome or myalgic encephalitis (or encephalopathy): Summary
with chronic fatigue. of NICE guidance. BMJ 335:446, 2007
The patient should be educated about the illness JONES JF et al: An evaluation of exclusionary medical/psychiatric
and what is known of its pathogenesis; potential impact conditions in the denition of chronic fatigue syndrome. BMC
on the physical, psychological, and social dimensions of Med 7:57, 2009
life; and prognosis. Periodic reassessment is appropriate KILMAS NG, KONERU AO: Chronic fatigue syndrome: inflamma-
to identify a possible underlying process that is late in tion, immune function, and neuroendocrine interactions. Curr
Rheumatol Rep 9:482, 2007
declaring itself and to address intercurrent symptoms
PRINS JB et al: Chronic fatigue syndrome. Lancet 367:346, 2006
SECTION V

PSYCHIATRIC
DISORDERS
 CHAPTER 48

BIOLOGY OF PSYCHIATRIC DISORDERS

Steven E. Hyman Eric Kandel

Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Challenges with Phenotyping . . . . . . . . . . . . . . . . . . . . . . . . 656
Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 657
Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

Psychiatric disorders are a diverse group of brain disor- disorders, schizophrenia, and to some extent other psychi-
ders with symptoms that primarily involve emotion, atric disorders constitute the most potent risk factors for
higher cognitive function, and the ability to control suicide, a leading cause of death worldwide.
complex behaviors. A compendium of psychiatric disor-
ders can be found in the Diagnostic and Statistical Manual ANATOMY
of Mental Disorders, 4th edition (DSM-IV) of the Ameri- Progress in understanding the pathophysiology of psychi-
can Psychiatric Association. This compendium illustrates atric disorders has been slow, despite its fundamental
that the boundary between psychiatric and neurologic importance. Perhaps the most signicant challenge is
disorders, another heterogeneous group of brain disor- posed by the difculties inherent in understanding the
ders, is arbitrary and shifting. In areas of overlap such as high-level cognitive and affective functions of the brain
autism, Tourettes disorder, and Alzheimers disease, the that are disrupted in psychiatric disorders. As a result,
disorder is often treated by either a psychiatrist or a neu- unlike many neurologic disorders, the common psychi-
rologist.The term mental disorders, while still widely used, atric disorders appear to involve widely distributed neural
fails to acknowledge the neural substrates of these distur- networks and lack an obvious, localized neuropathology,
bances and their effects on physiology and behavior. which, if present, would help to narrow the hunt for cel-
The major psychiatric disorders are common and lular pathology and for underlying biochemical and mol-
often run a chronic course.The chronic disorders include ecular causes.Thus, the motor disturbances in Parkinsons
anxiety disorders, attention decit hyperactivity disorder, disease, Huntingtons disease, and amyotrophic lateral scle-
autism, obsessive-compulsive disorder, and schizophrenia. rosis result from discrete macroscopic lesions in different
Other psychiatric disorders such as depressive disorders parts of the motor system. By contrast, in psychiatric dis-
recur across the life span, but even bipolar disorder, classi- orders, when candidate regions have been identied, as in
cally characterized as episodic, can run a chronic course. schizophrenia, depression, and autism, it has proven dif-
The symptoms of psychiatric disorders often begin cult to differentiate convincingly, these abnormalities from
early, impairing the ability of children and adolescents to normal variation partly because these target regions form
learn and compromising the functioning of adults at work only one component of a disorder involving a much
and in other life roles. As a result of their high prevalence, larger neural circuit (Chap. 15).
early onset, and persistence, psychiatric disorders con-
tribute substantially to the burden of illness in all coun- GENETIC CONSIDERATIONS
tries in which they have been studied. In the United Given the challenges of identifying relatively sub-
States they are not only a leading cause of disability but tle neuropathology, it has long been hoped that the
also a signicant cause of premature death, because mood
654
identication of genetic variants conferring risk for psy- powerful tools to investigate the neural basis of the dis- 655
chiatric disorders would provide effective clues to those ease by putting the mutated gene into worms, ies, or
underlying neural abnormalities that contribute to the mice in order to study the mechanisms of pathogenesis.

CHAPTER 48
psychiatric disorder in question. This hope is based on While such tools are only a beginning, and indeed have
the signicant body of data derived from family, twin, not yet led to development of therapies, gene identica-
and adoption studies demonstrating that heredity plays a tion and the study of its function have already created a
signicant role in the risk of major psychiatric disorders, strong platform for investigation. It permits, for example,
including schizophrenia, bipolar disorder, depressive dis- the spatiotemporal characterization in the brain of the
orders, and many others. For example, the rate of schiz- expression of disease-related genes, the generation of

Biology of Psychiatric Disorders

ophrenia in the general population is ~1%. However, antibodies against the normal and altered proteins, and
when one member of a monozygotic twin pair is diag- the production by genetic engineering of worm, y, and
nosed with schizophrenia, the other twin, who is geneti- mouse models that could serve as assays for testing pos-
cally identical, has nearly a 50% chance of also manifest- sible therapies. Moreover, the identication of rare,
ing the disease. A rst-degree relative of an affected Mendelian forms of Parkinsons disease, Alzheimers dis-
proband (who shares on average 50% of DNA ease, amyotrophic lateral sclerosis, and epilepsy has pro-
sequences) has a 9% risk of schizophrenia. Adoption-at- vided signicant insights into the more common forms
birth studies provide additional strong support for a of these disorders. Thus far, however, no Mendelian
genetic contribution to schizophrenia spectrum disor- form of any of the common early-onset psychiatric dis-
ders; in one study from Finland, a schizophrenia-related orders of the brain has been identied convincingly. A
illness was present in nearly one-quarter of adoptees small number of Mendelian disorders have symptoms
whose biologic mother carried a similar diagnosis. that overlap with those of common psychiatric disor-
While there continue to be promising leads in the ders. For example, Rett syndrome, which results from
search for risk-conferring alleles, research over the past mutations in the methyl DNA binding protein MECP2,
two decades has not succeeded in identifying with cer- includes autistic-like symptoms but also many severe
tainty risk genes for psychiatric disorders.There have been symptoms that are not characteristic of autism.
large efforts using a variety of strategies, including linkage In psychiatric disorders such as schizophrenia, genes
studies and candidate gene studies, in attempts to identify are not, by themselves, causative; other factors, a second
genes responsible for schizophrenia, and more recently hit, must contribute. Unfortunately, these potential envi-
several groups have begun to undertake whole-genome ronmental factors, the second hits, have been difcult
association studies. The strongest candidates include: dis- to identify. One interesting nding, documented in the
rupted in schizophrenia (DISC1), a gene that was dis- Netherlands following World War II and in China, is that
rupted by a balanced chromosomal translocation in a maternal famine during gestation is correlated with an
Scottish family with schizophrenia-like symptoms; distro- increased incidence of schizophrenia, perhaps by con-
brevin-binding protein 1 (DTNBP1); and neuroregulin 1 tributing to de novo germ-line mutations. Other poten-
(NRG1), which encodes a protein involved in neuronal tial risk factors include urban birth, migration, increasing
migration and in expression of N-methyl-D-aspartate paternal age, and intrauterine exposure to viral infection.
(NMDA) glutamate receptors. Other potential candidates New genetic technologies are now available for the
include DAOA, RGS4, and AKT1, but the evidence sup- investigation of genetically complex disorders; these
porting them is weaker (Table 48-1). include more complete maps of human genetic variabil-
One problem in identifying risk genes for psychiatric ity, high-density whole-genome association methods, and
diseases has been the failure to replicate convincingly efcient high-throughput sequencing technologies using
the discovery of putative risk genes.The failure stems in single nucleotide polymorphism (SNP) arrays.The use of
large part from the complex nature of risk for psychi- these tools has already begun to yield signicant results
atric disorders, which appears to involve multiple genes for several common complex disorders, such as inam-
of small effect interacting with nongenetic factors. In matory bowel disease, age-related macular degeneration,
addition, there appear to be different risk genes in dif- and type 2 diabetes mellitus. Psychiatric disorders are
ferent population groups, perhaps reecting new or well positioned to benet from these new approaches. In
recent mutations. addition, it is expected that additional emerging tech-
It is now relatively straightforward to identify genes nologies, including cost-efcient methods for whole-
that exert large causal effects on disease. Several less genome sequencing, will soon be available, further
common neurologic disorders result from deleterious increasing the likelihood that risk-conferring alleles for
mutations within single genes. Thus, genes have been psychiatric disorders will be identied within the next
identied that contribute to the muscular dystrophies, few years. To take full advantage of these new methods,
triplet repeat disorders such as Huntingtons disease and the psychiatric research community will need to collect
fragile X, and Downs syndrome. The discovery of the very large populations for sufciently powered genetic
Huntington gene was followed by the development of studies, and identify (by high-resolution imaging, gene
 656 TABLE 48-1
SCHIZOPHRENIA CANDIDATE GENES

PROTEIN GENE CH LOCATION EVIDENCE FUNCTION

SECTION V

Disrupted in DISC1 1q42 Initially identied through Roles in microtubular

schizophrenia a balanced translocation transport and neuronal
in a single family with migration (via interactions
schizophrenia and with Lis1 and NudEL);
affective disorder; inuences postsynaptic
conrmed by linkage and responses (interactions with
Psychiatric Disorders

association in different Citron); activates

populations. phosphodiesterase 4B,
increasing cAMP (target of
antidepressant rolipram).
Dysbindin (dystrobrevin- DTNBP1 6p22 Linkage and association; Wide distribution in CNS;
binding protein 1) no coding region mutations; expression in synaptic
no consistent allele or terminals of hippocampus;
haplotype implicated in in vitro, reduced levels
different studies; negative decrease glutamate in
symptoms of schizophrenia neurons.
may associate with a specic
haplotype of DTNBP1;
expression decreased in
schizophrenia brain.
Neuregulin 1 NRG1 8p12-21 Linkage and association; no Suppresses function of
coding region mutations; no NMDA receptors; role in
consistent allele or haplotype neuronal differentiation
implicated in different studies; and migration.
expression increased in
schizophrenia brain.
D-Amino oxidase activator DAOA 13q32-34 Linkage and association; no Activates D-amino oxidase
consistent allele or haplotype which oxidies D-serine, an
implicated in different studies. agonist at NMDA receptors;
reduced D-serine levels
reported in blood and CSF
in schizophrenia.
Regulator of G-protein RGS4 1q21-22 Linkage and association; Modulates postsynaptic
signaling 4 susceptibility allele may signal transduction,
impair working memory and including downregulation
regionally reduce brain of 5HT1a (serotonin)
volumes receptors.
V-akt murine thymoma AKT1 14q22-32 Inconsistent linkage, Phosphorylates and
viral oncogene association, and brain inactivates glycogen
homologue 1 expression studies. synthase kinase (GSK) 3 beta.

Note: CH, chromosome; CNS, central nervous system; CSF, cerebrospinal uid; NMDA, N-methyl-D-aspartate.

expression patterns, or other markers) biologically mean- The diagnostic classication scheme (e.g., DSM-IV) upon
ingful phenotypes for stratication of the genetic data. which both research and clinical practice rely is derived
from expert consensus based on clusters of symptoms and
signs and disease course. As a result, failure to delineate
CHALLENGES WITH PHENOTYPING
well-dened disease entities and to reliably assign individ-
Psychiatric disorders have an additional obstacle to the uals, to affected versus nonaffected status have bedeviled
identication of risk genes or pathophysiologic processes psychiatric research.
that cannot be addressed simply by improving genetic The lack of objective tests for phenotyping presents
technologies.There are at the moment no objective diag- enormous difculties for genetic and other forms of inves-
nostic measures for any of the common psychiatric disor- tigation. While type 2 diabetes mellitus and hypertension,
ders. There is not, as yet, a well-dened neuropathology for example, are both highly heterogeneous disorders,
for psychiatric disorders nor are there biologic markers. the measurement of glucose tolerance or of systolic and
diastolic blood pressure creates a strong framework within electroconvulsive therapy, had immediate and sustained 657
which subtyping can occur, generally based on additional responses; however, due to the invasiveness, risk, and cost,
objective measures. In contrast, it is not at all certain that this approach may not become a widespread treatment.

CHAPTER 48
the boundaries currently drawn around disorders in the Its signicance lies in the putative identication of a cir-
DSM-IV lead to an underlying and distinguishable set of cuit involved in mood regulation that can be manipu-
neurobiologic factors. For example, there is much debate lated to produce therapeutic benet.
about the boundaries of schizophrenia. The DSM-IV lists
three psychotic disorders as being independentschizo-
phrenia, schizoaffective disorder, and schizophreniform

Biology of Psychiatric Disorders

disorder (American Psychiatric Association, 2000). Yet Treatment:
there is little agreement on whether the latter two are suf- PSYCHIATRIC DISORDERS
ciently homogeneous clinical entities to warrant inde- The high prevalence and serious consequences of psy-
pendent recognition. chiatric disorders make the availability of effective treat-
Despite the problems with current disease classication ments a matter of great importance for public health.
in psychiatry, there is agreement on the core symptoms Since the middle of the twentieth century, several
and strong cross-cultural similarity of disease manifesta- classes of pharmacologic treatments (antipsychotic
tion. In addition, there is a strong familial nature to major drugs, antidepressant drugs, lithium, benzodiazepines,
psychiatric disorders and also a potent role for heredity, and anticonvulsants) and several standardized short-
which can be inferred from twin and adoption studies. term psychotherapies have been developed and found
These ndings suggest that the central criteria for diag- to be efcacious in clinical trials. The result is an arma-
nosing schizophrenia, bipolar disorder, autism, and other mentarium of useful treatments for many of the common
major psychiatric disorders identify, however imperfectly, disorders; however, as is the case for many common,
distinctive, naturally occurring brain diseases. chronic medical disorders, there are no cures for psychi-
atric disorders. Residual symptoms and recurrences are
NEUROIMAGING common, and many pharmacologic treatments have
signicant side effects.
In parallel with improved classication and genetic stud- This state of affairs is typied by schizophrenia,
ies, attempts are being made using neuroimaging to where a large number of drugs have been developed.
dene anatomic abnormalities as objective, measurable Initially these drugs were thought to be useful only in
phenotypes of the disease. For example, new quantitative the treatment of schizophrenia; however, they are now
methods combined with structural MRI have suggested commonly used to treat any psychosis, irrespective of
that, in schizophrenia, there may be disease-specic pat- origin. In schizophrenia, in addition to the psychotic
terns of gray matter loss in frontal and temporal cerebral symptoms of hallucinations and delusions, referred to
cortex. Longitudinal studies of individuals with child- as positive symptoms, there are also negative symptoms
hood-onset schizophrenia have documented an acceler- (social withdrawal, impoverished speech, lack of motiva-
ated loss of gray matter. More recently, attempts have tion) and cognitive symptoms (poor executive function).
been made to associate specic DISC1 haplotypes with Both positive and negative symptoms are thought to be
reduced frontal gray matter. While these approaches are related to dopaminergic systems in the brain (Fig. 48-2).
in their early stages, the effort to dene objective brain- The primary clinical benet of antipsychotic drugs is the
based phenotypes for genetic and clinical studies appears amelioration of the positive psychotic symptoms. With
very promising. the exception of clozapine, often described as an atypi-
Functional imaging of individuals with depression cal antipsychotic drug, which produces improvement in
similarly has pinpointed abnormal activity in Brodman some patients who do not respond to other drugs, all
area 25, the subgenual prefrontal cortex, a brain region the existing antipsychotic drugs have similar efcacy
that connects to the amygdala and is thought to play a and differ primarily in their pattern of side effects. Cloza-
critical role in the processing of emotion-related infor- pine and some other atypical drugs are thought to exert
mation (Fig. 48-1). Area 25 exhibits excessive metabolic at least a modest therapeutic effect on the negative
activity in major depression, which reverses with success- symptoms of schizophrenia. None of the drugs, how-
ful antidepressant treatment. This region is also activated ever, is effective against the symptoms that are central
in normal subjects in whom sadness is induced by means to the illness. Furthermore, their residual presence
of emotion laden stimuli. This information serves as the throughout the course of the illness contributes sub-
basis for an experimental approach to severe depression stantially to the persistence of disability over the
involving the use of deep-brain stimulation of the sub- patients lifetime. The search for new drugs to treat
genual prefrontal cortex using implanted electrodes. In schizophrenia now focuses extensively on the ability to
an initial series, four of six patients with severe depression modify its cognitive symptoms. All antipsychotic drugs
unresponsive to all currently proven treatments, including
 658
x = 3
SECTION V
Psychiatric Disorders

Subgenual t value
PFC 0
y = 31

2.8

CC

5.5

FIGURE 48-1
Some patients with unipolar and bipolar disease show a of Neural Science, 4th ed. New York, McGraw-Hill, 2000;
functional abnormality in the prefrontal cortex ventral to the with permission.)
genu of the corpus callosum. (From ER Kandel et al: Principles

in current use block or diminish the action of dopamine benet at all. When pharmacologic modalities fail in
at its D2 receptors (Fig. 48-3); they differ in their relative depression, electroconvulsive therapy continues to be an
afnity at D2 receptors and by their actions at other effective treatment option. Lithium and several anticonvul-
neurotransmitter receptors. These drugs represent sants dampen mood swings in bipolar disorder and also
important progress, but safer and more effective treat- treat acute manic episodes; however, residual depressive
ments are very much needed. symptoms, recurrences, and signicant side effects are the
Drugs useful in depression act by increasing synaptic rule. The exact mechanism of action of lithium is not
levels of serotonin, norepinephrine, or less commonly known. At therapeutic levels, lithium interacts with two
dopamine (Fig. 48-4). The term antidepressant is a mis- important signaling pathways: (1) it blocks inositol
nomer for this diverse class of drugs, however, because monophosphatase, thus inuencing signaling via inositol
their spectrum of action is much broader than depres- phosphates, such as IP3; and (2) it also blocks glycogen syn-
sion. These drugs are also effective in treating fear-based thase kinase 3 beta (GSK3beta).
anxiety disorders such as panic disorder and generalized Unfortunately, there are currently very few promising
anxiety disorder. In high doses, the selective serotonin drug targets that can be exploited to produce medica-
uptake inhibitors are effective for obsessive-compulsive tions with truly novel mechanisms of action. Indeed, all
disorder. The antidepressants are effective in the treat- of the major classes of drugs used to treat psychiatric
ment of depression, but only moderately so. Many disorders were identied through empirical observa-
patients require sequential trials with a number of differ- tions of drug effects in patient populations rather than
ent drugs alone or in combination to achieve clinically as a result of understanding pathophysiology. The mole-
meaningful benet, and ~30% of patients derive no cular targets of these drugs were identied by the study
 Neocortex
Mesocortical system: 659
involved in the
Nucleus negative symptoms
accumbens of schizophrenia

CHAPTER 48
(ventral striatum)
Limbic
forebrain
Frontal
cortex

Biology of Psychiatric Disorders

Hippocampal
formation

Mesolimbic and
mesocortical Ventral
system tegmental Mesolimbic
Midbrain area system:
involved in the
positive symptoms
Hippocampal Ventral of schizophrenia
formation tegmental
area

A Midsagittal section B Coronal section

FIGURE 48-2
The major dopaminergic tracts of the brain. (From ER Kandel et al: Principles of Neural Science, 4th ed. New York,
McGraw-Hill, 2000.)

1a Tyrosine Antipsychotic
Increase of synthesis
(L-DOPA) Can produce
Tyrosine psychotic symptoms
1b
Inhibition of synthesis
(-methyltyrosine)
DOPA
2
Interference with vesicular
storage (reserpine, Dopamine
tetrabenazine) 6
Inhibition of breakdown
(pargyline)
3
Stimulation of release of
DA at nerve terminal
(amphetamine, tyramide)
MAO
Autoreceptor
D3

Vesicular monoamine
transporter
Dopamine
4 transporter 5
Blocking of DA receptors Inhibition of reuptake
and autoreceptors (cocaine, amphetamine,
(antipsychotics: benztropine)
perphenazine, haloperidol)
COMT

D2 D2

FIGURE 48-3
The key steps in the synthesis and degradation of et al: Principles of Neural Science, 4th ed. New York,
dopamine and the sites of action of various psychoactive McGraw-Hill, 2000.)
substances at the dopaminergic synapse. (From ER Kandel
 660 Depressant
Antidepressant
1
Inhibition of synthesis Tryptophan
(p-chlorophenylalanine,
p-propyldopacetamide)
SECTION V

5-OH-Tryptophan
5-HIAA

5-HT

2
Interference with
vesicular storage 5-HT
(reserpine, 5
Psychiatric Disorders

tetrabenazine) 5-HT Inhibition of enzyme

that oxidizes 5-HT MAO inhibitors
3a (iproniazid, clorgyline)
Stimulation of MAO
autoreceptor agonist
8-Hydroxy-dipropylamino-
tetraline (8-OH-DPAT) 4
Inhibition of reuptake Tricyclics and
(imipramine, selective serotonin
3b 5-HT amitryptyline, fluoxetine,
Stimulation of 5-HT reuptake inhibitors
receptors as sertraline)
partial agonist
(lysergic acid
diethylamide)
5-HT receptor
A Serotonergic neurons

Tyrosine
1a hydroxylase
Inhibition of synthesis
Deaminated
(-methyltyrosine)
products
1b DOPA
Inhibition of synthesis
(FLA 63)

Dopamine

2
Interference with
vesicular storage NE
(reserpine, 7
Inhibition of enzyme
tetrabenazine) that oxidizes NE MAO inhibitors
(pargyline)
3 NE
Stimulation of release of MAO
NE at nerve terminals
(amphetamine)
6
Inhibition of reuptake
(desipramine) Tricyclics
Receptor NM
4a 5
Stimulation of receptors Inhibition of enzyme
(clonidine) that inactivates NE Inactivation inhibitor
COMT (tropolone)

4b
Blocking of receptors
(phenoxybenzamine
and phentolamine)

B Noradrenergic neurons

FIGURE 48-4
Actions of antidepressant and other drugs at serotonergic and noradrenergic synapses. (From ER Kandel et al:
Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.)

of efcacious drugs and then exploited to produce trials. Instruments such as the Depression Inventory and
improved compounds within the same class. Suicide Intent Scale are now available for measuring
Cognitive-behavioral psychotherapy designed to mental illness; these have helped to objectify research
focus on the management of specic symptoms has in psychopathology.
shown benet in mild to moderately severe depression, New insights into the etiology of depression have
fear-based anxiety disorders, and obsessive-compulsive also helped to guide therapy. Depressed patients have a
disorder. A signicant improvement in the treatment of systematic negative bias in their cognitive stylesin
depression in the past decade has been the standard- the way they think about themselves and their future.
ization of psychotherapy and its evaluation in clinical These distorted patterns of thinking reect not simply
an unconscious conict within the psyche but a disor-
Medication therapy
Pre Post
661
der in cognitive style and behavior that is a key etiologic
agent in maintaining the disorder.

CHAPTER 48
An approach that focuses on distorted thinking, cog-
nitive therapy has been shown in randomized trials to
be an effective psychological treatment for depression.
Psychotherapy
This approach is based on increasing the patients Pre Post
objectivity regarding their misinterpretations of every-
day situations (their cognitive distortions), their miseval-

Biology of Psychiatric Disorders

uation of their internal processes (body sensations,
intrusive thoughts and images), and their negative
expectancies. A wide range of professionals can use the
methods with highly positive results.
Cognitive therapy has also proved benecial in indi- FIGURE 48-5
viduals at risk for suicide. Validated instruments exist to Patients with obsessive-compulsive disorder tend to
classify and assess suicidal behaviors, making it possible show hyperactivity in the head of the caudate. (From ER
to identify high-risk individuals prospectively. Of partic- Kandel et al: Principles of Neural Science, 4th ed. New York,
ular importance has been the identication of clinical McGraw-Hill, 2000.)
and psychological variables that predict future suicide.
Hopelessness and consequent suicidal ideation, which
are better predictors of suicide than clinical depression
per se, can be quantied and substantially reduced by FURTHER READINGS
cognitive interventions. Several studies with individuals BORA E et al: Neurobiology of human afliative behaviour: implica-
who had recently attempted suicide have demon- tions for psychiatric disorders. Curr Opin Psychiatry 22:320,
strated that a short-term cognitive intervention can sig- 2009
nicantly reduce subsequent suicide attempts when CANNON T et al: Association of DISC1/TRAX haplotypes with
compared to a control group. schizophrenia, reduced prefrontal gray matter, and impaired
This therapy has been extended to the treatment of short- and long-term memory. Arch Gen Psychiatry 62:1205,
2005
other disorders including anxiety states and obsessive-
DORPH-PETERSEN KA et al: Primary visual cortex volume and total
compulsive disorder. With respect to obsessive-compul- neuron number are reduced in schizophrenia. J Comp Neurol
sive disorders, cognitive therapy has been shown to 501:290, 2007
reverse a metabolic abnormality, identied by neuroimag- HAHN CG et al: Altered neuregulin 1-erbB4 signaling contributes to
ing, in parallel with the clinical improvement (Fig. 48-5). NMDA receptor hypofunction in schizophrenia. Nature Med
Cognitive therapy has replaced psychoanalytically 12: 824, 2006
based dynamic psychotherapy as the principal psycho- HYMAN SE: Can neuroscience be integrated into the DSM-V? Nat
Rev Neurosci 9:725, 2007
logical treatment provided by specialists in certain
KANDEL ER et al: Principles of Neural Science, 4th ed. New York,
countries. Its success has stimulated the development McGraw-Hill, 2000
of other forms of short-term psychotherapy, including KENDLER KS et al: A Swedish national twin study of lifetime major
Interpersonal Psychiatry and Psychoanalytic-Oriented depression.Am J Psychiatry 163:107, 2006
Insight Therapy. These therapies are now also being MCCLELLAN JM et al: Maternal famine, de novo mutations, and
tested in controlled clinical trials and have been found schizophrenia. JAMA 296: 582, 2006 ODONOVAN MC et al:
to be effective in a variety of clinical situations. Genetics of psychosis; insights from views across the genome.
Hum Genet. 126:3, 2009
Thus, paradoxically, one of the signicant advances in
RESSLER KJ, MAYBERG HS: Targeting abnormal neural circuits in
the era of the new brain-based biologic psychiatry has mood and anxiety disorders: from the laboratory to the clinic.
been the development of evidence-based psychother- Nat Neurosci 10:1116, 2007
apy, a development based on the evidence that insofar ROSS CA et al: Neurobiology of schizophrenia. Neuron 52:139,
as psychotherapy and other psychiatric treatments 2006
work, they do so by altering the functioning and per-
haps even the structure of the brain.
 CHAPTER 49

MENTAL DISORDERS

Victor I. Reus

I Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 Depressive Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672

Panic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663 Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Generalized Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . 664 I Somatoform Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
Phobic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668 I Personality Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
Stress Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669 I Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . 670 I Assessment and Evaluation of Violence . . . . . . . . . . . . . . . . 684
I Mood Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671 I Mental Health Problems in the Homeless . . . . . . . . . . . . . . . 684
Depression in Association with Medical Illness . . . . . . . . . . . 671 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684

Mental disorders are common in medical practice and the clinician into targeted assessment. Prime MD (and a
may present either as a primary disorder or as a comor- self-report form, the PHQ) and the Symptom-Driven
bid condition. The prevalence of mental or substance Diagnostic System for Primary Care (SDDS-PC) are
use disorders in the United States is approximately 30%. inventories that require only 10 min to complete and
Only one-third of these individuals are currently receiv- link patient responses to the formal diagnostic criteria
ing treatment. Global burden of disease statistics indicate of anxiety, mood, somatoform, and eating disorders and
that 4 out of the 10 most important causes of disease to alcohol abuse or dependence.
worldwide are psychiatric in origin. A physician who refers patients to a psychiatrist
The revised fourth edition for use by primary care should know not only when doing so is appropriate
physicians of the Diagnostic and Statistical Manual of Mental but also how to refer, since societal misconceptions and
Disorders (DSM-IV-PC) provides a useful synopsis of the stigma of mental illness impede the process. Pri-
mental disorders most likely to be seen in primary care mary care physicians should base referrals to a psychia-
practice.The current system of classication is multiaxial trist on the presence of signs and symptoms of a men-
and includes the presence or absence of a major mental tal disorder and not simply on the absence of a physical
disorder (axis I), any underlying personality disorder explanation for a patients complaint. The physician
(axis II), general medical condition (axis III), psychoso- should discuss with the patient the reasons for request-
cial and environmental problems (axis IV), and overall ing the referral or consultation and provide reassurance
rating of general psychosocial functioning (axis V). that he or she will continue to provide medical care
Changes in health care delivery underscore the need and work collaboratively with the mental health pro-
for primary care physicians to assume responsibility for fessional. Consultation with a psychiatrist or transfer of
the initial diagnosis and treatment of the most common care is appropriate when physicians encounter evi-
mental disorders. Prompt diagnosis is essential to ensure dence of psychotic symptoms, mania, severe depres-
that patients have access to appropriate medical services sion, or anxiety; symptoms of posttraumatic stress
and to maximize the clinical outcome. Validated disorder (PTSD); suicidal or homicidal preoccupation;
patient-based questionnaires have been developed that or a failure to respond to rst-order treatment. The
systematically probe for signs and symptoms associated pathogenesis of psychiatric and addictive disorders are
with the most prevalent psychiatric diagnoses and guide discussed in Chap. 48.

662
 feelings of unreality are also common. Diagnostic crite- 663
ANXIETY DISORDERS
ria require at least 1 month of concern or worry about
Anxiety disorders, the most prevalent psychiatric ill- the attacks or a change in behavior related to them.The

CHAPTER 49
nesses in the general community, are present in 1520% lifetime prevalence of panic disorder is 13%. Panic
of medical clinic patients. Anxiety, dened as a subjec- attacks have a sudden onset, developing within 10 min
tive sense of unease, dread, or foreboding, can indicate a and usually resolving over the course of an hour, and
primary psychiatric condition or can be a component they occur in an unexpected fashion.The frequency and
of, or reaction to, a primary medical disease. The pri- severity of panic attacks vary, ranging from once a week
mary anxiety disorders are classied according to their to clusters of attacks separated by months of well-being.

Mental Disorders
duration and course and the existence and nature of The rst attack is usually outside the home, and onset is
precipitants. typically in late adolescence to early adulthood. In some
When evaluating the anxious patient, the clinician individuals, anticipatory anxiety develops over time and
must rst determine whether the anxiety antedates or results in a generalized fear and a progressive avoidance
postdates a medical illness or is due to a medication side of places or situations in which a panic attack might
effect. Approximately one-third of patients presenting recur. Agoraphobia, which occurs commonly in patients
with anxiety have a medical etiology for their psychi- with panic disorder, is an acquired irrational fear of
atric symptoms, but an anxiety disorder can also present being in places where one might feel trapped or unable
with somatic symptoms in the absence of a diagnosable to escape (Table 49-2).Typically, it leads the patient into
medical condition. a progressive restriction in lifestyle and, in a literal sense,
in geography. Frequently, patients are embarrassed that
they are housebound and dependent on the company of
PANIC DISORDER others to go out into the world and do not volunteer
Clinical Manifestations this information; thus physicians will fail to recognize the
syndrome if direct questioning is not pursued.
Panic disorder is dened by the presence of recurrent
and unpredictable panic attacks, which are distinct
episodes of intense fear and discomfort associated with a
variety of physical symptoms, including palpitations,
sweating, trembling, shortness of breath, chest pain, TABLE 49-2
dizziness, and a fear of impending doom or death DIAGNOSTIC CRITERIA FOR AGORAPHOBIA
(Table 49-1). Paresthesias, gastrointestinal distress, and
1. Anxiety about being in places or situations from which
escape might be difcult (or embarrassing) or in which
help may not be available in the event of having an
unexpected or situationally predisposed panic attack
TABLE 49-1 or panic-like symptoms. Agoraphobic fears typically
DIAGNOSTIC CRITERIA FOR PANIC ATTACK involve characteristic clusters of situations that
include being outside the home alone; being in a
A discrete period of intense fear or discomfort, in which crowd or standing in a line; being on a bridge; and
four or more of the following symptoms developed traveling in a bus, train, or automobile.
abruptly and reached a peak within 10 min: 2. The situations are avoided (e.g., travel is restricted) or
1. Palpitations, pounding heart, or accelerated heart rate else are endured with marked distress or with anxiety
2. Sweating about having a panic attack or panic-like symptoms,
3. Trembling or shaking or require the presence of a companion.
4. Sensations of shortness of breath or smothering 3. The anxiety or phobic avoidance is not better
5. Feeling of choking accounted for by another mental disorder, such as
6. Chest pain or discomfort social phobia (e.g., avoidance limited to social situa-
7. Nausea or abdominal distress tions because of fear of embarrassment), specic
8. Feeling dizzy, unsteady, lightheaded, or faint phobia (e.g., avoidance limited to a single situation
9. Derealization (feelings of unreality) or depersonaliza- like elevators), obsessive-compulsive disorder (e.g.,
tion (being detached from oneself) avoidance of dirt in someone with an obsession about
10. Fear of losing control or going crazy contamination), posttraumatic stress disorder (e.g.,
11. Fear of dying avoidance of stimuli associated with a severe stres-
12. Paresthesias (numbness or tingling sensations) sor), or separation anxiety disorder (e.g., avoidance of
13. Chills or hot ushes leaving home or relatives).

Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
Washington, DC, American Psychiatric Association, 2000. Washington, DC, American Psychiatric Association, 2000.
 664 Differential Diagnosis
Treatment:
A diagnosis of panic disorder is made after a medical eti- PANIC DISORDER
ology for the panic attacks has been ruled out. A variety
SECTION V

Achievable goals of treatment are to decrease the fre-

of cardiovascular, respiratory, endocrine, and neurologic
quency of panic attacks and to reduce their intensity.
conditions can present with anxiety as the chief com-
The cornerstone of drug therapy is antidepressant med-
plaint. Patients with true panic disorder will often focus
ication (Tables 49-3, 49-4, and 49-5). Selective sero-
on one specic feature to the exclusion of others. For
tonin reuptake inhibitors (SSRIs) benet the majority of
example, 20% of patients who present with syncope as a
panic disorder patients and do not have the adverse
primary medical complaint have a primary diagnosis of
Psychiatric Disorders

effects of tricyclic antidepressants (TCAs). Fluoxetine,

a mood, anxiety, or substance-abuse disorder, the most
paroxetine, and sertraline have received approval from
common being panic disorder. The differential diagnosis
the U.S. Food and Drug Administration (FDA) for this
of panic disorder is complicated by a high rate of
indication. SSRIs should be started at one-third to one-
comorbidity with other psychiatric conditions, espe-
half of their usual antidepressant dose (e.g., 510 mg
cially alcohol and benzodiazepine abuse, which patients
uoxetine, 2550 mg sertraline, 10 mg paroxetine).
initially use in an attempt at self-medication. Some 75%
Monoamine oxidase inhibitors (MAOIs) are also effective
of panic disorder patients will also satisfy criteria for
and may specically benet patients who have comor-
major depression at some point in their illness.
bid features of atypical depression (i.e., hypersomnia
When the history is nonspecic, physical examination
and weight gain). Insomnia, orthostatic hypotension,
and focused laboratory testing must be used to rule out
and the need to maintain a low-tyramine diet (avoid-
anxiety states resulting from medical disorders such as
ance of cheese and wine) have limited their use, how-
pheochromocytoma, thyrotoxicosis, or hypoglycemia.
ever. Antidepressants typically take 26 weeks to
Electrocardiogram (ECG) and echocardiogram may
become effective, and doses may need to be adjusted
detect some cardiovascular conditions associated with
based upon the clinical response.
panic, such as paroxysmal atrial tachycardia and mitral
Because of anticipatory anxiety and the need for
valve prolapse. In two studies, panic disorder was the
immediate relief of panic symptoms, benzodiazepines
primary diagnosis in 43% of patients with chest pain
are useful early in the course of treatment and sporadi-
who had normal coronary angiograms and was present
cally thereafter (Table 49-6). For example, alprazolam,
in 9% of all outpatients referred for cardiac evaluation.
starting at 0.5 mg qid and increasing to 4 mg/d in
Panic disorder has also been diagnosed in many patients
divided doses, is effective, but patients must be moni-
referred for pulmonary function testing or with symp-
tored closely, as some develop dependence and begin
toms of irritable bowel syndrome.
to escalate the dose of this medication. Clonazepam, at
a nal maintenance dose of 24 mg/d, is also helpful; its
longer half-life permits twice-daily dosing, and patients
Etiology and Pathophysiology appear less likely to develop dependence on this agent.
The etiology of panic disorder is unknown but appears to Early psychotherapeutic intervention and education
involve a genetic predisposition, altered autonomic respon- aimed at symptom control enhances the effectiveness
sivity, and social learning. Panic disorder shows familial of drug treatment. Patients can be taught breathing
aggregation; the disorder is concordant in 3045% of techniques, educated about physiologic changes that
monozygotic twins, and genome-wide screens have iden- occur with panic, and learn to expose themselves volun-
tied suggestive risk loci. Acute panic attacks appear to be tarily to precipitating events in a treatment program
associated with increased noradrenergic discharges in the spanning 1215 sessions. Homework assignments and
locus coeruleus. Intravenous infusion of sodium lactate monitored compliance are important components of
evokes an attack in two-thirds of panic disorder patients, as successful treatment. Once patients have achieved a
do the 2-adrenergic antagonist yohimbine, cholecys- satisfactory response, drug treatment should be main-
tokinin tetrapeptide (CCK-4), and carbon dioxide inhala- tained for 12 years to prevent relapse. Controlled trials
tion. It is hypothesized that each of these stimuli activates a indicate a success rate of 7585%, although the likeli-
pathway involving noradrenergic neurons in the locus hood of complete remission is somewhat lower.
coeruleus and serotonergic neurons in the dorsal raphe.
Agents that block serotonin reuptake can prevent attacks.
Panic-disorder patients have a heightened sensitivity to GENERALIZED ANXIETY DISORDER
somatic symptoms, which triggers increasing arousal, set-
ting off the panic attack; accordingly, therapeutic interven- Clinical Manifestations
tion involves altering the patients cognitive interpretation Patients with generalized anxiety disorder (GAD) have
of anxiety-producing experiences as well as preventing the persistent, excessive, and/or unrealistic worry associated
attack itself. with muscle tension, impaired concentration, autonomic
TABLE 49-3 665
ANTIDEPRESSANTS

CHAPTER 49
NAME USUAL DAILY DOSE, mg SIDE EFFECTS COMMENTS

SSRIs
Fluoxetine (Prozac) 1080 Headache; nausea and Once daily dosing, usually in
Sertraline (Zoloft) 50200 other GI effects; jitteriness; A.M.; uoxetine has very long
Paroxetine (Paxil) 2060 insomnia; sexual dysfunction; half-life; must not be combined
Fluvoxamine (Luvox) 100300 can affect plasma levels of other with MAOIs
Citalopram (Celexa) 2060 meds (except sertraline);

Mental Disorders
Escitalopram (Lexapro) 1030 akathisia rare
TCAs
Amitriptyline (Elavil) 150300 Anticholinergic (dry mouth, Once daily dosing, usually qhs;
Nortriptyline (Pamelor) 50200 tachycardia, constipation, blood levels of most TCAs
Imipramine (Tofranil) 150300 urinary retention, blurred vision); available; can be lethal in O.D.
Desipramine (Norpramin) 150300 sweating; tremor; postural (lethal dose = 2 g); nortriptyline
Doxepin (Sinequan) 150300 hypotension; cardiac conduction best tolerated, especially by
Clomipramine (Anafranil) 150300 delay; sedation; weight gain elderly
Mixed norepinephrine/
serotonin reuptake
inhibitors
Venlafaxine (Effexor) 75375 Nausea; dizziness; dry mouth; Bid-tid dosing (extended release
headaches; increased blood available); lower potential for
pressure; anxiety and insomnia drug interactions than SSRIs;
contraindicated with MAOI
Duloxetine (Cymbalta) 4060 Nausea, dizziness, headache, May have utility in treatment of
insomnia, constipation neuropathic pain and stress
incontinence
Mirtazapine (Remeron) 1545 Somnolence; weight gain; Once daily dosing
neutropenia rare
Mixed-action drugs
Bupropion (Wellbutrin) 250450 Jitteriness; ushing; seizures in Tid dosing, but sustained
at-risk patients; anorexia; release also available; fewer
tachycardia; psychosis sexual side effects than SSRIs
or TCAs; may be useful for
adult ADD
Trazodone (Desyrel) 200600 Sedation; dry mouth; ventricular Useful in low doses for sleep
irritability; postural hypotension; because of sedating effects
priapism rare with no anticholinergic side
effects
Nefazodone (Serzone) 300600 Sedation; headache; dry mouth; Discontinued sale in United
nausea; constipation States and several other
countries due to risk of liver
failure
Amoxapine (Asendin) 200600 Sexual dysfunction Lethality in overdose; EPS
possible
MAOIs
Phenelzine (Nardil) 4590 Insomnia; hypotension; May be more effective in
Tranylcypromine 2050 anorgasmia; weight gain; patients with atypical features
(Parnate) hypertensive crisis; toxic or treatment-refractory
Isocarboxazid (Marplan) 2060 reactions with SSRIs depression
Transdermal selegiline 612 Local skin reaction; hypertension No dietary restrictions with
(Emsam) 6-mg dose

Note: ADD, attention decit disorder; MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepres-
sant; EPS, extrapyramidal symptoms.

arousal, feeling on edge or restless, and insomnia diagnosis. Interestingly, family studies indicate that GAD
(Table 49-7). Onset is usually <20 years, and a history and panic disorder segregate independently. Over 80%
of childhood fears and social inhibition may be present. of patients with GAD also suffer from major depression,
The lifetime prevalence of GAD is 56%; the risk is dysthymia, or social phobia. Comorbid substance abuse
higher in rst-degree relatives of patients with the is common in these patients, particularly alcohol and/or
 666 TABLE 49-4
MANAGEMENT OF ANTIDEPRESSANT SIDE EFFECTS

SYMPTOMS COMMENTS AND MANAGEMENT STRATEGIES

SECTION V

Gastrointestinal
Nausea, loss of appetite Usually short-lived and dose-related; consider temporary dose reduction or
administration with food and antacids
Diarrhea Famotidine, 2040 mg/d
Constipation Wait for tolerance; try diet change, stool softener, exercise; avoid laxatives
Sexual dysfunction Consider dose reduction; drug holiday
Psychiatric Disorders

Anorgasmia/impotence; Bethanechol, 1020 mg, 2 h before activity, or cyproheptadine, 48 mg 2 h

impaired ejaculation before activity, or bupropion, 100 mg bid or amantadine, 100 mg bid/tid
Orthostasis Tolerance unlikely; increase uid intake, use calf exercises/support hose;
udrocortisone, 0.025 mg/d
Anticholinergic Wait for tolerance
Dry mouth, eyes Maintain good oral hygiene; use articial tears, sugar-free gum
Tremor/jitteriness Antiparkinsonian drugs not effective; use dose reduction/slow increase;
lorazepam, 0.5 mg bid, or propranolol, 1020 mg bid
Insomnia Schedule all doses for the morning; trazodone, 50100 mg qhs
Sedation Caffeine; schedule all dosing for bedtime; bupropion, 75100 mg in
afternoon
Headache Evaluate diet, stress, other drugs; try dose reduction; amitriptyline, 50 mg/d
Weight gain Decrease carbohydrates; exercise; consider uoxetine
Loss of therapeutic Related to tolerance? Increase dose or drug holiday;
benet over time add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2.5 mg bid

TABLE 49-5 Etiology and Pathophysiology

POSSIBLE DRUG INTERACTIONS WITH SELECTIVE
Anxiogenic agents share in common the property of alter-
SEROTONIN REUPTAKE INHIBITORS
ing the binding of benzodiazepines to the -aminobutyric
AGENT EFFECT acid (GABA)A receptor/chloride ion channel complex,
Monoamine oxidase Serotonin syndromea
implicating this neurotransmitter system in the patho-
inhibitors absolute contraindication genesis of anxiety and panic attacks. Benzodiazepines are
Serotonergic agonists, e.g., Potential serotonin thought to bind two separate GABAA receptor sites:
tryptophan, fenuramine syndrome type I, which has a broad neuroanatomic distribution,
Drugs that are metabolized Delayed metabolism and type II, which is concentrated in the hippocampus,
by P450 isoenzymes: resulting in increased striatum, and neocortex. The antianxiety effects of the
tricyclics, other SSRIs, blood levels and potential various benzodiazepines and side effects such as sedation
antipsychotics, beta toxicitypossible fatality
blockers, codeine, secondary to QT
and memory impairment are inuenced by their relative
triazolobenzodiazepines, prolongation with binding to type I and type II receptor sites. Serotonin
calcium channel blockers terfenadine or astemizole [5-hydroxytryptamine (5HT)] and 3-reduced neurac-
Drugs that are bound tightly Increased bleeding tive steroids (allosteric modulators of GABAA) also
to plasma proteins, e.g., secondary to appear to have a role in anxiety, and buspirone, a partial
warfarin displacement 5HT1A receptor agonist, and certain 5HT2A and 5HT2C
Drugs that inhibit the Increased SSRI side receptor antagonists (e.g., nefazodone) may have bene-
metabolism of SSRIs by effects
cial effects.
P450 isoenzymes, e.g.,
quinidine

a
See Rx Depressive Disorders, later.
Note: SSRI, selective serotonin reuptake inhibitor.
Treatment:
GENERALIZED ANXIETY DISORDER
A combination of pharmacologic and psychotherapeu-
sedative/hypnotic abuse. Patients with GAD worry tic interventions is most effective in GAD, but complete
excessively over minor matters, with life-disrupting symptomatic relief is rare. A short course of a benzodi-
effects; unlike in panic disorder, complaints of shortness azepine is usually indicated, preferably lorazepam,
of breath, palpitations, and tachycardia are relatively rare. oxazepam, or temazepam. (The rst two of these agents
TABLE 49-6 667
ANXIOLYTICS

CHAPTER 49
EQUIVALENT PO
NAME DOSE, mg ONSET OF ACTION HALF-LIFE, h COMMENTS

Benzodiazepines
Diazepam (Valium) 5 Fast 2070 Active metabolites; quite sedating
Flurazepam 15 Fast 30100 Flurazepam is a pro-drug; metabolites
(Dalmane) are active; quite sedating
Triazolam (Halcion) 0.25 Intermediate 1.55 No active metabolites; can induce

Mental Disorders
confusion and delirium, especially in
elderly
Lorazepam (Ativan) 1 Intermediate 1020 No active metabolites; direct hepatic
glucuronide conjugation; quite
sedating
Alprazolam (Xanax) 0.5 Intermediate 1215 Active metabolites; not too sedating;
may have specic antidepressant and
antipanic activity; tolerance and
dependence develop easily
Chlordiazepoxide 10 Intermediate 530 Active metabolites; moderately
(Librium) sedating
Oxazepam (Serax) 15 Slow 515 No active metabolites; direct
glucuronide conjugation; not too
sedating
Temazepam 15 Slow 912 No active metabolites; moderately
(Restoril) sedating
Clonazepam 0.5 Slow 1850 No active metabolites; moderately
(Klonopin) sedating
Non-benzodiazepines
Buspirone (BuSpar) 7.5 2 weeks 23 Active metabolites; tid dosingusual
daily dose 1020 mg tid; nonsedating;
no additive effects with alcohol; useful
for agitation in demented or brain-
injured patients

TABLE 49-7
DIAGNOSTIC CRITERIA FOR GENERALIZED ANXIETY DISORDER
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a
number of events or activities (such as work or school performance).
B. The person nds it difcult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms
present for more days than not for the past 6 months):
1. restlessness or feeling keyed up or on edge
2. being easily fatigued
3. difculty concentrating or mind going blank
4. irritability
5. muscle tension
6. sleep disturbance (difculty falling or staying asleep, or restless unsatisfying sleep)
D. The focus of the anxiety and worry is not conned to features of an Axis I disorder, e.g., the anxiety or worry is not about
having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in
obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining
weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having a serious
illness (as in hypochondriasis), and the anxiety and worry do not occur exclusively during posttraumatic stress disorder.
E. The anxiety, worry, or physical symptoms cause clinically signicant distress or impairment in social, occupational,
or other important areas of functioning.
F. The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a gen-
eral medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder,
or a pervasive developmental disorder.

Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association, 2000.
 668 are metabolized via conjugation rather than oxidation doses that are comparable to their efcacy in major
and thus do not accumulate if hepatic function is depression. Benzodiazepines are contraindicated dur-
altered.) Administration should be initiated at the lowest ing pregnancy and breast-feeding.
SECTION V

dose possible and prescribed on an as-needed basis as Anticonvulsants with GABAergic properties may also
symptoms warrant. Benzodiazepines differ in their mil- be effective against anxiety. Gabapentin, oxcarbazepine,
ligram per kilogram potency, half-life, lipid solubility, tiagabine, pregabalin, and divalproex have all shown
metabolic pathways, and presence of active metabo- some degree of benet in a variety of anxiety-related
lites. Agents that are absorbed rapidly and are lipid solu- syndromes. Agents that selectively target GABAA recep-
ble, such as diazepam, have a rapid onset of action and a tor subtypes are currently under development, and it
Psychiatric Disorders

higher abuse potential. Benzodiazepines should gener- is hoped that these will lack the sedating, memory-
ally not be prescribed for >46 weeks because of the impairing, and addicting properties of benzodiazepines.
development of tolerance and the risk of abuse and
dependence. Withdrawal must be closely monitored as
relapses can occur. It is important to warn patients that
concomitant use of alcohol or other sedating drugs may PHOBIC DISORDERS
be neurotoxic and impair their ability to function. An Clinical Manifestations
optimistic approach that encourages the patient to clar-
The cardinal feature of phobic disorders is a marked and
ify environmental precipitants, anticipate his or her reac-
persistent fear of objects or situations, exposure to which
tions, and plan effective response strategies is an essen-
results in an immediate anxiety reaction. The patient
tial element of therapy.
avoids the phobic stimulus, and this avoidance usually
Adverse effects of benzodiazepines generally parallel
impairs occupational or social functioning. Panic attacks
their relative half-lives. Longer-acting agents, such as
may be triggered by the phobic stimulus or may occur
diazepam, chlordiazepoxide, urazepam, and clon-
spontaneously. Unlike patients with other anxiety disor-
azepam, tend to accumulate active metabolites, with
ders, individuals with phobias usually experience anxiety
resultant sedation, impairment of cognition, and poor
only in specic situations. Common phobias include
psychomotor performance. Shorter-acting compounds,
fear of closed spaces (claustrophobia), fear of blood, and
such as alprazolam and oxazepam, can produce day-
fear of ying. Social phobia is distinguished by a specic
time anxiety, early morning insomnia, and, with discon-
fear of social or performance situations in which the
tinuation, rebound anxiety and insomnia. Although
individual is exposed to unfamiliar individuals or to pos-
patients develop tolerance to the sedative effects of
sible examination and evaluation by others. Examples
benzodiazepines, they are less likely to habituate to the
include having to converse at a party, use public
adverse psychomotor effects. Withdrawal from the
restrooms, and meet strangers. In each case, the affected
longer half-life benzodiazepines can be accomplished
individual is aware that the experienced fear is excessive
through gradual, stepwise dose reduction (by 10%
and unreasonable given the circumstance. The specic
every 12 weeks) over 612 weeks. It is usually more dif-
content of a phobia may vary across gender, ethnic, and
cult to taper patients off shorter-acting benzodi-
cultural boundaries.
azepines. Physicians may need to switch the patient to a
Phobic disorders are common, affecting ~10% of the
benzodiazepine with a longer half-life or use an adjunc-
population. Full criteria for diagnosis are usually satised
tive medication, such as a beta blocker or carba-
rst in early adulthood, but behavioral avoidance of
mazepine, before attempting to discontinue the benzo-
unfamiliar people, situations, or objects dating from early
diazepine. Withdrawal reactions vary in severity and
childhood is common.
duration; they can include depression, anxiety, lethargy,
In one study of female twins, concordance rates for
diaphoresis, autonomic arousal, and, rarely, seizures.
agoraphobia, social phobia, and animal phobia were
Buspirone is a nonbenzodiazepine anxiolytic agent.
found to be 23% for monozygotic twins and 15% for
It is nonsedating, does not produce tolerance or depen-
dizygotic twins. A twin study of fear conditioning, a
dence, does not interact with benzodiazepine recep-
model for the acquisition of phobias, demonstrated a
tors or alcohol, and has no abuse or disinhibition
heritability of 3545%, and a genome-wide linkage
potential. However, it requires several weeks to take
scan identied a risk locus on chromosome 14 in a
effect and requires thrice-daily dosing. Patients who
region previously implicated in a mouse model of fear.
were previously responsive to a benzodiazepine are
Animal studies of fear conditioning have indicated that
unlikely to rate buspirone as equally effective, but
processing of the fear stimulus occurs through the lat-
patients with head injury or dementia who have symp-
eral nucleus of the amygdala, extending through the
toms of anxiety and/or agitation may do well with this
central nucleus and projecting to the periaqueductal
agent. Escitalopram, paroxetine, and venlafaxine are
gray region, lateral hypothalamus, and paraventricular
FDA approved for the treatment of GAD, usually at
hypothalamus.
 TABLE 49-8 669
Treatment: DIAGNOSTIC CRITERIA FOR POSTTRAUMATIC
PHOBIC DISORDERS STRESS DISORDER

CHAPTER 49
Beta blockers (e.g., propranolol, 2040 mg orally 2 h A. The person has been exposed to a traumatic event in
before the event) are particularly effective in the treat- which both of the following were present:
ment of performance anxiety (but not general social 1. The person experienced, witnessed, or was con-
phobia) and appear to work by blocking the peripheral fronted with an event or events that involved actual
manifestations of anxiety, such as perspiration, tachycar- or threatened death or serious injury, or a threat to
dia, palpitations, and tremor. MAOIs alleviate social pho- the physical integrity of self or others
2. The persons response involved intense fear, help-

Mental Disorders
bia independently of their antidepressant activity, and
paroxetine, sertraline, and venlafaxine have received lessness, or horror
B. The traumatic event is persistently reexperienced in
FDA approval for treatment of social anxiety. Benzodi-
one (or more) of the following ways:
azepines can be helpful in reducing fearful avoidance, 1. Recurrent and intrusive distressing recollections
but the chronic nature of phobic disorders limits their of the event, including images, thoughts, or
usefulness. perceptions
Behaviorally focused psychotherapy is an important 2. Recurrent distressing dreams of the event
component of treatment, as relapse rates are high when 3. Acting or feeling as if the traumatic event were
medication is used as the sole treatment. Cognitive- recurring (includes a sense of reliving the experi-
ence, illusions, hallucinations, and dissociative
behavioral strategies are based upon the nding that
ashback episodes, including those that occur on
distorted perceptions and interpretations of fear-pro- awakening or when intoxicated)
ducing stimuli play a major role in perpetuation of pho- 3. Intense psychological distress at exposure to inter-
bias. Individual and group therapy sessions teach the nal or external cues that symbolize or resemble an
patient to identify specic negative thoughts associated aspect of the traumatic event
with the anxiety-producing situation and help to reduce 4. Physiologic reactivity on exposure to internal or
the patients fear of loss of control. In desensitization external cues that symbolize or resemble an aspect
therapy, hierarchies of feared situations are constructed of the traumatic event
C. Persistent avoidance of stimuli associated with the
and the patient is encouraged to pursue and master
trauma and numbing of general responsiveness (not
gradual exposure to the anxiety-producing stimuli. present before the trauma), as indicated by three or
Patients with social phobia, in particular, have a high more of the following:
rate of comorbid alcohol abuse, as well as of other psy- 1. Efforts to avoid thoughts, feelings, or conversations
chiatric conditions (e.g., eating disorders), necessitating associated with the trauma
the need for parallel management of each disorder if 2. Efforts to avoid activities, places, or people that
anxiety reduction is to be achieved. arouse recollections of the trauma
3. Inability to recall an important aspect of the trauma
4. Markedly diminished interest or participation in
signicant activities
5. Feeling of detachment or estrangement from others
STRESS DISORDERS 6. Restricted range of affect (e.g., unable to have
Clinical Manifestations loving feelings)
7. Sense of a foreshortened future (e.g., does not
Patients may develop anxiety after exposure to extreme expect to have a career, marriage, children, or a
traumatic events such as the threat of personal death or normal life span)
injury or the death of a loved one. The reaction may D. Persistent symptoms of increased arousal (not present
occur shortly after the trauma (acute stress disorder) or be before the trauma), as indicated by two (or more) of
the following:
delayed and subject to recurrence (PTSD) (Table 49-8).
1. Difculty falling or staying asleep
In both syndromes, individuals experience associated
2. Irritability or outbursts of anger
symptoms of detachment and loss of emotional respon- 3. Difculty concentrating
sivity.The patient may feel depersonalized and unable to 4. Hypervigilance
recall specic aspects of the trauma, though typically it is 5. Exaggerated startle response
reexperienced through intrusions in thought, dreams, or E. Duration of the disturbance (symptoms in criteria B, C,
ashbacks, particularly when cues of the original event and D) is >1 month.
are present. Patients often actively avoid stimuli that pre- F. The disturbance causes clinically signicant distress or
cipitate recollections of the trauma and demonstrate a impairment in social, occupational, or other important
areas of functioning
resulting increase in vigilance, arousal, and startle
response. Patients with stress disorders are at risk for the
Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
development of other disorders related to anxiety, mood, Washington, DC, American Psychiatric Association, 2000.
and substance abuse (especially alcohol). Between 5 and
 670 10% of Americans will at some time in their life satisfy everyday functioning. Fears of contamination and germs
criteria for PTSD, with women more likely to be are common, as are handwashing, counting behaviors,
affected than men. and having to check and recheck such actions as
SECTION V

Risk factors for the development of PTSD include a whether a door is locked. The degree to which the dis-
past psychiatric history and personality characteristics of order is disruptive for the individual varies, but in all
high neuroticism and extroversion. Twin studies show a cases obsessive-compulsive activities take up >1 h/d and
substantial genetic inuence on all symptoms associated are undertaken to relieve the anxiety triggered by the
with PTSD, with less evidence for an environmental core fear. Patients often conceal their symptoms, usually
effect. because they are embarrassed by the content of their
Psychiatric Disorders

thoughts or the nature of their actions. Physicians must

Etiology and Pathophysiology ask specic questions regarding recurrent thoughts and
behaviors, particularly if physical clues such as chafed
It is hypothesized that in PTSD there is excessive release and reddened hands or patchy hair loss (from repetitive
of norepinephrine from the locus coeruleus in response hair pulling, or trichotillomania) are present. Comorbid
to stress and increased noradrenergic activity at projec- conditions are common, the most frequent being depres-
tion sites in the hippocampus and amygdala. These sion, other anxiety disorders, eating disorders, and tics.
changes theoretically facilitate the encoding of fear- OCD has a lifetime prevalence of 23% worldwide.
based memories. Greater sympathetic responses to cues Onset is usually gradual, beginning in early adulthood,
associated with the traumatic event occur in PTSD, but childhood onset is not rare.The disorder usually has a
although pituitary adrenal responses are blunted. waxing and waning course, but some cases may show a
steady deterioration in psychosocial functioning.

Treatment: Etiology and Pathophysiology

STRESS DISORDERS
A genetic contribution to OCD is suggested by twin
Acute stress reactions are usually self-limited, and treat-
studies. Family studies show an aggregation with Tourettes
ment typically involves the short-term use of benzodi-
disorder. OCD is also more common in males and in rst-
azepines and supportive/expressive psychotherapy. The
born children.
chronic and recurrent nature of PTSD, however, requires
The anatomy of obsessive-compulsive behavior is
a more complex approach employing drug and behav-
thought to include the orbital frontal cortex, caudate
ioral treatments. PTSD is highly correlated with peritrau- nucleus, and globus pallidus.The caudate nucleus appears
matic dissociative symptoms and the development of to be involved in the acquisition and maintenance of
an acute stress disorder at the time of the trauma. TCAs habit and skill learning, and interventions that are suc-
such as imipramine and amitriptyline, the MAOI cessful in reducing obsessive-compulsive behaviors also
phenelzine, and the SSRIs can all reduce anxiety, symp- decrease metabolic activity measured in the caudate.
toms of intrusion, and avoidance behaviors, as can pra-
zosin, an 1 antagonist. Propranolol given during the
acute stress period may have benecial effects in pre-
venting the development of PTSD. Trazodone, a sedating
antidepressant, is frequently used at night to help with
Treatment:
insomnia (50150 mg qhs). Carbamazepine, valproic
OBSESSIVE-COMPULSIVE DISORDER
acid, or alprazolam have also independently produced
improvement in uncontrolled trials. Psychotherapeutic Clomipramine, uoxetine, uvoxamine, and sertraline
strategies for PTSD help the patient overcome avoid- are approved for the treatment of OCD. Clomipramine
ance behaviors and demoralization and master fear of is a TCA that is often tolerated poorly owing to anti-
recurrence of the trauma; therapies that encourage the cholinergic and sedative side effects at the doses
patient to dismantle avoidance behaviors through step- required to treat the illness (25250 mg/d). Its efcacy
wise focusing on the experience of the traumatic event in OCD is unrelated to its antidepressant activity. Fluox-
are the most effective. etine (560 mg/d), uvoxamine (25300 mg/d), and ser-
traline (50150 mg/d) are as effective as clomipramine
and have a more benign side-effect prole. Only
5060% of patients with OCD show adequate improve-
OBSESSIVE-COMPULSIVE DISORDER ment with pharmacotherapy alone. In treatment-
Clinical Manifestations resistant cases, augmentation with other serotonergic
agents, such as buspirone, or with a neuroleptic or ben-
Obsessive-compulsive disorder (OCD) is characterized by
zodiazepine may be benecial. When a therapeutic
obsessive thoughts and compulsive behaviors that impair
 response is achieved, long-duration maintenance ther- sometimes be necessary to undertake an empirical trial 671
apy is usually indicated. Recent studies are beginning to of an alternative medication.
explore the efcacy of deep brain stimulation (DBS) for Between 20 and 30% of cardiac patients manifest a

CHAPTER 49
refractory, severe OCD. depressive disorder; an even higher percentage experi-
For many individuals, particularly those with time- ence depressive symptomatology when self-reporting
consuming compulsions, behavior therapy will result in scales are used. Depressive symptoms following unstable
as much improvement as that afforded by medication. angina, myocardial infarction, cardiac bypass surgery, or
Effective techniques include the gradual increase in heart transplant impair rehabilitation and are associated
exposure to stressful situations, maintenance of a diary with higher rates of mortality and medical morbidity.

Mental Disorders
to clarify stressors, and homework assignments that Depressed patients often show decreased variability in
substitute new activities for compulsive behaviors. heart rate (an index of reduced parasympathetic nervous
system activity); this has been proposed as one mecha-
nism by which depression may predispose individuals to
ventricular arrhythmia and increased morbidity. Depres-
MOOD DISORDERS sion also appears to increase the risk of developing coro-
nary heart disease; increased serotonin-induced platelet
Mood disorders are characterized by a disturbance in aggregation has been implicated as a possible cause.
the regulation of mood, behavior, and affect. Mood dis- TCAs are contraindicated in patients with bundle
orders are subdivided into (1) depressive disorders, branch block, and TCA-induced tachycardia is an addi-
(2) bipolar disorders, and (3) depression in association tional concern in patients with congestive heart failure.
with medical illness or alcohol and substance abuse SSRIs appear not to induce ECG changes or adverse
(Chaps. 50, 51, and 52). Depressive disorders are differ- cardiac events and thus are reasonable rst-line drugs for
entiated from bipolar disorders by the absence of a patients at risk for TCA-related complications. SSRIs
manic or hypomanic episode. The relationship between may interfere with hepatic metabolism of anticoagu-
pure depressive syndromes and bipolar disorders is not lants, however, causing increased anticoagulation.
well understood; depression is more frequent in families In patients with cancer, the mean prevalence of
of bipolar individuals, but the reverse is not true. In the depression is 25%, but depression occurs in 4050% of
Global Burden of Disease Study conducted by the patients with cancers of the pancreas or oropharynx.
World Health Organization, unipolar major depression This association is not due to the effect of cachexia
ranked fourth among all diseases in terms of disability- alone, as the higher prevalence of depression in patients
adjusted life-years and was projected to rank second by with pancreatic cancer persists when compared to those
the year 2020. In the United States, lost productivity with advanced gastric cancer. Initiation of antidepressant
directly related to mood disorders has been estimated at medication in cancer patients has been shown to
$55.1 billion per year. improve quality of life as well as mood. Psychotherapeu-
tic approaches, particularly group therapy, may have
some effect on short-term depression, anxiety, and pain
DEPRESSION IN ASSOCIATION WITH symptoms.
MEDICAL ILLNESS Depression occurs frequently in patients with neurologic
Depression occurring in the context of medical illness is disorders, particularly cerebrovascular disorders, Parkinsons
difcult to evaluate. Depressive symptomatology may disease, dementia, multiple sclerosis, and traumatic brain
reect the psychological stress of coping with the dis- injury. One in ve patients with left-hemisphere stroke
ease, may be caused by the disease process itself or by involving the dorsolateral frontal cortex experiences
the medications used to treat it, or may simply coexist in major depression. Late-onset depression in otherwise
time with the medical diagnosis. cognitively normal individuals increases the risk of a
Virtually every class of medication includes some agent subsequent diagnosis of Alzheimers disease. Both TCA
that can induce depression. Antihypertensive drugs, anti- and SSRI agents are effective against these depressions,
cholesterolemic agents, and antiarrhythmic agents are as are stimulant compounds and, in some patients,
common triggers of depressive symptoms. Among the MAOIs.
antihypertensive agents, -adrenergic blockers and, to a The reported prevalence of depression in patients
lesser extent, calcium channel blockers are the most with diabetes mellitus varies from 827%, with the sever-
likely to cause depressed mood. Iatrogenic depression ity of the mood state correlating with the level of
should also be considered in patients receiving gluco- hyperglycemia and the presence of diabetic complica-
corticoids, antimicrobials, systemic analgesics, antiparkin- tions. Treatment of depression may be complicated by
sonian medications, and anticonvulsants. To decide effects of antidepressive agents on glycemic control.
whether a causal relationship exists between pharmaco- MAOIs can induce hypoglycemia and weight gain.TCAs
logic therapy and a patients change in mood, it may can produce hyperglycemia and carbohydrate craving.
 672 SSRIs, like MAOIs, may reduce fasting plasma glucose, TABLE 49-9
but they are easier to use and may also improve dietary CRITERIA FOR MAJOR DEPRESSIVE EPISODE
and medication compliance.
A. Five (or more) of the following symptoms have been
SECTION V

Hypothyroidism is frequently associated with features present during the same 2-week period and represent
of depression, most commonly depressed mood and a change from previous functioning; at least one of the
memory impairment. Hyperthyroid states may also pre- symptoms is either (1) depressed mood or (2) loss of
sent in a similar fashion, usually in geriatric populations. interest or pleasure. Note: Do not include symptoms
Improvement in mood usually follows normalization of that are clearly due to a general medical condition, or
thyroid function, but adjunctive antidepressant medica- mood-incongruent delusions or hallucinations.
1. Depressed mood most of the day, nearly every day,
Psychiatric Disorders

tion is sometimes required. Patients with subclinical

as indicated by either subjective report (e.g., feels
hypothyroidism can also experience symptoms of sad or empty) or observation made by others (e.g.,
depression and cognitive difculty that respond to thy- appears tearful)
roid replacement. 2. Markedly diminished interest or pleasure in all, or
The lifetime prevalence of depression in HIV-positive almost all, activities most of the day, nearly every
individuals has been estimated at 2245%. The relation- day (as indicated by either subjective account or
ship between depression and disease progression is mul- observation made by others)
tifactorial and likely to involve psychological and social 3. Signicant weight loss when not dieting or weight
gain (e.g., a change of >5% of body weight in a
factors, alterations in immune function, and central ner-
month), or decrease or increase in appetite nearly
vous system disease. Chronic hepatitis C infection is also every day
associated with depression, which may worsen with 4. Insomnia or hypersomnia nearly every day
interferon- treatment. 5. Psychomotor agitation or retardation nearly every
Some chronic disorders of uncertain etiology, such as day (observable by others, not merely subjective
chronic fatigue syndrome (Chap. 47) and bromyalgia, feelings of restlessness or being slowed down)
are strongly associated with depression and anxiety; 6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropri-
patients may benet from antidepressant treatment, usu-
ate guilt (which may be delusional) nearly every day
ally at lower than normal dosing. (not merely self-reproach or guilt about being sick)
8. Diminished ability to think or concentrate, or indeci-
DEPRESSIVE DISORDERS siveness, nearly every day (either by subjective
account or as observed by others)
Clinical Manifestations 9. Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specic plan,
Major depression is dened as depressed mood on a daily
or a suicide attempt or a specic plan for commit-
basis for a minimum duration of 2 weeks (Table 49-9). ting suicide
An episode may be characterized by sadness, indiffer- B. The symptoms do not meet criteria for a mixed episode.
ence, apathy, or irritability and is usually associated with: C. The symptoms cause clinically signicant distress or
changes in sleep patterns, appetite, and weight; motor impairment in social, occupational, or other important
agitation or retardation; fatigue; impaired concentration areas of functioning
and decision-making; feelings of shame or guilt; and D. The symptoms are not due to the direct physiologic
thoughts of death or dying. Patients with depression effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition (e.g.,
have a profound loss of pleasure in all enjoyable activi- hypothyroidism)
ties, exhibit early morning awakening, feel that the dys- E. The symptoms are not better accounted for by
phoric mood state is qualitatively different from sadness, bereavement; i.e., after the loss of a loved one, the
and often notice a diurnal variation in mood (worse in symptoms persist for >2 months or are characterized
morning hours). by marked functional impairment, morbid preoccupa-
Approximately 15% of the population experiences a tion with worthlessness, suicidal ideation, psychotic
major depressive episode at some point in life, and 68% symptoms, or psychomotor retardation
of all outpatients in primary care settings satisfy diagnostic
criteria for the disorder. Depression is often undiag- Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
Washington, DC, American Psychiatric Association, 2000.
nosed, and, even more frequently, it is treated inade-
quately. If a physician suspects the presence of a major
depressive episode, the initial task is to determine
whether it represents unipolar or bipolar depression or is signicant risk factors exist (e.g., a past history of suicide
one of the 1015% of cases that are secondary to gen- attempts, profound hopelessness, concurrent medical ill-
eral medical illness or substance abuse. Physicians should ness, substance abuse, or social isolation), the patient
also assess the risk of suicide by direct questioning, as must be referred to a mental health specialist for imme-
patients are often reluctant to verbalize such thoughts diate care. The physician should specically probe each
without prompting. If specic plans are uncovered or if of these areas in an empathic and hopeful manner, being
sensitive to denial and possible minimization of distress. are anergy, fatigue, weight gain, hypersomnia, and episodic 673
The presence of anxiety, panic, or agitation signicantly carbohydrate craving. The prevalence increases with dis-
increases near-term suicidal risk. Approximately 45% of tance from the equator, and improvement may occur by

CHAPTER 49
all depressed patients will commit suicide; most will altering light exposure.
have sought help from a physician within 1 month of
their death.
Etiology and Pathophysiology
In some depressed patients, the mood disorder does
not appear to be episodic and is not clearly associated Although evidence for genetic transmission of unipolar
with either psychosocial dysfunction or change from the depression is not as strong as in bipolar disorder, mono-

Mental Disorders
individuals usual experience in life. Dysthymic disorder zygotic twins have a higher concordance rate (46%)
consists of a pattern of chronic (at least 2 years), ongo- than dizygotic siblings (20%), with little support for any
ing, mild depressive symptoms that are less severe and effect of a shared family environment. There is some
less disabling than those found in major depression; the evidence that a functional polymorphism in the sero-
two conditions are sometimes difcult to separate, how- tonin transporter (5-HTT) gene may interact with
ever, and can occur together (double depression). stressful life events to markedly increase risk of depression
Many patients who exhibit a prole of pessimism, disin- and suicide. Positron emission tomography (PET) stud-
terest, and low self-esteem respond to antidepressant ies show decreased metabolic activity in the caudate
treatment. Dysthymic disorder exists in ~5% of primary nuclei and frontal lobes in depressed patients that returns
care patients. The term minor depression is used for indi- to normal with recovery. Single-photon emission com-
viduals who experience at least two depressive symp- puted tomography (SPECT) studies show comparable
toms for 2 weeks but who do not meet the full criteria changes in blood ow.
for major depression. Despite its name, minor depression Postmortem examination of brains of suicide victims
is associated with signicant morbidity and disability indicate altered noradrenergic activity, including increas-
and also responds to pharmacologic treatment. ed binding to 1-, 2-, and -adrenergic receptors in the
Depression is approximately twice as common in cerebral cortex and decreased numbers of noradrenergic
women as in men, and the incidence increases with age neurons in the locus coeruleus. Involvement of the sero-
in both sexes. Twin studies indicate that the liability to tonin system is suggested by ndings of reduced plasma
major depression in adult women is largely genetic in tryptophan levels, a decreased cerebrospinal uid level of
origin. Negative life events can precipitate and con- 5-hydroxyindolacetic acid (the principal metabolite of
tribute to depression, but genetic factors inuence the serotonin in brain), and decreased platelet serotonergic
sensitivity of individuals to these stressful events. In most transporter binding.An increase in brain serotonin recep-
cases, both biologic and psychosocial factors are involved tors in suicide victims and decreased expression of the
in the precipitation and unfolding of depressive episodes. cyclic AMP response element-binding (CREB) protein
The most potent stressors appear to involve death are also reported. Depletion of blood tryptophan, the
of a relative, assault, or severe marital or relationship amino acid precursor of serotonin, rapidly reverses the
problems. antidepressant benet in depressed patients who have
Unipolar depressive disorders usually begin in early been successfully treated. However, a decrement in mood
adulthood and recur episodically over the course of a after tryptophan reduction is considerably less robust in
lifetime. The best predictor of future risk is the number untreated patients, indicating that, if presynaptic seroton-
of past episodes; 5060% of patients who have a rst ergic dysfunction occurs in depression, it likely plays a
episode have at least one or two recurrences. Some contributing rather than a causal role.
patients experience multiple episodes that become more Neuroendocrine abnormalities that reect the neu-
severe and frequent over time. The duration of an rovegetative signs and symptoms of depression include
untreated episode varies greatly, ranging from a few (1) increased cortisol and corticotropin-releasing hor-
months to 1 year. The pattern of recurrence and clini- mone (CRH) secretion, (2) an increase in adrenal size,
cal progression in a developing episode are also variable. (3) a decreased inhibitory response of glucocorticoids to
Within an individual, the nature of episodes (e.g., spe- dexamethasone, and (4) a blunted response of thyroid-
cic presenting symptoms, frequency and duration) may stimulating hormone (TSH) level to infusion of thyroid-
be similar over time. In a minority of patients, a severe releasing hormone (TRH). Antidepressant treatment
depressive episode may progress to a psychotic state; in leads to normalization of these pituitary-adrenal abnor-
elderly patients, depressive symptoms may be associated malities. Major depression is also associated with an
with cognitive decits mimicking dementia (pseudo- upregulation of proinammatory cytokines, which nor-
dementia). A seasonal pattern of depression, called sea- malizes with antidepressant treatment.
sonal affective disorder, may manifest with onset and remis- Diurnal variations in symptom severity and alter-
sion of episodes at predictable times of the year. This ations in circadian rhythmicity of a number of neuro-
disorder is more common in women, whose symptoms chemical and neurohumoral factors suggest that biologic
 674 differences may be secondary to a primary defect in reg-
ulation of biologic rhythms. Patients with major depres- Determine whether there is a history of good response to a medication
in the patient or a first-degree relative; if yes, consider treatment with
sion show consistent ndings of a decrease in rapid eye this agent.
SECTION V

movement (REM) sleep onset (REM latency), an increase

in REM density, and, in some subjects, a decrease in If not, evaluate patient characteristics and match to drug; consider
stage IV delta slow-wave sleep. health status, side-effect profile, convenience, cost, patient preference,
drug interaction risk, suicide potential, and medication compliance
Although antidepressant drugs inhibit neurotransmit- history.
ter uptake within hours, their therapeutic effects typi-
cally emerge over several weeks, implicating adaptive
Begin new medication at 1/3 to 1/2 target dose if drug is a TCA,
Psychiatric Disorders

changes in second messenger systems and transcription bupropion, venlafaxine, or mirtazapine, or full dose as tolerated if drug
factors as possible mechanisms of action. Antidepressant is an SSRI.

drugs have been shown to regulate neural plasticity and

cell survival by increasing the expression of brain- If problem side effects occur, evaluate possibility of tolerance; consider
temporary decrease in dose or adjunctive treatment.
derived neurotrophic factor (BDNF) through upregula-
tion of the CREB protein and to alter stress responsivity
through an increase in glucocorticoid receptor tran- If unacceptable side effects continue, taper drug over 1 week and
initiate new trial; consider potential drug interactions in choice.
scription. Secondary effects on activation of the mitogen-
activated protein (MAP) kinase and phosphoinositol-3
Evaluate response after 6 weeks at target dose; if response is
kinase/AKT pathways and increased expression of the inadequate, increase dose in stepwise fashion as tolerated.
antiapoptotic protein, Bcl-2, are also thought to be criti-
cal to antidepressant actions. If inadequate response after maximal dose, consider tapering and
switching to a new drug vs. adjunctive treatment; if drug is a TCA,
obtain plasma level to guide further treatment.

Treatment: FIGURE 49-1

DEPRESSIVE DISORDERS A guideline for the medical management of major depres-
sive disorder. SSRI, selective serotonin reuptake inhibitor;
Treatment planning requires coordination of short-term
TCA, tricyclic antidepressant.
strategies to induce remission combined with longer
term maintenance designed to prevent recurrence. The
most effective intervention for achieving remission and
preventing relapse is medication, but combined treat- prole of the drug (Tables 49-4 and 49-5). A previous
ment, incorporating psychotherapy to help the patient response, or a family history of a positive response, to a
cope with decreased self-esteem and demoralization, specic antidepressant often suggests that that drug be
improves outcome (Fig. 49-1). Approximately 40% of tried rst. Before initiating antidepressant therapy, the
primary care patients with depression drop out of treat- physician should evaluate the possible contribution of
ment and discontinue medication if symptomatic comorbid illnesses and consider their specic treat-
improvement is not noted within a month, unless addi- ment. In individuals with suicidal ideation, particular
tional support is provided. Outcome improves with attention should be paid to choosing a drug with low
(1) increased intensity and frequency of visits during the toxicity if taken in overdose. The SSRIs and other newer
rst 46 weeks of treatment, (2) supplemental educa- antidepressant drugs are distinctly safer in this regard;
tional materials, and (3) psychiatric consultation as indi- nevertheless, the advantages of TCAs have not been
cated. Despite the widespread use of SSRIs and other completely superseded. The existence of generic equiv-
second-generation antidepressant drugs, there is no alents make TCAs relatively cheap, and for several tri-
convincing evidence that this class of antidepressant is cyclics, particularly nortriptyline, imipramine, and
more efcacious than TCAs. Between 60 and 70% of all desipramine, well-dened relationships among dose,
depressed patients respond to any drug chosen, if it is plasma level, and therapeutic response exist. The
given in a sufcient dose for 68 weeks. There is no ideal steady-state plasma level achieved for a given drug
antidepressant; no current compound combines rapid dose can vary more than tenfold between individuals.
onset of action, moderate half-life, a meaningful rela- Plasma levels may help in interpreting apparent resis-
tionship between dose and blood level, a low side-effect tance to treatment and/or unexpected drug toxicity.
prole, minimal interaction with other drugs, and safety The principal side effects of TCAs are antihistamine
in overdose. (sedation) and anticholinergic (constipation, dry
A rational approach to selecting which antidepres- mouth, urinary hesitancy, blurred vision). Cardiac toxic-
sant to use involves matching the patients preference ity due to conduction block or arrhythmias can also
and medical history with the metabolic and side effect occur but is uncommon at therapeutic levels. TCAs are
contraindicated in patients with serious cardiovascular difculty in achieving orgasm. Sexual dysfunction fre- 675
risk factors. Overdoses of tricyclic agents can be lethal, quently results in noncompliance and should be asked
with desipramine carrying the greatest risk. It is judi- about specically. Sexual dysfunction can sometimes be

CHAPTER 49
cious to prescribe only a 10-day supply when suicide is ameliorated by lowering the dose, by instituting week-
a risk. Most patients require a daily dose of 150200 mg end drug holidays (two or three times a month), or by
of imipramine or amitriptyline or its equivalent to treatment with amantadine (100 mg tid), bethanechol
achieve a therapeutic blood level of 150300 ng/mL (25 mg tid), buspirone (10 mg tid), or bupropion
and a satisfactory remission; some patients show a par- (100150 mg/d). Paroxetine appears to be more anti-
tial effect at lower doses. Geriatric patients may require cholinergic than either uoxetine or sertraline, and ser-

Mental Disorders
a low starting dose and slow escalation. Ethnic differ- traline carries a lower risk of producing an adverse drug
ences in drug metabolism are signicant; Hispanic, interaction than the other two. Rare side effects of SSRIs
Asian, and African-American patients generally require include angina due to vasospasm and prolongation of
lower doses than whites to achieve a comparable the prothrombin time. Escitalopram is the most specic
blood level. P450 proling using genetic chip technol- of currently available SSRIs and appears to have no spe-
ogy may be clinically useful in predicting individual cic inhibitory effects on the P450 system.
sensitivity. Venlafaxine and duloxetine block the reuptake of
Second-generation antidepressants include amoxap- both norepinephrine and serotonin but produce rela-
ine, maprotiline, trazodone, and bupropion. Amoxapine tively little in the way of traditional tricyclic side effects.
is a dibenzoxazepine derivative that blocks norepineph- Unlike the SSRIs, venlafaxine has a relatively linear dose-
rine and serotonin reuptake and has a metabolite that response curve. Patients should be monitored for a pos-
shows a degree of dopamine blockade. Long-term use sible increase in diastolic blood pressure, and multiple
of this drug carries a risk of tardive dyskinesia. Maproti- daily dosing is required because of the drugs short half-
line is a potent noradrenergic reuptake blocker that has life. An extended-release form is available and has a
little anticholinergic effect but may produce seizures. somewhat lower incidence of gastrointestinal side
Bupropion is a novel antidepressant whose mechanism effects. Mirtazapine is a tetracyclic antidepressant that
of action is thought to involve enhancement of nora- has a unique spectrum of activity. It increases noradren-
drenergic function. It has no anticholinergic, sedating, or ergic and serotonergic neurotransmission through a
orthostatic side effects and has a low incidence of blockade of central 2-adrenergic receptors and postsy-
sexual side effects. It may, however, be associated with naptic 5HT2 and 5HT3 receptors. It is also strongly anti-
stimulant-like side effects, may lower seizure threshold, histaminic and, as such, may produce sedation.
and has an exceptionally short half-life, requiring frequent With the exception of citalopram and escitalopram,
dosing. An extended-release preparation is available. each of the SSRIs may inhibit one or more cytochrome
SSRIs such as uoxetine, sertraline, paroxetine, citalo- P450 enzymes. Depending on the specic isoenzyme
pram, and escitalopram cause a lower frequency of anti- involved, the metabolism of a number of concomitantly
cholinergic, sedating, and cardiovascular side effects but administered medications can be dramatically affected.
a possibly greater incidence of gastrointestinal com- Fluoxetine and paroxetine, for example, by inhibiting
plaints, sleep impairment, and sexual dysfunction than 2D6, can cause dramatic increases in the blood level of
do TCAs. Akathisia, involving an inner sense of restless- type 1C antiarrhythmics, while sertraline, by acting on
ness and anxiety in addition to increased motor activity, 3A4, may alter blood levels of carbamazepine, or
may also be more common, particularly during the rst digoxin.
week of treatment. One concern is the risk of serotonin The MAOIs are highly effective, particularly in atypi-
syndrome, thought to result from hyperstimulation of cal depression, but the risk of hypertensive crisis follow-
brainstem 5HT1A receptors and characterized by ing intake of tyramine-containing food or sympath-
myoclonus, agitation, abdominal cramping, hyper- omimetic drugs makes them inappropriate as rst-line
pyrexia, hypertension, and potentially death. Serotoner- agents. Transdermal selegiline may avert this risk at low
gic agonists taken in combination should be monitored dose. Common side effects include orthostatic hypoten-
closely for this reason. Considerations such as half-life, sion, weight gain, insomnia, and sexual dysfunction.
compliance, toxicity, and drug-drug interactions may MAOIs should not be used concomitantly with SSRIs,
guide the choice of a particular SSRI. Fluoxetine and its because of the risk of serotonin syndrome, or with TCAs,
principal active metabolite, noruoxetine, for example, because of possible hyperadrenergic effects.
have a combined half-life of almost 7 days, resulting in a Electroconvulsive therapy is at least as effective as
delay of 5 weeks before steady-state levels are achieved medication, but its use is reserved for treatment-resis-
and a similar delay for complete drug excretion once its tant cases and delusional depressions.Transcranial mag-
use is discontinued. All the SSRIs may impair sexual netic stimulation (TMS) is an investigational treatment
function, resulting in diminished libido, impotence, or of depression that has been shown to have efcacy in
 676 several controlled trials; it is uncertain whether the
TABLE 49-10

observed benets were clinically meaningful, however. CRITERIA FOR A MANIC EPISODE
Vagus nerve stimulation (VNS) has recently been A. A distinct period of abnormally and persistently ele-
SECTION V

approved for treatment-resistant depression, but its vated, expansive, or irritable mood, lasting at least 1
degree of efcacy is controversial. week (or any duration if hospitalization is necessary)
Regardless of the treatment undertaken, the response B. During the period of mood disturbance, three (or more)
of the following symptoms have persisted (four if the
should be evaluated after ~2 months. Three-quarters of
mood is only irritable) and have been present to a sig-
patients show improvement by this time, but if remission nicant degree:
is inadequate the patient should be questioned about 1. Inated self-esteem or grandiosity
Psychiatric Disorders

compliance and an increase in medication dose should 2. Decreased need for sleep (e.g., feels rested after
be considered if side effects are not troublesome. If this only 3 hours of sleep)
approach is unsuccessful, referral to a mental health spe- 3. More talkative than usual or pressure to keep talking
cialist is advised. Strategies for treatment then include 4. Flight of ideas or subjective experience that
selection of an alternative drug, combinations of antide- thoughts are racing
5. Distractibility (i.e., attention too easily drawn to
pressants, and/or adjunctive treatment with other
unimportant or irrelevant external stimuli)
classes of drugs, including lithium, thyroid hormone, and 6. Increase in goal-directed activity (either socially, at
dopamine agonists. A large randomized trial (STAR-D) work or school, or sexually) or psychomotor agitation
was unable to show preferential efcacy. Patients whose 7. Excessive involvement in pleasurable activities that
response to an SSRI wanes over time may benet from have a high potential for painful consequences
the addition of buspirone (10 mg tid) or pindolol (e.g., engaging in unrestrained buying sprees, sex-
(25 mg tid) or small amounts of a TCA such as ual indiscretions, or foolish business investments)
C. The symptoms do not meet criteria for a mixed episode.
desipramine (25 mg bid or tid). Most patients will show
D. The mood disturbance is sufciently severe to cause
some degree of response but aggressive treatment marked impairment in occupational functioning or in
should be pursued until remission is achieved, and drug usual social activities or relationships with others, or to
treatment should be continued for at least 69 more necessitate hospitalization to prevent harm to self or
months to prevent relapse. In patients who have had others, or there are psychotic features.
two or more episodes of depression, indenite mainte- E. The symptoms are not due to the direct physiologic
nance treatment should be considered. effects of a substance (e.g., a drug of abuse, a med-
ication, or other treatment) or a general medical condi-
It is essential to educate patients both about depres-
tion (e.g., hyperthyroidism).
sion and the benets and side effects of medications
they are receiving. Advice about stress reduction and
Note: Manic-like episodes that are clearly caused by somatic antide-
cautions that alcohol may exacerbate depressive symp- pressant treatment (e.g., medication, electroconvulsive therapy, light
toms and impair drug response are helpful. Patients therapy) should not count toward a diagnosis of bipolar I disorder.
should be given time to describe their experience, their Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
outlook, and the impact of the depression on them and Washington, DC, American Psychiatric Association, 2000.

their families. Occasional empathic silence may be as

helpful for the treatment alliance as verbal reassurance.
Controlled trials have shown that cognitive-behavioral
thinking indistinguishable from schizophrenia. Half of
and interpersonal therapies are effective in improving
patients with bipolar disorder present with a mixture of
psychological and social adjustment and that a com-
psychomotor agitation and activation with dysphoria,
bined treatment approach is more successful than med-
anxiety, and irritability. It may be difcult to distinguish
ication alone for many patients.
mixed mania from agitated depression. In some bipolar
patients (bipolar II disorder), the full criteria for mania are
lacking, and the requisite recurrent depressions are sepa-
BIPOLAR DISORDER rated by periods of mild activation and increased energy
(hypomania). In cyclothymic disorder, there are numerous
Clinical Manifestations hypomanic periods, usually of relatively short duration,
Bipolar disorder is characterized by unpredictable swings alternating with clusters of depressive symptoms that
in mood from mania (or hypomania) to depression. fail, either in severity or duration, to meet the criteria of
Some patients suffer only from recurrent attacks of major depression. The mood uctuations are chronic
mania, which in its pure form is associated with and should be present for at least 2 years before the
increased psychomotor activity; excessive social extro- diagnosis is made.
version; decreased need for sleep; impulsivity and Manic episodes typically emerge over a period of days
impairment in judgment; and expansive, grandiose, and to weeks, but onset within hours is possible, usually in
sometimes irritable mood (Table 49-10). In severe the early morning hours. An untreated episode of either
mania, patients may experience delusions and paranoid depression or mania can be as short as several weeks or
last as long as 812 months, and rare patients have an TABLE 49-11 677
unremitting chronic course.The term rapid cycling is used CLINICAL PHARMACOLOGY OF MOOD STABILIZERS
for patients who have four or more episodes of either

CHAPTER 49
SIDE EFFECTS AND OTHER
depression or mania in a given year. This pattern occurs AGENT AND DOSING EFFECTS
in 15% of all patients, almost all of whom are women. In
some cases, rapid cycling is linked to an underlying thy- Lithium Common side effects: Nausea/
Starting dose: 300 mg anorexia/diarrhea, ne tremor,
roid dysfunction and, in others, it is iatrogenically trig-
bid or tid thirst, polyuria, fatigue, weight
gered by prolonged antidepressant treatment. Approxi- Therapeutic blood level: gain, acne, folliculitis, neu-
mately half of patients have sustained difculties in work 0.81.2 meq/L trophilia, hypothyroidism

Mental Disorders
performance and psychosocial functioning. Blood level is increased by
Bipolar disorder is common, affecting ~1.5% of the thiazides, tetracyclines, and
population in the United States. Onset is typically NSAIDs
between 20 and 30 years of age, but many individuals Blood level is decreased by
report premorbid symptoms in late childhood or early bronchodilators, verapamil,
and carbonic anhydrase
adolescence. The prevalence is similar for men and inhibitors
women; women are likely to have more depressive and Rare side effects: Neurotoxic-
men more manic episodes over a lifetime. ity, renal toxicity, hypercal-
cemia, ECG changes
Valproic acid Common side effects: Nausea/
Differential Diagnosis
Starting dose: anorexia, weight gain, seda-
The differential diagnosis of mania includes toxic effects 250 mg tid tion, tremor, rash, alopecia
of stimulant or sympathomimetic drugs as well as sec- Therapeutic blood Inhibits hepatic metabolism of
level: 50125 g/mL other medications
ondary mania induced by hyperthyroidism, AIDS, or
Rare side effects: Pancreatitis,
neurologic disorders, such as Huntingtons or Wilsons hepatotoxicity, Stevens-
disease, or cerebrovascular accidents. Comorbidity with Johnson syndrome
alcohol and substance abuse is common, either because Carbamazepine/ Common side effects: Nausea/
of poor judgment and increased impulsivity or because oxcarbazepine anorexia, sedation, rash,
of an attempt to self-treat the underlying mood symp- Starting dose: 200 mg dizziness/ataxia
toms and sleep disturbances. bid for carbamazepine, Carbamazepine, but not
150 bid for oxcarbazepine, induces
oxcarbazepine hepatic metabolism of other
Etiology and Pathophysiology Therapeutic blood level: medications
412 g/mL for Rare side effects: Hypona-
Genetic predisposition to bipolar disorder is evident carbamazepine tremia, agranulocytosis,
from family studies; the concordance rate for monozy- Lamotrigine Stevens-Johnson syndrome
gotic twins approaches 80%. Multiple genes are likely to Starting dose: 25 mg/d Common side effects: Rash,
be involved. dizziness, headache, tremor,
The pathophysiologic mechanisms underlying the sedation, nausea
profound and recurrent mood swings of bipolar disorder Rare side effect: Stevens-
Johnson syndrome
remain unknown. Neuroimaging studies have reported
anatomic changes in amygdala volume as well as
Note: NSAID, nonsteroidal anti-inammatory drug; ECG, electrocar-
increases in white matter hyperintensities. Molecular diogram.
studies have implicated changes in membrane Na+- and
K+-activated ATPase and disordered signal transduction
involving the phosphoinositol system and GTP-binding
proteins as possible contributing mechanisms. Patients
with bipolar disorder also appear to have altered circa- mania, as is lamotrigine in the depressed phase. The
dian rhythmicity, and lithium may exert its therapeutic response rate to lithium carbonate is 7080% in acute
benet through a resynchronization of intrinsic rhythms mania, with benecial effects appearing in 12 weeks.
keyed to the light/dark cycle. Lithium also has a prophylactic effect in prevention of
recurrent mania and, to a lesser extent, in the prevention
of recurrent depression. A simple cation, lithium is
rapidly absorbed from the gastrointestinal tract and
Treatment: remains unbound to plasma or tissue proteins. Some
BIPOLAR DISORDER
95% of a given dose is excreted unchanged through the
(Table 49-11) Lithium carbonate is the mainstay of kidneys within 24 h.
treatment in bipolar disorder, although sodium val- Serious side effects from lithium are rare, but minor
proate and olanzapine are equally effective in acute complaints such as gastrointestinal discomfort, nausea,
 678 diarrhea, polyuria, weight gain, skin eruptions, alopecia,
TABLE 49-12
and edema are common. Over time, urine-concentrat- CONSENSUS GUIDELINES FOR DRUG TREATMENT
ing ability may be decreased, but signicant nephrotox- OF ACUTE MANIA AND BIPOLAR DEPRESSION
SECTION V

icity does not usually occur. Lithium exerts an antithy- CONDITION PREFERRED AGENTS
roid effect by interfering with the synthesis and release
Euphoric mania Lithium
of thyroid hormones. More serious side effects include
Mixed/dysphoric mania Valproic acid
tremor, poor concentration and memory, ataxia, Mania with psychosis Valproic acid with olanzapine,
dysarthria, and incoordination. There is suggestive, but conventional antipsychotic,
not conclusive, evidence that lithium is teratogenic, or risperidone
Psychiatric Disorders

inducing cardiac malformations in the rst trimester. Hypomania Lithium, lamotrigine, or

In the treatment of acute mania, lithium is initiated valproic acid alone
at 300 mg bid or tid, and the dose is then increased by Severe depression with Venlafaxine, bupropion, or
psychosis paroxetine plus lithium plus
300 mg every 23 days to achieve blood levels of
olanzapine, or risperidone;
0.81.2 meq/L. Because the therapeutic effect of lithium consider ECT
may not appear until after 710 days of treatment, Severe depression Bupropion, paroxetine,
adjunctive usage of lorazepam (12 mg every 4 h) or without psychosis sertraline, venlafaxine, or
clonazepam (0.51 mg every 4 h) may be benecial to citalopram plus lithium
control agitation. Antipsychotics are indicated in Mild to moderate Lithium or lamotrigine alone;
patients with severe agitation who respond only par- depression add bupropion if needed
tially to benzodiazepines. Patients using lithium should
be monitored closely, since the blood levels required to Note: ECT, electroconvulsive therapy.
Source: From GS Sachs et al: Postgrad Med, April, 2000.
achieve a therapeutic benet are close to those associ-
ated with toxicity.
Valproic acid may be better than lithium for patients
who experience rapid cycling (i.e., more than four In such situations, an alternative agent or combina-
episodes a year) or who present with a mixed or dys- tion therapy is usually helpful.
phoric mania. Tremor and weight gain are the most Consensus guidelines for the treatment of acute mania
common side effects; hepatotoxicity and pancreatitis and bipolar depression are described in Table 49-12.
are rare toxicities.
Carbamazepine and oxcarbazepine, although not for-
mally approved by the FDA for bipolar disorder, have
clinical efcacy in the treatment of acute mania. SOMATOFORM DISORDERS
Second-generation antipsychotic drugs (olanzapine,
quetiapine, risperidone, ziprasidone, and aripiprazole) Clinical Manifestations
have also been shown to be effective, either alone or in
Patients with multiple somatic complaints that cannot
combination with a mood stabilizer. An increased risk of
be explained by a known medical condition or by the
weight gain and other metabolic abnormalities is a con-
effects of alcohol or of recreational or prescription drugs
cern with these agents.
are commonly seen in primary care practice; one survey
The recurrent nature of bipolar mood disorder
indicated a prevalence of such complaints of 5%. In som-
necessitates maintenance treatment. A sustained
atization disorder, the patient presents with multiple phys-
blood lithium level of at least 0.8 meq/L is important
ical complaints referable to different organ systems
for optimal prophylaxis and has been shown to
(Table 49-13). Onset is usually <30 years, and the dis-
reduce risk of suicide, a finding not yet apparent for
order is persistent. Formal diagnostic criteria require the
other mood stabilizers. Compliance is frequently an
recording of at least four pain, two gastrointestinal, one
issue and often requires enlistment and education of
sexual, and one pseudoneurologic symptom. Patients
concerned family members. Efforts to identify and
with somatization disorder often present with dramatic
modify psychosocial factors that may trigger
complaints, but the complaints are inconsistent. Symp-
episodes are important, as is an emphasis on lifestyle
toms of comorbid anxiety and mood disorder are com-
regularity. Antidepressant medications are some-
mon and may be the result of drug interactions due to
times required for the treatment of severe break-
regimens initiated independently by different physicians.
through depressions, but their use should generally
Patients with somatization disorder may be impulsive
be avoided during maintenance treatment because
and demanding and frequently qualify for a formal
of the risk of precipitating mania or accelerating the
comorbid psychiatric diagnosis. In conversion disorder, the
cycle frequency. Loss of efficacy over time may be
symptoms focus on decits that involve motor or sen-
observed with any of the mood-stabilizing agents.
sory function and on psychological factors that initiate
TABLE 49-13 poor relationships with physicians stemming from their 679
DIAGNOSTIC CRITERIA FOR SOMATIZATION sense that they have been evaluated and treated inappro-
DISORDER priately or inadequately. Hypochondriasis can be dis-

CHAPTER 49
A. A history of many physical complaints beginning <30
abling in intensity and is persistent, with waxing and
years that occur over a period of several years and waning symptomatology.
result in treatment being sought or signicant impair- In factitious illnesses, the patient consciously and volun-
ment in social, occupational, or other important areas tarily produces physical symptoms of illness. The term
of functioning. Munchausens syndrome is reserved for individuals with par-
B. Each of the following criteria must have been met, with ticularly dramatic, chronic, or severe factitious illness. In
individual symptoms occurring at any time during the

Mental Disorders
true factitious illness, the sick role itself is gratifying. A
course of the disturbance:
1. Four pain symptoms: a history of pain related to at
variety of signs, symptoms, and diseases have been either
least four different sites or functions (e.g., head, simulated or caused by factitious behavior, the most com-
abdomen, back, joints, extremities, chest, rectum, mon including chronic diarrhea, fever of unknown ori-
during menstruation, during sexual intercourse, or gin, intestinal bleeding or hematuria, seizures, and hypo-
during urination) glycemia. Factitious disorder is usually not diagnosed until
2. Two gastrointestinal symptoms: a history of at least 510 years after its onset, and it can produce signicant
two gastrointestinal symptoms other than pain social and medical costs. In malingering, the fabrication
(e.g., nausea, bloating, vomiting other than during
derives from a desire for some external reward, such as a
pregnancy, diarrhea, or intolerance of several differ-
ent foods) narcotic medication or disability reimbursement.
3. One sexual symptom: a history of at least one
sexual or reproductive symptom other than pain
(e.g., sexual indifference, erectile or ejaculatory Treatment:
dysfunction, irregular menses, excessive menstrual SOMATOFORM DISORDERS
bleeding, vomiting throughout pregnancy)
4. One pseudoneurologic symptom: a history of at least Patients with somatization disorders are frequently sub-
one symptom or decit suggesting a neurologic con- jected to many diagnostic tests and exploratory surg-
dition not limited to pain (conversion symptoms such eries in an attempt to nd their real illness. Such an
as impaired coordination or balance, paralysis or approach is doomed to failure and does not address the
localized weakness, difculty swallowing or lump core issue. Successful treatment is best achieved through
in throat, aphonia, urinary retention, hallucinations,
behavior modication, in which access to the physician is
loss of touch or pain sensation, double vision, blind-
ness, deafness, seizures; dissociative symptoms tightly regulated and adjusted to provide a sustained
such as amnesia; or loss of consciousness other and predictable level of support that is less clearly con-
than fainting) tingent on the patients level of presenting distress. Visits
C. Either of the following: can be brief and should not be associated with a need
1. After appropriate investigation, each of the symp- for a diagnostic or treatment action. Although the litera-
toms in criterion B cannot be fully explained by a ture is limited, some patients with somatization disorder
known general medical condition or the direct
may benet from antidepressant treatment.
effects of a substance (e.g., a drug of abuse, a
medication)
Any attempt to confront the patient usually creates a
2. When there is a related general medical condition, sense of humiliation and causes the patient to abandon
the physical complaints or resulting social or occu- treatment from that caregiver. A better strategy is to
pational impairment are in excess of what would be introduce psychological causation as one of a number
expected from the history, physical examination, or of possible explanations and to include factitious illness
laboratory ndings as an option in the differential diagnoses that are dis-
D. The symptoms are not intentionally produced or feigned cussed. Without directly linking psychotherapeutic inter-
(as in factitious disorder or malingering).
vention to the diagnosis, the patient can be offered a
face-saving means by which the pathologic relationship
Source: Diagnostic and Statistical Manual of Mental Disorders, 4th ed.
Washington, DC, American Psychiatric Association, 2000.
with the health care system can be examined and alter-
native approaches to life stressors developed.

or exacerbate the medical presentation. Like somatiza-

tion disorder, the decit is not intentionally produced or PERSONALITY DISORDERS
simulated, as is the case in factitious disorder (malinger-
Clinical Manifestations
ing). In hypochondriasis, the essential feature is a belief of
serious medical illness that persists despite reassurance Personality disorders are characteristic patterns of think-
and appropriate medical evaluation. As with somatization ing, feeling, and interpersonal behavior that are relatively
disorder, patients with hypochondriasis have a history of inexible and cause signicant functional impairment or
 680 subjective distress for the individual. The observed dyscontrol, and/or rejection hypersensitivity. Anxious or
behaviors are not secondary to another mental disorder, fearful cluster C patients often respond to medications
nor are they precipitated by substance abuse or a general used for axis I anxiety disorders (see earlier). It is impor-
SECTION V

medical condition. This distinction is often difcult to tant that the physician and the patient have reasonable
make in clinical practice, as personality change may be expectations vis--vis the possible benet of any med-
the rst sign of serious neurologic, endocrine, or other ication used and its side effects. Improvement may be
medical illness. Patients with frontal lobe tumors, for subtle and observable only over time.
example, can present with changes in motivation and
personality while the results of the neurologic examina-
Psychiatric Disorders

tion remain within normal limits. Individuals with per-

sonality disorders are often regarded as difcult
patients in clinical medical practice because they are SCHIZOPHRENIA
seen as excessively demanding and/or unwilling to fol-
low recommended treatment plans. Although DSM-IV Clinical Manifestations
portrays personality disorders as qualitatively distinct Schizophrenia is a heterogeneous syndrome character-
categories, there is an alternative perspective that per- ized by perturbations of language, perception, thinking,
sonality characteristics vary as a continuum between social activity, affect, and volition. There are no pathog-
normal functioning and formal mental disorder. nomonic features. The syndrome commonly begins in
Personality disorders have been grouped into three late adolescence, has an insidious (and less commonly
overlapping clusters. Cluster A includes paranoid, schi- acute) onset, and, often, a poor outcome, progressing
zoid, and schizotypal personality disorders. It includes from social withdrawal and perceptual distortions to
individuals who are odd and eccentric and who main- recurrent delusions and hallucinations. Patients may pre-
tain an emotional distance from others. Individuals have sent with positive symptoms (such as conceptual disor-
a restricted emotional range and remain socially isolated. ganization, delusions, or hallucinations) or negative
Patients with schizotypal personality disorder frequently symptoms (loss of function, anhedonia, decreased emo-
have unusual perceptual experiences and express magical tional expression, impaired concentration, and dimin-
beliefs about the external world. The essential feature of ished social engagement) and must have at least two of
paranoid personality disorder is a pervasive mistrust and these for a 1-month period and continuous signs for at
suspiciousness of others to an extent that is unjustied least 6 months to meet formal diagnostic criteria. As
by available evidence. Cluster B disorders include antiso- individuals age, positive psychotic symptoms tend to
cial, borderline, histrionic, and narcissistic types and attenuate and some measure of social and occupational
describe individuals whose behavior is impulsive, exces- function may be regained. Negative symptoms pre-
sively emotional, and erratic. Cluster C incorporates dominate in one-third of the schizophrenic population
avoidant, dependent, and obsessive-compulsive personal- and are associated with a poor long-term outcome and a
ity types; enduring traits are anxiety and fear. The poor response to drug treatment. However, marked vari-
boundaries between cluster types are to some extent ability in the course and individual character of symp-
articial, and many patients who meet criteria for one toms is typical.
personality disorder also meet criteria for aspects of The four main subtypes of schizophrenia are cata-
another.The risk of a comorbid major mental disorder is tonic, paranoid, disorganized, and residual. Many indi-
increased in patients who qualify for a diagnosis of per- viduals have symptoms of more than one type. Catatonic-
sonality disorder. type describes patients whose clinical presentation is
dominated by profound changes in motor activity, nega-
tivism, and echolalia or echopraxia. Paranoid-type describes
patients who have a prominent preoccupation with a spe-
Treatment: cic delusional system and who otherwise do not qualify
PERSONALITY DISORDERS
as having disorganized-type disease, in which disorganized
Dialectical behavior therapy (DBT) is a cognitive-behav- speech and behavior are accompanied by a supercial or
ioral approach that focuses on behavioral change while silly affect. In residual-type disease, negative symptomatol-
providing acceptance, compassion, and validation of the ogy exists in the absence of delusions, hallucinations, or
patient. Several randomized trials have demonstrated motor disturbance. The term schizophreniform disorder
the efcacy of DBT in the treatment of personality disor- describes patients who meet the symptom requirements
ders. Antidepressant medications and low-dose antipsy- but not the duration requirements for schizophrenia,
chotic drugs have some efcacy in cluster A personality and schizoaffective disorder is used for those who manifest
disorders, while anticonvulsant mood-stabilizing agents symptoms of schizophrenia and independent periods
and MAOIs may be considered for patients with cluster B of mood disturbance. Prognosis depends not on symptom
diagnoses who show marked mood reactivity, behavioral severity but on the response to antipsychotic medication.
A permanent remission without recurrence does occa- synapses, and DISC1 is a scaffolding protein that partici- 681
sionally occur. About 10% of schizophrenic patients pates in a variety of protein-protein interactions impor-
commit suicide. tant in neuronal development. One group has reported

CHAPTER 49
Schizophrenia is present in 0.85% of individuals world- risk variants in the 7 nicotinic acetylcholine receptor
wide, with a lifetime prevalence of ~11.5%. An estimated subunit gene and linked it to a specic auditory process-
300,000 episodes of acute schizophrenia occur annually in ing decit.
the United States, resulting in direct and indirect costs of Schizophrenia is also associated with gestational and
$62.7 billion. perinatal complications, including Rh factor incompati-
bility, fetal hypoxia, prenatal exposure to inuenza during

Mental Disorders
the second trimester, and prenatal nutritional deciency.
Differential Diagnosis
Studies of monozygotic twins discordant for schizophre-
The diagnosis is principally one of exclusion, requiring nia have reported neuroanatomic differences between
the absence of signicant associated mood symptoms, any affected and unaffected siblings, supporting a two-
relevant medical condition, and substance abuse. Drug strike etiology involving both genetic susceptibility and
reactions that cause hallucinations, paranoia, confusion, or an environmental insult. The latter might involve local-
bizarre behavior may be dose-related or idiosyncratic; ized hypoxia during critical stages of brain development.
parkinsonian medications, clonidine, quinacrine, and pro- A number of structural and functional abnormalities
caine derivatives are the most common prescription med- have been identied in schizophrenia, including (1) cor-
ications associated with these symptoms. Drug causes tical atrophy and ventricular enlargement; (2) specic
should be ruled out in any case of newly emergent psy- volume losses in the amygdala, hippocampus, right pre-
chosis. The general neurologic examination in patients frontal cortex, fusiform gyrus, and thalamus; (3) progres-
with schizophrenia is usually normal, but motor rigidity, sive reduction in cortical volume over time; (4) reduced
tremor, and dyskinesias are noted in one-quarter of metabolism in the thalamus and prefrontal cortex;
untreated patients. (5) abnormalities of the planum temporale; and (6) changes
in the size, orientation, and density of cells in the hippocam-
pus and prefrontal cortex, and decreased numbers of cortical
Epidemiology and Pathophysiology
interneurons.These observations have suggested that schizo-
Epidemiologic surveys identify several risk factors for phrenia may result from a disturbance in a cortical
schizophrenia including genetic susceptibility, early devel- striatalthalamic circuit resulting in abnormalities in sensory
opmental insults, winter birth, and increasing parental age. ltering and attention.
Genetic factors are involved in at least a subset of individ- Schizophrenic individuals are highly distractible and
uals who develop schizophrenia. Schizophrenia is demonstrate decits in perceptual-motor speed, ability
observed in ~6.6% of all rst-degree relatives of an to shift attention, and ltering out of background stim-
affected proband. If both parents are affected, the risk for uli. Event-related evoked potential studies of schizo-
offspring is 40%. The concordance rate for monozygotic phrenia have dened a reduction in P300 amplitude to a
twins is 50%, compared to 10% for dizygotic twins. novel stimulus, which implicates an impairment in cog-
Schizophrenia-prone families are also at risk for other nitive processing. Impaired information processing is
psychiatric disorders, including schizoaffective disorder also found in unaffected family members.
and schizotypal and schizoid personality disorders, the latter The dopamine hypothesis of schizophrenia is based on
terms designating individuals who show a lifetime pattern the discovery that agents that diminish dopaminergic
of social and interpersonal decits characterized by an activity also reduce the acute symptoms and signs of psy-
inability to form close interpersonal relationships, eccen- chosis, specically agitation, anxiety, and hallucinations.
tric behavior, and mild perceptual distortions. Amelioration of delusions and social withdrawal is less
Despite evidence for a genetic causation, the results dramatic. Thus far, however, evidence for increased
of molecular genetic linkage studies in schizophrenia are dopaminergic activity in schizophrenia is indirect,
inconclusive. Major gene effects appear unlikely. Possible although decreased D2 receptor occupancy by dopamine
susceptibility genes include: neuregulin-1 (chromosome has been shown in drug-nave patients. An increase in
8p21); dysbindin (6p22.3); proline dehydrogenase the activity of nigrostriatal and mesolimbic systems and a
(22q11); D-amino-acid oxidase activator (13q34); dis- decrease in mesocortical tracts innervating the prefrontal
rupted in schizophrenia 1, (DISC1), (1q42); and catechol- cortex is hypothesized, although it is likely that other
O-methyl transferase (COMT). Neuregulin-1, dysbindin, neurotransmitters, including serotonin, acetylcholine, glu-
and D-amino-acid oxidase activator appear to be tamate, and GABA, also contribute to the pathophysiol-
involved in glutamatergic function, increasing interest in ogy of the illness. Possible involvement of excitatory
N-methyl-D-aspartate (NMDA)mediated glutamate amino acids is supported by the genetic data cited above
signaling as a possible therapeutic target for treatment. and ndings that NMDA receptor antagonists and chan-
COMT is involved in the removal of dopamine from nel blockers, such as phencyclidine (PCP) and ketamine,
 682 produce characteristic signs of schizophrenia in normal newer atypical agents exert some degree of D2 recep-
individuals; cycloserine, an NMDA receptor agonist, can tor blockade. All neuroleptics induce expression of the
decrease the negative symptoms of psychosis. immediate-early gene c-fos in the nucleus accumbens, a
SECTION V

dopaminergic site connecting prefrontal and limbic cor-

tices. The clinical efcacy of newer atypical neuroleptics,
Treatment: however, may involve NMDA receptor blockade, 1- and
SCHIZOPHRENIA 2-noradrenergic activity, altering the relationship
Antipsychotic agents (Table 49-14) are the cornerstone between 5HT2 and D2 receptor activity, as well as faster
of acute and maintenance treatment of schizophrenia dissociation of D2 binding and effects on neuroplasticity.
Psychiatric Disorders

and are effective in the treatment of hallucinations, Conventional neuroleptics differ in their potency and
delusions and thought disorders, regardless of etiology. side-effect prole. Older agents, such as chlorpromazine
The mechanism of action involves, at least in part, bind- and thioridazine, are more sedating and anticholinergic
ing to dopamine D2/D3 receptors in the ventral striatum; and more likely to cause orthostatic hypotension, while
the clinical potencies of traditional antipsychotic drugs higher potency antipsychotics, such as haloperidol, per-
parallel their afnities for the D2 receptor, and even the phenazine, and thiothixene, are more likely to induce

TABLE 49-14
ANTIPSYCHOTIC AGENTS

USUAL PO
DAILY
NAME DOSE, mg SIDE EFFECTS SEDATION COMMENTS

First-Generation Antipsychotics

Low-potency
Chlorpromazine 1001000 Anticholinergic effects; +++ EPSEs usually not prominent;
(Thorazine) orthostasis; photosensitivity; can cause anticholinergic
cholestasis; QT prolongation delirium in elderly patients
Thioridazine (Mellaril) 100600
Clozapine (Clozaril) 150600 Agranulocytosis (1%); weight ++ Requires weekly WBC for
gain; seizures; drooling; rst 6 months, then biweekly
Mid-potency hyperthermia if stable
Triuoperazine 250 Fewer anticholinergic side ++ Well tolerated by most
(Stelazine) effects; fewer EPSEs than patients
with higher potency agents.
Perphenazine (Trilafon) 464 ++
Loxapine (Loxitane) 30100 Frequent EPSEs ++
Molindone (Moban) 30100 Frequent EPSEs 0 Little weight gain
High-potency
Haloperidol (Haldol) .520 No anticholinergic side 0/+ Often prescribed in doses that
effects; EPSEs often are too high; long-acting
prominent injectable forms of haloperidol
and uphenazine available
Fluphenazine (Prolixin) 120 Frequent EPSEs 0/+
Thiothixene (Navane) 250 Frequent EPSEs 0/+

Second-Generation Antipsychotics
Risperidone (Risperdal) 28 Orthostasis + Requires slow titration; EPSEs
observed with doses >6 mg qd
Olanzapine (Zyprexa) 1030 Weight gain ++ Mild prolactin elevation
Quetiapine (Seroquel) 350800 Sedation; weight gain; +++ Bid dosing
anxiety
Ziprasidone (Geodon) 120200 Orthostatic hypotension +/++ Minimal weight gain; increases
QT interval
Aripiprazole (Abilify) 1030 Nausea, anxiety, insomnia 0/+ Mixed agonist/antagonist

Note: EPSEs, extrapyramidal side effects; WBC, white blood count.

extrapyramidal side effects. The model rst-generation improvement, but a prolonged delay in response in 683
antipsychotic agent is clozapine, a dibenzodiazepine some cases necessitates a 6- to 9-month trial for maxi-
that has a greater potency in blocking the 5HT2 than the mal benet to occur.

CHAPTER 49
D2 receptor and a much higher afnity for the D4 than Antipsychotic medications can cause a broad range of
the D2 receptor. Its principal disadvantage is a risk of side effects, including lethargy, weight gain, postural
blood dyscrasias. Unlike other antipsychotics, clozapine hypotension, constipation, and dry mouth. Extrapyramidal
does not cause a rise in prolactin level. Approximately symptoms such as dystonia, akathisia, and akinesia are
30% of patients who do not benet from conventional also frequent with rst-generation agents and may con-
antipsychotic agents will have a better response to this tribute to poor adherence if not specically addressed.

Mental Disorders
drug, which also has a demonstrated superiority to Anticholinergic and parkinsonian symptoms respond well
other antipsychotic agents in preventing suicide; how- to trihexyphenidyl, 2 mg bid, or benztropine mesylate,
ever, its side-effect prole makes it most appropriate for 12 mg bid. Akathisia may respond to beta blockers. In
treatment-resistant cases. Risperidone, a benzisoxazole rare cases, more serious and occasionally life-threatening
derivative, is more potent at 5HT2 than D2 receptor sites, side effects may emerge, including ventricular arrhyth-
like clozapine, but it also exerts signicant 2 antago- mias, gastrointestinal obstruction, retinal pigmentation,
nism, a property that may contribute to its perceived obstructive jaundice, and neuroleptic malignant syn-
ability to improve mood and increase motor activity. drome (characterized by hyperthermia, autonomic dys-
Risperidone is not as effective as clozapine in treat- function, muscular rigidity, and elevated creatine phos-
ment-resistant cases but does not carry a risk of blood phokinase levels). The most serious adverse effects of
dyscrasias. Olanzapine is similar neurochemically to clozapine are agranulocytosis, which has an incidence of
clozapine but has a signicant risk of inducing weight 1%, and induction of seizures, which has an incidence
gain. Quetiapine is distinct in having a weak D2 effect of 10%. Weekly white blood cell counts are required, par-
but potent 1 and histamine blockade. Ziprasidone ticularly during the rst 3 months of treatment.
causes minimal weight gain and is unlikely to increase The risk of type 2 diabetes mellitus appears to be
prolactin but may increase QT prolongation. Aripiprazole increased in schizophrenia, and second-generation agents
also has little risk of weight gain or prolactin increase as a group produce greater adverse effects on glucose
but may increase anxiety, nausea, and insomnia as a regulation, independent of effects on obesity, than tradi-
result of its partial agonist properties. tional agents. Clozapine, olanzapine, and quetiapine seem
Antipsychotic agents are effective in 70% of patients more likely to cause hyperglycemia, weight gain, and
presenting with a rst episode. Improvement may be hypertriglyceridemia than other atypical antipsychotic
observed within hours or days, but full remission usually drugs. Close monitoring of plasma glucose and lipid levels
requires 68 weeks. The choice of agent depends princi- are indicated with the use of these agents.
pally on the side-effect prole and cost of treatment or A serious side effect of long-term use of rst genera-
on a past personal or family history of a favorable tion antipsychotic agents is tardive dyskinesia, character-
response to the drug in question. Atypical agents ized by repetitive, involuntary, and potentially irreversible
appear to be more effective in treating negative symp- movements of the tongue and lips (bucco-linguo-
toms and improving cognitive function. An equivalent masticatory triad), and, in approximately one-half of cases,
treatment response can usually be achieved with rela- choreoathetosis. Tardive dyskinesia has an incidence of
tively low doses of any drug selected, i.e., 46 mg/d of 24% per year of exposure, and a prevalence of 20% in
haloperidol, 1015 mg of olanzapine, or 46 mg/d of chronically treated patients.The prevalence increases with
risperidone. Doses in this range result in >80% D2 recep- age, total dose, and duration of drug administration. The
tor blockade, and there is little evidence that higher risk associated with second-generation agents appears to
doses increase either the rapidity or degree of response. be much lower. The cause may involve formation of free
Maintenance treatment requires careful attention to the radicals and perhaps mitochondrial energy failure. Vita-
possibility of relapse and monitoring for the develop- min E may reduce abnormal involuntary movements if
ment of a movement disorder. Intermittent drug treat- given early in the syndrome.
ment is less effective than regular dosing, but gradual The CATIE study, a large scale investigation of the
dose reduction is likely to improve social functioning in effectiveness of antipsychotic agents in real world
many schizophrenic patients who have been main- patients, revealed a high rate of discontinuation of treat-
tained at high doses. If medications are completely ment over 18 months. Olanzapine showed greater effec-
discontinued, however, the relapse rate is 60% within tiveness than quetiapine, risperidone, perphenazine, or
6 months. Long-acting injectable preparations (risperi- ziprasidone but also a higher discontinuation rate due
done) are considered when noncompliance with oral to weight gain and metabolic effects. Surprisingly, per-
therapy leads to relapses. In treatment-resistant phenazine, a rst-generation agent, showed little evi-
patients, a transition to clozapine usually results in rapid dence of inferiority to newer drugs. A recent long-term
 684 study of schizophrenic patients transitioning from older total number of homeless individuals in the United
to newer-generation antipsychotics did not demon- States range from 800,0002 million, one-third of
strate any effect on mortality. whom qualify as having a serious mental disorder. Poor
SECTION V

Drug treatment of schizophrenia is by itself insuf- hygiene and nutrition, substance abuse, psychiatric ill-
cient. Educational efforts directed toward families and ness, physical trauma, and exposure to the elements
relevant community resources have proved to be neces- combine to make the provision of medical care chal-
sary to maintain stability and optimize outcome. A treat- lenging. Only a minority of these individuals receive
ment model involving a multidisciplinary case-manage- formal mental health care; the main points of contact are
ment team that seeks out and closely follows the patient outpatient medical clinics and emergency departments.
Psychiatric Disorders

in the community has proved particularly effective. Primary care settings represent a critical site in which
housing needs, treatment of substance dependence, and
evaluation and treatment of psychiatric illness can most
efciently take place. Successful intervention is depen-
ASSESSMENT AND EVALUATION dent on breaking down traditional administrative
OF VIOLENCE barriers to health care and recognizing the physical con-
straints and emotional costs imposed by homelessness.
Primary care physicians may encounter situations in
Simplifying health care instructions and follow-up,
which family, domestic, or societal violence is discovered
allowing frequent visits, and dispensing medications in
or suspected. Such an awareness can carry legal and
limited amounts that require ongoing contact are possi-
moral obligations; many state laws mandate reporting of
ble techniques for establishing a successful therapeutic
child, spousal, and elder abuse. Physicians are frequently
relationship.
the rst point of contact for both victim and abuser.
Approximately 2 million older Americans and 1.5 mil-
lion U.S. children are thought to experience some form FURTHER READINGS
of physical maltreatment each year. Spousal abuse is AMERICAN PSYCHIATRIC ASSOCIATION: American Psychiatric Associ-
thought to be even more prevalent. An interview study ation Practice Guidelines for the Treatment of Psychiatric Disor-
of 24,000 women in 10 countries found a lifetime ders: Compendium 2006.Washington, DC,APA Press, 2006
prevalence of physical or sexual violence that ranged CIPRIANI A et al: Comparative efcacy and acceptability of 12 new-
from 1571%; these individuals are more likely to suffer generation antidepressants: A multiple-treatments meta-analysis.
Lancet 373:746, 2009
from depression, anxiety, somatization disorder, and sub- GALE C, DAVIDSON O: Generalised anxiety disorder. BMJ 334:579,
stance abuse and to have attempted suicide. In addition, 2007
abused individuals frequently express low self-esteem, LESPERANCE F et al: Effects of citalopram and interpersonal psy-
vague somatic symptomatology, social isolation, and a chotherapy on depression in patients with coronary artery dis-
passive feeling of loss of control. Although it is essential ease: The Canadian Cardiac Randomized Evaluation of Antide-
to treat these elements in the victim, the rst obligation pressant and Psychotherapy Efcacy (CREATE) trial. JAMA
is to ensure that the perpetrator has taken responsibility 297:367, 2007
MALLET L et al:Treatment of subthalamic nucleus stimulation in severe
for preventing any further violence. Substance abuse
obsessivecompulsive disorder. N Engl J Med 359:2121, 2008
and/or dependence and serious mental illness in the MAURER D, Colt R: An evidence-based approach to the manage-
abuser may contribute to the risk of harm and require ment of depression. Prim Care 33:923, 2007
direct intervention. Depending on the situation, law MITCHELL AJ et al: Clinical diagnosis of depression in primary care:
enforcement agencies, community resources such as A meta-analysis. Lancet 374:609, 2009
support groups and shelters, and individual and family RAY WA et al: Atypical antipsychotic drugs and the risk of sudden
counseling can be appropriate components of a treat- cardiac death. N Engl J Med 360:225, 2009
ROBINSON RG et al: Escitalopram and problem-solving therapy for
ment plan. A safety plan should be formulated with the
prevention of post-stroke depression. JAMA 299:2391, 2008
victim, in addition to providing information about SACHS GS et al: Effectiveness of adjunctive antidepressant treatment
abuse, its likelihood of recurrence, and its tendency to for bipolar depression. N Engl J Med 356:1711, 2007
increase in severity and frequency. Antianxiety and anti- SCHANZER B et al: Homelessness, health status, and health care use.
depressant medications may sometimes be useful in Am J Public Health 97:464, 2007
treating the acute symptoms, but only if independent STEIN DJ et al: Post-traumatic stress disorder: Medicine and politics.
evidence for an appropriate psychiatric diagnosis exists. Lancet 369:139, 2007
TIIHONEN J et al: Eleven-year follow-up of mortality in patients with
schizophrenia: A population-based cohort study (FIN11 study).
Lancet 374:620, 2009
MENTAL HEALTH PROBLEMS TYLEE A,WALTERS P: Underrecognition of anxiety and mood disor-
IN THE HOMELESS ders in primary care: Why does the problem exist and what can
be done? J Clin Psychiatry 68(Suppl 2):27, 2007
There is a high prevalence of mental disorders and sub- WHOOLEY MA et al: Depressive symptoms, health behaviors, and risk
stance abuse among homeless and impoverished individ- of cardiovascular events in patients with coronary heart disease.
uals. Depending on the denition used, estimates of the JAMA 300:2379, 2008
SECTION VI

ALCOHOLISM
AND DRUG
DEPENDENCY
 CHAPTER 50

ALCOHOL AND ALCOHOLISM

Marc A. Schuckit

Pharmacology and Nutritional Impact of Ethanol . . . . . . . . . . 686 Other Effects of Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690
Behavioral Effects, Tolerance, and Dependence . . . . . . . . . . 687 Alcoholism (Alcohol Abuse or Dependence) . . . . . . . . . . . . . 690
The Effects of Ethanol on Organ Systems . . . . . . . . . . . . . . . 688 Denitions and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . 690
Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688 Genetics of Alcoholism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
The Gastrointestinal System . . . . . . . . . . . . . . . . . . . . . . . . . 689 Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Identication of the Alcoholic and Intervention . . . . . . . . . . . . 691
Hematopoietic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 The Alcohol Withdrawal Syndrome . . . . . . . . . . . . . . . . . . . . 692
Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689 Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Genitourinary System Changes, Sexual Functioning,
and Fetal Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 690

Alcohol, a drug, is consumed at some time by up to about 0.02 g/dL resulting from the ingestion of one
80% of the population. At low doses alcohol can have typical drink. In round gures, 340 mL (12 oz) of beer,
some benecial effects such as decreased rates of 115 mL (4 oz) of nonfortied wine, and 43 mL (1.5 oz)
myocardial infarction, stroke, gallstones, and possibly (a shot) of 80-proof beverage such as whisky, gin, or
vascular and Alzheimers dementias. However, the con- vodka each contain ~1015 g of ethanol; 0.5 L (1 pint)
sumption of more than two standard drinks per day of 80-proof beverage contains ~160 g (about 16 stan-
increases the risk for health problems in many organ dard drinks), and 1 L of wine contains ~80 g of ethanol.
systems. Heavy repetitive drinking, as is seen in alcohol These beverages also have additional components, called
abuse and dependence, cuts short the life span by an congeners, that affect the taste and effects; congeners
estimated decade in both genders, all cultural groups, include low-molecular-weight alcohols (e.g., methanol
and all socioeconomic strata. Unless an individual stops and butanol), aldehydes, esters, histamine, phenols, tan-
drinking, a diagnosis of alcohol dependence carries a nins, iron, lead, and cobalt. Such congeners might also
80% risk for continued severe problems over the next contribute to the adverse health consequences associated
5 years. In addition, even relatively low doses of alcohol with heavy drinking.
can adversely affect many preexisting disease states and Ethanol is a central nervous system (CNS) depressant
alter the effectiveness or blood levels of most over-the- that decreases neuronal activity, although some behav-
counter and prescribed medications. ioral stimulation is observed at low blood levels. This
drug has cross-tolerance with other depressants, includ-
ing benzodiazepines and barbiturates, and all produce
PHARMACOLOGY AND NUTRITIONAL
similar behavioral alterations. Alcohol is absorbed from
IMPACT OF ETHANOL
mucous membranes of the mouth and esophagus (in
Ethanol is a weakly charged molecule that moves easily small amounts), from the stomach and large bowel (in mod-
through cell membranes, rapidly equilibrating between est amounts), and from the proximal portion of the small
blood and tissues. The level of alcohol in the blood is intestine (the major site).
expressed as milligrams or grams of ethanol per deciliter The rate of absorption is increased by rapid gastric
(e.g., 100 mg/dL or 0.10 g/dL), with blood values of emptying (as can be induced by carbonated beverages);
686
by the absence of proteins, fats, or carbohydrates (which lactate, and a -hydroxybutyrate/lactate ratio of between 687
interfere with absorption); by the absence of congeners; 2:1 and 9:1 (with normal being 1:1).
and by dilution to a modest percentage of ethanol (max-
imum at ~20% by volume).
BEHAVIORAL EFFECTS, TOLERANCE,
Between 2% (at low blood alcohol concentrations)
AND DEPENDENCE
and 10% (at high blood alcohol concentrations) of
ethanol is excreted directly through the lungs, urine, or The acute effects of a drug depend on many factors.
sweat, but the greater part is metabolized to acetaldehyde, These include the dose, the rate of increase in plasma, the
primarily in the liver. The most important pathway concomitant presence of other drugs, and the past expe-

CHAPTER 50
occurs in the cell cytosol where alcohol dehydrogenase rience with the agent. With alcohol, an additional factor
(ADH) produces acetaldehyde, which is then rapidly is whether blood alcohol levels are rising or falling; the
destroyed by aldehyde dehydrogenase (ALDH) in the effects are more intense during the former period.
cytosol and mitochondria (Fig. 50-1). A second path- Legal intoxication in the United States requires a
way in the microsomes of the smooth endoplasmic blood alcohol concentration of at least 0.080.10 g/dL,
reticulum (the microsomal ethanol-oxidizing system, or while levels of 0.04 or even lower are cited in some other
MEOS), is responsible for 10% of ethanol oxidation at countries. However, behavioral, psychomotor, and cogni-

Alcohol and Alcoholism

high blood alcohol concentrations. tive changes are seen at levels as low as 0.020.03 g/dL
While alcohol supplies calories (a drink contains (i.e., after one to two drinks) (Table 50-1). Deep but
~300 kJ, or 70100 kcal), these are devoid of nutrients disturbed sleep can be seen at twice the legal intoxication
such as minerals, proteins, and vitamins. Alcohol can level, and death can occur with levels between 0.30 and
also interfere with absorption of vitamins in the small 0.40 g/dL. Beverage alcohol is probably responsible for
intestine and decreases their storage in the liver with more overdose deaths than any other drug.
modest effects on folate (folacin or folic acid), pyridox- The intoxicating effects of alcohol reect the actions
ine (B6), thiamine (B1), nicotinic acid (niacin, B3), and of this drug on a wide range of neurotransmitters, recep-
vitamin A. tors, and transporters. Most prominently, alcohol acutely
An ethanol load in a fasting, healthy individual is enhances actions at -aminobutyric acid A (GABAA)
likely to produce transient hypoglycemia within 636 h, receptors and inhibits N-methyl-D-aspartate (NMDA)
secondary to the acute actions of ethanol on gluconeo- receptors. There are also effects on adenosine, with an
genesis. This can temporarily result in abnormal glucose inhibition of uptake of this transmitter, and a transloca-
tolerance tests (with a resulting erroneous diagnosis of tion of the cyclic AMPdependent protein kinase cat-
diabetes mellitus) until the alcoholic has abstained for alytic subunit from the cytoplasm to the nucleus. Alcohol
24 weeks. Alcohol ketoacidosis, probably reecting a also affects opioid systems and cannabinol receptors,
decrease in fatty acid oxidation coupled with poor diet enhances activity of the dopamine-rich reward system,
or recurrent vomiting, can be misdiagnosed as diabetic increases serotonin actions, and directly or indirectly
ketosis. With the former, patients show an increase in affects most other neurochemical systems. As with most
serum ketones along with a mild increase in glucose but depressants, neurons adapt quickly to these actions, and
a large anion gap, a mild to moderate increase in serum tolerance to many effects develops; after repeated expo-
sure, abrupt decreases in blood alcohol levels are likely to
produce physiologic changes that are opposite to the
MEOS
20% Acetaldehyde

Ethanol TABLE 50-1

Alcohol EFFECTS OF BLOOD ALCOHOL LEVELS IN THE
80% Acetaldehyde
dehydrogenase ABSENCE OF TOLERANCE
Aldehyde
dehydrogenase BLOOD
LEVEL, g/dL USUAL EFFECT
Acetyl CoA
Acetate 0.02 Decreased inhibitions, a slight feeling of
Citric acid intoxication
cycle
0.08 Decrease in complex cognitive functions
and motor performance
Fatty acids 0.20 Obvious slurred speech, motor incoordina-
CO2 + Water
tion, irritability, and poor judgment
FIGURE 50-1 0.30 Light coma and depressed vital signs
The metabolism of alcohol. MEOS, microsomal ethanol- 0.40 Death
oxidizing system.
 688 acute effects of this drug (i.e., withdrawal). The presence Alcohol relaxes muscles in the pharynx, which can cause
of tolerance and/or withdrawal characterizes physical snoring and exacerbate sleep apnea; symptoms of the
dependence. latter occur in 75% of alcoholic men >60 years. Another
Tolerance is a complex phenomenon involving at common consequence of alcohol use is impaired judg-
least three types of compensatory mechanisms. (1) After ment and coordination, increasing the risk of accidents
12 weeks of daily drinking, metabolic or pharmacokinetic and injury; 40% of drinkers in the United States have at
tolerance can be seen, with up to a 30% increase in the some time driven while intoxicated. Heavy drinking can
rate of hepatic ethanol metabolism.This alteration disap- also be associated with headache, thirst, nausea, vomit-
pears almost as rapidly as it develops. (2) Cellular or phar- ing, and fatigue the following day, a hangover syndrome
SECTION VI

macodynamic tolerance develops through neurochemical that is responsible for signicant nancial losses in most
changes that maintain relatively normal physiologic work environments.
functioning despite the presence of alcohol. Subsequent The effect of alcohol on the nervous system is even
decreases in blood levels contribute to symptoms of more pronounced among alcohol-dependent individu-
withdrawal. (3) Individuals learn to adapt their behavior als. Chronic high doses cause peripheral neuropathy in
so that they can function better than expected under 515% of alcoholics: similar to diabetes, patients experi-
inuence of the drug (behavioral tolerance). ence bilateral limb numbness, tingling, and paresthesias,
Alcoholism and Drug Dependency

The cellular changes caused by chronic ethanol expo- all of which are more pronounced distally. Approxi-
sure may not resolve for several weeks or longer following mately 1% of alcoholics develop cerebellar degeneration
cessation of drinking.The resulting withdrawal syndrome or atrophy. This is a syndrome of progressive unsteady
is most intense during the rst 5 days, but some symp- stance and gait often accompanied by mild nystagmus;
toms (e.g., disturbed sleep and anxiety) can take up to neuroimaging studies reveal atrophy of the cerebellar
46 months to resolve. vermis. Fortunately, very few alcoholics (perhaps as few
as 1 in 500) develop Wernickes (ophthalmoparesis, ataxia,
and encephalopathy) and Korsakoffs (retrograde and
THE EFFECTS OF ETHANOL anterograde amnesia) syndromes. These occur as the result
ON ORGAN SYSTEMS of thiamine deciency, especially in predisposed indi-
viduals, e.g., those with transketolase deciency. Alco-
Although one to two drinks per day in an otherwise holics can manifest cognitive problems lasting for weeks to
healthy and nonpregnant individual can have some ben- months after an alcoholic binge. Brain atrophy, evident
ecial cardiovascular effects, at higher doses alcohol is as ventricular enlargement and widened cortical sulci
toxic to most organ systems. Knowledge about the dele- on MRI and CT scans, occurs in ~50% of chronic
terious effects of alcohol helps the physician to identify alcoholics; these changes are often reversible if absti-
alcoholic patients and provides information that can be nence is maintained. There is no single alcoholic
used to help motivate patients to abstain. The informa- dementia syndrome; rather, this label is used to describe
tion offered here generally applies to all, regardless of patients who have apparently irreversible cognitive
age or gender, although some differences apply. It is changes (possibly from diverse causes) in the context of
important to remember that the typical white- or blue- chronic alcoholism.
collar alcoholic often functions at a fairly high level for As many as two-thirds of alcohol-dependent individ-
years, holding a job and maintaining ties with friends and uals meet the criteria for a psychiatric syndrome in
relatives who may be unaware of the severity of the drink- the Fourth Diagnostic and Statistical Manual of Mental
ing problem. Not everyone develops each of the problems Disorders, (DSM-IV) of the American Psychiatric Asso-
described below. ciation (Chap. 49). One-half of these relate to a preexist-
ing antisocial personality manifesting as impulsivity and
disinhibition.The lifetime risk is 3% in males, and 80%
NERVOUS SYSTEM
of such individuals demonstrate alcohol and/or drug
Approximately 35% of drinkers (and a much higher per- dependence. Another common comorbidity occurs with
centage of alcoholics) experience a blackout, an episode dependence on illicit substances. The remaining third of
of temporary anterograde amnesia, in which the person alcoholics with psychiatric syndromes have preexisting
forgets all or part of what occurred during a drinking conditions such as schizophrenia or manic depressive disease
evening. Another common problem, one seen after as and anxiety disorders such as panic disorder.The reasons for
few as several drinks, is disturbed sleep. Although alcohol the comorbidities of alcoholism with independent psychi-
might initially help a person to fall asleep, it disrupts atric disorders are not known, but they might represent
sleep throughout the rest of the night. The stages of an overlap in genetic vulnerabilities, impaired judgment
sleep are also altered, and time spent in rapid eye move- resulting from the independent psychiatric condition, or
ment (REM) and deep sleep is reduced. Patients may an attempt to use alcohol to alleviate some of the symptoms
experience prominent and sometimes disturbing dreams. of the disorder or side effects of medications.
 Many psychiatric syndromes can be seen temporarily CANCER 689
during heavy drinking and subsequent withdrawal.These
Drinking as few as 1.5 drinks per day increases a
include an intense sadness lasting for days to weeks in
womans risk of breast cancer 1.4-fold. For both gen-
the midst of heavy drinking seen in 40% of alcoholics
ders, four drinks per day increases the risk for oral and
(alcohol-induced mood disorder); temporary severe
esophageal cancers approximately threefold and rectal
anxiety in 1030% of alcoholics, often beginning during
cancers by a factor of 1.5; seven to eight or more drinks
alcohol withdrawal, and which can persist for a month
per day enhances approximately vefold the risks for
or more after cessation of drinking (alcohol-induced anx-
many cancers.
iety disorder); and auditory hallucinations and/or paranoid

CHAPTER 50
delusions in a person who is alert and oriented, seen in
35% of alcoholics (alcohol-induced psychotic disorder). HEMATOPOIETIC SYSTEM
Treatment of all forms of alcohol-induced psy-
chopathology includes helping patients achieve absti- Ethanol causes an increase in red blood cell size [mean
nence and offering supportive care, as well as reassurance corpuscular volume, (MCV)], which reects its effects
and talk therapy such as cognitive-behavioral approaches. on stem cells. If heavy drinking is accompanied by folic
However, with the exception of short-term antipsychotics acid deciency, there can also be hypersegmented neu-

Alcohol and Alcoholism

for substance-induced psychosis, substance-induced psychi- trophils, reticulocytopenia, and a hyperplastic bone mar-
atric conditions only rarely require medications. Recovery row; if malnutrition is present, sideroblastic changes can
is likely within several days to 4 weeks of abstinence. A be observed. Chronic heavy drinking can decrease pro-
history of alcohol intake is an important consideration in duction of white blood cells, decrease granulocyte mobility
any patient with one of these psychiatric symptoms. and adherence, and impair delayed-hypersensitivity
The distinction between long-term, independent responses to novel antigens (with a possible false-negative
psychiatric conditions and temporary alcohol-induced tuberculin skin test). Finally, many alcoholics have mild
syndromes is important because their prognoses and thrombocytopenia, which usually resolves within a week
optimal treatments are quite different. Independent syn- of abstinence unless there is hepatic cirrhosis or con-
dromes can be recognized because they often began gestive splenomegaly.
before the alcohol dependence and/or remain after a
period of a month or more of abstinence.
CARDIOVASCULAR SYSTEM
Acutely, ethanol decreases myocardial contractility and
THE GASTROINTESTINAL SYSTEM causes peripheral vasodilation, with a resulting mild
Esophagus and Stomach decrease in blood pressure and a compensatory increase
in cardiac output. Exercise-induced increases in cardiac
Alcohol intake can result in inammation of the esopha- oxygen consumption are higher after alcohol intake.
gus and stomach causing epigastric distress and gastroin- These acute effects have little clinical signicance for the
testinal bleeding. Alcohol is one of the most common average healthy drinker but can be problematic in men
causes of hemorrhagic gastritis. Violent vomiting can and women with persisting cardiac disease.
produce severe bleeding through a Mallory-Weiss lesion, The consumption of three or more drinks per day
a longitudinal tear in the mucosa at the gastroe- results in a dose-dependent increase in blood pressure,
sophageal junction. which returns to normal within weeks of abstinence.
Thus, heavy drinking is an important factor in mild to
moderate hypertension. Chronic heavy drinkers have a
Pancreas and Liver
sixfold increased risk for coronary artery disease as well
The incidence of acute pancreatitis (~25 per 1000 per as an increased risk for cardiomyopathy. Symptoms range
year) is almost threefold higher in alcoholics than in the from unexplained arrhythmias in the presence of left
general population, accounting for an estimated 10% or ventricular impairment to heart failure with dilation of
more of the total cases. Alcohol impairs gluconeogenesis all four heart chambers and hypocontractility of heart
in the liver, resulting in a fall in the amount of glucose muscle. Perhaps one-third of cases of cardiomyopathy
produced from glycogen, increased lactate production, are alcohol-induced. Mural thrombi can form in the left
and decreased oxidation of fatty acids. This contributes atrium or ventricle, while heart enlargement >25% can
to an increase in fat accumulation in liver cells. In cause mitral regurgitation. Atrial or ventricular arrhyth-
healthy individuals these changes are reversible, but with mias, especially paroxysmal tachycardia, can also occur
repeated exposure to ethanol, more severe changes in after a drinking binge in individuals showing no other
the liver occur, including alcohol-induced hepatitis, evidence of heart diseasea syndrome known as the
perivenular sclerosis, and cirrhosis, with the latter holiday heart.This condition is observed transiently in
observed in an estimated 15% of alcoholics. the majority of alcoholics entering treatment.
 690 Chronic intake of modest doses of alcohol can have and enhanced secretion at falling blood alcohol concen-
some benecial effects.A maximum of one to two drinks trations (with the nal result that most alcoholics are
per day may decrease the risk for cardiovascular death, likely to be slightly overhydrated); a modest and
perhaps through an increase in high-density lipoprotein reversible decrease in serum thyroxine (T4); and a more
(HDL) cholesterol or changes in clotting mechanisms. In marked decrease in serum triiodothyronine (T3). Hor-
one large national study, cardiovascular mortality was mone irregularities should be reevaluated after a month
reduced by 3040% among individuals reporting one or of abstinence.
more drinks daily compared to nondrinkers, with overall
mortality lowest among those consuming approximately
ALCOHOLISM (ALCOHOL ABUSE
SECTION VI

one drink per day. Recent data have also corroborated

that regular light drinking decreases the risk for ischemic, OR DEPENDENCE)
but not hemorrhagic, stroke.
Because many drinkers occasionally imbibe to excess,
temporary alcohol-related pathology is common in
GENITOURINARY SYSTEM CHANGES, nonalcoholics, especially those in the late teens to the
SEXUAL FUNCTIONING, AND FETAL late twenties. When repeated problems in multiple life
Alcoholism and Drug Dependency

DEVELOPMENT areas develop, the individual is likely to meet criteria for

alcohol abuse or dependence.
Acutely, modest ethanol doses (e.g., blood alcohol con-
centrations of 0.06 gm/dL) can increase sexual drive but
also decrease erectile capacity in men. Even in the DEFINITIONS AND EPIDEMIOLOGY
absence of liver impairment, a signicant minority of Alcohol dependence is dened in DSM-IV as repeated
chronic alcoholic men show irreversible testicular atro- alcohol-related difculties in at least three of seven areas
phy with shrinkage of the seminiferous tubules, decreases of functioning that cluster together over a 12-month
in ejaculate volume, and a lower sperm count. period. Two of these seven items, tolerance and with-
The repeated ingestion of high doses of ethanol by drawal, may have special importance as they are associated
women can result in amenorrhea, a decrease in ovarian with a more severe clinical course. Alcohol dependence
size, absence of corpora lutea with associated infertility, is seen in all countries where alcohol is available and occurs
and an increased risk of spontaneous abortion. Heavy in men and women from all socioeconomic strata and
drinking during pregnancy results in the rapid placental all racial backgrounds. The diagnosis of alcohol depen-
transfer of both ethanol and acetaldehyde, which may dence predicts a course of recurrent problems with the
have serious consequences for fetal development. The use of alcohol and the consequent shortening of the life
fetal alcohol syndrome can include any of the following: span by a decade on average.
facial changes with epicanthal eye folds; poorly formed Alcohol abuse is dened as repetitive problems with
ear concha; small teeth with faulty enamel; cardiac atrial alcohol in any one of four life areassocial, interper-
or ventricular septal defects; an aberrant palmar crease and sonal, legal, and occupationalor repeated use in haz-
limitation in joint movement; and microcephaly with ardous situations such as driving while intoxicated. If an
mental retardation. The amount of ethanol required and individual is not alcohol dependent, he or she still may
the time of vulnerability during pregnancy have not be given a diagnosis of alcohol abuse.
been dened, making it advisable for pregnant women The lifetime risk for alcohol dependence in most
to abstain completely. western countries is about 1015% for men and 58%
for women. Rates are generally similar in the United
States, Canada, Germany, Australia, and England; rates
OTHER EFFECTS OF ETHANOL
tend to be lower in most Mediterranean countries, such
Between one-half and two-thirds of alcoholics have as Italy, Greece, and Israel, and may be higher in Ireland,
skeletal muscle weakness caused by acute alcoholic myopa- France, and Scandinavia. Even higher rates have been
thy, a condition that improves but which might not fully reported for several native cultures including Native
remit with abstinence. Effects of repeated heavy drink- Americans, Eskimos, Maori groups, and aboriginal
ing on the skeletal system include changes in calcium tribes of Australia. These differences reflect both cul-
metabolism, lower bone density, and decreased growth tural and genetic influences, as described later in the
in the epiphyses, leading to an increased risk for frac- chapter.When alcohol abuse is also considered, the rates
tures and osteonecrosis of the femoral head. Hormonal of alcohol use disorders increase. In western countries,
changes include an increase in cortisol levels, which can the typical alcoholic does not fulll the common stereo-
remain elevated during heavy drinking; inhibition of type of a skid-row denizen but is more often a blue-
vasopressin secretion at rising blood alcohol concentrations or white-collar worker or homemaker. The lifetime
risk for alcoholism among physicians is similar to that with the leading causes of death, in decreasing order, the 691
of the general population. result of heart disease, cancer, accidents, and suicide.

IDENTIFICATION OF THE ALCOHOLIC

GENETICS OF ALCOHOLISM AND INTERVENTION
Several separate and distinct characteristics appear to Even in afuent areas ~20% of patients have an alcohol
contribute to the risk. For example, some families carry use disorder. It is important to pay attention to the
a risk for both alcoholism and drug dependence associ- alcohol-related symptoms and signs as well as laboratory
ated with the characteristic of high levels of impulsivity,

CHAPTER 50
tests that are likely to be abnormal in the context of reg-
as can be seen in the antisocial personality disorder. In ular consumption of six to eight or more drinks per day.
other families, the risk for both alcohol and drug depen- The two blood tests with 70% sensitivity and speci-
dence may relate to a genetic vulnerability to schizo- city for heavy alcohol consumption are -glutamyl
phrenia, panic disorder, or manic depressive disease. A
transferase (GGT) (>35 units) and carbohydrate-decient
third and different mechanism increases only the alco-
transferrin (CDT) (>20 units/L); the combination of the
holism risk (e.g., in some offspring of alcoholics and
two is likely to be more accurate than either alone.

Alcohol and Alcoholism

Native Americans) through a low response to alcohol
Physicians should consider using these tests to screen all
and subsequent drinking higher doses to achieve the
patients as indicators of possible alcoholism. These sero-
desired effects. The relatively low response to alcohol
logic markers of heavy drinking can also be useful in
contributes to attitudes and drinking patterns that
monitoring abstinence, as they are likely to return
increase the risk for alcohol-related problems and alco-
toward normal within several weeks of the cessation of
holism. By contrast, a decreased risk for heavy drinking
drinking; thus, increases in values of as little as 10% are
can result from a more intense response to alcohol, as
likely to indicate a resumption of heavy alcohol intake.
seen in approximately one-half of Asian men and
Other blood tests that can be useful in identifying indi-
women. This is due primarily to a mutation that causes
viduals consuming six or more standard drinks per day
the production of an inactive form of the enzyme
include high-normal MCVs (91 m3) and serum uric
ALDH, which results in higher levels of acetaldehyde
acid (>416 mol/L, or 7 mg/dL). Physical signs and
following alcohol ingestion.
symptoms that can be useful in identifying alcoholism
include mild and uctuating hypertension, repeated
infections such as pneumonia, and otherwise unex-
NATURAL HISTORY
plained cardiac arrhythmias. Other disorders suggestive
Although the age of the rst drink is similar in alco- of dependence include cancer of the head and neck,
holics and nonalcoholics, earlier onset of regular drink- esophagus, or stomach as well as cirrhosis, unexplained
ing and drunkenness is associated with a higher risk for hepatitis, pancreatitis, bilateral parotid gland swelling, and
later problems. By the early to mid-twenties, most non- peripheral neuropathy.
alcoholic men and women moderate their drinking The clinical diagnosis of alcohol abuse or dependence
(perhaps learning from minor problems), whereas alco- ultimately rests on the documentation of a pattern of
holics are likely to escalate their patterns of drinking repeated difculties associated with alcohol use; the def-
despite difculties. The rst major life problem from inition is not based on the quantity and frequency of
alcohol often appears in the early to mid-twenties. alcohol consumption. Thus, in screening it is important
Once established, the course of alcoholism is likely to to probe for life problems and then attempt to tie in use
be one of exacerbations and remissions. As a rule, there of alcohol or another substance. Information regarding
is little difculty in stopping alcohol use when prob- marital or job problems, legal difculties, histories of
lems develop, and this step is often followed by days to accidents, medical problems, evidence of tolerance, etc.,
months of abstinence and then a period of carefully are important. While all physicians should be able to
controlled drinking. Unless abstinence is maintained, take the time needed to gather such information, some
however, these phases almost inevitably give way to standardized questionnaires can be helpful, including the
escalations in alcohol intake and subsequent problems. 10-item Alcohol Use Disorder Screening Test (AUDIT)
The course is not hopeless; following treatment, (Table 50-2). However, these are only screening tools,
between one-half and two-thirds of alcoholics maintain and a careful face-to-face interview is still required for a
abstinence for years, and often permanently. Even with- meaningful diagnosis.
out formal treatment or self-help groups there is at least After alcoholism is identified, the diagnosis must
a 20% chance of spontaneous remission with long-term be shared with the patient as part of an intervention.
abstinence. However, should the alcoholic continue to The presenting complaint can be used as an entre to the
drink, the life span is shortened by 1015 years on average, alcohol problem. For instance, the patient with insomnia
 692 TABLE 50-2 reminder. Motivational interviewing uses the clinicians
THE ALCOHOL USE DISORDERS IDENTIFICATION level of concern and understanding of the need for
TEST (AUDIT)a patients to progress through their own stages of enhanced
understanding of their problems to optimize their ability
5-POINT SCALE
ITEM (LEAST TO MOST) to alter their drinking behaviors.
The process of intervention is rarely accomplished
1. How often do you have a drink Never (0) to 4+ per
in one session. Multiple sessions to explain the prob-
containing alcohol? week (4)
2. How many drinks containing alco- 1 or 2 (0) to 10+ (4)
lem, the optimal treatments, and the benefits of making
hol do you have on a typical day? certain lifestyle changes are often required. For the
SECTION VI

3. How often do you have six or Never (0) to daily person who refuses to stop drinking at the first inter-
more drinks on one occasion? or almost daily (4) vention, a logical step is to keep the door open,
4. How often during the last year Never (0) to daily establishing future meetings so that help is available as
have you found that you were or almost daily (4) problems escalate. In the meantime the family may
not able to stop drinking once benefit from counseling or referral to self-help groups
you had started?
5. How often during the last year Never (0) to daily
such as Al-Anon (the Alcoholics Anonymous group for
family members) and Alateen (for teenage children of
Alcoholism and Drug Dependency

have you failed to do what was or almost daily (4)

normally expected from you alcoholics).
because of drinking?
6. How often during the last year Never (0) to daily
have you needed a rst drink in or almost daily (4)
the morning to get yourself going
THE ALCOHOL WITHDRAWAL SYNDROME
after a heavy drinking session? Once the brain has been repeatedly exposed to high
7. How often during the last year Never (0) to daily doses of alcohol, any sudden decrease in intake can pro-
have you had a feeling of guilt or or almost daily (4)
duce withdrawal symptoms, many of which are the
remorse after drinking?
8. How often during the last year Never (0) to daily
opposite of those produced by intoxication. Features
have you been unable to remem- or almost daily (4) include tremor of the hands (shakes or jitters); agitation
ber what happened the night and anxiety; autonomic nervous system overactivity
before because you had been including an increase in pulse, respiratory rate, and body
drinking? temperature; and insomnia, sometimes accompanied by
9. Have you or someone else been No (0) to yes, dur- frightening dreams. Because alcohol has a short half-life,
injured as a result of your drinking? ing the last year (4) these withdrawal symptoms generally begin within 510 h
10. Has a relative, friend, doctor or No (0) to yes, dur-
other health worker been con- ing the last year (4)
of decreasing ethanol intake, peak in intensity on day
cerned about your drinking or sug- 2 or 3, and improve by day 4 or 5. Anxiety, insomnia,
gested that you should cut down? and mild levels of autonomic dysfunction may persist to
some degree for 46 months as a protracted abstinence
Note: a The AUDIT is scored by simply summing the values associ- syndrome, which may contribute to the tendency to
ated with the endorsed response. return to drinking.
Source: Adapted from DF Reinert, GP Allen: Alcoholism: Clinical At some point in their lives, between 2 and 5% of
& Experimental Research 26:272, 2002, and from MA Schuckit,
alcoholics experience withdrawal seizures, often within
2006.
48 h of stopping drinking. These rare events usually
involve a single generalized seizure, and electroen-
cephalographic abnormalities generally return to normal
or hypertension can be told that these are clinically within several days.
important problems which, in conjunction with other The term delirium tremens (DTs) refers to an uncom-
physical ndings and laboratory tests, indicate that alcohol mon state of intense acute withdrawal that includes delir-
is increasing the risk for further medical and psychologi- ium (mental confusion, agitation, and uctuating levels of
cal problems. The physician should share information consciousness) associated with a tremor and autonomic
about the course of alcoholism and explore possible avenues overactivity (e.g., marked increases in pulse, blood pres-
of addressing the problem. This process can be carried sure, and respirations). Fortunately, this serious and
out by any physician or other health care provider. Sev- potentially life-threatening complication of alcohol with-
eral protocols, categorized as brief interventions and drawal is seen in <5% of alcohol-dependent individuals;
motivational interviewing, are available for health care the chance of DTs during any single withdrawal is <1%.
workers to follow. The technique of brief interventions DTs are most likely to develop in patients with con-
has been shown to be effective in decreasing alcohol comitant severe medical disorders and can usually be
use and problems when instituted as two 15-min ses- avoided by identifying and treating the underlying med-
sions 1 month apart, along with a telephone follow-up ical conditions.
 can be controlled by administering any drug of this 693
Treatment:
class in doses that decrease the agitation, and gradu-
ALCOHOL-RELATED CONDITIONS
ally taper the dose over 35 days. While most CNS
ACUTE INTOXICATION The rst priority is to
depressants are effective, benzodiazepines (Chap. 49)
assess vital signs and manage respiratory depression, have the highest margin of safety and lowest cost and
cardiac arrhythmia, or blood pressure instability, if pre- are, therefore, the preferred class of drugs. Benzodi-
sent. The possibility of intoxication with other drugs azepines with short half-lives are especially useful for
should be considered, and blood and urine samples are patients with serious liver impairment or evidence of
obtained to screen for opioids or other CNS depressants preexisting encephalopathy or brain damage. However,

CHAPTER 50
such as benzodiazepines or barbiturates. Other medical short-acting benzodiazepines such as lorazepam can
conditions that must be considered include hypoglycemia, produce rapidly changing drug blood levels and must
hepatic failure, or diabetic ketoacidosis. be given every 4 h to avoid abrupt uctuations that
Patients who are medically stable should be placed may increase the risk for seizures. Therefore, most clini-
in a quiet environment. If recumbent, patients should lie cians use drugs with longer half-lives, such as diazepam
on their side to minimize the risk of aspiration. When the or chlordiazepoxide, administering enough drug on
intoxicated person is aggressive or violent, hospital pro-

Alcohol and Alcoholism

day 1 to alleviate most of the symptoms of withdrawal
cedures should be followed, including planning for the (e.g., the tremor and elevated pulse) and then gradually
possibility of a show of force with an intervention team. decreasing the dose over a period of 35 days. The
In the context of aggressiveness, patients should be approach is exible; the dose is increased if signs of
reminded in a clear and nonthreatening way that the withdrawal escalate, and the medication is withheld if
staff wants to help them to feel better and to avoid the patient is sleeping or shows signs of increasing
problems. If the aggressive behavior continues, rela- orthostatic hypotension. The average patient requires
tively low doses of a short-acting benzodiazepine such 2550 mg of chlordiazepoxide or 10 mg of diazepam
as lorazepam (e.g., 12 mg PO or IV) may be used and given PO every 46 h on the rst day.
can be repeated as needed, but care must be taken so Treatment of the patient with DTs can be challeng-
that the addition of this second CNS depressant does ing, and the condition is likely to run a course of 35
not destabilize vital signs or worsen confusion. An alter- days regardless of the therapy employed. The focus of
native approach is to use an antipsychotic medication care is to identify and correct medical problems and to
(e.g., 0.55 mg of haloperidol PO or IM every 4-8 h if control behavior and prevent injuries. Many clinicians
needed), but this has the potential danger of lowering recommend the use of high doses of a benzodiazepine
the seizure threshold. Two other medications useful for (as much as 800 mg/d of chlordiazepoxide has been
agitation are ziprasidone (10 mg IM every 2 h as needed, reported), a treatment that will decrease agitation and
up to 40 mg) and olanzapine (2.510 mg IM repeated at raise the seizure threshold but probably does little to
2 h and 6 h, if needed). If aggression escalates, the improve the confusion. Other clinicians recommend
patient might require a short-term admission to a locked the use of antipsychotic medications, such as haloperi-
ward, where medications can be used more safely and dol, ziprasidone, or olanzapine as discussed above,
vital signs more closely monitored. although these drugs have not been directly evaluated
WITHDRAWAL The rst step is to perform a thor- for DTs. Antipsychotics are less likely to exacerbate
ough physical examination in all alcoholics who are confusion but may increase the risk of seizures; they
considering stopping drinking, including a search for have no place in the treatment of mild withdrawal
evidence of liver failure, gastrointestinal bleeding, car- symptoms.
diac arrhythmia, infection, and glucose or electrolyte Generalized withdrawal seizures rarely require
imbalance. aggressive pharmacologic intervention beyond that
The second step is to offer reassurance that the acute given to the usual patient undergoing withdrawal, i.e.,
withdrawal is short lived and to offer adequate nutrition adequate doses of benzodiazepines. There is little evi-
and rest. All patients should be given oral multiple B vit- dence that anticonvulsants such as phenytoin or
amins, including 50100 mg of thiamine daily for a week gabapentin are effective in drug-withdrawal seizures,
or more. Because most alcoholics who enter withdrawal and the risk of seizures has usually passed by the
are either normally hydrated or mildly overhydrated, IV time effective drug levels are reached. The rare patient
uids should be avoided unless there is evidence of sig- with status epilepticus must be treated aggressively
nicant recent bleeding, vomiting, or diarrhea. Medica- (Chap. 20).
tions can usually be administered orally. While alcohol withdrawal is often treated in a hospi-
The third step in treatment is to recognize that most tal, efforts at reducing costs have resulted in the devel-
withdrawal symptoms are caused by the rapid removal opment of outpatient detoxication for relatively mild
of a CNS depressant, in this case, alcohol. The symptoms abstinence syndromes. This is appropriate for patients in
 694 good physical condition who demonstrate mild signs of Whether the treatment begins in an inpatient or
withdrawal despite low blood alcohol concentrations an outpatient setting, subsequent outpatient contact
and for those without prior history of DTs or withdrawal should be maintained for a minimum of 6 months and
seizures. Such individuals still require a careful physical preferably a full year after abstinence is achieved. Coun-
examination, appropriate blood tests, and vitamin sup- seling with an individual physician or through groups
plementation. Benzodiazepines can be given in a 1- to focuses on day-to-day living, emphasizing areas of
2-day supply to be administered to the patient by a improved functioning in the absence of alcohol (i.e.,
spouse or other family member four times a day. why it is a good idea to continue to abstain) and help-
Patients are asked to return daily for evaluation of vital ing the patient to manage free time without alcohol,
SECTION VI

signs and to come to the emergency room if signs and develop a nondrinking peer group, and handle stresses
symptoms of withdrawal escalate. on the job.
The physician serves an important role in identifying
REHABILITATION OF ALCOHOLICS After the alcoholic, diagnosing and treating associated med-
completing alcoholic rehabilitation, 60% of alcoholics, ical or psychiatric syndromes, overseeing detoxication,
especially middle class patients, maintain abstinence for referring the patient to rehabilitation programs, and
Alcoholism and Drug Dependency

at least a year, and many achieve lifetime sobriety. providing counseling. Physicians are also responsible for
The core of treatment begins with helping patients selecting which (if any) medication might be appropri-
recognize the need to change, while working with them ate during alcoholism rehabilitation. Patients often com-
to alter their behaviors to enhance compliance. Thera- plain of continuing sleep problems or anxiety when
peutic maneuvers fall into several general categories, acute withdrawal treatment is over, problems that may
which are applied to all patients regardless of age or be a component of protracted withdrawal. In general,
ethnic group. The manner in which the treatments are hypnotics or antianxiety drugs should be avoided in this
used should be sensitive to the practices and needs of situation. Patients should be reassured that the trouble
specic populations. The rst step is to help the alco- sleeping is normal after alcohol withdrawal and will
holic achieve and maintain a high level of motivation improve over the subsequent weeks and months.
toward abstinence. This includes education about alco- Patients should follow a rigid bedtime and awakening
holism and instructions to family and/or friends to stop schedule and avoid naps or the use of caffeine in the
protecting the patient from problems caused by alco- evenings. The sleep pattern will improve with time, and
hol. The second step is to help the patient readjust to the patient can avoid the rebound insomnia associated
life without alcohol and to reestablish a functional with most hypnotics and the risk for developing depen-
lifestyle through counseling, vocational rehabilitation, dence on another depressant. Anxiety can be addressed
and self-help groups such as Alcoholics Anonymous by helping the person to gain insight into the tempo-
(AA). The third component, called relapse prevention, rary nature of the symptoms and to develop strategies
helps the patient to identify situations in which a return to achieve relaxation as well as by using forms of cogni-
to drinking is likely, formulate ways of managing these tive therapy.
risks, and develop coping strategies that increase the While the mainstay of alcoholic rehabilitation involves
chances of a return to abstinence if a slip occurs. counseling, education, and cognitive approaches, several
For many patients, especially those who are highly medications might be useful. The optimal length of time
motivated and have supportive social systems, treat- to continue these drugs in the context of a positive
ment can be on an outpatient basis. However, more response is unclear, but most clinicians would recom-
intense interventions work better than less intensive mend 612 months. The rst is the opioid-antagonist
measures, and some alcoholics do not respond to out- drug naltrexone, 50150 mg/d, which has been reported
patient approaches. The decision to hospitalize or utilize to decrease the probability of a return to drinking and to
residential care can be made if (1) the patient has med- shorten periods of relapse. Recently a once-per-month
ical problems that are difcult to treat outside a hospi- injection of this drug (380 mg) has been developed to
tal; (2) depression, confusion, or psychosis interferes help improve compliance. By blocking opioid receptors,
with outpatient care; (3) there is a severe life crisis that naltrexone may decrease activity in the dopamine-
makes it difcult to work in an outpatient setting; (4) rich ventral tegmental reward system, or decrease the
outpatient treatment has failed; or (5) the patient lives feeling of pleasure or reward if alcohol is imbibed.
too far from the treatment center to participate in an The improved rate of functioning and abstinence with
outpatient program. The best predictors of continued this drug is modest. The side effects are relatively few
abstinence include evidence of higher levels of life at the recommended doses and include gastrointestinal
stability (e.g., supportive family and friends) and higher distress. A second medication, acamprosate (Campral),
levels of functioning (e.g., job skills, higher levels of edu- 2 g/d, has been widely tested in patients in the United
cation, and absence of crimes unrelated to alcohol). States and Europe; results are generally similar to those
reported for naltrexone. This drug inhibits the actions high-risk drinking situations for them (such as the 695
of NMDA receptors and has been hypothesized to act Christmas holiday). Other drugs under investigation for
by decreasing mild symptoms of protracted withdrawal. possible use in alcoholism rehabilitation include the
There are few side effects, aside from mild gastroin- serotonin antagonist ondansetron; topiramate, an anti-
testinal distress. Several long-term trials of combined convulsant with possible effects on dopamine; and the
naltrexone and acamprosate using doses similar to cannabinol receptor antagonist ramonibant; at present,
those noted above have reported that the combination there are insufcient data to support their use in clini-
may be superior to either drug alone, although not all cal settings.
studies agree. Additional support for alcoholics and their relatives

CHAPTER 50
Disulram, an ALDH inhibitor, has been used and friends is available through self-help programs such
extensively in the past for treatment of alcoholism. In as AA. These groups, which typically consist of recover-
doses of 250 mg/d this drug produces an unpleasant ing alcoholics, offer an effective model of abstinence,
(and potentially dangerous) reaction in the presence of provide a sober peer group, and make crisis interven-
alcohol, a phenomenon related to rapidly rising blood tion freely available when the urge to drink escalates.
levels of the rst metabolite of alcohol, acetaldehyde. This can help patients optimize their chances for recov-

Alcohol and Alcoholism

Few adequate controlled trials have demonstrated a ery, especially when incorporated into a more struc-
clear superiority of disulram over placebo. Drinking tured treatment milieu.
alcohol while taking disulram produces a reaction
involving an increased pulse, changes in blood pressure,
and vomiting and diarrhea. This can be dangerous, FURTHER READINGS
especially for patients with heart disease, stroke, dia-
ANDERSON P et al: Effectiveness and cost-effectiveness of policies
betes mellitus, or hypertension. The drug itself has also
and programmes to reduce the harm caused by alcohol. Lancet
been reported to carry potential risks of depression, 373:2173, 2009
psychotic symptoms, peripheral neuropathy, and liver CASSWELL S, THAMARANGSI T: Reducing harm from alcohol: Call to
damage. Thus, most clinicians reserve this medication action. Lancet 373:2247, 2009
for patients who have a clear history of longer-term GELERNTER J et al: Opioid receptor gene (OPRM1, OPRK1, and
abstinence associated with prior use of disulfiram, and OPRD1) variants and response to naltrexone treatment for alco-
for those who might take the drug under the supervi- hol dependence: Results from the VA Cooperative Study. Alcohol
sion of another individual (such as a spouse), especially Clin Exp Res 31:555, 2007
LAWRENCE AJ: Therapeutics for alcoholism: Whats the future? Drug
during discrete periods identified as representing
Alcohol Rev 26:3, 2007
 CHAPTER 51

OPIOID DRUG ABUSE AND DEPENDENCE

Marc A. Schuckit

I Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
I Acute and Chronic Effects of Opioids . . . . . . . . . . . . . . . . . . 697
I Opioid Abuse and Dependence . . . . . . . . . . . . . . . . . . . . . . 698
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701

It is difcult to imagine modern medical practice without of these actions include nalorphine, levallorphan, cycla-
the use of opioid analgesics.These drugs have been part of zocine, butorphanol, buprenorphine, and pentazocine,
health care since 300 B.C. Opium and codeine were iso- each of which has mixed agonist and antagonist properties,
lated in the early nineteenth century, opioid-like substances as well as naloxone, nalmefene, and naltrexone, which
produced by the body were recognized in the 1970s, and are pure opiate antagonists.
the rst endogenous opioid was isolated in 1995.As impor- The availability of relatively specic antagonists has
tant as these substances are to modern medicine, opioid helped identify at least three receptor subtypes. These
drugs have many disadvantages, including overdosage and include receptors, which inuence some of the more
dependency; close to 1 million individuals in the United classic opioid actions such as pain control, reinforcement,
States are opioid-dependent. All opioid drugs are capable constipation, hormone levels, and respiration; receptors,
of producing a heroin-like intoxication, as well as toler- with possible similar functions along with sedation and
ance and withdrawal. effects on hormones; and receptors, thought to relate
mostly to analgesia, mood, reinforcement, and breathing.
PHARMACOLOGY A fourth possible receptor subtype, sensitive to another
endogenous peptide, is sometimes called nociceptin or
The prototypic opiates, morphine and codeine orphanin and may inuence pain. The major features of
(3-methoxymorphine), are derived from the juice of the tolerance, dependence, and withdrawal are thought to be
poppy Papaver somniferum. The semisynthetic drugs pro- mediated primarily by receptors, and these are affected
duced from morphine or thebane molecules include by all prescription opioids.
hydromorphone, diacetylmorphine (heroin), and oxy- The most rapid and pronounced effects of opioids
codone. The purely synthetic opioids and their cousins occur through IV administration, with only slightly less
include meperidine, propoxyphene, diphenoxylate, fentanyl, efcient absorption after smoking or inhaling the vapor
buprenorphine, tramadol, methadone, and pentazocine. (chasing the dragon).The slowest onset and least intense
The bodys own endogenous opioid peptides (e.g., effects occur after oral consumption. Most of the metab-
enkephalins, endorphins, dynorphins, and others) have olism of opioids occurs in the liver, primarily through
distinct distributions in the central nervous system (CNS) conjugation with glucuronic acid, and only small amounts
and appear to be natural ligands for opioid receptors. are excreted directly in the urine or feces. The plasma
As summarized in Table 51-1, the receptors with which half-lives of these drugs range from 2.53 h for mor-
opioid peptides interact differentially produce analgesia, phine to >22 h for methadone.
respiratory depression, constipation, euphoria, and other Street heroin is typically only 510% pure and is usually
actions. Substances capable of antagonizing one or more mixed with sugars, quinine, powdered milk, phenacetin,
696
TABLE 51-1 as an antitussive) and respiratory depression, which result 697
ACTIONS OF OPIOID RECEPTORS from a decreased response of the brainstem to carbon
dioxide tension, a component of the drug overdose syn-
RECEPTOR TYPE ACTIONS
drome described below.At even low drug doses, this effect
Mu () (e.g., Analgesia, reinforcement euphoria, can be clinically signicant for individuals with pulmonary
morphine) cough and appetite suppression, disease. Aspiration pneumonia is an additional risk. The
decreased respirations, decreased gastrointestinal effects of opioids can include decreased gut
GI motility, sedation, hormone motility (useful in treating diarrhea), nausea, constipation,
changes, dopamine and acetyl-
choline release
and anorexia with weight loss. Cardiovascular changes

CHAPTER 51
Kappa () (e.g., Decreased dysphoria, decreased GI following modest doses tend to be relatively mild, with
butorphanol) motility, decreased appetite, no direct opioid effect on heart rhythm or myocardial
decreased respiration, psychotic contractility, but orthostatic hypotension can occur,
symptoms, sedation, diuresis, probably secondary to histamine release and dilation of
analgesia peripheral vessels. Bacterial endocarditis with septic emboli
Delta () (e.g., Hormone changes, appetite and stroke can occur from contaminated needles.
etorphine) suppression, dopamine release

Opioid Drug Abuse and Dependence

Note: GI, gastrointestinal. Opioid Toxicity and Overdosage
High doses of opioids can result in a potentially lethal
overdose.This occurs at some point in over half of opioid-
caffeine, antipyrine, and strychnine. Unexpected increases dependent persons, especially with the more potent drugs
in the purity of street drugs can cause unintentional lethal such as fentanyl (80100 times more powerful than
overdoses. morphine).The typical syndrome, which occurs immedi-
ately with IV overdose, includes shallow and slow respira-
ACUTE AND CHRONIC EFFECTS tions, pupillary miosis (with mydriasis once brain anoxia
develops), bradycardia, hypothermia, and stupor or coma
OF OPIOIDS
(Chap. 14). If not treated rapidly, respiratory depression,
With the exception of overdose and physical depen- cardiorespiratory arrest, and death can ensue. Postmortem
dence, most opioid effects are rapidly reversible. A major examination reveals few specic changes except for diffuse
danger, however, comes through the use of contaminated cerebral edema. An allergic-like reaction to IV heroin,
needles by IV users, which increases the risk of hepatitis perhaps in part related to adulterants, can also occur and is
B and C, bacterial endocarditis, and infection with HIV characterized by decreased alertness, frothy pulmonary
(Chap. 37). edema, and an elevation in the blood eosinophil count.

Effects on Organ Systems

Euphoria and rewarding effects of opioids are due, at least
Treatment:
in part, to stimulation of dopaminergic pathways origi- OPIOID OVERDOSE
nating in the midbrain and terminating in the nucleus
accumbens. Effects on other neurotransmitter systems also The rst step in managing overdose is to support vital
occur. CNS effects of opioid drugs include nausea and signs, using intubation if needed. Denitive treatment is
vomiting (medulla), decreased pain perception (spinal cord, the administration of a narcotic antagonist such as nalox-
thalamus, and periaqueductal gray region), and sedation one, 0.42 mg IV or IM. A response should occur in 12 min,
(reticular activating system).The adulterants added to street but if needed, the dose can be repeated every 23 min
drugs may contribute to nervous system damage, including up to 10 mg. With the exception of buprenorphene over-
peripheral neuropathy, amblyopia, myelopathy, and leukoen- doses, a lack of response after 10 mg makes a toxic reac-
cephalopathy. Acute opioid administration inhibits release tion due solely to opioids unlikely. It is important to titrate
of some hormones from the hypothalamus, including the dose relative to the patients symptoms to amelio-
corticotropin-releasing factor (CRF) and luteinizing hor- rate the respiratory depression but not provoke a severe
mone, with a subsequent reduction in some sex hormones, withdrawal state; the latter cannot be aggressively treated
actions that might contribute to a decreased sex drive and until overdose-related vital signs are relatively stable.
problems in handling stress. Other hormonal changes Because the effects of naloxone diminish within several
include a decrease in the release of thyrotropin and increases hours, the individual must be monitored for at least 24 h
in prolactin and possibly growth hormone. after a heroin overdose and 72 h after an overdose of a
Acute changes in the respiratory system include a CNS- longer-acting drug such as methadone. If there is little
mediated decrease in the cough reex (which can be useful response to an opioid antagonist, the possibility of a
 698 concomitant overdose with a benzodiazepine should be at ~50%. Specic genes potentially include variations in
considered and a challenge with IV umazenil, 0.2 mg/min the 2 subunit of the -aminobutyric acid (GABA)-A
up to a maximum of 3 mg in an hour, might be used. receptor; this might affect the risk of abuse or dependence
This drug should be administered with caution as it can on a wide range of substances through effects on impulsiv-
precipitate seizures and increase intracranial pressure. ity and sensation-seeking. All genetic inuences operate
Treatment of either the typical or the allergic type of in the context of environmental factors as well.
opioid toxic reaction requires continued respiratory sup-
port (often with oxygen supplementation and positive- Natural History
pressure breathing for the allergic type of overdose),
While an opioid use disorder can develop in anyone, at
SECTION VI

IV uids, and pressor agents when needed to support

least three groups are at increased risk for dependence or
blood pressure. Activated charcoal (e.g., 1 g/kg suspended
misuse. First, a minority of persons with chronic pain syn-
in water) should be considered if ingestion of large doses
dromes (e.g., back, joint, and muscle disorders) misuse their
of oral opioids is suspected; alternatively, gastric lavage
prescribed drugs. If physical dependence is established,
can be used to remove any remaining drug. Intubation is
any drop in opioid blood levels can intensify the pain and
often required to prevent aspiration in the stuporous or
promote continued drug intake. Physicians can avoid con-
Alcoholism and Drug Dependency

comatose patient. Cardiac arrhythmias and/or seizures

tributing to physical dependence by helping the patient
may also be part of the opioid toxic reaction, especially
to accept the goal of moderation rather than disappearance
with codeine, propoxyphene, or meperidine.
of the pain, and to recognize that discomfort may not be
completely eliminated.Analgesic medication should be only
one component of treatment and should be limited to
the oral administration of the least potent analgesic that
OPIOID ABUSE AND DEPENDENCE is able to take the edge off the pain (e.g., naproxen or
ibuprofen). Behavior-modication techniques, such as
Denition and Epidemiology muscle relaxation and meditation, and carefully selected
The Fourth Diagnostic and Statistical Manual of Mental exercises should be used as appropriate to help increase
Disorders, (DSM-IV) of the American Psychiatric Associ- function and decrease pain. Finally, nonmedicinal approaches,
ation denes dependence as repeated use of a drug to the including electrical transcutaneous neurostimulation for
point of causing repetitive problems in multiple life areas. muscle and joint disease, may be useful.
The denition requires evidence of three or more such The second group at high risk consists of physicians,
problems clustered together within the same 12-month nurses, and pharmacists, primarily because of easy access
period of time, including tolerance, withdrawal, use of to opioids. Physicians may begin use to help with sleep
greater amounts of opiates than intended, and use despite or to reduce stress or physical aches and pains, and then
consequences. Patients who do not have dependence but escalate doses as tolerance develops. Because of the growing
demonstrate repeated opioid-related difculties with the awareness of these problems, programs have been devel-
law, impaired ability to meet obligations, use in hazardous oped to identify and aid substance-impaired physicians,
situations, or continued use despite problems can be labeled providing peer support and education before problems
as having abuse. escalate to the point of licensure revocation.All physicians
The use of opioids for intoxication is less prevalent are advised never to prescribe opioids for themselves or
than the use of alcohol, marijuana, and stimulants such as family members
cocaine or amphetamines. A national survey of adoles- The third group is those who buy illicit drugs to get
cents and young adults published in 2005 reported that high.While some of these individuals have severe antisocial
13.5% of 12th graders (high school seniors) had tried an problems, many had a relatively high level of premorbid
opioid outside of a doctors prescription, including 1.5% functioning. The typical person begins using opioids
who had used heroin. Figures for young adults and col- occasionally, often after experimenting with tobacco,
lege students were almost 17.6% and 1.9%, respectively. then alcohol, then marijuana, and then brain depressants
In all studies, prevalence rates were only slightly higher in or stimulants. Occasional opioid use, or chipping, might
males than females.The prevalence of opioid dependence continue for some time, and some individuals never esca-
is estimated as a lifetime risk of about 1%. late their intake to the point of developing dependence. For
others, the frequency of use and quantity needed increase,
tolerance develops, excuses are made for associated prob-
Genetics
lems, and a full dependence syndrome appears.
Genetic factors appear to inuence an individuals specic Opioid-dependent individuals are not likely to give up
risk for opioid dependence as well as a more general their intake of other drugs.Alcohol may be used to mod-
vulnerability toward substance-related problems.The pro- erate withdrawal problems, to enhance the opioid high, and
portion of the total risk explained by genes is estimated to serve as a substitute when the opioid is not available,
including during methadone or other maintenance or SYMPTOMS OF WITHDRAWAL Withdrawal symp- 699
antagonist treatments. Problematic drinking, including toms (which are generally the opposite of the acute
alcohol dependence, is seen in about half of opioid- effects of the drug) include nausea, diarrhea, coughing,
dependent persons. Cocaine appears to be taken for many lacrimation, mydriasis, rhinorrhea, profuse sweating,
of the same reasons, and is often administered IV with twitching of muscles, and piloerection (or goose bumps)
the opioid in a mixture known as a speedball. Another as well as mild elevations in body temperature, respiratory
relevant class of drugs is the benzodiazepines, taken for a rate, and blood pressure. In addition, diffuse body pain,
high or alleviation of withdrawal symptoms, especially insomnia, and yawning occur, along with intense drug
among people in methadone maintenance. craving. Withdrawal from opioids with shorter half-lives,

CHAPTER 51
Once persistent opioid use is established, severe problems such as morphine or heroin, usually causes symptoms
are likely to develop. At least 25% of opioid-dependent within 816 h of the last dose; intensity peaks within
individuals die within 1020 years (a mortality rate 15-fold 3672 h after discontinuation of the drug; and the acute
higher than the general population) from suicide, homi- syndrome disappears within 58 days. A protracted absti-
cide, accidents, or infectious diseases such as tuberculosis, nence phase of mild moodiness, autonomic dysfunction,
hepatitis, or AIDS. The latter has become an epidemic and changes in pain threshold and sleep patterns may per-
among injection drug users, with as many as 60% of these

Opioid Drug Abuse and Dependence

sist for 6 months and probably contributes to relapse. For
men and women in some locales carrying the HIV virus longer-acting opioids such as methadone or continuous-
(Chap. 37). Although the majority of opioid-dependent release morphine, symptoms may not appear for several
persons experience frequent exacerbations and remissions, days, and may not peak until 710 days later.
it is important to remember that even without treatment
~35% achieve long-term, often permanent, abstinence, TREATMENT OF THE WITHDRAWAL SYN-
especially after 40 years of age.As is true with most drugs DROME A thorough physical examination, including
of abuse, a favorable prognosis is associated with a prior an assessment of neurologic function and a search for focal
history of marital and employment stability and fewer and systemic infections, especially abscesses, is essential.
prior criminal activities unrelated to drugs. Laboratory testing includes assessment of liver function
and, in IV users, HIV and hepatitis B and C status.
One treatment approach to withdrawal is to administer
an opioid (e.g., 1025 mg of methadone bid) on day 1 to
Treatment: decrease symptoms. After several days of a stabilized drug
OPIOID ABUSE AND DEPENDENCE dose, the opioid is then decreased by 1020% of the
original days dose each day. However, the use of opioids
The rst step in treatment is to identify the problem. It is
for detoxication is proscribed or limited in most states.
important to discard the erroneous stereotype that opioid-
Thus, pharmacologic treatments often center on relief
dependent individuals are unemployed and homeless.
of symptoms of diarrhea with loperamide, of snifes
Abuse or dependence is possible in any patient who
with decongestants, and pain with nonopioid anal-
demonstrates symptoms of what might be opioid with-
gesics (e.g., ibuprofen). Comfort can be enhanced with
drawal; anyone who has a chronic pain syndrome; physi-
administration of the 2-adrenergic agonist clonidine in
cians, nurses, and pharmacists or others with easy access to
doses up to 0.3 mg given two to four times a day to
opioids; and patients who repeatedly seek out prescrip-
decrease sympathetic nervous system overactivity. Blood
tion analgesics. Before prescribing an opioid analgesic, it
pressure must be closely monitored. Some clinicians
is important to gather a complete history that elucidates
augment this regimen with low to moderate doses of
patterns of life problems and any history of opioid use. If
benzodiazepines for 25 days to decrease agitation and
a problem with opioids is suspected, gathering further
promote sleep. An ultra-rapid detoxication procedure
data from a relative or close friend can be helpful. Addi-
using deep sedation and withdrawal precipitated by
tionally, clinicians should search for physical stigmata of
naltrexone has been proposed but has many inherent
misuse (e.g., needle marks) and, when appropriate, screen
dangers and few, if any, advantages.
blood or urine for opioids.
After identifying opioid dependence, the next step is REHABILITATION The basic strategy, similar to that
intervention as described for alcoholism in Chap. 50. for alcoholics, includes detoxication and the establish-
Motivational interviewing techniques of empathy, careful ment of realistic goals for abstinence and improvement
listening, presenting options, and gauging the patients of life functioning, along with counseling and education
motivational readiness to change are important, as are to increase motivation toward abstinence. A long-term
efforts to enlist the help of relatives and friends. Ongo- commitment by the patient to maintain a lifestyle with-
ing treatment even after the patient achieves abstinence out illicit substances is essential for preventing relapse.
is important; this includes offering help in establishing a In most programs, patients are educated about their
drug-free lifestyle. responsibility for improving their lives, and motivation
 700 for abstinence is increased by providing information Buprenorphine is available as monotherapy or in
about the medical and psychological problems that can combination with the antagonist naltrexone (28 mg
be expected if dependence continues. Patients and fam- buprenorphine with 0.52 mg naltrexone), which pre-
ilies are encouraged to establish an opioid-free lifestyle by cipitates withdrawal if the patient dissolves the pills and
learning to cope with chronic pain and develop realistic injects them IV. Buprenorphine has several advantages
vocational planning.The dependent person is also advised including low overdose danger, potentially easier detox-
to establish a drug-free peer group and to participate in ication than is seen with methadone, and a probable
self-help groups such as Narcotics Anonymous or Alco- ceiling effect in which higher doses do not increase
holics Anonymous; the latter is appropriate for substance- euphoria. It can also be given in the doctors ofce by
SECTION VI

dependent persons regardless of their usual drug of physicians who have completed a required training pro-
abuse. Another important treatment component is relapse gram. While some studies report equal effectiveness of
prevention aimed at identifying triggers for a return to buprenorphine and methadone, others suggest higher
drugs and developing appropriate coping strategies. dropout rates or more concomitant illicit drug use with
Much of this advice and counseling can be given by buprenorphine compared to methadone. As with all
the physician or by referring patients to formal drug opioids, there is a danger of misuse of this drug.
Alcoholism and Drug Dependency

programs, including methadone maintenance clinics, In the past, the British have used heroin maintenance
programs using narcotic antagonists, and therapeutic with goals and guidelines similar to those of current
communities. Long-term follow-up of treated patients methadone programs. There is no evidence that heroin
indicates that approximately one-third are completely maintenance has any advantages over methadone main-
drug free, and 60% no longer use opioids. tenance, but the heroin approach increases the risk that
the drug will be sold on the streets.
Opioid Maintenance Maintenance programs with
Opioid Antagonists The opioid antagonists (e.g.,
methadone or buprenorphene should be used only in
naltrexone) compete with heroin and other opioids at
combination with education and counseling. The goal is
receptors, reducing the effects of the opioid agonists.
to provide a substitute drug that is legally accessible,
Administered over long periods with the intention of
safer, can be taken orally, and has a relatively long half-life
blocking the opioid high, these drugs can be useful as
so that it can be taken once a day. This can help persons
part of an overall treatment approach that includes
who have repeatedly failed in drug-free programs to
counseling and support. Naltrexone doses of 50 mg/d
improve functioning within the family and job, to decrease
antagonize 15 mg of heroin for 24 h, and the possibly
legal problems, and to improve health. Individuals who
more effective higher doses (125150 mg) block the
stay in methadone maintenance are likely to show less
effects of 25 mg of IV heroin for up to 3 days. To avoid
antisocial behavior and improvement in employment
precipitating a withdrawal syndrome, patients must be
status.
free of opioids for a minimum of 5 days before begin-
Methadone is a long-acting opioid optimally dosed at
ning treatment with naltrexone and should rst be chal-
80120 mg/d (a goal met through slow, careful increases
lenged with 0.4 or 0.8 mg of the shorter-acting agent
over time). This dose is effective in blocking heroin-
naloxone to be certain they can tolerate the long-acting
induced euphoria while decreasing craving, thereby
antagonist. A test dose of 10 mg of naltrexone is then
helping patients to maintain abstinence from illegal
given, which can produce withdrawal symptoms in
opioids. Over three-quarters of patients in well-supervised
0.52 h. If none appear, the patient can begin with the
methadone clinics are likely to remain heroin-free for
usual dose of 40150 mg three times per week.
6 months. Methadone is usually administered as an
oral liquid given once a day at the program, with week- Drug-Free Programs Most opioid-dependent indi-
end doses taken at home. After a period of maintenance viduals enter treatment programs that are based primar-
(usually 6 months to 1 year), the clinician can work to ily on the cognitive behavioral approaches of enhancing
slowly decrease the dose by ~5% per week. Some indi- commitment to abstinence, helping individuals to rebuild
viduals, however, are unable to taper off the drug and their lives without substances, and preventing relapse.
require long-term maintenance. Whether carried out in inpatient, residential, or outpa-
An alternative medication that has been used for tient settings, patients usually do not receive mainte-
maintenance treatment is buprenorphine, a opioid nance medications.
agonist and antagonist. A dose of 612 mg buprenor- A variation of this approach can be used for persons
phine is roughly equivalent to 3560 mg of methadone. who are having problems maintaining a drug-free state.
Administered either as a sublingual liquid or tablet, Here, the basic elements of treatment are incorporated into
doses can be gradually increased to 816 mg/d over the long-term (often a year or more) residence in a therapeutic
rst 2 months. Doses of 1632 mg per treatment day may community.The person begins with almost full immersion
be needed if the drug is given three times per week. in the environment in which other individuals at various
stages of recovery become the primary support group, warrant in the average person. Physicians must be vigi- 701
offering advice and a drug-free atmosphere in which lant regarding their own risk for opioid abuse and depen-
the opioid-dependent person progresses through ever- dence, never prescribing these drugs for themselves. For
increasing levels of independence, including assuming the nonmedical IV drugdependent person, all possible
a job outside the therapeutic atmosphere. efforts must be made to prevent AIDS, hepatitis, bacterial
As is true for treatments of all substance-use disorders, endocarditis, and other consequences of contaminated
it is likely that counseling, behavioral treatments, and needles both through methadone maintenance and by
relatively simple approaches to psychotherapy add sig- considering needle-exchange programs.
nicantly to a positive outcome. Most programs focus

CHAPTER 51
on teaching participants to cope with stress, enhancing
their understanding of personality attributes, teaching
better cognitive styles, and, through the process of relapse FURTHER READINGS
prevention, addressing issues that might contribute to JOHNSTON LD et al: Monitoring the Future: National Results on Adolescent
increased craving, easy access to drugs, or periods of Drug Use: Overview of Key Findings, 2005. Bethesda, MD, National
decreased motivation. A combination of these therapies Institute on Drug Abuse

Opioid Drug Abuse and Dependence

with the approaches described above appears to give PASSIK SD: Issues in long-term opioid therapy: unmet needs, risks,
the best results. and solutions. Mayo Clin Proc 84:593, 2009
SCHUCKIT MA: Drug and Alcohol Abuse: A Clinical Guide to Diagnosis
Finally, it is important to discuss prevention. Except for
and Treatment, 6th ed. New York, Springer, 2006
the terminally ill, physicians should carefully monitor opi- STRANG J et al: Does prescribing for opiate addiction change after
oid drug use in their patients, keeping doses as low as is national guidelines? Methadone and buprenorphine prescribing
practical while still controlling pain, and administering to opiate addicts by general practitioners and hospital doctors in
opioids over as short a period as the level of pain would England, 19952005.Addiction 102(5):761, 2007
 CHAPTER 52

COCAINE AND OTHER COMMONLY

ABUSED DRUGS

Jack H. Mendelson I Nancy K. Mello

I Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
I Marijuana and Cannabis Compounds . . . . . . . . . . . . . . . . . . 704
I Methamphetamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
I Lysergic Acid Diethylamide (LSD) . . . . . . . . . . . . . . . . . . . . . 706
I Phencyclidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
I Polydrug Abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707

Initiation and perpetuation of the abuse of cocaine and (the speedball) is frequently associated with needle-
other psychostimulants are determined by a complex inter- sharing by IV drug users. Intravenous drug abusers continue
action between the pharmacologic properties and relative to represent the largest single group of persons with HIV
availability of each drug, the personality and expectations infection in several major metropolitan areas in the United
of the user, and the environmental context in which the States as well as in urban areas in Scotland, Italy, Spain,
drug is used. Polydrug abuse, the concurrent use of several Thailand, and China.
drugs with different pharmacologic effects, is increasingly
common. Some forms of polydrug abuse, such as the com- COCAINE
bined use of heroin and cocaine intravenously, are espe-
cially dangerous and remain a major problem in hospital Cocaine is a stimulant and local anesthetic with potent
emergency departments. Sometimes one drug is used to vasoconstrictor properties. The leaves of the coca plant
enhance the effects of another, as with the combined use (Erythroxylon coca) contain ~0.51% cocaine.The drug pro-
of benzodiazepines and methadone, or cocaine and heroin duces physiologic and behavioral effects when administered
in methadone-maintained patients. PO, intranasally, IV, or via inhalation following pyrolysis
Chronic cocaine and psychostimulant abuse may cause (smoking).The reinforcing effects of cocaine appear to be
a number of adverse health consequences, ranging from related to activation of dopaminergic neurons in the
pulmonary disease to reproductive dysfunction. Preexisting mesolimbic system. Cocaine increases synaptic concentra-
disorders such as hypertension and cardiac disease may be tions of the monamine neurotransmitters dopamine,
exacerbated by drug abuse, and the combined use of two norepinephrine, and serotonin by binding to transporter
or more drugs may accentuate medical complications proteins in presynaptic neurons and blocking reuptake.
associated with abuse of one of them.The adverse health
consequences of drug abuse are further complicated by Prevalence of Cocaine Use
increased vulnerability to infections. Cocaine is widely available throughout the United States,
Drug abuse increases the risk of exposure to HIV. and cocaine abuse occurs in virtually all social and eco-
Cocaine and psychostimulant abuse contribute to the nomic strata of society. The prevalence of cocaine abuse
risk for HIV infection in part by suppression of immune in the general population has been accompanied by an
function. In addition, concurrent use of cocaine and opiates increase in cocaine abuse by heroin-dependent persons,

Deceased.
702
including those in methadone maintenance programs. effects of cocaine and to residual contaminants in the 703
Intravenous cocaine is often used concurrently with IV smoked material. Hepatic necrosis has been reported to
heroin. This combination purportedly attenuates the occur following crack/cocaine use.
postcocaine crash and substitutes a cocaine high for Although men and women who abuse cocaine may
the heroin high blocked by methadone. report that the drug enhances libidinal drive, chronic
cocaine use causes signicant loss of libido and adversely
Acute and Chronic Intoxication affects reproductive function. Impotence and gyneco-
mastia have been observed in male cocaine abusers, and
There has been an increase in both IV administration and these abnormalities often persist for long periods fol-

CHAPTER 52
inhalation of pyrolyzed cocaine via smoking. Following lowing cessation of drug use.Women who abuse cocaine
intranasal administration, changes in mood and sensation may experience major derangements in menstrual cycle
are perceived within 35 min, and peak effects occur at function including galactorrhea, amenorrhea, and infer-
1020 min.The effects rarely last more than 1 h. Inhalation tility. Chronic cocaine abuse may cause persistent hyper-
of pyrolyzed materials includes inhaling crack/cocaine or prolactinemia as a consequence of disordered dopaminergic
smoking coca paste, a product made by extracting cocaine inhibition of prolactin secretion by the anterior pitu-
preparations with ammable solvents, and cocaine free- itary. Cocaine abuse by pregnant women, particularly

Cocaine and Other Commonly Abused Drugs

base smoking. Free-base cocaine, including the free base the smoking of crack, has been associated with both an
prepared with sodium bicarbonate (crack), has become increased risk of congenital malformations in the fetus
increasingly popular because of the relative high potency and perinatal cardiovascular and cerebrovascular disease
of the compound and its rapid onset of action (810 s in the mother. However, cocaine abuse per se is proba-
following smoking). bly not the sole cause of these perinatal disorders, since
Cocaine produces a brief, dose-related stimulation and many problems associated with maternal cocaine abuse,
enhancement of mood and an increase in cardiac rate and including poor nutrition and health care status as well
blood pressure. Body temperature usually increases follow- as polydrug abuse, also contribute to the risk for peri-
ing cocaine administration, and high doses of cocaine may natal disease.
induce lethal pyrexia or hypertension. Because cocaine Protracted cocaine abuse may cause paranoid ideation
inhibits reuptake of catecholamines at adrenergic nerve and visual and auditory hallucinations, a state that resem-
endings, the drug potentiates sympathetic nervous sys- bles alcoholic hallucinosis. Psychological dependence on
tem activity. Cocaine has a short plasma half-life of cocaine, indicated by inability to abstain from frequent
approximately 4560 min. Cocaine is metabolized by compulsive use, has also been reported. Although the
plasma esterases, and cocaine metabolites are excreted in occurrence of withdrawal syndromes involving psychomo-
urine. The very short duration of the euphorigenic tor agitation and autonomic hyperactivity remains contro-
effects of cocaine observed in chronic abusers is proba- versial, severe depression (crashing) following cocaine
bly due to both acute and chronic tolerance. Frequent intoxication may accompany drug withdrawal.
self-administration of the drug (two to three times per
hour) is often reported by chronic cocaine abusers.
Alcohol is used to modulate both the cocaine high and Treatment:
the dysphoria associated with the abrupt disappearance COCAINE OVERDOSE AND CHRONIC
of cocaines effects. A metabolite of cocaine, cocaethyl- ABUSE
ene, has been detected in blood and urine of persons who Treatment of cocaine overdose is a medical emergency
concurrently abuse alcohol and cocaine. Cocaethylene that is usually best managed in an intensive care unit.
induces changes in cardiovascular function similar to Cocaine toxicity produces a hyperadrenergic state char-
those of cocaine alone, and the pathophysiologic conse- acterized by hypertension, tachycardia, tonic-clonic
quences of alcohol abuse plus cocaine abuse may be seizures, dyspnea, and ventricular arrhythmias. Intra-
additive when both are used together. venous diazepam in doses up to 0.5 mg/kg adminis-
The prevalent assumption that cocaine inhalation or IV tered over an 8-h period has been shown to be effective
administration is relatively safe is contradicted by reports of for control of seizures. Ventricular arrhythmias have been
death from respiratory depression, cardiac arrhythmias, and managed successfully by administration of 0.51.0 mg
convulsions associated with cocaine use. In addition to of propranolol IV. Because many instances of cocaine-
generalized seizures, neurologic complications may include related mortality have been associated with concurrent
headache, ischemic or hemorrhagic stroke, or subarachnoid use of other illicit drugs (particularly heroin), the physi-
hemorrhage. Disorders of cerebral blood ow and perfu- cian must be prepared to institute effective emergency
sion in cocaine-dependent persons have been detected with treatment for multiple drug toxicities.
magnetic resonance spectroscopy (MRS) studies. Severe Treatment of chronic cocaine abuse requires the
pulmonary disease may develop in individuals who inhale combined efforts of primary care physicians, psychiatrists,
crack cocaine; this effect is attributed both to the direct
 704 and psychosocial care providers. Early abstinence from Prevalence of Use
cocaine use is often complicated by symptoms of depres- Marijuana is the most commonly used illegal drug in the
sion and guilt, insomnia, and anorexia, which may be as United States. Use is particularly prevalent among adoles-
severe as those observed in major affective disorders. cents; studies suggest that ~37% of high school students in
Individual and group psychotherapy, family therapy, and the United States have used marijuana. Marijuana is rela-
peer group assistance programs are often useful for tively inexpensive and is often considered to be less haz-
inducing prolonged remission from drug use. A number ardous than other controlled drugs and substances. Very
of medications used for the treatment of various medical potent forms of marijuana (sinsemilla) are now available
and psychiatric disorders have been administered to in many communities, and concurrent use of marijuana
SECTION VI

reduce the duration and severity of cocaine abuse and with crack/cocaine and phencyclidine is increasing.
dependence. However, no available medication is both
safe and highly effective for either cocaine detoxication Acute and Chronic Intoxication
or maintenance of abstinence. Some psychotherapeutic
interventions may be effective; however, no specic Acute intoxication from marijuana and cannabis com-
form of psychotherapy or behavioral modication is pounds is related to both the dose of THC and the route of
Alcoholism and Drug Dependency

uniquely benecial. administration. THC is absorbed more rapidly from mari-

juana smoking than from orally ingested cannabis com-
pounds. Acute marijuana intoxication usually consists of
a subjective perception of relaxation and mild euphoria
MARIJUANA AND CANNABIS resembling mild to moderate alcohol intoxication. This
COMPOUNDS condition is usually accompanied by some impairment in
thinking, concentration, and perceptual and psychomotor
Cannabis sativa contains >400 compounds in addition to function. Higher doses of cannabis may produce behavioral
the psychoactive substance, delta-9-tetrahydrocannabinol effects analogous to severe alcohol intoxication. Although
(THC). Marijuana cigarettes are prepared from the leaves the effects of acute marijuana intoxication are relatively
and owering tops of the plant, and a typical marijuana benign in normal users, the drug can precipitate severe
cigarette contains 0.51 g of plant material. Although the emotional disorders in individuals who have antecedent
usual THC concentration varies between 10 and 40 mg, psychotic or neurotic problems.As with other psychoactive
concentrations >100 mg per cigarette have been detected. compounds, both set (users expectations) and setting (envi-
Hashish is prepared from concentrated resin of C. sativa ronmental context) are important determinants of the
and contains a THC concentration of between 8 and type and severity of behavioral intoxication.
12% percent by weight. Hash oil, a lipid-soluble plant As with abuse of cocaine, opioids, and alcohol, chronic
extract, may contain a THC concentration of 2560% marijuana abusers may lose interest in common socially
and may be added to marijuana or hashish to enhance its desirable goals and steadily devote more time to drug
THC concentration. Smoking is the most common mode acquisition and use. However, THC does not cause a
of marijuana or hashish use. During pyrolysis, >150 specic and unique amotivational syndrome.The range
compounds in addition to THC are released in the smoke. of symptoms sometimes attributed to marijuana use is
Although most of these compounds do not have psychoac- difcult to distinguish from mild to moderate depression
tive properties, they do have potential physiologic effects. and the maturational dysfunctions often associated with
THC is quickly absorbed from the lungs into blood protracted adolescence. Chronic marijuana use has also
and is then rapidly sequestered in tissues. It is metabo- been reported to increase the risk of psychotic symptoms
lized primarily in the liver, where it is converted to in individuals with a past history of schizophrenia. Persons
11-hydroxy-THC, a psychoactive compound, and >20 who initiate marijuana smoking before the age of 17 may
other metabolites. Many THC metabolites are excreted subsequently develop severe cognitive and neuropsycho-
through the feces at a rate of clearance that is relatively slow logical disorders, and they may also be at higher risk for
in comparison to that of most other psychoactive drugs. polydrug and alcohol abuse problems in later life.
Specic cannabinoid receptors (CB1 and CB2) have
been identied in the central nervous system, including
Physical Effects
the spinal cord, and in the peripheral nervous system.
High densities of these receptors have been found in the Conjunctival injection and tachycardia are the most fre-
cerebral cortex, basal ganglia, and hippocampus.T and B quent immediate physical concomitants of smoking
lymphocytes also have cannabinoid receptors, and these marijuana. Tolerance for marijuana-induced tachycardia
appear to mediate anti-inammatory and immunoregu- develops rapidly among regular users. However, marijuana
latory properties of cannabinoids. A naturally occurring smoking may precipitate angina in persons with a history
THC-like ligand has been identied in the nervous sys- of coronary insufciency. Exercise-induced angina may
tem, where it is widely distributed. be increased after marijuana use to a greater extent than
after tobacco cigarette smoking. Patients with cardiac chemotherapy recipients, appetite-promoting effects in 705
disease should be strongly advised not to smoke mari- AIDS patients, reduction of intraocular pressure in glau-
juana or use cannabis compounds. coma, and reduction of spasticity in multiple sclerosis and
Signicant decrements in pulmonary vital capacity have other neurologic disorders.With the possible exception of
been found in regular daily marijuana smokers. Because AIDS-related cachexia, none of these attributes of mari-
marijuana smoking typically involves deep inhalation and juana compounds is clearly superior to other readily
prolonged retention of marijuana smoke, marijuana smok- available therapies.
ers may develop chronic bronchial irritation. Impairment
of single-breath carbon monoxide diffusion capacity (DLCO)

CHAPTER 52
is greater in persons who smoke both marijuana and METHAMPHETAMINE
tobacco than in tobacco smokers.
Although marijuana has also been associated with a Methamphetamine is also referred to as meth, speed,
number of other adverse effects, many of these studies crank, chalk, ice, glass, or crystal. In the United
await replication and conrmation.A reported correlation States, hospital admissions for treatment of methamphet-
between chronic marijuana use and decreased testosterone amine abuse increased substantially (from 38%) between
levels in males has not been conrmed. Decreased sperm 1994 and 2004. This increase occurred despite drug

Cocaine and Other Commonly Abused Drugs

count and sperm motility and morphologic abnormali- seizures, closures of clandestine laboratories that produce
ties of spermatozoa following marijuana use have been methamphetamine illegally, and an increase in metham-
reported. Prospective studies demonstrated a correlation phetamine abuse prevention programs.
between impaired fetal growth and development and heavy Methamphetamine can be self-administered PO or
marijuana use during pregnancy. Marijuana has also been by smoking, snorting, and IV injection. Individuals who
implicated in derangements of the immune system; in abuse or become dependent upon methamphetamine
chromosomal abnormalities; and in inhibition of DNA, report that use of this drug induces feelings of euphoria
RNA, and protein synthesis; however, these ndings have and decreases fatigue associated with difcult life situa-
not been conrmed or related to any specic physiologic tions. Adverse consequences of methamphetamine abuse
effect in humans. include headache, difculty concentrating, diminished
appetite, abdominal pain, vomiting or diarrhea, disordered
sleep, paranoid or aggressive behavior, and psychosis.
Tolerance and Physical Dependence Chronic methamphetamine abuse can result in severe
Habitual marijuana users rapidly develop tolerance to the dental caries, described as blackened, rotting, crumbling
psychoactive effects of marijuana and often smoke more teeth. Severe, life-threatening methamphetamine toxicity
frequently and try to secure more potent cannabis com- may present as hypertension, cardiac arrhythmia or failure,
pounds.Tolerance for the physiologic effects of marijuana subarachnoid hemorrhage, ischemic stroke, intracerebral
develops at different rates; e.g., tolerance develops rapidly hemorrhage, convulsions, or coma. Methamphetamines
for marijuana-induced tachycardia but more slowly for increase the release of monoamine neurotransmitters
marijuana-induced conjunctival injection. Tolerance for (dopamine, norepinephrine, and serotonin) from presy-
both behavioral and physiologic effects of marijuana naptic neurons. It is thought that the euphoric and rein-
decreases rapidly upon cessation of marijuana use. forcing effects of this class of drugs are mediated through
Withdrawal signs and symptoms have been reported dopamine and the mesolimbic system, whereas the car-
in chronic cannabis users, with the severity of symptoms diovascular effects are related to norepinephrine. MRS
related to dosage and duration of use. These include studies of the brain suggest that chronic abusers have
tremor, nystagmus, sweating, nausea, vomiting, diarrhea, neuronal damage in the frontal areas and basal ganglia.
irritability, anorexia, and sleep disturbances. Withdrawal Therapy of acute methamphetamine overdose is largely
signs and symptoms observed in chronic marijuana users symptomatic.Ammonium chloride may be useful to acid-
are usually relatively mild in comparison to those observed ify the urine and enhance clearance of the drug. Hyperten-
in heavy opiate or alcohol users and rarely require medical sion may respond to sodium nitroprusside or -adrenergic
or pharmacologic intervention. More severe and protracted antagonists. Sedatives may reduce agitation and other signs
abstinence syndromes may occur after sustained use of high- of central nervous system hyperactivity. Treatment of
potency cannabis compounds. chronic methamphetamine dependence may be accom-
plished in either an inpatient or outpatient setting using
strategies similar to those described earlier for cocaine
Therapeutic Use of Marijuana
abuse.
Marijuana, administered as cigarettes or as a synthetic oral MDMA (3,4-methylenedioxymethamphetamine), or
cannabinoid (dronabinol), has been proposed to have a Ecstasy, is a derivative of methamphetamine. Ecstasy is
number of medicinal properties that may be clinically use- usually taken PO but may be injected or inhaled; its effects
ful in some situations.These include antiemetic effects in last for 36 h. In addition to amphetamine-like effects,
 706 MDMA can induce hyperthermia and vivid hallucinations anesthetic. PCP binds to ionotropic N-methyl-D-aspartate
and other perceptual distortions. (NMDA) receptors in the nervous system, blocking ion
During the past decade, an eighteenfold increase in current through these channels. PCP is easily synthesized;
MDMA-related emergency department incidents has been its abusers are primarily young people and polydrug users.
reported in the United States. Recent studies have revealed It is used PO, by smoking, or by IV injection. It is also used
that MDMA use is associated with cognitive and memory as an adulterant in THC, LSD, amphetamine, or cocaine.
impairment and a mild withdrawal syndrome after cessa- The most common street preparation, angel dust, is a
tion of use.The long-term consequences of recreational use white granular powder that contains 50100% of the
of MDMA by young persons are poorly understood. drug. Low doses (5 mg) produce agitation, excitement,
SECTION VI

impaired motor coordination, dysarthria, and analgesia.

Users may have horizontal or vertical nystagmus, ushing,
LYSERGIC ACID DIETHYLAMIDE (LSD) diaphoresis, and hyperacusis. Behavioral changes include
distortions of body image, disorganization of thinking, and
The discovery of the psychedelic effects of LSD in 1947
feelings of estrangement. Higher doses of PCP (510 mg)
led to an epidemic of LSD abuse during the 1960s. Impo-
may produce profuse salivation, vomiting, myoclonus, fever,
sition of stringent constraints on the manufacture and dis-
stupor, or coma. PCP doses of 10 mg cause convulsions,
Alcoholism and Drug Dependency

tribution of LSD (classied as a Schedule I substance by

opisthotonus, and decerebrate posturing, which may be
the U.S. Food and Drug Administration), as well as public
followed by prolonged coma.
recognition that psychedelic experiences induced by LSD
The diagnosis of PCP overdose is difcult because the
were a health hazard, have resulted in a reduction in LSD
patients initial symptoms may suggest an acute schizo-
abuse. LSD still remains popular among adolescents and
phrenic reaction. Conrmation of PCP use is possible by
young adults, and there are indications that LSD use
determination of PCP levels in serum or urine. PCP assays
among young persons has been increasing in some com-
are available at most toxicologic centers. PCP remains in
munities in the United States.
urine for 15 days following high-dose intake.
LSD is a very potent drug; oral doses as low as 20 g
PCP overdose requires life-support measures, includ-
may induce profound psychological and physiologic effects.
ing treatment of coma, convulsions, and respiratory
Tachycardia, hypertension, pupillary dilation, tremor, and
depression in an intensive care unit. There is no specic
hyperpyrexia occur within minutes following oral admin-
antidote or antagonist for PCP. PCP excretion from the
istration of 0.52 g/kg. A variety of bizarre and often
body can be enhanced by gastric lavage and acidication
conicting perceptual and mood changes, including visual
of urine. Death from PCP overdose may occur as a con-
illusions, synesthesias, and extreme lability of mood, usu-
sequence of some combination of pharyngeal hyper-
ally occur within 30 min after LSD intake. These effects
secretion, hyperthermia, respiratory depression, severe
of LSD may persist for 1218 h, even though the half-life
hypertension, seizures, hypertensive encephalopathy, and
of the drug is only 3 h.
intracerebral hemorrhage.
Tolerance develops rapidly for LSD-induced changes
Acute psychosis associated with PCP use should be
in psychological function when the drug is used one or
considered a psychiatric emergency since patients may be
more times per day for >4 days. Abrupt abstinence fol-
at high risk for suicide or extreme violence toward others.
lowing continued use does not produce withdrawal signs
Phenothiazines should not be used for treatment because
or symptoms.There have been no clinical reports of death
these drugs potentiate PCPs anticholinergic effects.
caused by the direct effects of LSD.
Haloperidol (5 mg IM) has been administered on an hourly
The most frequent acute medical emergency associated
basis to induce suppression of psychotic behavior. PCP, like
with LSD use is a panic episode (the bad trip), which
LSD and mescaline, produces vasospasm of cerebral arteries
may persist up to 24 h. Management of this problem is
at relatively low doses. Chronic PCP use has been shown
best accomplished by supportive reassurance (talking
to induce insomnia, anorexia, severe social and behavioral
down) and, if necessary, administration of small doses of
changes, and, in some cases, chronic schizophrenia.
anxiolytic drugs. Adverse consequences of chronic LSD
use include enhanced risk for schizophreniform psychosis
and derangements in memory function, problem solving,
and abstract thinking. Treatment of these disorders is best POLYDRUG ABUSE
carried out in specialized psychiatric facilities. Although drug abusers often report a preference for a
particular drug, such as alcohol or opiates, the concurrent
PHENCYCLIDINE use of other drugs is common. Polydrug abuse often
involves substances that may have different pharmacologic
Phencyclidine (PCP), a cyclohexylamine derivative, is effects from the preferred drug. For example, concurrent
widely used in veterinary medicine to briey immobilize use of such dissimilar compounds as stimulants and opiates
large animals and is sometimes described as a dissociative or stimulants and alcohol is not unusual.The diversity of
reported drug use combinations suggests that achieving detoxication, a process that may be difcult because of 707
some perceptible change in state, rather than any partic- the abuse of several drugs with different pharmacologic
ular direction of change (stimulation or sedation), may actions (e.g., alcohol, opiates, and cocaine). Because
be the primary reinforcer in polydrug use and abuse. patients may not recall or may deny simultaneous multi-
There is also evidence that intoxication with alcohol or ple drug use, diagnostic evaluation should always
opiates is associated with increased tobacco smoking. include urinalysis for qualitative detection of psychoac-
There is relatively little systematic information available tive substances and their metabolites. Treatment of
about multiple drug abuse interactions. However, the polydrug abuse often requires hospitalization or inpa-
combined use of cocaine, heroin, and alcohol increases the tient residential care during detoxication and the initial

CHAPTER 52
risk for toxic effects and adverse medical consequences phase of drug abstinence. When possible, specialized
over risks associated with use of a single drug. One deter- facilities for the care and treatment of chemically depen-
minant of polydrug use patterns is the relative availability dent persons should be used. Outpatient detoxication
and cost of the drugs. There are many examples of situa- of polydrug abuse patients is likely to be ineffective and
tionally determined drug use patterns. For example, alcohol may be dangerous.
abuse, with its attendant medical complications, is one of Drug abuse disorders often respond to effective treat-
the most serious problems encountered in former heroin

Cocaine and Other Commonly Abused Drugs

ment, but episodes of relapse may occur unpredictably.
addicts participating in methadone maintenance programs. The physician should continue to assist patients during
The physician must recognize that perpetuation of relapse and recognize that occasional recurrent drug use
polydrug abuse and drug dependence is not necessarily is not unusual in this complex behavioral disorder.
a symptom of an underlying emotional disorder. Neither
alleviation of anxiety nor reduction of depression accounts
for initiation and perpetuation of polydrug abuse. Severe
depression and anxiety are as frequently the consequences FURTHER READINGS
of polydrug abuse as they are the antecedents.There is also
CAMI J, FARRE M: Mechanisms of disease: Drug addiction. N Engl J
evidence that some of the most adverse consequences of
Med 349:975, 2003
drug use may be reinforcing and contribute to the contin- HABER PS et al: Management of injecting drug users admitted to
uation of polydrug abuse. hospital. Lancet 384:1284, 2009
MONTOYA ID,VOCCI F: Novel medications to treat addictive disorders.
Curr Psychiatry Rep 10:392, 2008
TOUMBOUROU JW et al: Interventions to reduce harm associated
Treatment:
with adolescent substance use. Lancet 369:1391, 2007
POLYDRUG ABUSE
VOCCI FJ et al: Medication development for addictive disorders: The
Adequate treatment of polydrug abuse, as well as other state of the science.Am J Psychiatry 162:1432, 2005
forms of drug abuse, requires innovative programs of VOLKOW ND et al: Cocaine cues and dopamine in dorsal striatum:
intervention. The rst step in successful treatment is Mechanism of craving in cocaine addiction. J Neurosci 26:6583,
2006
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 REVIEW AND SELF-ASSESSMENT
Charles Wiener IGerald Bloomeld I Cynthia D. Brown
I Joshua Schiffer I Adam Spivak
QUESTIONS
DIRECTIONS: Choose the one best response for each 2. (Continued )
question. D. Sumatriptan, 50 mg orally, at the onset of an attack
E. Surgical consultation for microvascular decompression
1. Delirium, an acute confusional state, is a common of the trigeminal nerve
disorder that remains a major cause of morbidity and
mortality in the United States. Which patient is at 3. You are seeing your patient with polymyositis in
the highest risk for developing delirium? follow-up. He has been taking prednisone at high
doses for 2 months, and you initiated mycophenolate
A. A 36-year-old man admitted to the medical ward with mofetil at the last clinic visit for a steroid-sparing
a deep venous thrombosis effect. He began a steroid taper 2 weeks ago. His
B. A 55-year-old man postoperative day 2 from a total symptoms were predominantly in the lower extrem-
colectomy ities and face, and he has improved considerably. He
C. A 68-year-old woman admitted to the intensive care no longer needs a cane and his voice has returned to
unit (ICU) with esophageal rupture normal. Laboratory data show a creatine kinase (CK)
D. A 74-year-old woman in the preoperative clinic before of 1300 U/L, which is unchanged from 2 months
hip surgery ago. What is the most appropriate next step in this
E. An 84-year-old man living in an assisted living facility patients management?
2. A 46-year-old man presents for evaluation of severe A. Continue current management
unilateral headache. He states that he has had episodes B. Continue high-dose steroids with no taper
of intermittent headache for the past 3 years. He C. Switch mycophenolate to methotrexate
describes the headaches as a stabbing pain located near D. Repeat muscle biopsy
his right temple. They occur abruptly and last up to
4. A patient complains of numbness in his neck. Over
3 h at a time, during which he feels incapacitated, rat-
months, the numbness has become more pronounced
ing the pain as a 10 out of 10. Most of the time, the
and involves a dense area bilaterally from the sternal
headaches begin in the early morning hours. When
notch to the area behind the ear. On examination,
they occur, he nds it impossible to sleep. He feels that
scalp sensation, cranial nerve function, and upper
rubbing his head improves the pain but has noticed no
extremity motor examination are normal.The patient
other factors that relieve the pain. Specically, he has
has decreased pain and temperature sensation in the
had no improvement with acetaminophen, naprosyn,
distribution of C4.Vibration sense is normal. Cranial
or oxycodone.When the headaches occur, he develops
and caudal to the affected area, sensation is intact.
nasal congestion and tearing on the side of the pain.
Bladder and anal sphincter function are also normal.
He believes the headaches occur in cycles. He will
What is the most likely cause of this patients neuro-
have the headaches almost daily for up to 2 weeks at a
logic disorder?
time, but then have no headaches at all for as long as
3 months. He has decided to seek medical advice A. Amyotrophic lateral sclerosis
because he is worried about the possibility of a brain B. Disc herniation
tumor because of the severity of the headaches. He C. Intramedullary tumor
takes no medicines regularly. His vital signs and physi- D. Knife or bullet injury
cal examination are normal.What is the best approach E. Neurosyphilis
to treatment of these headaches?
5. A 56-year-old man is admitted to the intensive care
A. Fluticasone nasal spray and loratadine, 10 mg orally unit with a hypertensive crisis after cocaine use. Ini-
B. Indomethacin, 25 mg three times daily tial blood pressure is 245/132. On physical examina-
C. Oxygen at 1012 L/min by nasal cannula at the onset tion the patient is unresponsive except to painful
of an attack stimuli. He has been intubated for airway protection

Questions and answers were taken from Wiener C, et al (eds). Harrisons Principles of Internal Medicine Self-Assessment and Board Review, 17th ed.
New York: McGraw-Hill, 2008.
709
710 Review and Self-Assessment

5. (Continued ) 8. (Continued )
and is being mechanically ventilated, with a respira- A 33-year-old woman comes to your ofce for eval-
tory rate of 14. His pupils are reactive to light, and uation of a bilateral tingling sensation in the nger-
there are normal corneal, cough, and gag reexes.The tips. She describes the sensation as affecting all the
patient has a dense left hemiparesis. When presented ngers on both hands. She has no medical problems
with painful stimuli, the patient responds with exure and takes no medications. She is a vegetarian and is
posturing on the right side. Computed tomography visiting the area from San Diego, California. She
(CT) reveals a large area of intracranial bleeding in the denies any other symptoms, including headache,
right frontoparietal area. Over the next several hours nausea, vomiting, shortness of breath, and urinary
the patient deteriorates.The most recent examination frequency. On physical examination the patient has a
reveals a blood pressure of 189/100. The patient now normal sensory examination, including reaction to
has a dilated pupil on the right side.The patient con- light touch and pinprick and vibratory sensation.
tinues to have corneal reexes. You suspect rising She is able to stand normally with the arms extended
intracranial pressure related to the intracranial bleed. and the eyes closed. A cerebellar examination reveals
All but which of the following can be done to decrease normal nger-to-nose testing and no dysdiadochoki-
the patients intracranial pressure? nesis. Her gait is normal, including tandem gait, toe
walking, and heel walking. What would you recom-
A. Administer intravenous mannitol at a dose of 1 g/kg mend as the next step?
body weight
B. Administer hypertonic uids to achieve a goal sodium A. Blood tests for serum vitamin B12
level of 155 to 160 meq/L B. Fasting blood glucose level
C. Consult neurosurgery for an urgent ventriculostomy. C. Reassurance
D. Initiate intravenous nitroprusside to decrease the mean D. Serologic testing for syphilis
arterial pressure to a goal of 100 mmHg E. Treatment with acetazolamide for altitude sickness
E. Increase the respiratory rate to 30
9. You are doing rounds and see a patient admitted with
6. For the last 5 weeks a 35-year-old woman has had weakness. He is a 46-year-old man who noticed the
episodes of intense vertigo that last several hours. gradual onset of facial weakness and slurred speech
Each episode is associated with tinnitus and a sense 1 day prior to presentation. At the onset of his symp-
of fullness in the right ear; during the attacks she toms, he also complained of right arm weakness and
prefers to lie on the left side. Examination during an double vision. He went to bed and woke up the next
attack shows that she has ne rotary nystagmus that morning without any residual neurologic decits. He
is maximal on gaze to the left. There are no ocular came to the emergency department for evaluation.
palsies, cranial nerve signs, or long-tract signs. An On examination of the patient on evening rounds,
audiogram shows high-tone hearing loss in the right you note 3/5 weakness in the upper and lower
ear, with recruitment but no tone decay. The most extremities, with increasing weakness with exertion.
likely diagnosis in this patient is He has intact phonation and mental status, but you
also note a disconjugate gaze. He denies any pain.
A. labyrinthitis
Sensation is intact.What is the most likely location of
B. Mnires disease
C. vertebral-basilar insufciency
his neurologic disease?
D. acoustic neuroma A. Brainstem
E. multiple sclerosis B. Muscle
C. Neuromuscular junction
7. Lumbar puncture should be preceded by CT or D. Peripheral nerve
MRI in all of the following subsets of patients sus- E. Spinal root
pected of having meningitis except those with:
A. depressed consciousness
10. A 34-year-old woman complains of lower extremity
B. focal neurologic abnormality weakness for the last 3 days. She has noted progres-
C. known central nervous system (CNS) mass lesion sive weakness in the lower extremities with loss of
D. positive Kernigs sign sensation below the belly button and inconti-
E. recent head trauma nence. She had had some low-grade fevers for the
last week. She denies recent travel. Past medical his-
8. You are a physician practicing in a small community tory is unremarkable. Physical examination is notable
in the Rocky Mountains near Aspen, Colorado. for a sensory level at the level of the umbilicus.
 Review and Self-Assessment 711

10. (Continued ) 12. (Continued )

The lower extremities show +3/5 strength bilaterally, lately; she describes him as very energetic prior to his
proximally, and distally. Reexes, cerebellar examina- concussion. The patients physical examination is
tion, and mental status are normal. All the following entirely normal except for a somewhat attened
are appropriate steps in evaluating this patient except affect. Which of the following statements regarding
his condition is true?
A. antinuclear antibodies
B. electromyography A. He has an excellent prognosis.
C. lumbar puncture B. He meets criteria for postconcussive syndrome and
D. MRI of the spine should improve over 12 months.
E. viral serologies C. He should avoid contact sports for the next month.
D. He is most likely malingering.
11. Which clinical signs would you expect in a 53-year- E. Low-dose narcotics should be started for headache.
old man with gait ataxia and these MRI ndings
(see Fig. 11)? 13. Variant Creutzfeldt-Jakob disease (vCJD) has been
diagnosed in which of the following populations?
A. Family members with well-dened germ-line muta-
tions leading to autosomal dominant inheritance of a
fatal neurodegenerative disease
B. New Guinea natives practicing cannibalism
C. Patients accidentally inoculated with infected material
during surgical procedures
D. Worldwide, in sporadic cases mostly during the fth
and sixth decades of life
E. Young adults in Europe thought to have been exposed
to tainted beef products

14. A 44-year-old man with a history of hypertension

and Pagets disease has had lower back pain for the
past 3 months. The pain is worse with standing and
improves with sitting. Walking does not necessarily
exacerbate his symptoms. He has no leg or buttock
pain. On examination, he has mild weakness on the
right at the hip exors, knee extenders, and knee
exors and more distally to the same degree. Reexes
are diminished in the right lower extremity. He has
FIGURE 11
no sensory ndings in the lower extremities or in the
perineum.What is the most likely diagnosis?
A. Gait instability, urinary incontinence, dementia
B. Hypertension, tachycardia, diaphoresis A. Intervertebral disk herniation
C. Migraine headache, limb weakness, breathing difculties B. Lumbar spinal stenosis
D. Scanning speech, oscillatory tremor of the head, C. Metastatic malignancy
nystagmus D. Occlusive aortoiliac atherosclerosis
E. Tethered cord syndrome
12. A 17-year-old adolescent is seen in clinic several
weeks after he suffered a concussion during a high- 15. On the neurologic consultation service, you are
school football game. At the time of the event, para- asked to evaluate a patient with mesial temporal
medics reported that he experienced no loss of lobe epilepsy syndrome. The patient has a history of
consciousness but was confused for a period of about intractable complex partial seizures that rarely gener-
10 min. Head imaging was normal. He describes a alize. Her seizures often begin with an aura and
generalized headache that is present all the time since commonly manifest as behavioral arrests, complex
his trauma, and he occasionally feels dizzy. His automatisms, and unilateral posturing. MRI ndings
mother is concerned that he is having a hard time include small temporal lobes and a small hippocam-
concentrating in school and seems depressed to her pus with increased signal on T2-weighted sequences.
712 Review and Self-Assessment

15. (Continued ) 20. (Continued )

Which of these additional historic factors are also are getting progressively worse. She has great difculty
likely to be present in this patient? walking from the waiting room to the examination
room but is not dizzy while doing so. On further
A. History of febrile seizures questioning she denies numbness or tingling. On
B. Hypothyroidism physical examination, her cranial nerves are intact, and
C. Neurobromas strength examination shows 5 out of 5 strength in
D. Recurring genital ulcers
both upper and lower extremities. Reexes are nor-
E. Type 2 diabetes mellitus
mal throughout. Light touch sensation is normal, and
she is not orthostatic. You order a noncontrast head
16. The patient in the preceding scenario was admitted
CT and it is read as normal.Which test is most likely
with refractory seizures. You are asked to see the
to reveal the correct diagnosis?
patient and offer treatment options. What treatment
option will be the most efcacious in a patient with A. Cerebrospinal uid viral polymerase chain reaction
mesial temporal lobe epilepsy (MTLE) syndrome? B. Lithium level
C. Rapid plasma reagent (RPR)
A. Acyclovir
D. Serum alcohol level
B. Amygdalohippocampectomy
E. Vitamin B12 deciency
C. Levetiracetam
D. Primidone
E. Vagus nerve stimulation
21. A 78-year-old woman with a long history of vascu-
lar disease presents after an embolic cerebrovascular
17. The deep tendon reex requires all of the following accident (CVA) with severe and unrelenting pain on
structures to be functional except the right side. She describes the pain as burning as if
she had been bathed in acid. Where is the most
A. a motor neurons likely site of the recent embolic CVA?
B. motor neurons
C. pyramidal neurons A. Frontal lobe
D. spindle afferent neurons B. Hypothalamus
C. Pons
18. The most common presenting nding or symptom D. Temporal lobe
of multiple sclerosis is E. Thalamus

A. internuclear ophthalmoplegia 22. A 34-year-old man presents with complaints of

B. transverse myelitis 1 week of dizziness, vertigo, tinnitus, and right-sided
C. cerebellar ataxia gait ataxia. Electronystagmography (calorics) with
D. optic neuritis sequential administration of warm and cold water
E. urinary retention into the ear canal is performed. On the left, cold
water causes right-beating nystagmus and warm water
19. You are evaluating a patient with neck pain and you
causes left-beating nystagmus. On the right ear, there
suspect cervical degenerative disk disease based on
is no response to the cold caloric. What is the cause
the history. Based on the most common ndings
of this patients dizziness and vertigo?
with cervical disk disease, which nding do you
expect when you examine this patient? A. Acoustic neuroma
B. Aminoglycoside antibiotics
A. Biceps weakness
C. Cerebellar ischemia
B. Decreased light touch sensation in the axilla and
D. Otoconia (ear otoliths)
medial arm
C. Decreased pin-prick sensation over the lateral deltoid
D. Weak nger exors 23. A 49-year-old man is admitted to the hospital with a
seizure. He does not have a history of seizures and he
20. A 64-year-old woman is brought to the emergency currently takes no medications. He has AIDS and is
department by her family with complaint of weak- not under any care at this time. His physical exam-
ness. The patient reports difculty walking and fre- ination is most notable for small, shoddy lym-
quent falls. She also has blurry vision bilaterally. She phadenopathy in the cervical region. A head CT
denies light headedness or vertigo. These symptoms shows a ring-enhancing lesion in the right temporal
have been present for at least the past 9 months and lobe, with edema but no mass effect.A lumbar puncture
 Review and Self-Assessment 713

23. (Continued ) 27. A 49-year-old woman presents for a second opinion

shows no white or red blood cells, and the Gram stain regarding symptoms of tremors, difculty with
is negative. His serum Toxoplasma IgG is positive. ambulation, and periodic ushing. Her symptoms
Which of the following is the best course of action originally began ~3 years ago. At that time, she was
for this patient at this time? hospitalized for a syncopal episode, after which she
was told to increase her salt intake. Since then, she
A. Biopsy of the central nervous system (CNS) lesion has had progressive motor difculties including bilat-
B. Dexamethasone eral tremors and a stiff slow gait. She also has had
C. Search for systemic malignancy several more episodes of syncope. She states that she
D. Treatment for CNS toxoplasmosis knows when these syncopal events will occur
E. Whole-brain radiation therapy because she feels faint and weak. She has never had
an injury from syncope. A nal recent symptom has
24. The patient in the preceding scenario returns for been periodic ushing and sweating. A neurologist
reevaluation after 2 weeks of appropriate therapy. previously diagnosed her with Parkinsons disease
The CNS lesion has not changed in size, and he has and prescribed therapy with ropinirole. Despite
not had any more seizures. All microbiologic cul- increasing doses, she does not feel improved, but
tures and viral studies, including Epstein-Barr virus rather has recently noticed uncontrollable move-
DNA from the cerebrospinal uid are negative. ments that she describes at tics of her face. Her only
What is the best course of action for this patient at other medical history is recent recurrent urinary
this time? tract infections. Her medications are ropinirole,
24 mg daily, and nitrofurantoin, 100 mg daily. She
A. Continue treatment for CNS toxoplasmosis reports no history of drug use. On physical examina-
B. Dexamethasone tion, her blood pressure is 130/70 mmHg with a
C. Intravenous acyclovir heart rate of 78 beats/min while sitting. Upon
D. Stereotactic brain biopsy standing, her blood pressure drops to 90/50 mmHg
E. Whole-brain radiation therapy with a heart rate of 110 beats/min. Her ocular
movements are full and intact. She has recurrent
25. Which of the following statements about syringomyelia motor movements of the right side of her face. Her
is true? neurologic examination shows increased muscle
tone in the lower extremities with bilateral
A. More than half the cases are associated with Chiari 4-Hz tremor. Deep tendon reexes are brisk and 3+
malformations. in upper and lower extremities. Three beats of
B. Symptoms typically begin in middle age. myoclonus is present at the ankles bilaterally. She
C. Vibration and position sensation are usually diminished. walks with a spastic gait. Strength is normal. What is
D. Syrinx cavities are always congenital. the most likely diagnosis?
E. Neurosurgical decompression is usually effective in
relieving the symptoms. A. Corticobasal degeneration
B. Diffuse Lewy body dementia
C. Drug-induced Parkinsons disease
26. A 34-year-old woman presents with complaints of
D. Multiple systems atrophy with parkinsonian
weakness and double vision for the last 3 weeks. She
features (Shy-Drager syndrome)
has also noted a change in her speech, and her
E. Parkinsons disease with inadequate
friends tell her that she is more nasal. She has treatment
noticed decreased exercise tolerance and difculty
lifting objects and getting out of a chair.The patient
denies pain. The symptoms are worse at the end of 28. A 68-year-old man is brought to clinic for evalua-
the day and with repeated muscle use. You suspect tion by his wife. She has noticed that over past
myasthenia gravis. All the following are useful in the 23 months he has had increasingly slowed thinking
diagnosis of myasthenia gravis except and a change in his personality in that he has become
very withdrawn. His only complaint is a mild, but
A. acetylcholine receptor (AChR) antibodies persistent, diffuse headache. There is no history of
B. edrophonium head trauma, prior neurologic or psychiatric disease,
C. electrodiagnostic testing or family history of dementia. Physical examination
D. muscle-specic kinase (MuSK) antibodies is only notable for a moderate cognitive decit with
E. voltage-gated calcium channel antibodies a mini-mental examination of 19/30. His head
714 Review and Self-Assessment

28. (Continued ) 30. (Continued )

CT is shown in Fig. 28. What is the most likely addition, he states that his right hand shakes more so
diagnosis? than his left, and he is right-handed. He believes it to
be worse when not moving but states there are times
when he spills his morning coffee because of the
tremors. He has retired but states he is not able to
play tennis and golf any longer because of his motor
symptoms. He denies syncope or presyncope, dif-
culty swallowing, changes to his voice, or memory
difculties. His past medical history is signicant for
hypertension and hypercholesterolemia. His medica-
tions are hydrochlorothiazide, 25 mg daily, ezetimibe,
10 mg daily, and lovastatin, 40 mg daily. He drinks a
glass of wine with dinner daily and is a lifelong non-
smoker. On physical examination, he has masked
facies. His gait shows decreased arm swing with slow
shufing steps. He turns en bloc. A pill-rolling tremor
is present on the right side. There is cogwheel rigid-
ity bilaterally. Eye movements are full and intact.
There is no orthostatic hypotension. A brain MRI
with gadolinium shows no evidence of mass lesions,
hydrocephalus, or vascular disease. You diagnose the
patient with Parkinsons disease. The patient asks
about his prognosis and likelihood of disability.
FIGURE 28 Which of the following is correct about the clinical
course and treatment of Parkinsons disease?
A. Acute epidural hematoma
B. Acute subarachnoid hemorrhage A. Early initiation of therapy with levodopa will not affect
C. Alzheimers disease the risk of a higher likelihood of dyskinesias early in
D. Chronic subdural hematoma the disease.
E. Normal-pressure hydrocephalus B. Early therapy with bilateral deep-brain stimulation of
the subthalamic nuclei slows progression of Parkinsons
29. You are evaluating a patient who has complaint of disease.
vertigo. The patient complains of seeing the room C. Initial treatment with a dopamine agonist such as
spin and feeling faint with certain head movements pramipexole is likely to be effective in controlling his
to the left. In your ofce, you perform provocative motor symptoms for 13 years before the addition of
levodopa or another agent is necessary.
maneuvers to differentiate the cause of this patients
D. Levodopa should be started immediately to prevent
vertigo. He has been diagnosed with benign parox-
development of disabling rigidity.
ysmal positional vertigo (BPPV), but symptoms have
E. Monotherapy with selegiline, a monoamine oxydase
remained for many months. Which of the following (MAO) inhibitor, causes a marked improvement in
ndings would be suggestive of a central positional tremors in most individuals with Parkinsons disease.
vertigo?
A. Disappearance of the symptoms with maintenance of
31. A 74-year-old woman comes to clinic with a com-
the offending position plaint of muscle weakness. She has bilateral deltoid
B. Immediate vertigo and nystagmus with head turning to weakness, which has been present for 4 months. She
the affected side has myalgias as well throughout the day. Her symp-
C. Lessening of symptoms with repeated trials toms are exacerbated by activity and when she ini-
D. Increased severity of symptoms with provocative testing tially lays down to sleep. Neurologic examination
shows intact cranial nerves II through XII, except
30. A 65-year-old man presents to your ofce with com- for poor vision due to cataracts. She has hyperesthe-
plaints of a tremor and progressive gait abnormalities. sia in her arms in the area of her deltoids, but other-
He states that he rst noticed a slowing of his gait wise sensation is normal. Deep tendon reexes are
~6 months ago. He has difculty rising to a standing normal. Strength examination shows weakness ini-
position and states that he shufes when he walks. In tially, but it improves with encouragement. Creatine
 Review and Self-Assessment 715

31. (Continued ) 36. A young man with a history of a low-grade astrocy-

kinase, erythrocyte sedimentation rate, and C-reactive toma comes into your ofce with complaints of
protein are within normal limits. An MRI of the del- weight gain and low energy. He is status post resec-
toid muscles shows joint degeneration and a partial tion of his low-grade astrocytoma and had a course
rotator cuff tear on the left. You are considering a of whole-brain radiation therapy (WBRT) 1 year ago.
muscle biopsy. What is the biopsy most likely to A laboratory workup reveals a decreased morning
show? cortisol level of 1.9 g/dL. In addition to depressed
adrenocorticotropic hormone (ACTH) function,
A. Endomysial deposits of amyloid which of the following hormones is most sensitive to
B. Necrotic muscle damage from whole-brain radiation therapy?
C. Normal muscle
D. Scattered inammatory foci surrounding muscle bers A. Growth hormone
B. Follicle stimulating hormone
32. Which of the following criteria suggests the diagno- C. Prolactin
sis of trigeminal neuralgia? D. Thyroid stimulating hormone
A. Deep-seated steady facial pain
B. Elevated erythrocyte sedimentation rate (ESR) 37. A 29-year-old man being treated for lung cancer
C. Known metastatic brain tumor comes into your ofce for an acute visit. He has had
D. Objective signs of sensory loss on physical examination backache for a few weeks that has improved with
E. None of the above ibuprofen but has developed right lower abdominal
pain and inguinal pain. On physical examination, he
33. CT scanning is superior to MRI of the back in has tenderness over the lower thoracic spinous
which setting? processes and hyperesthesia in the T11 distribution on
the right. Strength is normal in the upper extremities,
A. Delineation of the extent of a syrinx but he has symmetric weakness in the lower extremi-
B. Evaluation of old lumbar-spine fracture ties with hyperreexia. He also has decreased sensa-
C. Evaluation of paraspinal mass tion below the T11 distribution symmetrically. What
D. Imaging of the lateral recesses of the spinal canal is the next step in the management of this patient?
A. Add gabapentin to his pain regimen
34. All the following cause primarily a sensory neuropa- B. Order a paraneoplastic antibody panel
thy except C. Start treatment with glucocorticoids
D. Order thoracic and lumbar radiographs
A. acromegaly
B. critical illness
C. HIV infection 38. A 50-year-old man presents with complaint of weak-
D. hypothyroidism ness. His symptoms began as difculty with buttoning
E. vitamin B12 deciency his shirt and using keys to open doors about 2 years
ago. He was treated empirically with nonsteroidal anti-
inammatory medications for arthritis, but responded
35. A 45-year-old woman presents for evaluation of a
only minimally. His symptoms have slowly progressed
tingling sensation in her feet that has become more
to the point where he has weakness in both hands and
apparent over the past 5 months. She states that it
feet. He avoids going outside because of frequent falls.
currently is causing a painful sensation and is inter-
On examination, he has weakness and atrophy of the
fering with her sleep at night. On physical examina-
foot extensor and nger exors. Proximal muscle
tion, you identify decreased sensation to pinprick
strength is normal. Reexes are normal, and sensation
and light touch in her feet extending to her mid-calf
is intact. He is able to rise out of a chair, but the
area. All of the following laboratory tests may be
Romberg test is not able to be performed due to
useful in determining the cause of her peripheral
weakness once standing. Cranial nerves are intact.
neuropathy except
Serum creatine kinase is 600 units/L. Complete blood
count, differential, electrolytes, and thyroid-stimulating
A. blood lead level hormone (TSH) are normal. Based on the clinical pre-
B. fasting blood glucose sentation, what is the most likely diagnosis?
C. hemoglobin A1C
D. rapid plasma reagin for syphilis A. Dermatomyositis
E. red blood cell folate levels B. Eosinophilic myofasciitis
716 Review and Self-Assessment

38. (Continued ) 42. A 24-year-old woman seeks evaluation for headaches.

She rst began having recurrent headaches her senior
C. Inclusion body myositis year of high school. The headaches increased in fre-
D. Polymyositis quency during college, and she has always attributed
E. Hyperthyroidism her headaches to tension. The headaches would be
more prominent during times of sleep loss, stress, and in
39. You are conducting research on a cellular model of the perimenstrual period. She states that she expected
myasthenia gravis in which you measure features of her headaches to improve now that she has nished
the acetylcholine (ACh) neuromuscular junction and college and has a more regular schedule. She works as a
its microenvironment. In a patient with untreated nancial counselor for a university in the human
myasthenia gravis, which of the following do you resources department and denies a large degree of stress
expect to nd at the neuromuscular junction after in her job. She has had this job for 2 years, but the
release of ACh from the presynaptic neuron? headaches continue to disrupt her life. She states the
A. Decreased levels of ACh-esterase headaches occur about seven times monthly. She esti-
B. Decreased numbers of available ACh receptors mates that the headaches occur >90% of the time on
C. Decreased release of ACh from the presynaptic neuron the right side and have a throbbing nature. She has no
D. High numbers of mitochondria in the postsynaptic neuron aura before the onset of a headache but describes occa-
sional visual disturbance and photophobia during the
40. You have just admitted a young man with a prior headache. She also states that she frequently develops
history of seizure disorder who was witnessed to sensitivity of her scalp on the side of the headache with
have a seizure. His familys description suggests a associated paresthesias. She rates the pain as about 7 to
simple partial seizure involving the left hand that 8 out of 10 for a usual headache. On two occasions
spread to involve the entire arm. He did not lose over the past 6 months, she has developed severe ver-
consciousness. He was brought in 2 h after symptom tigo that resolved over the course of several hours in
onset and is currently awake, alert, and oriented. He association with a mild headache. She has never had to
has not had any further seizures but has been unable miss work because of headache, but feels like her pro-
to move his left hand since his seizure. His elec- ductivity is limited when she feels unwell. Other trig-
trolytes and complete blood count are within nor- gers for her headaches include red wine and aged
mal limits. A noncontrast CT scan of his head is cheese, which she has restricted from her diet for this
unremarkable. On examination, sensation is intact in reason. Ibuprofen, acetaminophen, and naprosyn
the affected limb but his strength is 0 out of 5 in the sodium have no effect on the duration of her
musculature of the left hand.What is the best course headaches. She is otherwise healthy and denies associ-
of action at this time? ated rhinorrhea or lacrimation. Her only medication is
oral contraceptive pills. Her family history is signicant
A. Cerebral angiogram for a maternal aunt with classic migraine headaches
B. Lumbar puncture with aura.The physical examination is normal without
C. Magnetic resonance angiogram any evidence of neurologic decits and normal blood
D. Psychiatric evaluation pressure.What is the most appropriate next step in eval-
E. Reassess in a few hours uation and management of this patient?
41. A 78-year-old man with diabetes mellitus presents A. Ask the subject to keep a headache diary for the next
with fever, headache and altered sensorium. On phys- 2 months to assess the frequency and severity of
ical exam his temperature is 40.2C, heart rate is 103 headaches and assess for specic triggers.
beats/min, blood pressure is 84/52 mmHg. His neck B. Encourage the patient to keep a regular routine
is stiff and he has photophobia. His cerebrospinal including consistent sleep-wake cycle and regular exer-
uid (CSF) examination shows 2100 cells/L, with cise such as yoga.
100% neutrophils, glucose 10 mg/dL, and protein C. Initiate therapy with rizatriptan, 10 mg orally, at onset
78 mg/dL. CSF gram stain is negative. Empirical of attacks.
therapy should include which of the following? D. Perform an MRI of the brain.
E. A, B, and C
A. Amphotericin F. All of the above
B. Dexamethasone after antibiotics
C. Dexamethasone prior to antibiotics 43. Which of the following cranial nerve physical exam-
D. Doxycycline ination techniques represents the correct approach
E. Piperacillin/tazobactam to the patient with suspected neurologic disease?
 Review and Self-Assessment 717

43. (Continued ) 46. All of the following myopathies would be inherited

A. Olfactory nerve:With eyes closed, ask the patient to from the female parent except
sniff a pungent stimulus such as ammonia or alcohol.
B. Optic nerve: Check visual acuity in both eyes using a A. Becker muscular dystrophy
Snellen chart without having the patient use their cor- B. Duchenne muscular dystrophy
rective lenses. C. Kearns-Sayre syndrome
C. Trigeminal nerve: Examine the motor territories on D. limb-girdle muscular dystrophy
each side of the face by testing jaw clench, eyebrow E. myoclonic epilepsy with ragged red bers (MERFF)
elevation and forehead wrinkling.
D. Accessory nerve: Check shoulder shrug and head rota- 47. A patient is brought to the emergency room after a
tion on each side against resistance. head-on motor vehicle collision. The patient is unre-
sponsive even to painful stimuli and is apneic; however,
44. You are going on morning rounds to see a 38-year- he does have a pulse. Which of the following clinical
old woman who presented the prior day with ndings would exclude a diagnosis of brain death?
weakness and double vision. It is reported that on
examination at that time she had pronounced A. Bilateral positive Babinski signs
weakness in cranial nerves VII and XII. She also had B. Constricted pupils
weakness in the extraocular muscles, which is C. Invariant pulse rate
described to you as googly eyes with repeat exam- D. Positive deep tendon reexes
inations. The patient reports that she has profound E. Presence of diabetes insipidus
double vision almost exclusively when she watches
television in the evening. On your examination, you 48. A 45-year-old man presents with a daily headache.
nd no neurologic abnormalities. A head CT is He describes two attacks per day over the last 3 weeks.
unremarkable. The patient denies any other past Each attack lasts about 1 h and awakens the patient
medical history and has a mini-mental status exami- from sleep. The patient has noted associated tearing
nation score of 30/30. What is the next appropriate and reddening of the right eye as well as nasal stuf-
step in the management of this patient? ness. The pain is deep, excruciating, and limited to
the right side of the head. The neurologic examina-
A. Formal psychiatric evaluation tion is nonfocal. The most likely diagnosis of this
B. MRI of the brain patients headache is
C. Serum anti-acetylcholine receptor antibodies
D. Serum lead level A. migraine headache
E. Slit-lamp examination B. cluster headache
C. tension headache
45. A 37-year-old man is witnessed by his family to have D. brain tumor
a generalized tonic-clonic seizure at a party. He does E. giant cell arteritis
not have a known seizure disorder. There is no his-
tory of head trauma, stroke, or tumor. The patient is 49. A 72-year-old woman presents with recurrent
unemployed, married, and takes no medication. Phys- episodes of incapacitating facial pain lasting from
ical examination shows no skin abnormalities and no second to minutes and then dissipating.The episodes
stigmata of chronic liver or renal disease. The patient occur usually twice per day, usually without warn-
is postictal. His neck is difcult to maneuver due to ing, but are also occasionally provoked by brushing
stiffness. His white blood cell count is 19,000/L, of her teeth. On physical examination, she appears
hematocrit 36%, and platelets 200,000/L. Glucose well with normal vital signs. Detailed cranial nerve
is 102 mg/dL, sodium 136 meq/ dL, calcium 9.5 examination reveals no sensory or motor abnormali-
mg/dL, magnesium 2.2 mg/dL, SGOT 18 U/L, blood- ties.The remainder of her neurologic examination is
urea nitrogen 7 mg/dL, and creatinine 0.8 mg/dL. normal.What is the next step in her management?
Urine toxicology screen is positive for cocaine metabo-
A. Brain MRI
lites. A head CT was negative. Which next step is
B. Brain MRI plus carbamazepine therapy
most appropriate in this patients management?
C. Carbamazepine therapy
A. Electroencephalogram (EEG) D. Glucocorticoid therapy
B. Intravenous loading with antiepileptic medication E. Referral to Otolaryngology for surgical cure
C. Lumbar puncture
D. Magnetic resonance imaging 50. A 26-year-old man presents to the emergency room
E. Substance abuse counseling with complaints of weakness and difculty breathing.
718 Review and Self-Assessment

50. (Continued ) 52. (Continued )

He rst noticed a feeling of weakness in his legs with A. Passive dorsiexion of the foot during the maneuver
difculty climbing the stairs to his third-oor apart- will elicit pain from the contralateral nerve root.
ment 5 days ago. Over the ensuing days, his weakness B. The crossed straight leg raise is more specic for disk
has progressed such that he feels like he is tripping herniation than the straight leg raise.
when he walks on at surfaces and was unable to C. The reverse straight leg raise is indicative of back pain
climb to his apartment yesterday. In addition, he now referred from visceral organs.
states that he is having difculty lifting his arms above D. The straight leg raise test is positive if there is restricted
his head to comb his hair and twice dropped a bottle range of motion of the affected limb.
of soda on the oor due to a feeling of weakness in his 53. A 37-year-old woman presents with complaints of
arms. He also states that he feels short of breath, espe- headache and blurry vision that have been present
cially if lying at. He complains of a tingling in his for a year and are slowly getting worse. As part of
hands and feet. His past medical history is notable for her evaluation an MRI is obtained and shown in
sickle cell trait. Three weeks ago, he was treated for Fig. 53 below:
dehydration in the emergency department for food
poisoning with diarrhea, abdominal pain, and low-
grade fevers. This resolved within 2 days, and he had
been feeling in his usual state of health prior to the
onset of the current symptoms. He is on no medica-
tion and has no history of illicit drug use. He has no
recent travel and has not eaten shellsh, honey, or
home-canned foods. On physical examination, he
appears breathless, has difculty completing sentences,
and is using accessory muscles of respiration. His vital
signs show a respiratory rate of 32 breaths/min, a
heart rate of 95 beats/min, a blood pressure of 112/76
mmHg, and a temperature of 37.6C. His weight is
80 kg. His ocular movements are full.There is no pap-
illary dilatation. On pulmonary examination, his
breath sounds are clear.There is paradoxical motion of
the abdomen with inspiration. Neurologic examina-
tion shows 3/5 strength symmetrically in the upper
and lower extremities with absent deep tendon reexes.
Cardiovascular, gastrointestinal, and skin examinations FIGURE 53
are normal. Arterial blood gases show a pH of 7.55, a
PaCO2 of 28 mmHg, and a PaO2 of 84 mmHg while What is the most likely diagnosis in this patient?
breathing room air. His vital capacity is 800 mL.What A. Brain abscess
is the most appropriate treatment for this individual? B. Glioblastoma
C. Low-grade astrocytoma
A. Botulinum antitoxin
D. Meningioma
B. Intravenous immunoglobulin (IVIg)
E. Oligodendroglioma
C. IVIg and mechanical ventilation
D. IVIg, mechanical ventilation, and ciprooxacin 54. All but which of the following statements regarding
E. Plasmapheresis and glucocorticoids epilepsy are true?
51. The most common cause of a cerebral embolism is A. The incidence of suicide is higher in epileptic patients
than it is in the general population.
A. cardiac prosthetic valves B. Mortality is no different in patients with epilepsy than
B. rheumatic heart disease it is in age-matched controls.
C. dilated cardiomyopathy C. A majority of patients with epilepsy that is completely
D. endocarditis controlled with medication eventually will be able to
E. atrial brillation discontinue therapy and remain seizure free.
D. Surgery for mesial temporal lobe epilepsy (MTLE)
52. When evaluating a patient for low back pain, which decreases the number of seizures in over 70% of patients.
statement is true regarding the utility of the straight E. Tricyclic antidepressants lower the seizure threshold
leg raise test? and may precipitate seizures.
 Review and Self-Assessment 719

55. A 54-year-old man is referred to your clinic for 56. (Continued )

evaluation of atrial brillation. He rst noted the A. Acid maltase deciency (Pompes disease)
irregular heartbeat 2 weeks ago and presented to his B. Becker muscular dystrophy
primary care physician. He denies chest pain, short- C. Duchenne muscular dystrophy
ness of breath, nausea, or gastrointestinal symptoms. D. Myotonic dystrophy
Past medical history is unremarkable. There is no E. Nemaline myopathy
history of hypertension, diabetes, or tobacco use.
His medications include metoprolol. The examina- 57. A 20-year-old woman is brought to the emergency
tion is notable for a blood pressure of 126/74 department after a witnessed generalized tonic-clonic
mmHg and a pulse of 64 beats/min. The jugular seizure. She has no identifying information, and her
venous pressure is not elevated. His heart is irregu- past medical history is unknown. What is the most
larly irregular, with normal S1 and S2. The lungs likely cause of her seizure?
are clear, and there is no peripheral edema. An
A. Amyloid angiopathy
echocardiogram shows a left atrial size of 3.6 cm. Left
B. Fever
ventricular ejection fraction is 60%. There are no
C. Genetic disorder
valvular or structural abnormalities. Which of the D. Illicit drug use
following statements regarding his atrial brillation E. Uremia
and stroke risk is true?
A. He requires no antiplatelet therapy or anticoagulation 58. The presence of startle myoclonus in a 60-year-old
because the risk of embolism is low. man with rapidly progressive decits in cortical dys-
B. Lifetime warfarin therapy is indicated for atrial brilla- function is which one of the following?
tion in this situation to reduce the risk of stroke.
A. Neither sensitive nor specic for Creutzfeldt-Jacob
C. He should be admitted to the hospital for intravenous
disease (CJD) but does represent grounds to explore
heparin and undergo electrical cardioversion; afterward
further for this condition with an electroencephalo-
there is no need for anticoagulation.
gram (EEG)
D. His risk of an embolic stroke is less than 1%, and he
B. Neither sensitive nor specic for CJD but does repre-
should take a daily aspirin.
sent grounds to explore further for this condition with
E. He should be started on subcutaneous low-molecular-
an EEG and brain MRI
weight heparin and transitioned to warfarin.
C. Sensitive but not specic for CJD and is not enough to
56. A 34-year-old woman seeks evaluation for weakness. prompt a further workup for this condition unless
She has noted tripping when walking, particularly in other clinical criteria are met
her left foot, for the past 2 years. She recently also D. Specic but not sensitive for CJD and should therefore
prompt immediate referral for brain biopsy to conrm
began to drop things, once allowing a full cup of
the diagnosis
coffee to spill onto her legs. In this setting, she also
E. Virtually diagnostic for CJD, and further workup
feels as if the appearance of her face has changed
including EEG, brain MRI, and perhaps brain biopsy
over the course of many years, stating that she feels serves only a prognostic purpose
as if her face is becoming more hollow and elon-
gated although she hasnt lost any weight recently.
59. Which nerve functions are spared in a patient with
She has not seen a physician in many years and has
ventral cord syndrome due to an anterior spinal cord
no past medical history. Her only medications are a
infarct?
multivitamin and calcium with vitamin D. Her fam-
ily history is signicant for similar symptoms of A. Bladder sphincter control
weakness in her brother who is 2 years older. Her B. Motor strength
mother, who is 58 years old, was diagnosed with C. Pain sensation
mild weakness after her brother was evaluated, but is D. Proprioception
not symptomatic. On physical examination, the E. Tendon reexes
patients face appears long and narrow with wasting
of the temporalis and masseter muscles. Her speech 60. A 33-year-old woman presents with complaint of a
is mildly dysarthric, and the palate is high and rash on her chest. She has had a nonpruritic red rash
arched. Strength is 4/5 in the intrinsic muscles of the on the upper chest for 4 weeks associated with a
hand, wrist extensors, and ankle dorsiexors. After raised erythematous rash on her hands. She does not
testing handgrip strength, you notice that there is a wear V-neck shirts, but the chest rash is in a V-neck
delayed relaxation of the muscles of the hand. What distribution. Her hands have a scaly reddish-purple
is the most likely diagnosis? eruption, and her nger pads have become thicker
720 Review and Self-Assessment

60. (Continued ) 62. (Continued )

and rougher (see Fig. 60). She also has a slight red notable for distal atrophy below the midcalves and
hue on the upper eyelids. for prominent high arches.There is obvious footdrop,
What other ndings are likely to be present in this and dorsiexion of the foot is severely diminished
patient? bilaterally. You suspect a form of Charcot-Marie-
Tooth disease and order nerve conduction studies.
Which of the following statements about CMT
disease is true?
A. CMT disease is usually a motor neuropathy; sensory fea-
tures are rare and should prompt an alternative diagnosis.
B. Immunotherapy with intravenous immune globulin
and/or plasmapheresis may slow the progression of
CMT disease.
C. CMT disease affects approximately 1 in 100,000
individuals.
D. Transmission is most commonly autosomal dominant
but may be autosomal recessive or X-linked.
E. The age of this patient at presentation is atypical;
patients usually present in the fourth and fth decades
of life.

63. Which of the following groups of patients should

receive empirical antibiotic therapy that includes
coverage of Listeria monocytogenes in cases of presumed
FIGURE 60 meningitis?

A. Immunocompromised patients
B. Elderly patients
A. Delayed relaxation phase of deep tendon reexes
C. Infants
B. Hepatosplenomegaly
D. All of the above
C. Muscle weakness
D. Situs inversus
E. Subcutaneous nodules on the back of the forearm 64. Which of the following neurologic phenomena is
classically associated with herniation of the brain
61. A 65-year-old man presents with severe right-sided through the foramen magnum?
eye and facial pain, nausea, vomiting, colored halos
around lights, and loss of visual acuity. His right eye A. Third-nerve compression and ipsilateral papillary dilation
is quite red, and that pupil is dilated and xed. B. Catatonia
Which of the following diagnostic tests would con- C. Locked-in state
D. Miotic pupils
rm the diagnosis?
E. Respiratory arrest
A. CT of the head
B. MRI of the head 65. A 72-year-old woman presents with brief, intermit-
C. Cerebral angiography tent excruciating episodes of lancinating pain in the
D. Tonometry lips, gums, and cheek. These intense spasms of pain
E. Slit-lamp examination may be initiated by touching the lips or moving the
tongue. The results of a physical examination are
62. A 21-year-old man presents to your clinic with normal. MRI of the head is also normal. The most
complaint of progressive weakness in the feet for the likely cause of this patients pain is
last 2 years. He describes slowly progressive difculty
in lifting his feet off the ground when walking. The A. acoustic neuroma
legs have gotten smaller in bulk. Past medical his- B. meningioma
tory is unremarkable.The family history is signicant C. temporal lobe epilepsy
for his father, brother, and paternal grandmother all D. trigeminal neuralgia
having similar weaknesses. The examination is E. facial nerve palsy
 Review and Self-Assessment 721

66. A 38-year-old woman patient with facial and ocular 69. (Continued )
weakness has just been diagnosed with myasthenia A. Factors such as cigarette smoking and hypertension have
gravis. You intend to initiate therapy with anti- no modifying risk on the development of ischemic
cholinesterase medications and glucocorticoids. All stroke in individuals who have migraine with aura.
of the following tests are necessary before instituting B. In both women and men, migraine with aura is
this therapy except associated with an increased risk of ischemic stroke.
C. Migraines generally persist unchanged in severity
A. CT or MRI of the chest throughout life.
B. puried protein derivative skin test D. Migraine with or without aura is associated with an
C. lumbar puncture increased risk of subclinical posterior circulation
D. pulmonary function tests infarction on MRI.
E. thyroid-stimulating hormone E. Women on oral contraceptives who have migraines
without aura should discontinue these medications
67. A 76-year-old nursing home resident is brought to because of a marked increased risk of ischemic stroke.
the local emergency department after falling out of
bed.The fall was not witnessed; however, she was sus- 70. A 40-year-old man has recurrent bouts of tinnitus.
pected to have hit her head. She is not responsive to Except for a fairly severe upper respiratory tract infec-
verbal or light tactile stimuli.At baseline she is able to tion 1 year ago, he has been healthy for all of his life.
converse but is frequently disoriented to place and In the last year he has had two self-limited episodes of
time. She has a medical history that includes stable tinnitus associated with dizziness and a decrement in
coronary disease, mild emphysema, and multi-infarct his hearing. His symptoms are always unilateral on the
dementia. Immediately after triage she is taken for a same side and have required him to take off from
CT scan of the head. Which of the following is true work for a few days each time. He comes into your
regarding head injury and hematomas? ofce at the outset of his third bout of tinnitus. He
has taken meclizine at home with no relief. In your
A. More than 80% of patients with subdural hematomas will ofce, he has tinnitus and vertigo while seated,
experience a lucid interval prior to loss of consciousness. which is exacerbated with ambulation. His symp-
B. Epidural hematomas generally arise from venous sources. toms of dizziness are not reproduced with Dix-
C. Epidural hematomas are common among the elderly Hallpike maneuvers. Which is the best long-term
with minor head trauma.
treatment option for the patient at this time?
D. Most patients presenting with epidural hematomas are
unconscious. A. Diuretic
E. Subdural hematomas lead to rapid increases in intracra- B. Glucocorticoid
nial pressure and can require arterial ligation. C. Epley procedure
D. Metoclopramide
68. A 45-year-old man presents with complaint of severe E. Scopolamine transdermal
right arm pain. He gives a history of having slipped
on the ice and severely contusing his right shoulder 71. While you are working in the urgent care center, a
approximately 1 month ago. At this time he has sharp babysitter brings in a 7-year-old boy who complains of
knifelike pain in the right arm and forearm. Physical visual changes. He complains of difculty with blue-yel-
examination reveals a right arm that is more moist low color discrimination. He has no other past medical
and hairy than the left arm. There is no specic history. On examination, visual acuity in the right eye is
weakness or sensory change. However, the right arm 20/60 and in the left eye 20/80. He has blue-yellow
is clearly more edematous than the left, and the skin color blindness. He has cerebellar ataxia on neurologic
appears somewhat atrophic in the affected limb. The examination as well as ophthalmoparesis. His strength is
patients pain most likely is due to 5 out of 5 in all major muscle groups, and all reexes are
normal except for extensor plantar responses.When the
A. subclavian vein thrombosis mother arrives, you nd out that many relatives on the
B. brachial plexus injury fathers side of the family, including the father, have been
C. reex sympathetic dystrophy diagnosed with cerebellar ataxia but she does not know
D. acromioclavicular separation more than that. You decide to perform a funduscopic
E. cervical radiculopathy
examination.What do you expect to nd on examina-
69. Which of the following statements regarding the long- tion of this patients fundi?
term outcomes in individuals with severe migraines is A. Lipemia retinalis
true? B. Normal examination
722 Review and Self-Assessment

71. (Continued ) 77. (Continued )

C. Papilledema A. carotid artery stenosis
D. Proliferative retinopathy B. hypokalemia
E. Retinal pigmentary degeneration D. multiple sclerosis
E. myasthenia gravis
72. All the following have been shown to reduce the
F. transient ischemic attack
risk of atherothrombotic stroke in primary or sec-
ondary prevention except 78. You are examining a 78-year-old patient in your
A. aspirin clinic who is referred to you for difculty in walking.
B. blood pressure control During your motor examination with the patient
C. clopidogrel lying supine, you place your hands behind one knee
D. statin therapy and rapidly raise the knee off the bed. During the
E. warfarin maneuver, the ankle (of the same leg) is also lifted off
the examining table. On repeat examination of the
73. All the following are associated with a decreased same leg, you nd varying levels of resistance, and the
sense of smell except ankle drags for varying distances before being lifted
A. head trauma off the bed. The nding is not seen in the other leg
B. HIV infection nor in the upper extremities when examining the
C. inuenza B infection elbow/wrist. What is the signicance of this nding?
D. Kallmann syndrome
E. parainuenza virus type 3 infection A. The patient has decreased motor tone, which may be
indicative of a motor neuron disease.
74. All the following are side effects of phenytoin except B. The patient has decreased motor tone related to
musculoskeletal injury.
A. ataxia C. The patients paratonia may be a normal
B. gum hyperplasia reaction.
C. hirsutism D. The patients rigidity is a manifestation of
D. leukopenia parkinsonism.
E. lymphadenopathy
79. Which of the following medicines has been most
commonly implicated in the development of nonin-
75. All but which of the following statements about
fectious chronic meningitis?
Beckers muscular dystrophy are true?
A. Acetaminophen
A. The inheritance is X-linked. B. Acyclovir
B. Serum creatinine kinase levels are elevated. C. -lactam antibiotics
C. The underlying genetic defect is in the myosin gene. D. Ibuprofen
D. Survival is better than it is in patients with Duchennes E. Phenobarbital
muscular dystrophy (DMD).
E. Cardiomyopathy may occur, resulting in heart failure. 80. A 72-year-old right-handed man with a history of
atrial brillation and chronic alcoholism is evaluated
76. You are following a patient who has a ruptured L4- for dementia. His son gives a history of a stepwise
L5 intervertebral disk with herniation. He has had decline in the patients function over the last 5 years
left lower extremity weakness that has been constant with the accumulation of mild focal neurologic
for 6 months. He is still able to perform his daily decits. On examination he is found to have a
activities. His pain is intermittent and he uses chronic pseudobulbar affect, mildly increased muscle tone,
narcotics on an as-needed basis.What ndings would and brisk deep tendon reexes in the right upper
prompt you to refer this patient for surgery? extremity and an extensor plantar response on the
left.The history and examination are most consistent
A. Absent deep tendon reexes on the right with which of the following?
B. MRI shows L3-L4 herniation as well
C. Nighttime symptoms A. Binswangers disease
D. Physical examination demonstrates progressive weakness B. Alzheimers disease
C. Creutzfeldt-Jakob disease
77. All of the following conditions may cause episodic D. Vitamin B12 deciency
generalized paresis except E. Multi-infarct dementia
 Review and Self-Assessment 723

81. A 50-year-old man presents with complaints of 81. (Continued )

weakness and numbness in the hands for the last median nerve distribution. All the following are
month. He describes paresthesias in the thumb and causes of carpal tunnel syndrome except
the index and middle ngers. The symptoms are
worse at night. He also describes decreased grip A. amyloidosis
strength bilaterally. He works as a mechanical engi- B. chronic lymphocytic leukemia
neer. The patient denies fevers, chills, or weight loss. C. diabetes mellitus
The examination is notable for atrophy of the thenar D. hypothyroidism
eminences bilaterally and decreased sensation in a E. rheumatoid arthritis

ANSWERS
1. The answer is C. head for relief, whereas those with migraines tend to
(Chap. 13) Confusion is dened as a mental and behav- remain motionless during attacks. Interestingly, unilateral
ioral state of reduced comprehension, coherence, and phonophobia and photophobia can occur with cluster
capacity to reason. Delirium is used to describe an acute headaches but do not with migraines. Treatment of acute
confusional state. Delirium often goes unrecognized attacks of cluster headaches requires a treatment with a
despite clear evidence that it is often a cognitive manifes- fast onset as the headaches reach peak intensity very
tation of many medical and neurologic illnesses. Delirium quickly but are of relatively short duration. High-ow
is a clinical diagnosis that may be hyperactive (e.g., alco- oxygen (1012 L/min for 1520 min) has been very
hol withdrawal) or hypoactive (e.g., opiate intoxication). effective in relieving the headaches. Alternatively, subcuta-
There is often dramatic uctuation between states. Delir- neous or intranasal delivery of sumatriptan will also halt
ium is associated with a substantial mortality with in- an attack. The oral-route triptan medications are less
hospital mortality estimates ranging from 2533%. Overall effective because of the time to onset of effect is too
estimates of delirium in hospitalized patients range from great. Preventive treatment may be considered in individ-
1555% with higher rates in the elderly. Patients in the uals with prolonged bouts of cluster headaches or chronic
ICU have especially high rates of delirium, ranging from cluster headaches that occur without a pain-free interval.
7087%. The clinic setting would represent the lowest The other TAC syndromes are paroxysmal hemicra-
risk. Postoperative patients, especially status post hip nia and short-lasting unilateral neuralgiform headache
surgery, have an incidence of delirium that is somewhat attacks with conjunctival injection and tearing (com-
higher than patients admitted to the medical wards. monly known as SUNCT). Paroxysmal hemicrania is
characterized by unilateral severe headaches lasting only
2. The answer is C. 245 min but occurring up to ve times daily. There is
(Chap. 6) This patient is presenting with typical cluster marked autonomic symptoms, and paroxysms of
headaches, one of the three recognized trigeminal auto- headaches last <3 days. Indomethacin is very effective at
nomic cephalgias (TACs). TACs are characterized by preventing this syndrome. SUNCT is a rare syndrome in
intense episodes of head pain associated with cranial auto- which the headaches last <4 min at a time. Diagnosis
nomic symptoms such as tearing, rhinorrhea, and con- requires at least 20 attacks. There is no acute treatment of
junctival injection. Because of these associated symptoms, SUNCT because of their short duration, but preventative
patients may be misdiagnosed as having sinus headache therapy with lamotrigine, topiramate, gabapentin, or car-
due to allergic rhinitis and treated inappropriately with bamazepine may be effective.
antihistamine and nasal steroids. A typical presentation of
cluster headaches is one of episodic severe headaches that 3. The answer is A.
occur at least once daily at about the same time for a (Chap. 44) A common mistake in the management of
period of 810 weeks. An attack usually lasts from 15180 patients with inammatory myopathy is to chase the
minutes, and 50% of headaches will have nocturnal onset. CK instead of adjusting therapy based on the clinical
Between episodes of headache, the patient is generally response. The goal of therapy is to improve strength. If
well. The period between headache cycles typically lasts that goal is being achieved, no augmentation of therapy is
about 1 year. Men are affected three times more com- necessary. In this case, the plan to switch to long-term
monly with cluster headaches than women, and alcohol maintenance with steroid-sparing immunosuppressants
ingestion may trigger cluster headaches. A distinguishing should still be pursued. There have been no controlled
feature between cluster headaches and migraine studies comparing mycophenolate to methotrexate for the
headaches is that individuals with cluster headaches tend long-term use in polymyositis, and in the absence of an
to move about during attacks and frequently rub their adverse reaction to mycophenolate, therapy should not be
724 Review and Self-Assessment

changed. Despite an elevated CK, patients with polymyosi- 6. The answer is B.

tis who are responding to therapy do not need a repeat (Chap. 9) The symptoms and signs described in this ques-
muscle biopsy. tion are most consistent with Mnires disease. In this
disorder paroxysmal vertigo resulting from labyrinthine
4. The answer is C. lesions is associated with nausea, vomiting, rotary nystag-
(Chap. 10) The central cord syndrome manifests clinically mus, tinnitus, high-tone hearing loss with recruitment,
as a sensory disorder as the spinothalamic bers in the and, most characteristically, fullness in the ear. Labyrinthi-
ventral commissure of the spinal cord are disrupted. Der- tis would be an unlikely diagnosis in this case because of
matomes above and below the level of the destruction are the hearing loss and multiple episodes. Vertebral-basilar
usually spared, creating a suspended sensory level on insufciency and multiple sclerosis typically are associated
physical examination. As the lesion grows, corticospinal with brainstem signs. Acoustic neuroma only rarely causes
tract or anterior horn involvement can produce weakness vertigo as the initial symptom, and the vertigo it does
in the affected myotome. Common causes include cause is mild and intermittent.
syringomyelia, intramedullary tumor, and hyperextension
in a patient with cervical spondylosis. Tabes dorsalis
impairs proprioception and sensation and causes weak-
7. The answer is D.
(Chap. 35) In a patient with suspected bacterial meningitis
ness. Disc herniation most commonly affects posterior
empirical therapy should be administered promptly to
cord function and nerve roots. A lateral hemisection syn-
reduce mortality and morbidity.The decision to obtain an
drome (the Brown-Squard syndrome) is classically due to
imaging study prior to lumbar puncture is based on the
penetrating trauma from a knife or bullet injury and pro-
concern of precipitating herniation in a patient with ele-
duces ipsilateral weakness and contralateral loss of pain
vated intracranial pressure or focal CNS lesions.Therefore,
and temperature sensation. Amyotrophic lateral sclerosis
patients with the presence of papilledema on physical
presents with combined upper and lower motor neuron
examination, history of recent head trauma, known or sus-
ndings; sensory decits are uncommon.
pected intracranial lesions (immunosuppressed, known
malignancy), focal neurologic ndings, or depressed level of
5. The answer is D. consciousness should have a head CT or MRI prior to
(Chap. 22) This patient has evidence of increased intracra-
lumbar puncture. Kernigs sign is elicited in a supine patient
nial pressure and needs to be managed urgently. A variety
by exing the thigh and knee. A positive sign occurs when
of maneuvers may decrease intracranial pressure acutely.
the patient has head/neck pain when passively straighten-
Hyperventilation causes vasoconstriction, reducing cere-
ing the knee.The sensitivity and specicity of this sign (also
bral blood volume and decreasing intracranial pressure.
Brudzinskis) for bacterial meningitis are unknown, but
However, this can be used only for a short period as the
they imply meningeal irritation, not an intracranial lesion
decrease in cerebral blood ow is of limited duration.
or elevated intracranial pressure. While cerebrospinal uid
Mannitol, an osmotic diuretic, is recommended in cases of
cultures may be impacted by administration of antibiotics
increased intracranial pressure resulting from cytotoxic
prior to lumbar puncture, stains, antigen tests, and poly-
edema. Hypotonic uids should be avoided. Instead,
merase chain reaction tests will not be affected.
hypertonic saline is given to elevate sodium levels and
prevent worsening of edema. A more denitive treatment
to decrease intracranial pressure is to have a ventricu- 8. The answer is C.
lostomy placed by which excessive pressure can be (Chap. 12) The patients nonspecic dysesthesia is related
relieved by draining cerebrospinal uid (CSF). Further to hyperventilation in response to the patients change in
decreases in mean arterial pressure may worsen the altitude from sea level to a mountainous area.The normal
patients clinical status. The patient already has had more respiratory response to decreased atmospheric oxygen
than a 20% reduction in mean arterial pressure, which is tension is to increase the respiratory rate.This hyperventi-
the recommended reduction in cases of hypertensive lation causes a mild respiratory alkalosis and is experi-
emergency. In addition, the patient is exhibiting signs enced as acral and periorbital dysesthesias. Acetazolamide
of increased intracranial pressure, which indicates that is often given to patients who have a past history of alti-
cerebral perfusion pressure [mean arterial pressure tude sickness manifested as headache, nausea with vomit-
(MAP)intracranial pressure (ICP) ] has been lowered. ing, and in severe cases pulmonary edema. This patient is
Paradoxically, the patient may need a vasopressor agent to experiencing none of those symptoms, and in fact, dyses-
increase MAP and thus improve cerebral perfusion. thesias are a common side effect related to treatment with
Finally, in cases of increased intracranial pressure, nitro- acetazolamide. No further blood testing is necessary as the
prusside is not a recommended intravenous antihyperten- symptoms are not associated with any neurologic abnor-
sive agent because it causes arterial vasodilation and may malities. Diabetes mellitus, vitamin B12 deciency, and ter-
decrease cerebral perfusion pressure and worsen neuro- tiary syphilis are all associated with a sensory neuropathy,
logic function. which this patient does not demonstrate.
 Review and Self-Assessment 725

9. The answer is C. the skull.Transient loss of consciousness is common, as are

(Chap. 1) This patient demonstrates increasing weakness confusion and amnesia. Head imaging is typically normal.
with repeated exertion, which is characteristic of neuro- Postconcussive syndrome is a constellation of symptoms
muscular junction diseases such as myasthenia gravis. The including fatigue, headache, dizziness, and difculty con-
course can uctuate over the course of a day, which may centrating that follows a concussion.The patient described
explain why his symptoms appear worse at the end of the above ts this diagnosis; strict diagnostic criteria do not
day. The absence of any sensory decit is also characteris- exist. Typically patients will improve over a 6- to 12-
tic of a neuromuscular junction disorder. Diseases of the month period. Patients who were energetic and highly
muscle usually do not exhibit such a marked difference functioning prior to their trauma have an excellent prog-
on the examination over the course of hours. Spinal root nosis. Treatment is aimed at reassurance and relieving
disorders are symptomatic in a nerve root distribution, prominent symptoms. Dizziness can be treated with phen-
and limb pain is usually a prominent component. Clues to ergan, which acts as a vestibular suppressant. He should
a brainstem disease are isolated cranial nerve palsies and avoid contact sports at least until his symptoms resolve.
crossed weakness and sensory abnormalities of the head
and limbs.
13. The answer is E.
(Chap. 38) Prions are infectious particles that cause central
10. The answer is B. nervous system degeneration. The human prion diseases
(Chap. 30) This patient has a history and examination
described to date include Creutzfeldt-Jacob disease, kuru,
consistent with a myelopathy. The rapidity of onset and
Gerstmann-Strassler-Scheinker disease, and fatal insom-
the lack of other antecedent symptoms (e.g., pain) make a
nia. The most common prion disease is sporadic CJD
noncompressive etiology most likely. An MRI is the initial
(sCJD) which occurs in a seemingly random pattern in
test of choice and will easily identify a structural lesion
adults in their fth and sixth decades of life. sCJD
such as a neoplasm or subluxation. Non-compressive
accounts for about 85% of cases of CJD and occurs in ~1
myelopathies result from ve basic causes: spinal cord
per 1 million population.Variant CJD (vCJD) results from
infarction; systemic disorders such as vasculitis, systemic
infection from bovine exposure to tainted beef from cattle
lupus erythematosus (SLE), and sarcoidosis; infections
with bovine spongiform encephalopathy (BSE). Infectious
(particularly viral); demyelinating disease such as multiple
CJD (iCJD) has resulted from injection of tainted human
sclerosis; and idiopathic. Therefore, serologies for antinu-
growth hormone, as well as transplant of infected dura
clear antibodies, viral serologies such as HIV and HTLVI,
mater grafts into humans. Familial CJD (fCJD) is due to
and lumbar puncture are all indicated. Because the clinical
germ-line mutations that follow an autosomal dominant
scenario is consistent with a myelopathy, an electromyo-
inheritance. Kuru is due to infection through ritualistic
gram is not indicated.
cannibalism. Gerstmann-StrasslerScheinker disease and
familial fatal insomnia (FFI) occur as dominantly inher-
11. The answer is D. ited prion diseases. Sporadic cases of fatal insomnia (sFI)
(Chap. 26) This MRI shows cerebellar atrophy consistent have been described.
with the diagnosis of spinocerebellar ataxia (SCA). The
SCAs are a group of autosomal dominant diseases. SCA1,
previously known as olivopontocerebellar atrophy, is a dis- 14. The answer is B.
ease of early or middle adult life. Patients develop cerebel- (Chap. 7) Neurogenic claudication (back or leg pain
lar ataxia of the trunk and limbs with impairment of induced by walking or standing and relieved by sitting) is
equilibrium and gait, scanning speech, nystagmus, and the most common symptom of lumbar spinal stenosis.
oscillatory tremor of the head and trunk. There may also Unlike vascular claudication, symptoms are provoked by
be mild dementia. Cerebellar and brainstem atrophy are standing without walking. Symptoms are often not pre-
evident on MRI. Migraine headache, limb weakness, and sent, and severe ndings such as paralysis and urinary
breathing difculties are nonspecic but may be seen in incontinence are rare. Lumbar spinal stenosis can be con-
serotonin syndrome or alcohol withdrawal. Gait instabil- genital or acquired. Acquired factors that contribute to
ity, urinary incontinence, and dementia constitute the spinal stenosis include trauma, osteoporosis, hypoparathy-
clinical triad for normal-pressure hydrocephalus, which roidism, renal osteodystrophy, and Pagets disease. Teth-
does not have cerebellar atrophy on MRI. Hypertension, ered cord syndrome usually presents as a cauda equina
tachycardia, and diaphoresis may be seen in a patient with disorder (urinary incontinence, perineal anesthesia) in a
an Arnold-Chiari malformation. MRI will often show young adult. Pain associated with disk herniation is dif-
abnormalities in the base of the skull. ferentiated from spinal stenosis when the pain is made
worse with sitting. Vertebral metastases are a common
12. The answer is A. cause of back pain in patients at risk of common malig-
(Chap. 31) Concussions result from blunt head trauma that nancies.The pain tends to be constant, dull, unrelieved by
causes anterior-posterior movement of the brain within rest, and worst at night.
726 Review and Self-Assessment

15. The answer is A. deltoid would be mediated by injury to the C5 nerve root.
(Chap. 20) Complex partial seizures are characterized by Finger exors and sensation to the axilla and medial arm
focal seizure activity plus impairment of the patients abil- are mediated by C8 and T1. (See Table 7-4)
ity to maintain contact with the environment. Mesial
temporal lobe epilepsy is the most common syndrome 20. The answer is C.
associated with complex partial seizures. Patients are (Chap. 26) The patient describes cerebellar ataxia, which is
unable to respond to verbal or visual commands during differentiated from ataxia associated with vestibular or
the seizure and they often manifest complex automatisms labyrinthine disease by the absence of vertiginous com-
or complex posturing. An aura is common before the plaints. True cerebellar ataxia is devoid of vertiginous
seizures. There is postictal memory loss or disorientation. symptoms and is clearly an unsteady gait due to imbal-
Patients often have a history of febrile seizures or a family ance. CT scanning can miss pathology in the cerebellum
history of seizures. MRI will show hippocampal sclerosis, due to the surrounding bony structures. Alcohol intoxica-
a small temporal lobe, or enlarged temporal horn. tion, lithium toxicity, and viral cerebritis usually cause
Hypothyroidism, herpes virus infection, diabetes, and acute or subacute (days to weeks) cerebellar ataxia. Ter-
tuberous sclerosis are not associated with mesial temporal tiary syphilis is a common cause of chronic cerebellar
lobe epilepsy. ataxia (months to years).

16. The answer is B.

(Chap. 20) MTLE is important to recognize because it 21. The answer is E.
tends to be refractory to treatment with anticonvulsants (Chap. 12) Thalamic pain syndrome may follow an
but responds extremely well to surgical intervention. embolic or lacunar thalamic infarct if it affects the ventral
Primidone is an alternative for treatment of partial and posterolateral (VPL) nucleus or the adjacent white matter.
generalized tonic-clonic seizures. Levetiracetam is an The pain is persistent and severe, affecting only the con-
alternative for simple partial, complex partial, and secon- tralateral side of the body. Other symptoms that may be
darily generalized seizures. Vagus nerve stimulation is an associated with thalamic infarcts include hemianesthesia,
option for patients refractory to antiepileptic medication hemiataxia, choreoathetoid movements, and athetoid pos-
with seizures arising from more than one site. Herpes ture. The eponym applied to this syndrome is Djerine-
virus infection is not a cause of MTLE. Roussy syndrome.

17. The answer is C. 22. The answer is A.

(Chap. 10) A deep tendon reex is elicited when a tap on (Chap. 9) In the acute evaluation of vertigo, vestibular func-
a tendon stretches muscle spindles which are chronically tion tests can help to establish the side of the abnormality
activated by motor neurons. Spindle afferent neurons and differentiate between central and peripheral etiologies.
directly stimulate a motor neurons in the spinal cord, When performing electronystagmography using cold and
causing a muscle contraction.The reex arc operates inde- warm water sequentially, the velocity of the slow-phase of
pendent of upper motor neurons (pyramidal neurons); nystagmus is compared from side to side. When warm
however, loss of the inhibitory input from upper motor water at 44C is infused into an ear, the normal response is
neurons produces an exaggerated deep tendon reex. nystagmus with the fast component toward the infused ear.
The opposite response occurs when cold water at 30C is
18. The answer is D. infused; the normal response is nystagmus with the fast
(Chap. 34) Optic neuritis is the initial symptom in component away from the cold waterinfused ear.The vol-
approximately 40% of persons who are eventually diag- ume of water can be increased if no response occurs with
nosed with multiple sclerosis. This rapidly developing the initial attempt. Velocity of the slow phase should be
ophthalmologic disorder is associated with partial or total similar in patients without vestibular nerve abnormalities.
loss of vision, pain on motion of the involved eye, sco- An absence of response to the cold caloric indicates a
toma affecting macular vision, and a variety of other labyrinth system that is dead and nonfunctional, such as
visual eld defects. Ophthalmoscopically visible optic in complete destruction of the neural input with acoustic
papillitis occurs in about half these patients. neuroma. Otoconia are not a result of and do not cause
peripheral nerve dysfunction. The caloric testing is normal
19. The answer is A. in patients with otoconia.The peripheral nerve dysfunction
(Chap. 7) The most commonly affected nerve roots in cer- seen with aminoglycoside antibiotics is usually bilateral.
vical disk disease are C7 and C6. As such, common motor Unilateral symptoms should raise the suspicion for an
ndings include biceps and triceps weakness. Common anatomic as opposed to a systemic cause of the vertigo.
sensory ndings include abnormal sensation in the thumb Labyrinthine ischemia will also manifest as a dead
and ngers (except the little nger), radial hand, and dorsal labyrinth; however, the patients age makes ischemic brain-
forearm. Decreased pin-prick sensation over the lateral stem lesions less likely than a schwannoma.
 Review and Self-Assessment 727

23. The answer is D. secondary to trauma or infection is treated with decom-

(Chap. 32) This scenario represents a common dilemma in pression and a drainage procedure, with a shunt often
the care of patients with HIV infection. The differential inserted that drains into the subarachnoid space. Although
diagnosis usually falls between CNS toxoplasmosis or relief may occur, recurrence is common.
CNS lymphoma. The standard approach in a neurologi-
cally stable patient is to treat the patient for toxoplasmosis 26. The answer is E.
for 23 weeks then repeat neuroimaging. If the imaging (Chap. 42) Myasthenia gravis (MG) is a neuromuscular dis-
shows clear improvement, continue antibiotics. If not, order characterized by weakness and fatigability of skeletal
then a stereotactic brain biopsy is indicated. Whole-brain muscles.The primary defect is a decrease in the number of
radiation therapy is part of the treatment for CNS lym- acetylcholine receptors at the neuromuscular junction sec-
phoma, which is not yet diagnosed in this patient, and ondary to autoimmune antibodies. MG is not rare, affecting
should not be instituted empirically. In the absence of at least 1 in 7500 individuals.Women are affected more fre-
neurologic collapse, it is reasonable to treat empirically for quently than are men.Women present typically in the sec-
toxoplasmosis in such a patient. The leptomeninges are a ond and third decades of life, and men present in the fth
common site for metastases for patients with systemic and sixth decades. The key features of MG are weakness
lymphoma and those patients usually have a B cell lym- and fatigability. Clinical features include weakness of the
phoma or leukemia. Dexamethasone is indicated for focal cranial muscles, particularly the lids and extraocular mus-
CNS lesions with evidence of mass effect or extensive cles. Diplopia and ptosis are common initial complaints.
surrounding edema. Weakness in chewing is noticeable after prolonged effort.
Speech may be affected secondary to weakness of the palate
24. The answer is D. or tongue weakness. Swallowing may result from weakness
(Chap. 32) In this immunocompromised patient who has of the palate, tongue, or pharynx. In the majority of
not responded to treatment for CNS toxoplasmosis, a patients the weakness becomes generalized.The diagnosis is
positive CNS EBV DNA would be diagnostic of CNS suspected after the appearance of the characteristic symp-
lymphoma. However, in the absence of a definitive diag- toms and signs. Edrophonium is an acetylcholinesterase
nosis, a biopsy should be pursued for a denitive diagno- inhibitor that allows ACh to interact repeatedly with the
sis. If there is no response to therapy after 2 weeks, limited number of AChRs, producing improvement in the
therapy does not need to be continued. Treatments strength of myasthenic muscles. False-positive tests may
directed at viral infections of the CNS or CNS lym- occur in patients with other neurologic diseases. Electrodi-
phomas are not indicated at this time since a diagnosis is agnostic testing may show evidence of reduction in the
still yet to be made. In the absence of a change in neuro- amplitude of the evoked muscle action potentials with
logic status or evidence of mass effect on CT, there is no repeated stimulation. Testing for the specic antibodies to
indication for dexamethasone. AChR are diagnostic. In addition to anti-AChR antibod-
ies, antibodies to MuSK have been found in some patients
25. The answer is A. with clinical MG. Antibodies to voltage-gated calcium
(Chap. 30) Syringomyelia is a developmental, slowly channels are found in patients with the Lambert-Eaton
enlarging cavitary expansion of the cervical cord that pro- syndrome.
duces a progressive myelopathy. Symptoms typically begin
in adolescence or early adulthood. They may undergo 27. The answer is D.
spontaneous arrest after several years. More than half are (Chap. 24) The differential diagnosis of Parkinsons disease
associated with Chiari malformations. Acquired cavitations is broad, and the disease can be difcult to diagnose, with
of the spinal cord are referred to as syrinx cavities. They an estimated misdiagnosis of 1025% even by experi-
may result from trauma, myelitis, infection, or tumor. The enced physicians. This patient exhibits several atypical
classic presentation is that of a central cord syndrome with features that should alert the physician to search for
sensory loss of pain and temperature sensation and weak- alternative diagnoses. These include early age of onset,
ness of the upper extremities.Vibration and position sensa- prominent orthostasis, autonomic symptoms of ushing
tion are typically preserved. Muscle wasting in the lower and diaphoresis, and failure to respond to dopaminergic
neck, shoulders, arms, and hands with asymmetric or agents. In addition, recurrent urinary tract infections
absent reexes reects extension of the cavity to the ante- should prompt an evaluation for urinary retention due to
rior horns.With progression, spasticity and weakness of the autonomic dysfunction in this patient. These symptoms
lower extremities and bladder and bowel dysfunction may are most consistent with multiple systems atrophy with
occur. MRI scans are the diagnostic modality of choice. parkinsonian features (MSA-p). The average age of onset
Surgical therapy is generally unsatisfactory. Syringomyelia is 50 years, and these individuals more frequently present
associated with Chiari malformations may require exten- with bilateral, symmetric tremor and more prominent
sive decompressions of the posterior fossa. Direct decom- spasticity than those with Parkinsons disease. Orthostasis
pression of the cavity is of debatable benet. Syringomyelia and autonomic symptoms are typically prominent. On
728 Review and Self-Assessment

MRI, one would expect to nd volume loss and T2- while the head position is maintained, and repeat trials
hyperintensity in the area of the putamen, globus pallidus, lessen the symptoms each time and may extinguish them
and white matter. On pathologic examination, a-synuclein- completely. With central causes of vertigo, symptoms are
positive inclusions would be seen in the affected areas. often less severe than with peripheral vertigo. Isolated
Median survival after diagnosis is 69 years. Dopaminer- horizontal nystagmus without a torsional component is
gic agents are not helpful in treatment of this disorder and also more suggestive of a central cause of vertigo.
are usually associated with drug-induced dyskinesias of
the face and neck, rather than the limbs and trunk. Corti- 30. The answer is C.
cobasal degeneration is a sporadic tauopathy that presents (Chap. 24) Therapy for Parkinsons disease should be initi-
in the sixth to seventh decades. In contrast to Parkinsons ated when symptoms interfere with the patients quality
disease, this disorder is frequently associated with of life. Choice of initial drug therapy is usually with
myoclonic jerks and involuntary purposeful movements of dopamine agonists, levodopa, or MAO inhibitors. The
a limb. Its progressive nature leads to spastic paraplegia. initial choice in most individuals is a dopamine agonist
Diffuse Lewy body disease has prominent dementia with (pramipexole, ropinirole), and monotherapy with dopamine
parkinsonian features. Neuropsychiatric complaints agonists usually controls motor symptoms for several years
including paranoia, delusions, and personality changes are before levodopa therapy becomes necessary. Over this
more common than in Parkinsons disease. Drug-induced period, escalating doses are frequently required, and side
Parkinsons disease is not seen with nitrofurantoin, and the effects may be limiting. It is thought that dopamine ago-
patient has no history of illicit drugs such as MTPT, nists delay the onset of dyskinesias and on-off motor
which could cause Parkinsons disease. Finally, this is symptoms, such as freezing. By 5 years, over one-half of
unlikely to be inadequately treated Parkinsons disease individuals will require levodopa to control motor symp-
because one would expect at least an initial improvement toms. Levodopa remains the most effective therapy for the
on dopaminergic agents. motor symptoms of Parkinsons disease, but once lev-
odopa is started, dyskinesias and on-off motor uctuations
28. The answer is D. become more common. MAO inhibitors work by decreas-
(Chap. 31) The head CT shows bilateral hypodense uid ing postsynaptic breakdown of dopamine. As monother-
collections in the subdural space. Acute hematomas apy, these agents have only small effects and are most often
(which would be as bright as the resolving blood shown used as adjuncts to levodopa. Surgical procedures such as
in arrows) become hypodense in comparison with adja- pallidotomy and deep-brain stimulation are reserved for
cent brain after ~2 months. During the isodense phase advanced Parkinsons disease with intractable tremor or
(26 weeks after injury), they may be difcult to discern. drug-induced motor uctuations or dyskinesias. In this
Chronic subdural hematoma may present without a his- setting, deep-brain stimulation can alleviate disabling
tory of trauma or injury in 2030% of patients. Headache symptoms.
is common. Other symptoms may be vague as in this
patient, or there may be focal signs including hemiparesis 31. The answer is C.
mimicking stroke. Underlying cortical damage may serve (Chap. 44) This patient does not have signs of an inam-
as a seizure focus. In relatively asymptomatic patients with matory myositis. In particular, the give-away weakness
small hematomas, observation and serial imaging may be and improvement with encouragement suggests that this
reasonable; however, surgical evacuation is often necessary patients weakness may actually be due to muscular
for large or symptomatic chronic hematomas. pain. Fibrositis, polymyalgia rheumatica or bromyalgia
may present this way, although the normal erythrocyte
29. The answer is B. sedimentation rate makes polymyalgia rheumatica less
(Chap 9) Positional vertigo is precipitated by a recumbent likely. Necrotic muscle can be seen in any of the inam-
head position, either to the right or the left. The benign matory myopathies or necrotizing myositis. Endomysial
form that affects the posterior semicircular canal is the deposits of amyloid can be seen in inclusion body myosi-
most common and is due to the accumulation of otoco- tis. Scattered inammatory foci are seen in polymyositis.
nia. Central positional vertigo (CPV) is due to lesions of
the fourth ventricle and is much less common than 32. The answer is E.
BPPV. BPPV can be diagnosed and potentially treated (Chap. 29) Trigeminal neuralgia is a clinical diagnosis based
with characteristic maneuvers (i.e., Dix-Hallpike posi- entirely on patient history.The disorder is characterized by
tion). With the head supine, the head is turned to the paroxysms of excruciating pain in the lips, gums, cheeks,
affected side (left ear down, in this case).Torsional nystag- and chin that resolves over seconds to minutes. It is caused
mus and vertigo will result with characteristic eye move- by ectopic action potentials in afferent pain bers of the
ments. In BPPV, the time from assuming head position fth cranial nerve, due either to nerve compression or
and onset of symptoms is 340 s, whereas in CPV, the other cause of demyelination. Symptoms are often, but not
onset is immediate. With BPPV, symptoms will abate always, elicited by tactile stimuli on the face, tongue or
 Review and Self-Assessment 729

lips. An elevated ESR is not part of the clinical syndrome. and time course. Specic features of the history and phys-
Elevated ESR is associated with temporal arteritis, a vas- ical examination should lead the clinician toward a possi-
culitis associated with jaw claudication, unilateral vision ble diagnosis. For example, lead toxicity is frequently asso-
loss, and symptoms of polymyalgia rheumatica. Trigeminal ciated with motor abnormalities in addition to sensory
neuralgia is specically notable for a lack of sensory nd- neuropathy. Laboratory examination with specic testing
ings on examination, unless the diagnosis comes in con- may be useful in assessing for a variety of etiologies of
junction with another disorder such as midbrain mass peripheral neuropathy, including diabetes mellitus, heavy
lesion or aneurysm. First-line therapy is with carba- metal toxicity, metabolic abnormalities, vasculitis, and
mazepine followed by phenytoin, rather than gabapentin. infections (syphilis, Lyme disease, HIV). Of the choices
Deep-seated facial and head pain is more a feature of listed in the question, folate deciency is not associated
migraine headache, dental pathology, or sinus disease. with peripheral neuropathy.

33. The answer is B.

(Chap. 7) MRI is the radiologic test of choice for evaluation 36. The answer is A.
of most serious processes involving the spine. However, CT (Chap. 32) Endocrine dysfunction resulting in hypopitu-
scanning is the preferred test when imaging of the bony itarism frequently follows exposure of the hypothalamus or
structures is most important. In acute processes such as frac- pituitary gland to therapeutic radiation. Growth hormone
ture or dislocation, MRI may reveal the edema associated is the most sensitive to the damaging effects of WBRT, and
with the acute inammation, but for more chronic bony thyroid-stimulating hormone is the least sensitive. ACTH,
conditions, CT scanning is the test of choice. MRI is better prolactin, and gonadotropins have an intermediate sensitiv-
than CT scanning for imaging the soft tissues surrounding ity. Other complications of radiation therapy to the brain
the spine. Imaging the spinal cord itself, in the case of include acute radiation injury manifest by headache, sleepi-
syringomyelia, is also better accomplished with MRI. Simi- ness, and worsening of preexisting neurologic defects. Early
larly, MRI is better than CT scanning for imaging the lateral delayed radiation injury occurs within the rst 4 months
recesses of the spinal cord; however, CTmyelography is pre- after therapy. It is associated with increased white matter
ferred over MRI for that indication. signal on MRI and is steroid-responsive. Late delayed radia-
tion injury occurs >4 months after therapy, typically 824
34. The answer is B. months.There may be dementia, gait apraxia, focal necrosis
(Chap. 40) Peripheral neuropathy is a general term indicat- (after focal irradiation), or development of secondary
ing peripheral nerve disorders of any cause.The causes are malignancies.
legion, but peripheral neuropathy can be classied by a
number of means: axonal versus demyelinating, mononeu- 37. The answer is C.
ropathy versus polyneuropathy versus mononeuritis multi- (Chap. 32) Spinal cord compression from solid tumor
plex, sensory versus motor, and the tempo of the onset of metastases usually results from growth of a bony vertebral
symptoms. Mononeuropathy typically results from local metastasis into the epidural space.The most common pri-
compression, trauma, or entrapment of a nerve. Polyneu- mary tumors that metastasize to the bone include lung,
ropathy often results from a more systemic process. The breast, and prostate. The thoracic cord is most often
distinction between axonal and demyelinating can often be involved. Back pain is a prominent symptom in 90% of
made only with nerve conduction studies. HIV infection patients with vertebral metastases and spinal cord com-
causes a common, distal, symmetric, mainly sensory pression. Concerning features of this patients presentation
polyneuropathy. Vitamin B12 deciency typically causes a include the symptoms of radicular injury as well as the
sensory neuropathy that predominantly involves the dorsal signs of radicular and spinal cord impingement on physi-
columns. Hypothyroidism and acromegaly may both cause cal examination. Once signs of spinal cord compression
compression and swelling of nerve bers, resulting rst in develop, they usually progress rapidly and warrant rapid
sensory symptoms and later in disease with motor symp- therapy. Appropriate therapy includes emergent scanning
toms. Critical illness polyneuropathy is predominantly with an MRI as well as immediate glucocorticoids if
motor in presentation.These patients may recover over the there are signs of spinal cord impingement. Subsequent
course of weeks to months. The etiology is unknown, but management will depend on the extent of involvement
an association may exist with neuromuscular blockade and and the primary tumor. Conservative pain management
corticosteroids. measures are not appropriate in this patient since he has
very concerning neurologic ndings for spinal cord com-
35. The answer is E. pression and delay will increase the likelihood of irreversible
(Chap. 40) Peripheral neuropathy is a common disorder defects. Antibody-mediated paraneoplastic neurologic syn-
affecting 28% of the adult population and increasing dromes are unlikely to cause focal ndings such as in this
with age. The causes of peripheral neuropathy are myriad patient. Radiographs may show bony metastases but will
and can be classied by location, ber type, histopathology, not show spinal cord damage.
730 Review and Self-Assessment

38. The answer is C. cytokine response in the subarachnoid space. This inam-
(Chap. 44) The inammatory myopathies (polymyositis, der- mation may lead to increased damage of the blood brain
matomyositis, and inclusion body myositis) are associated barrier and central nervous system damage. Glucocorti-
with unique clinical features. Inclusion body myositis is usu- coids can blunt this response by inhibiting tumor necrosis
ally seen in patients 50 years and initially involves the distal factor and interleukin-1. They work best if administered
muscles, especially the foot extensors and nger exors. before antibiotics. Clinical trials have demonstrated that
Atrophy is seen along with weakness as this inammatory dexamethasone, 10 mg IV administered 20 min before
myopathy runs a slowly progressive course, compared to antibiotics, reduced unfavorable outcomes, including
polymyositis or dermatomyositis. Polymyositis is a rare disor- death. The dexamethasone was continued for 4 days. The
der that usually involves the proximal not distal muscles. It is benets were most striking in pneumococcal meningitis.
a diagnosis of exclusion after a thorough medical examina- Because this is the most common cause of meningitis in
tion and muscle biopsy. Dermatomyositis is distinguished by the elderly, empirical coverage should include this inter-
the classic heliotrope rash and associated skin ndings, vention as well. Empirical antibiotics in this case should
which may precede the development of clinical muscular include a third-generation cephalosporin, vancomycin,
weakness. Eosinophilic myofasciitis is associated with myal- and ampicillin. However, dexamethasone may decrease
gias, skin induration, fatigue, and eosinophilia in the periph- vancomycin penetration into the CSF, so its use should be
eral blood as well as in endomysial tissue. Hyperthyroidism considered carefully in cases where the most likely organ-
would cause a reduced TSH. It may cause weakness, but is ism requires vancomycin coverage.
generally associated with other ndings such as tremor, skin
changes, and irritability. 42. The answer is E.
(Chap. 6) This patient has typical symptoms of migraine
39. The answer is B. headaches without concerning features for an underlying
(Chap. 42) In myasthenia gravis, the primary defect is disorder. Specically, there is no report of worsening
decreased number of available ACh receptors in the severity of headaches, fever, intractable vomiting, or
postsynaptic neuron at the neuromuscular junction abnormal neurologic examination that would be worri-
(NMJ). This occurs as a result of antibody-mediated some for an intracranial process.Vertigo is not an indica-
cross-linking of the ACh receptor, which causes tion of a more serious intracranial process, as an estimated
increased turnover of ACh receptors, blockage of the 33% of individuals with migraine experience vertigo both
active site, and damage to the postsynaptic muscle. The with and without accompanying headache. Therefore,
defect is not due to a defect in the release of ACh. Low imaging of the brain is unnecessary in this clinical situa-
levels of ACh-esterase would cause increased activation tion. Migraine headaches are the second most common
at the NMJ. Finally, the defect in myasthenia gravis headache syndromes after tension headaches and affect
occurs at the NMJ, not at nerve synapses. 15% of women and 6% of men. The onset of headaches
is usually in late adolescence, with peak prevalence of
40. The answer is E. migraine occurring in the mid-thirties. Migraine
(Chap. 20) Simple partial seizures cause motor, sensory, headaches are typically classified as occurring with aura
autonomic, or psychic symptoms without an obvious (previously called classic migraine) or without an aura. A
alteration in consciousness.The phenomenon of abnormal more simplied diagnostic criterion for migraine has
motor movements beginning in a restricted area then been adopted by the International Headache Society.
progressing to involve a larger area is termed Jacksonian Migraine is dened as repeated attacks of headache lasting
march. The patient is describing Todds paralysis, which 472 h in individuals with a normal physical examination.
may take minutes to many hours to return to normal. To be classied as a migraine, the headaches must fulll at
Although meningitis is a common cause of seizure in least two of the following symptoms: unilateral pain,
young patients, it is unlikely to be the cause in someone throbbing quality, aggravation by movement, and moder-
who has a known seizure disorder. If his symptoms were ate to severe intensity. At least one additional accompany-
to persist beyond many hours, it would be reasonable to ing feature should be present, including either nausea/
investigate a different etiology of his hand weakness with vomiting, phonophobia, or photophobia. Patient educa-
imaging studies. Overt decits in strength are not com- tion and trigger avoidance are important in the manage-
patible with a primary psychiatric disorder. Magnetic res- ment of migraine headaches. Migraines can frequently be
onance angiogram and cerebral angiogram are useful to controlled, but not eliminated, by lifestyle modications,
evaluate for cerebrovascular disorders, but there is no evi- and it is important to understand an individuals triggers
dence of subarachnoid bleeding or vasculitis. for migraine. A headache diary will help identify patterns
of headaches as well as triggers. It will also provide an
41. The answer is C. estimate of headache frequency and severity to aid in
(Chap. 35) The release of bacterial cell wall components determining whether prophylactic medication would
after killing by antibiotics may evoke a marked inammatory be required. Other nonpharmacologic treatment of
 Review and Self-Assessment 731

migraines includes regular exercise, maintain a regular sleep- for this patient, and lumbar puncture must be performed
wake cycle, and stressor avoidance.Yoga, biofeedback, hypno- to rule this out. In addition, acute cocaine intoxication is a
sis, and meditation are interventions that may help alleviate plausible reason for this new-onset seizure. Figure 20-2
stress and may have benet in migraine treatment. Once an illustrates the evaluation of the adult patient with a seizure.
acute migraine is experienced, timely treatment is warranted MRI would be indicated if the patient had a negative
to decrease the duration of the attack and minimize loss of metabolic and toxicologic screening. Substance abuse
productivity. If attacks are mild, analgesics such as nons- counseling, while indicated, is not indicated at this point in
teroidal anti-inammatory drugs or acetaminophen may be his workup since he is postictal. The patient is not having
useful. However, the most effective drugs for the treatment of seizures, does not have a known seizure disorder, and has
moderate to severe migraines are the 5-hydroxytriptamine not been treated for the underlying metabolic abnormality,
agonistsergotamines and the triptan drugs. Rizatriptan and making intravenous loading with an antiepileptic medica-
almotriptan are the most efcacious of the triptan drugs. If tion premature at this time.
migraine attacks occur more than ve times monthly or are
poorly responsive to abortive treatment, additional drug ther- 46. The answer is D.
apy for prevention is indicated. (Chap. 43) Becker and Duchenne muscular dystrophy are
both X-linked recessive disorders associated with different
43. The answer is D. mutations of the dystrophin gene located on the short arm
(Chap. 1) Cranial nerve XI (accessory nerve) is correctly of the X chromosome. This 2000-kb gene is among the
paired with the proper examination technique. Testing largest identied human genes. In both Becker and
cranial nerve I (olfactory nerve) should be performed Duchenne muscular dystrophy, the most common muta-
with a mild stimulus (e.g., coffee or toothpaste) to elimi- tion is a deletion. However, deletions in Becker muscular
nate any potential stimulation of pain bers in the dystrophy do not result in frame-shift mutations, yielding a
nasopharynx (trigeminal nerve) by noxious stimuli such as delayed presentation and milder presentation of disease.
ammonia or alcohol. When testing visual acuity (cranial Limb-girdle muscular dystrophy designates a clinical syn-
nerve II), corrective lenses should be worn by the patient, drome that presents as progressive weakness of pelvic and
if necessary.This allows for testing of the neuronal aspects shoulder girdle muscles. There are 12 recognized limb-
of vision without confounding by problems within the girdle muscular dystrophies with unique mutations. This
lens. It is also important to test each eye individually. The disorder can be inherited in both an autosomal dominant
trigeminal (cranial nerve V) is predominantly a sensory or recessive fashion, depending on the mutation present.
nerve and has three sensory branches.The motor compo- Kearns-Sayre syndrome and myoclonic epilepsy with
nent of the trigeminal nerve predominantly innervates the ragged red bers (MERFF) are mitochondrial myopathies.
masseter muscles used for chewing. Eyebrow elevation Each mitochondrion possesses a DNA genome unique
and forehead wrinkling are functions of cranial nerve VII. from the nuclear genome and is inherited primarily from
the oocytes, accounting for the maternal inheritance of
44. The answer is C. mitochondrial disorders. Kearns-Sayre syndrome is a mul-
(Chap. 42) This patients presentation with facial and ocular tisystem disorder with chronic progressive external oph-
weakness in a nocturnal pattern is consistent with a typical thalmoplegia (CPEO).Varying degrees of proximal muscle
presentation of myasthenia gravis. It is not uncommon for weakness are present. MERFF presents in late childhood
symptoms to be mostly nocturnal and be relatively asymp- to adulthood with clinical features of myoclonic epilepsy,
tomatic in the early morning hours. Examining these progressive weakness, and cerebellar ataxia.
patients in the evening or doing repetitive strength testing
may bring out more subtle ndings and requires a height- 47. The answer is B.
ened index of suspicion. Lead poisoning would be uncom- (Chap. 14) Brain death is dened by the cessation of cere-
mon in a woman of this age, and the ndings would not bral function while somatic function is maintained by arti-
be restricted to the cranial region. Psychiatric diagnoses do cial means and the heart continues to pump. It is the only
not correlate with myasthenia gravis, and repeat examina- type of brain damage that is considered equivalent to
tion to corroborate the reported physical examination death. The diagnosis of brain death should be conrmed
should be performed rst. MRI of the brain is not indi- with the following clinical ndings: unresponsiveness to
cated at this time as the physical examination ndings any stimuli, indicating widespread cortical destruction;
point towards a serologic diagnosis. Slit-lamp examination brainstem damage, as evidenced by enlarged or mid-sized
is useful for nding abnormalities in the anterior portion pupils without light reaction; absent corneal and
of the eye, such as the iris, lens, and cornea. oculovestibular reexes; and apnea, indicating medullary
destruction. The heart rate should be invariant. Because
45. The answer is C. the spinal cord is intact, spinal reexes may be present.The
(Chap. 20) Nuchal rigidity and an elevated white blood presence or absence of the Babinski sign does not con-
cell count is very concerning for meningitis as the etiology tribute to the diagnosis of brain death. Central diabetes
732 Review and Self-Assessment

insipidus occurs with dysfunction of the hypothalamus or muscle use, and paradoxical respiration. His arterial blood
posterior pituitary. It has been described in patients with gas shows a respiratory alkalosis with an increase in the Aa
brain death but is not a component of the diagnosis. gradient to 33 mmHg. His vital capacity is 12.5 mL/kg
body weight. Laboratory ndings would include normal
48. The answer is B. serum chemistries with an increased cerebrospinal uid
(Chap. 6) Cluster headaches, which can cause excruciating protein without pleocytosis. Electromyography would show
hemicranial pain, are notable for their occurrence during evidence of demyelination. Treatment for this individual
characteristic episodes. Usually attacks occur during a should include endotracheal intubation with mechanical
4- to 8-week period in which the patient experiences ventilation in addition to IVIg or plasmapheresis. IVIg is
one to three severe brief headaches daily. There may then administered as ve daily infusions of 2 g/kg body weight.
be a prolonged pain-free interval before the next episode. Plasmapheresis is equally effective in treating GBS and is
Men between 20 and 50 years are most commonly performed four times over the rst week. Mechanical ven-
affected. The unilateral pain is usually associated with tilation is indicated in GBS when the vital capacity <20
lacrimation, eye reddening, nasal stufness, ptosis, and mL/kg (ND Lawn et al: Arch Neurol 58(6):893, 2001).
nausea. During episodes alcohol may provoke the attacks. There is no role for glucocorticoids in the treatment of
Even though the pain caused by brain tumors may GBS. Ciprooxacin is an effective treatment to decrease
awaken a patient from sleep, the typical history and nor- symptom duration in C. jejuni infection if given early in the
mal neurologic examination do not mandate evaluation course of the illness, but has no effect in treatment of GBS
for a neoplasm of the central nervous system. Acute ther- following C. jejuni infection. Botulism also presents as an
apy for a cluster headache attack consists of oxygen ascending symmetric paralysis. Cranial nerves are more fre-
inhalation, although intranasal lidocaine and subcutaneous quently involved than in GBS. In this patient, there is no
sumatriptan may also be effective. Prophylactic therapy associated risk factor for botulism such as home-canned
with prednisone, lithium, methysergide, ergotamine, or foods or injection wounds from drug use.
verapamil can be administered during an episode to pre-
vent further cluster headache attacks. 51. The answer is E.
(Chap. 21) Cardioembolism accounts for up to 20% of all
49. The answer is C. ischemic strokes. Stroke caused by heart disease is due to
(Chap. 29) Trigeminal neuralgia is a clinical diagnosis based thrombotic material forming on the atrial or ventricular
entirely on patient history, and as such should be treated wall or the left heart valves. If the thrombus lyses quickly,
once a patient comes with the virtually pathognomonic only a transient ischemic attack may develop. If the arterial
complaints of paroxysms of excruciating pain in the lips, occlusion lasts longer, brain tissue may die and a stroke will
gums, cheeks, and chin that resolve over seconds to minutes. occur. Emboli from the heart most often lodge in the mid-
Carbamazepine is rst-line therapy, followed by phenytoin dle cerebral artery (MCA), the posterior cerebral artery
for the ~3050% of patients who do not respond adequately (PCA), or one of their branches. Atrial brillation is the
to therapy. Surgical approaches, such as radiofrequency ther- most common cause of cerebral embolism overall. Other
mal rhizotomy, gamma-knife radiosurgery, and microvascu- signicant causes of cardioembolic stroke include myocar-
lar decompression, should be considered only when medical dial infarction, prosthetic valves, rheumatic heart disease,
options fail. Steroids have no therapeutic role, as trigeminal and dilated cardiomyopathy. Furthermore, paradoxical
neuralgia is not an inammatory condition. Neuroimaging embolization may occur when an atrial septal defect or a
is not indicated, unless other clinical features or a focal neu- patent foramen ovale exists. This may be detected by
rologic decit elicited on history or physical examination bubble-contrast echocardiography. Bacterial endocarditis
suggest another possible diagnosis such as intracranial mass may cause septic emboli if the vegetation is on the left side
or multiple sclerosis. of the heart or if there is a paradoxical source.

50. The answer is C. 52. The answer is B.

(Chap. 41) The patient fullls the diagnostic criteria for (Chap. 7) The crossed straight leg raise is positive when
GuillainBarr syndrome (GBS) with progressive weakness exion of one leg reproduces the pain in the opposite leg
of two or more limbs, areexia, disease course <4 weeks, or buttocks. This sign is more specic for disk herniation
and no other identiable cause. Other characteristic fea- than the straight leg raise. The nerve or nerve root lesion
tures include lack of a fever, symmetric weakness, and min- is always on the side of the pain.The straight leg raise test
imal sensory symptoms. The diagnosis is further suggested is positive if passive exion of the leg reproduces the
by an antecedent gastrointestinal illness. In the United patients usual back pain. The reverse straight leg raise is
States, 2030% of all cases of GBS are associated with a performed by standing the patient next to the examina-
preceding infection with Campylobacter jejuni. This patient tion table and passively extending the leg with the knee
also has evidence of impending respiratory failure from exed. This maneuver stretches the L2-L4 nerve roots.
neuromuscular weakness manifested by tachypnea, accessory Back pain referred from visceral organs may be palpated
 Review and Self-Assessment 733

on abdominal examination but should not be reproduced to threefold increase in mortality for patients with epilepsy
by straight leg raise. Passive dorsiexion of the foot during compared with age-matched controls. Although most of
the straight leg raise will add to the stretch but does not the increased mortality results from the underlying etiology
add any more diagnostic information. of epilepsy, a signicant number of these patients die from
accidents, status epilepticus, and a syndrome known as sud-
53. The answer is D. den unexpected death in epileptic patients (SUDEP). The
(Chap. 32) This gure illustrates a mass attached to the cause is unknown, but research has centered on brainstem-
meninges with a dural tail. Other dural tumors may mediated effects of seizures on cardiopulmonary function.
appear this way, but of the options listed, the meningioma
is by far the most likely to appear this way. Meningiomas 55. The answer is D.
derive from the cells that give rise to the arachnoid gran- (Chap. 21) Nonrheumatic atrial brillation is the most
ulations.They are usually benign and attached to the dura. common cause of cerebral embolism overall. The pre-
They rarely invade the brain. They are more frequent in sumed stroke mechanism is thrombus formation in the
women than men and have a peak incidence in middle brillating atrium or atrial appendage.The average annual
age. Total surgical resection of a meningioma is curative. risk of stroke is around 5%. However, the risk varies with
Low-grade astrocytoma and high-grade astrocytoma certain factors: age, hypertension, left ventricular function,
(glioblastoma) often inltrate into adjacent brain and prior embolism, diabetes, and thyroid function. Patients
rarely have the clear margins seen in this gure. Oligo- younger than 60 years of age without structural heart dis-
dendroma comprise ~15% of all gliomas and show calci- ease or without one of these risk factors have a very low
cation in roughly 30% of cases. They have a more benign annual risk of cardioembolism: <0.5%.Therefore, it is rec-
course and are more responsive than other gliomas to ommended that these patients only take aspirin daily for
cytotoxic therapy. For low-grade oligodendromas, the stroke prevention. Older patients with numerous risk fac-
median survival is 78 years. Brain abscess will have dis- tors may have annual stroke risks of 1015% and must
tinctive ring-enhancing features with a capsule, often have take warfarin indenitely. Cardioversion is indicated for
mass effect, and will have evidence of inammation on symptomatic patients who want an initial opportunity to
MRI scanning. remain in sinus rhythm. However, studies have shown that
there is an increased stroke risk for weeks to months after
54. The answer is B. a successful cardioversion, and these patients must remain
(Chap. 20) Optimal medical therapy for epilepsy depends on anticoagulation for a long period. Similarly, recent
on the underlying cause, type of seizure, and patient factors. studies have shown that patients who do not respond to
The goal is to prevent seizures and minimize the side cardioversion and do not want catheter ablation have
effects of therapy.The minimal effective dose is determined mortality and morbidity with rate control and anticoagu-
by trial and error. In choosing medical therapies, drug lation similar to those of patients who opt for cardiover-
interactions are a key consideration. Certain medications, sion. Low-molecular-weight heparin may be used as a
such as tricyclic antidepressants, may lower the seizure bridge to warfarin therapy and may facilitate outpatient
threshold and should be avoided. Patients who respond well anticoagulation in selected patients.
to medical therapy and have completely controlled seizures
are good candidates for the discontinuation of therapy, with 56. The answer is D.
about 70% of children and 60% of adults being able to dis- (Chap. 43) There are two recognized clinical forms of
continue therapy eventually. Patient factors that aid in this myotonic dystrophy, both of which are characterized by
include complete medical control of seizures for 1 to 5 years, autosomal dominant inheritance. Myotonic dystrophy 1
a normal neurologic examination, a normal EEG, and sin- (DM1) is the most common form and the most likely dis-
gle seizure type. On the other end of the spectrum, about order in this patient. Characteristic clinical features of this
20% of these patients are completely refractory to medical disorder include a hatchet-faced appearance, due to
therapy and should be considered for surgical therapy. In wasting of the facial muscles, and weakness of the neck
the best examples, such as mesial temporal sclerosis, resec- muscles. In contrast to the muscular dystrophies (Becker
tion of the temporal lobe may result in about 70% of these and Duchenne), distal limb muscle weakness is more
patients becoming seizure free and an additional 1525% common in DM1. Palatal, pharyngeal, and tongue
having a signicant reduction in the incidence of seizures. involvement are also common and produce the dysarthric
In patients with epilepsy other considerations are critical. voice that is frequently heard. The failure of relaxation
Psychosocial sequelae such as depression, anxiety, and after a forced hand grip is characteristic of myotonia.
behavior problems may occur. Approximately 20% of Myotonia can also be elicited by percussion of the thenar
epileptic patients have depression, with their suicide rate eminence. In most individuals, myotonia is present by age
being higher than that of age-matched controls.There is an 5, but clinical symptoms of weakness that lead to diagnosis
impact on the ability to drive, perform certain jobs, and may not be present until adulthood. Cardiac conduction
function in social situations. Furthermore, there is a twofold abnormalities and heart failure are also common in
734 Review and Self-Assessment

myotonic dystrophy. Diagnosis can often be made by clin- must be warned to use standard precautions under these
ical features alone in an individual with classic symptoms circumstances. These proteins cannot be measured from
and a positive family history. An electromyogram would cerebrospinal uid (CSF). CSF in CJD is usually normal
conrm myotonia. Genetic testing for DM1 would show except for a minimally elevated protein. Many patients with
a characteristic trinucleotide repeat on chromosome 19. CJD have elevated CSF stress protein 14-3-3. This test
Genetic anticipation occurs with an increasing number of alone is neither sensitive nor specic, as patients with her-
repeats and worsening clinical disease over successive gen- pes simplex virus encephalitis, multi-infarct dementia, and
erations. Myotonic dystrophy 2 (DM2) causes proximal stroke may have similar elevations.
muscle weakness primarily and is also known by the
name proximal myotonic myopathy (PROMM). Other 59. The answer is D.
features of the disease overlap with DM1. Acid maltase (Chap. 10) The ventral spinal cord includes the corti-
deciency (glucosidase deciency, or Pompes disease) has cospinal tracts, spinothalamic tracts, and descending auto-
three recognized forms, only one of which has onset in nomic tracts. Disruption of these tracts causes weakness/
adulthood. In the adult-onset form, respiratory muscle areexia, loss of pain/temperature sensation, and bladder
weakness is prominent and often is the presenting symp- sphincter dysfunction, respectively. The dorsal columns
toms. As stated previously, Becker and Duchenne muscu- include vibratory sense and proprioception, which are
lar dystrophies present with primarily proximal muscle spared in the ventral cord syndrome. Other causes of the
weakness and are X-linked recessive disorders. Becker syndrome include disc herniation, radiation myelitis, and
muscular dystrophy presents at a later age than Duchenne human T-lymphocyte virus 1 infection.
muscular dystrophy and has a more prolonged course.
Otherwise, features are similar to one another. Nemaline 60. The answer is C.
myopathy is a heterogeneous disorder marked by the (Chap. 44) This patients skin ndings are an example of
threadlike appearance of muscle bers on biopsy. Nema- Gottrons sign of the hands and the heliotrope facial rash
line myopathy usually presents in childhood and has a of dermatomyositis. Usually the rash precedes the muscular
striking facial appearance similar to myotonic dystrophy weakness. In addition to the V-sign, as described in the sce-
with a long, narrow face. This disease is inherited in an nario, one can also see the shawl sign, in which the erythe-
autosomal dominant fashion. matous rash is found around the shoulders and posterior
neck region. In addition to the skin manifestations, skeletal
57. The answer is D. muscle weakness, particularly the proximal muscles, is part
(Chap. 20) Adolescence and early adulthood mark the of the presentation of dermatomyositis. Extra-muscular
period where idiopathic or genetic epilepsy syndromes manifestations include constitutional symptoms, joint con-
become less common and seizures due to acquired CNS tractures, dysphagia, cardiac disturbances, pulmonary dys-
lesions become more common.The most common causes function, and arthralgias. Hepatosplenomegaly is not an
of seizures in the young adults are head trauma, central associated clinical nding. Situs inversus is not associated
nervous system (CNS) infections, brain tumors, congeni- with dermatomyositis. Hypothyroidism is associated with
tal CNS lesions, illicit drug use, or alcohol withdrawal. delayed deep tendon relaxation. In hypothyroidism the
Fever rarely causes seizure in patients >12 years. Amyloid skin appears swollen, dry, and coarse with a cool waxy
angiopathy and uremia are more common in older adults. appearance. Subcutaneous nodules on the elbows, back of
the forearms, and metacarpophalangeal joints of the hands
58. The answer is B. are characteristic of rheumatoid arthritis, particularly in the
(Chap. 38) Startle myoclonus is a worrisome sign but is not active phase.
specic for CJD, though it is more so if it occurs during
sleep. Lewy body dementia,Alzheimers disease, central ner- 61. The answer is D.
vous system infections, and myoclonic epilepsy can all cause (Chap. 17) This patient has acute angle-closure glaucoma
myoclonus. EEG and MRI can both help differentiate CJD resulting from obstruction of the outow of aqueous humor
from these disorders. The MRI nding of cortical ribbon- at the iris. The buildup of intraocular pressure can be con-
ing and intensity in the basal ganglia on uid-attenuated rmed by measurement and requires urgent treatment with
inversion recovery sequences are characteristic of CJD. hyperosmotic agents. Permanent treatment requires laser or
EEG is useful if stereotypical periodic bursts every 12 s are surgical iridotomy. Angle-closure glaucoma is less common
present, but this is seen in only 60% of cases, and other than is primary open-angle glaucoma, which is asympto-
ndings may be less specic. Demonstration of specic matic and is usually detectable only through measurements
immunoassays for proteolytic products of disease-causing of intraocular pressure at a routine eye examination.
prion proteins (PrPSc) at brain biopsy may be necessary to
conrm diagnosis in some cases. However, these proteins 62. The answer is D.
are not uniformly distributed throughout the brain and (Chap. 40) CMT disease is a heterogeneous group of
false-negative biopsies occur. Both surgeons and pathologists inherited peripheral neuropathies. Transmission is usually
 Review and Self-Assessment 735

autosomal dominant but may be recessive or X-linked. this idiopathic condition is carbamazepine or phenytoin if
Numerous genetic defects are associated with CMT dis- carbamazepine is not tolerated.When drug treatment is not
ease. It is very common, affecting up to 1 in 2500 persons. successful, surgical therapy, including the commonly applied
Clinically, patients usually present in the rst or second percutaneous retrogasserian rhizotomy, may be effective. A
decade of life, but later presentations may occur.The neu- possible complication of this procedure is partial facial
ropathy affects both motor and sensory nerves. Symptoms numbness with a risk of corneal anesthesia, which increases
may vary, ranging from distal muscle weakness and severe the potential for ulceration.
atrophy and disability to only pes cavus and minimal
weakness. Although sensory ndings and involvement are 66. The answer is C.
common, these patients often do not have dominant sen- (Chap. 42) Except for lumbar puncture, all of the options
sory complaints. However, if patients have no evidence of listed are indicated at this time. Thymic abnormalities are
sensory involvement on detailed neurologic examination present in 75% of patients with myasthenia gravis. A CT
or electrodiagnostic studies, an alternative diagnosis or MRI of the mediastinum may show enlargement or
should be considered.There is no known effective therapy neoplastic changes in the thymus and is recommended
for CMT disease. Orthotics and physical therapy are upon diagnosis. Hyperthyroidism occurs in 38% of
mainstays for preserving function. patients with myasthenia gravis and may aggravate weak-
ness. Testing for rheumatoid factor and antinuclear anti-
63. The answer is D. bodies should also be obtained because of the association
(Chap. 35) Listeria has become an increasingly important of myasthenia gravis to other autoimmune diseases. Due
cause of bacterial meningitis in neonates (<1 month of age), to side effects of immunosuppressive therapy, a thorough
pregnant women, individuals >60 years, and immunocom- evaluation should be undertaken to rule out latent or
promised individuals. Infection is acquired by eating conta- chronic infections such as tuberculosis. Measurements of
minated foods such as unpasteurized dairy products, cole ventilatory function are valuable as a baseline because of
slaw, milk, soft cheeses, delicatessen meats, and uncooked hot the frequency and seriousness of respiratory impairment
dogs. Ampicillin is the agent most often added to the initial in myasthenic patients, and they can be used as an objec-
empirical regimen to cover L. monocytogenes. tive measure of response to therapy.

64. The answer is E. 67. The answer is D.

(Chap. 14) Foraminal herniation, which forces the cere- (Chap. 31) Hemorrhages beneath the dural layer (subdural)
bellar tonsils into the foramen magnum, leads to compres- or between the skull and the dura (epidural) are common
sion of the medulla and subsequent respiratory arrest. sequelae of head trauma. They can be life-threatening, and
Central transtentorial herniation occurs when the medial prompt evaluation and management are imperative. Several
thalamus compresses the midbrain as it moves through the clinical features allow these conditions to be distinguished
tentorial opening; miotic pupils and drowsiness are the from one another. Acute subdural hematomas typically arise
classic clinical signs. A locked-in state is usually caused by from venous sources, often the bridging veins located imme-
infarction or hemorrhage of the ventral pons; other causes diately under the dura mater. As the brain volume decreases
include Guillain-Barr syndrome and certain neuromus- with age, traction on these venous structures increases and
cular blocking agents. Catatonia is a semi-awake state seen even minor head trauma in the elderly can lead to a subdural
most frequently as a manifestation of psychotic disorders hematoma. Approximately 33% of patients with an acute
such as schizophrenia. Third-nerve palsies arise from an subdural bleed will experience a lucid interval after the
uncal transtentorial herniation where the anterior medial event, which is followed by obtundation. Subdural bleeding
temporal gyrus herniates into the anterior portion of the is typically slower than epidural bleeding due to their
tentorial opening anterior to the adjacent midbrain. different sources. Small subdural bleeds are asymptomatic
Coma may occur due to compression of the midbrain. and often do not require evacuation. Epidural hematomas,
on the other hand, can arise quickly and typically represent
65. The answer is D. arterial bleeding.They are often caused by a lacerated middle
(Chap. 29) Brief paroxysms of severe, sharp pains in the face meningeal artery from an overlying skull fracture. Rapid
without demonstrable lesions in the jaw, teeth, or sinuses are increase in intracranial pressure from these bleeds can neces-
called tic douloureux, or trigeminal neuralgia.The pain may sitate arterial ligation or emergent craniotomy. Most patients
be brought on by stimuli applied to the face, lips, or tongue with epidural bleeding are unconscious when rst evaluated;
or by certain movements of those structures. Aneurysms, a lucid interval can occasionally be seen.
neurobromas, and meningiomas impinging on the fth
cranial nerve at any point during its course typically present 68. The answer is C.
with trigeminal neuropathy, which will cause sensory loss (Chap. 29) Pain, loss of function (without clear-cut sensory
on the face, weakness of the jaw muscles, or both; neither or motor decits), and a localized autonomic impairment
symptom is demonstrable in this patient. The treatment for are called reex sympathetic dystrophy (also known as
736 Review and Self-Assessment

shoulder-hand syndrome or causalgia). Precipitating events 71. The answer is E.

in this unusual syndrome include myocardial infarction, (Chap. 26) Cerebellar ataxia with a strong family history
shoulder trauma, and limb paralysis. In addition to the suggests one of the autosomal spinocerebellar ataxias
neuropathic-type pain, autonomic dysfunction, possibly (SCA). SCA7 is distinguished from all of the other SCAs
resulting from neuroadrenergic and cholinergic hypersen- by the presence of retinal pigmentary degeneration. The
sitivity, produces localized sweating, changes in blood ow, visual abnormalities rst appear as blue-yellow color
and abnormal hair and nail growth as well as edema or blindness and proceed to frank visual loss with macular
atrophy of the affected limb. Treatment is difcult; how- degeneration. Proliferative retinopathy would be expected
ever, anticonvulsants such as phenytoin and carbamazepine in someone who has poorly controlled diabetes. Lipemia
may be effective, as they are in other conditions in which retinalis is often seen in patients with hypertriglyc-
neuropathic pain is a major problem. eridemia. Papilledema is seen in increased intracranial
pressure, which is not present in SCA.
69. The answer is B.
(Chap. 6) The peak prevalence of migraine headaches 72. The answer is E.
occurs in the fourth to fth decades of life. Many women (Chap. 21) Numerous studies have identied key risk fac-
experience decreased severity and frequency of headaches tors for ischemic stroke. Old age, family history, diabetes,
after menopause, and some individuals cease to have hypertension, tobacco smoking, and cholesterol are all
migraines as they age. Migraine has been demonstrated to risk factors for atherosclerosis and therefore stroke.
be a risk factor for ischemic stroke in both men and Hypertension is the most signicant among these risk
women. In addition, women who have migraine with factors. All cases of hypertension must be controlled in
aura appear to be at greater risk of ischemic stroke if they the setting of stroke prevention. Antiplatelet therapy has
are concurrently taking oral contraceptives.The American been shown to reduce the risk of vascular atherothrom-
College of Gynecology has recommended that women botic events. The overall relative risk reduction of nonfa-
who are >35 years or have focal neurologic symptoms tal stroke is about 2530% across most large clinical trials.
with their migraine attacks should not take oral contra- The true absolute benet is dependent on the individ-
ceptives, but low-dose contraceptive can otherwise be ual patients risk; therefore, patients with a low risk for
taken safely in women with migraine headaches. Any risk stroke (e.g., younger, with minimal cardiovascular risk
factors that are known to increase stroke risk such as factors) may have a relative risk reduction with
hypertension or cigarette smoking also contribute to antiplatelet therapy but a meaningless benet. Numer-
stroke in individuals with migraine. Interestingly, asymp- ous studies have shown the benet of statin therapy in
tomatic women with migraines have been shown to have the reduction of stroke risk even in the absence of hyper-
a greater likelihood of white matter changes on MRI, and cholesterolemia. Although anticoagulation is the treat-
those with aura had a signicant increased risk of subclin- ment of choice for atrial brillation and cardioembolic
ical posterior circulation infarcts. causes of stroke, there is no proven benet in regard to the
prevention of atherothrombotic stroke; therefore, warfarin
70. The answer is A. cannot be recommended.
(Chap. 9) This patient has classic symptoms and history
consistent with Mnires disease. Patients have recurrent 73. The answer is C.
unilateral labyrinthine dysfunction marked by hearing loss (Chap. 18) Head trauma is the most common etiology of a
and tinnitus. The symptoms are very debilitating, and decreased sense of smell in young adults and children. In
patients may be incapacitated by the tinnitus and vertigo. most cases this is permanent, with only 10% of these
The severity and recurrent nature suggest Mnires dis- patients experiencing recovery. In older adults viral infec-
ease and argue against a central process. Mnires disease tions predominate. Parainuenza virus type 3 is the most
responds to diuretic therapy and/or a low-salt diet. In common associated virus. Patients with HIV also frequently
addition, patients should attempt to ambulate in an have a distorted sense of smell, and this is associated with
attempt to induce central compensatory mechanisms. HIV wasting syndrome. Although rare, genetic defects such
Scopolamine transdermal patches and anticholinergic as Kallmann syndrome and albinism are also causes of anos-
medications are useful only for motion sickness. The mia. Inuenza virus is not a cause of anosmia.
Epley procedure attempts to reposition particulate debris
within the semicircular canals such as in benign paroxys- 74. The answer is D.
mal positional vertigo. Glucocorticoids are useful for the (Chap. 20) Phenytoin is a commonly used anticonvulsant.
acute treatment of vertigo but are used only in the acute Its principal use is in patients with tonic-clonic seizures. It
setting and have no role in the long-term treatment of may be given either orally or intravenously.Typical dosing
Mnires disease. Metoclopramide may be used to treat is about 300 to 400 mg/d in adults.The therapeutic range
nausea but has no role in the tinnitus and vertigo of is between 10 and 20 g/mL. Neurologic side effects
Mnires disease. include dizziness, ataxia, diplopia, and confusion. Systemic
 Review and Self-Assessment 737

side effects include gum hyperplasia, hirsutism, facial brainstem, but not in any other part of the brain, may also
coarsening, and osteomalacia. These patients may develop cause episodic generalized weakness. Multiple sclerosis
lymphadenopathy and Stevens-Johnson syndrome. Toxic- may cause episodic generalized weakness. Atherosclerotic
ity may be enhanced by liver disease and competition occlusive carotid disease may cause focal but not general-
with other medications. Phenytoin alters folate metabo- ized weakness.
lism and is teratogenic. Leukopenia is not a typical side
effect and is seen more often with carbamazepine. 78. The answer is C.
(Chap. 1) The patient in this scenario is demonstrating
75. The answer is C. paratonia (uctuating changes in resistance during testing of
(Chap. 43) The muscular dystrophies are hereditary pro- motor tone). Paratonia may be seen in patients who have
gressive diseases. Beckers muscular dystrophy is a less difculty relaxing during the examination or may be evi-
severe form of X-linked recessive muscular dystrophy dence of aberrant frontal lobe pathways, as in some forms
than Duchennes muscular dystrophy. It occurs 10 times of dementia. The patient has increased tone, making mus-
less frequently than DMD.The underlying defect is in the cle injury less likely. Dystonia, as seen in parkinsonism,
same protein, dystrophin, which is part of a large complex manifests as cogwheel rigidity and jerky interruptions of
of sarcolemmal proteins and glycoproteins. Clinically, resistance without the focality that is seen in this scenario.
Beckers muscular dystrophy (BMD) shows a similar pat- Motor neuron diseases, such as amyotrophic lateral sclero-
tern of proximal muscle weakness. Weakness becomes sis, may present with either accidity or spasticity. Usually
generalized with progression of the disease. Hypertrophy patients with motor neuron disease have abnormalities that
of muscles, particularly the calves, is an early feature. Most can be elicited in more than one muscle group (although
patients experience the initial symptoms in the rst and asymmetry is common).
second decades of life, but a later onset may occur. These
patients have reduced life expectancy but are signicantly 79. The answer is D.
more functional than are patients with DMD. Mental (Chap. 36) Ibuprofen, isoniazid, ciprooxacin, tolmetin,
retardation may also occur in patients with BMD, and car- sulfa-containing medicines, and phenazopyridine have
diac involvement may result in congestive heart failure. been implicated in drug hypersensitivity leading to menin-
Serum creatinine kinase (CK) levels are elevated, and gitis. The cerebrospinal uid (CSF) will typically show
electrodi-agnostic ndings are similar to those seen in neutrophils, but mononuclear cells or eosinophils are occa-
DMD. The diagnosis is made by demonstrating a reduced sionally present. Most causes of chronic (not recurrent)
amount of dystrophin on Western blot analysis. meningitis cause a predominance of mononuclear cells.
The differential for chronic meningitis is broad and a diag-
76. The answer is D. nosis is often difcult to make. The treating physician
(Chap. 7) There are four indications for surgical repair of needs to consider a diverse array of viral, fungal, bacterial,
an intervertebral disk herniation: objective progressive mycobacterial, helminthic, and protozoal pathogens, both
motor weakness, signs of spinal cord compression (e.g., common and exotic, and therefore should obtain a
bowel or bladder incontinence), incapacitating nerve root detailed social history and consult an expert in the eld.
pain despite conservative treatment, and recurrent inca- Recurrent meningitis is often due to herpes simplex virus
pacitating nerve root pain. Absent deep tendon reexes, type 2 infection and this should be ruled out, particularly
nighttime symptoms, and more than one level of disk her- if active genital ulcers develop concurrently. Malignancy,
niation are not uncommon ndings in patients with a sarcoidosis, and vasculitis are all potential causes, and his-
disk herniation and do not mandate surgery. tory, physical examination, and appropriate further testing
should dictate the degree to which these possibilities are
77. The answer is A. explored. Medications are often overlooked as a cause of
(Chap. 10) Episodic generalized weakness is caused by dis- chronic meningitis and should always be carefully consid-
orders of the central nervous system (CNS) or the motor ered.When CSF neutrophils predominate after 3 weeks of
unit. Weakness from CNS disorders is usually associated illness, nocardia, actinomyces, brucella, tuberculosis (<10%
with altered consciousness or cognition, increased muscle of cases), fungal, and noninfectious causes of chronic
tone and reexes, and changes in sensation. Motor unit meningitis should be considered.
disorders include a variety of electrolyte disturbances
(hypokalemia, hyperkalemia, hypercalcemia, hyperna- 80. The answer is E.
tremia, hyponatremia, hypophosphatemia, hypermagne- (Chaps. 15 and 23) All the choices given in the question
semia), inborn errors of metabolism (carbohydrate or fatty are causes of or may be associated with dementia. Bin-
acid metabolism, mitochondrial function), toxins (botu- swangers disease, the cause of which is unknown, often
lism, curare), neuromuscular junction disorders (myasthe- occurs in patients with long-standing hypertension and/or
nia gravis, Lambert-Eaton syndrome), and channelopathies atherosclerosis; it is associated with diffuse subcortical
(periodic paralysis). Transient ischemic attacks of the white matter damage and has a subacute insidious course.
738 Review and Self-Assessment

Alzheimers disease, the most common cause of dementia, bilateral focal neurologic decits. Brain imaging demon-
is also slowly progressive and can be conrmed at autopsy strates multiple areas of stroke.
by the presence of amyloid plaques and neurobrillary
tangles. Creutzfeldt-Jakob disease, a prion disease, is associ- 81. The answer is B.
ated with a rapidly progressive dementia, myoclonus, (Chap. 40) Carpal tunnel syndrome is caused by entrap-
rigidity, a characteristic EEG pattern, and death within ment of the median nerve at the wrist. Symptoms begin
12 years of onset.Vitamin B12 deciency, which often is with paresthesias in the median nerve distribution. With
seen in the setting of chronic alcoholism, most commonly worsening, atrophy and weakness may develop.This condi-
produces a myelopathy that results in loss of vibration and tion is most commonly caused by excessive use of the
joint position sense and brisk deep tendon reexes (dorsal wrist. Rarely, systemic disease may result in carpal tunnel
column and lateral corticospinal tract dysfunction). This syndrome. This may be suspected when bilateral disease is
combination of pathologic abnormalities in the setting of apparent. Tenosynovitis with arthritis as in the case of
vitamin B12 deciency is also called subacute combined rheumatoid arthritis and thickening of the connective tis-
degeneration. Vitamin B12 deciency may also lead to a sue as in the case of amyloid or acromegaly are also causes.
subcortical type of dementia. Multi-infarct dementia, as in Other systemic diseases, such as hypothyroidism and dia-
this case, presents with a history of sudden stepwise betes mellitus, are also possible etiologies. Leukemia is not
declines in function associated with the accumulation of typically associated with carpal tunnel syndrome.
 INDEX

Bold number indicates the start of the main discussion of the topic; numbers with f and t refer to gure and table pages.

AAA. See Abdominal aortic aneurysm Acute angle-closure glaucoma, 178 AIDS dementia. See HIV infection, dementia in
AAN. See Autoimmune autonomic neuropathy tonometry for, 720, 734 AIF. See Apoptosis-inducing factor
ABC family. See ATP-binding cassette family Acute autonomic syndromes, 374 AION. See Anterior ischemic optic neuropathy
Abdominal aortic aneurysm (AAA), 72, 79 Acute bilateral labyrinthine dysfunction, 98 Akathisia, 344, 675
Abdominal reexes, assessment of, 8 Acute disseminated encephalomyelitis (ADEM), 449 Akinetic mutism, 130131
Abducens nerve clinical manifestations of, 450 V-akt murine thymoma viral oncogene homologue
diplopia in disorders of, 190 diagnosis of, 450 (AKT1), 655, 656t
examination of, 6 features of, 449 AKT1. See V-akt murine thymoma viral oncogene
palsy, 533 neuroimaging for, 643f homologue
Abducens palsy, 190 treatment of, 450 Albendazole, 479
Abscess, 127 Acute infectious myelitis, 394 ALBP. See Acute low back pain
Absence seizures, 224 Acute inammatory demyelinating polyneuropathy Alcohol. See also Ethanol
atypical, 224225 (AIDP), 551552, 551t absorption of, 686687
Abstract thought, 6 Acute intoxication, 693 abuse of, 690
Abulia, 131 Acute low back pain (ALBP), 7374 behavioral effects of, 687688
ACA. See Anterior cerebral artery back pain treatment for, 8081, 81f blood level of, 687, 687t
Acalculia, 145 epidural glucocorticoids for, 80 cancer and, 689
Acamprosate, 694695 NSAIDS for, 80 cardiovascular system and, 689690
Acanthamoeba, 468469, 487t, 504 Acute motor axonal neuropathy (AMAN), 551 consumption of, 686
Acanthocytes, 341 Acute motor sensory axonal neuropathy (AMSAN), delirium from withdrawal from, 126
ACAS. See Asymptomatic Carotid Atherosclerosis 551 dependence on, 687688, 690
Study Acute MS, 449 gastrointestinal system and, 689
Accessory nerve examination, 716717, Acute otitis media (AOM), 202 hematopoietic system and, 689
730731 Acute quadriplegic myopathy, 292 insomnia and, 162
ACE. See Angiotensin-converting enzyme Acute spinal cord disease, 388394 metabolism of, 687f
Acephalgic migraine, 247 Acute stress disorder, 669 nervous system and, 688689
Acetaminophen, 80 Acute subdural hematoma, 403, 403f organ systems, effects of, 688690
adverse effects of, 44 Acute transverse myelitis, 642f peripheral neuropathy and, 688
for pain, 4446, 45t Acute transverse myelopathy (ATM), 392 sexual dysfunction and, 690
Acetazolamide, 120, 351t evaluation of, 392t sleep impacted by, 688
for ataxia, 354 Acute unilateral labyrinthine dysfunction, 97 tolerance and, 687688, 687t
for headache, 66 Acutely appearing masses, 132 withdrawal syndrome, 692
for insomnia, 161 Acyclovir, 470, 541, 652 Alcohol dehydrogenase (ALDH), 687, 687f
for papilledema, 182 Addisons disease, 164 Alcohol Use Disorder Screening Test (AUDIT),
Acetylcholine (ACh) ADEM. See Acute disseminated encephalomyelitis 691, 692t
Alzheimers disease and, 307 Adenine nucleotide translocator 1 (ANT1), 588 Alcoholic myopathy, 690
clinical aspects of, 214t Adenoma. See Pituitary tumors Alcoholic neuropathy, 373
delirium and deciency of, 124 ADH. See Antidiuretic hormone Alcohol-induced psychotic disorder, 689
MG and, 716, 729730 Adies syndrome,172173, 370 Alcoholics Anonymous, 694
role of, 366 Adjustment insomnia, 161 Alcoholism, 302, 690
synthesis of, 559, 560f ADNFLE. See Autosomal dominant nocturnal frontal anxiety and, 694
Acetylcholine receptors (AChRs) lobe epilepsy for benzodiazepine, 693694
antibodies to, 561 Adolescence, epilepsy in, 229 chronic, 161
deciency of, 562, 562t ADPEAF. See Autosomal dominant partial epilepsy dementia and, 315316
in MG, 559560 with auditory features denitions of, 690
Acetylcholinesterase (AChE), 559 Adrenal disorders, 593 disulram for, 695
deciency of, 562, 562t Adrenocorticotropin hormone (ACTH), 423 epidemiology of, 690691
MG, test for, 561 efciency tests for, 427t genetics of, 691
MG treatment with medications of, 564 reserve, 426 identication of, 691, 692t
Acetylsalicylic acid, for pain, 45t Adrenomyeloneuropathy, 397 intervention for, 691692
ACh. See Acetylcholine Adult Tay-Sachs disease, 363 brief, 692
ACHE. See American Council for Headache Adults motivational interviewing for, 692
Education epilepsy for young, 229 natural history of, 691
AChE. See Acetylcholinesterase seizures in older, 230 psychiatric disorders from, 688689
Achilles reex, 8 Advanced sleep phase disorder (ASPD), 168169 treatment for, 693695
Achromatopsia, 150 Aerophobia, 469 acute intoxication in, 693
AChRs. See Acetylcholine receptors Ageusia rehabilitation in, 694695
Acid maltase deciency, 585586 partial, 196 relapse prevention in, 694
Acoustic neuromas, 380 specic, 196 withdrawal in, 693694
dizziness/vertigo from, 712, 726 total, 196 withdrawal and, 692
Acoustic reex, 205 Agitated depression, 676 ALDH. See Alcohol dehydrogenase
decay, 205 Agnosia, 193 Alien hand, 313, 336
Acquired hypopituitarism, 425 spatial, 264 Allergic conjunctivitis, 175
Acquired vascular lesions, 281 Agoraphobia, 663, 668 Allergic reactions to contrast media,
Acromegaly, 428t diagnostic criteria for, 663t 15, 15t
familial, 429 Agraphesthesia, 120 Allodynia, 117
screening test for, 432t Agraphia, 142 Allopurinol, 566
Acrylamide, 535 pure alexia without, 142t, 144145 Allyl chloride, 536t
Acrylamide monomer, 536t AIDP. See Acute inammatory demyelinating Alphaviruses, 466
ACST. See Asymptomatic Carotid Surgery Trial polyneuropathy Alport syndrome, 201
ACTH. See Adrenocorticotropin hormone AIDS, 290, 347. See also HIV infection Alprazolam, 667t, 668
Actinin, 585 classication of, 493, 494t ALS. See Amyotrophic lateral sclerosis
Actinomyces, 486t PML from, 474 Alternative splicing, 211
Action dystonia, 338 primary CNS lymphoma and, 414 Altitude insomnia, 161

739
 740 Index

Alzheimers disease, 146, 305 Anaplasma phagocytophilum, 458 Antiepileptic drugs

ACh reduction in, 307 Anaplastic astrocytomas, 411 alternative, 237t
age and, 305, 307 Anaplastic oligodendroglioma, 413 discontinuing, 241
apo gene and, 308309 Andersen-Tawil syndrome, 592 dosage/adverse effects of common,
Capgras syndrome and, 305 Aneurysm, 12t. See also specic types 238t239t
caregiver burnout in, 309, 319 Angiography, 22. See also Computed tomography; epilepsy and, 232
cholinesterase inhibitors treating, 319 Magnetic resonance angiography epilepsy/seizure treatment for, 236241
clinical manifestations of, 305306 CNS vasculitis and, 636f rst-line, 237t
clinical presentation of, 302t complications with, 23 monitoring of therapy with, 240241
depression from, 310 contrast media and, 23 for partial seizures, 239240
differential diagnosis of, 306, 306f morbidity and, 2223 refractory epilepsy treated with, 241
epidemiology of, 306307 spinal, 23 risks of, 237
functional anatomy of, 298299 Angiostrongylus, 488t seizures and, 232
genetic considerations for, 307309, 655 Angiotensin-converting enzyme (ACE), 393 selection of, 237, 237t, 239
genetic mutations in, 219 Ankylosing spondylitis, back pain/neck pain in, 77, 84 for generalized seizures, 240
ginkgo biloba for, 309 Anomia, 141 for partial seizures, 239240
MCI leading to, 305 Anomic aphasia, 142t, 144 therapy initiation with, 237
MMSE for, 303, 303t Anosmia, 193, 402 Anti-glycolipid antibodies, GBS and, 553, 553t
molecular basis for, 301t Anosognosia, 148, 247, 305 Antihistamines, 160
pathology of, 307 ANS. See Autonomic nervous system Anti-Hu paraneoplastic neuropathy, 558
presenilins in, 308 ANS dysfunction Anti-jo-1, 600
selegiline for, 309 AAN and, 373 Antineuronal antibodies, 516, 518t
smell and, 195 acute, 374375 Antiplatelet agents, 260262
treatment of, 309310 alcoholic neuropathy and, 373 Antipsychotic agents
AMAN. See Acute motor axonal neuropathy amyloidosis and, 372 for schizophrenia, 682684
Amantadine, 322323, 329, 331, 342, 448 approach to, 369371 TD from, 683
Amaurosis fugax, 178180, 179f botulism and, 373 types of, 682t
causes of, 260 causalgia and, 375 Antiretroviral drugs, toxic neuropathy from, 540
Ambient warming, 370 classication of, 366367, 368t Antisense oligonucleotides (ASOs), 363
AmBisome, 473 clinical evaluation of, 366371 Antithrombotic treatment
American Council for Headache Education (ACHE), CRPS and, 375 anticoagulation in, 251
5556 diabetes mellitus and, 372 for ischemic stroke, 250251
Amifostine, 538 gastrointestinal, 369 platelet inhibition in, 250251
D-Amino oxidase activator (DAOA), 655, 656t GBS and, 373 Antons syndrome, 268
-Aminobutyric acid (GABA), 214t inherited, 374 Anxiety. See also Psychophysiologic insomnia
Aminoglycosides, adverse effects of, 4 MSA and, 371372 alcoholism and, 694
Amiodarone, 535 neuromuscular junction disorders and, 372 disorders, 161, 663. See also specic types
toxicity of, 537t PAF and, 373 from Parkinsons disease, 322
Amitriptyline, 60t, 529 peripheral neuropathies and, 372 lorazepam for, 33
autonomic storm from, 374 porphyria and, 373 syncope v., 91
for depression, 448 POTS and, 373374 Anxiolytics, 667t
for pain control, 45t primary hyperhidrosis and, 374 AOM. See Acute otitis media
Amnesia, 150 with spinal cord involvement, 368t, 372 Aphasia. See also Primary progressive aphasia
anterograde, 151 symptoms of, 367, 369 anomic, 142t, 144
with concussion, 400401 syndromes of, 371375 Brocas, 142t, 143
hysterical posttraumatic, 401 testing for, 370371, 370t clinical features of, 142, 142t
psychogenic, 318 heart rate variation with deep breathing in, 370 conduction, 142t, 144
retrograde, 151 pharmacologic, 371 crossed, 141
transient global, 151152 sudomotor function in, 371 diagnosing, 141
characteristics of, 317 valsalva response in, 371 uent transcortical, 142t, 144
Amnesic state, 150151 ANT1. See Adenine nucleotide translocator 1 global, 142t, 143144
Amoxapine, 665t Anterior cerebral artery (ACA), 252 hemorrhage and, 277
risks of, 675 occlusion of, 265 isolation, 142t, 144
Amphotericin, 473 stroke in, 265 nonuent transcortical, 142t, 144
AMSAN. See Acute motor sensory axonal Anterior choroidal artery, 265266 progressive, 146
neuropathy Anterior cord syndrome, 392 pure word deafness and, 142t, 144
Amygdalohippocampectomy, 712, 725726 Anterior ischemic optic neuropathy (AION), 180, 180f subcortical, 146
Amyloid angiopathy, 307 Anterior spinal artery syndrome, 388, 392 Wernickes, 142143, 142t, 154
cerebral, of aging, 310 Anterior uveitis, 177 Aphemia, 143
Amyloid precursor protein (APP), 307, 600 Anterograde amnesia, 151 Apnea testing, 138
cleavage of, 307308, 308f Anterolateral system, 117118 Apo gene, 308309
Amyloidosis, 372 Antiarrhythmic drugs, 48 Apomorphine, subcutaneous injectable, 329
Amyotrophic lateral sclerosis (ALS), 215, 303, 358 Antibiotics, 483. See also specic drugs Aponeurotic ptosis, 188
clinical manifestations of, 359360 for spinal epidural abscess, 391 Apoptosis, 217, 283284
differential diagnosis for, 362 Anticholinergics, 100t, 331 cell death and, 218219
epidemiology of, 360361 delirium and, 124 mitochondria controlling pathways of, 219
familial, 361362 intoxication of, 134 Apoptosis-inducing factor (AIF), 219
FTD and, 360 overdose of, 139 APP. See Amyloid precursor protein
genetic, 361t side effects of, 165 Apraxia, 305
glucose metabolism in, 359 for sleep, 448 buccofacial, 145
Guam complex of, 317318 Anticoagulation therapy, 262, 278 construction, 150
MRI of, 360f Anticonvulsant medication, 479 denition of, 102
mutations in, 219 discontinuation after EEG, 26 dressing, 150
neurodegeneration and, 362 for migraine treatment, 60t ideational, 145
pathogenesis for, 362 neuropathic pain and, 48 ideomotor, 145
pathology of, 358359 Antidepressants, 658. See also Tricyclic antidepressants; limb, 145
treatment for, 362363 specic types limb-kinetic, 145
weakness from, 360 actions of, 660f oculomotor, 149
Amyotrophic Lateral Sclerosis Association, 364 for panic disorder, 664, 665t optic, 149
Amyotrophy, 358 management of side effects in, 666t Aprosodia, 146
Analgesia rational selection of, 674 Aqueous penicillin, 473
denition of, 117 Antidiuretic hormone (ADH), 424 Arachnoid cysts, 430
for LP, 33 inappropriate secretion of, 465 Arbovirus infections, 463
 Index 741

ARCO. See Autosomal recessive cardiomyopathy and Ataxic hemiparesis, 257 Back pain. See also Spine
ophthalmoplegia Atherosclerotic disease, 14f AAA and, 72, 79
Aripiprazole, 682t, 683 Atherothrombosis, 270 acute low, 7374
ARSACS. See Autosomal recessive spastic ataxia Atherothrombotic stroke, warfarin for, epidural glucocorticoids for, 80
of Charlevoix-Saguenay 721, 736 NSAIDS for, 80
Arsenic, 535, 536t, 538 Athetosis, 338t in ankylosing spondylitis, 77, 84
Arterial TOS, 84 Ativan, 667t approach to, 7274
Arteriovenous malformation (AVM) Atlastin, 364 in arthritis, 77
asymptomatic, 280 ATM. See Acute transverse myelopathy causes of, 7480, 74t
headache and, 280 Atonic seizures, 225 CES and, 76
imaging in, 12t Atopic conjunctivitis, 176 chronic low, 79
MRI of, 395f ATP-binding cassette family (ABC family), NSAIDS for, 82
symptoms of, 394395 397 risk factors for, 8182
typical presentation of, 394 Atraumatic needle, 35, 36f costs of, 70
vascular anomalies and, 280281 Atrial brillation CPGs for, 80, 81f
Artery of Adamkiewicz, 392 cardioembolic stroke and, 253, 254t, 718, CT scanning for, 73
Artery-to-artery embolic stroke 732 CT-myelography for, 7374
carotid atherosclerosis producing, 254 stroke risk and, 719, 733 EMG determining weakness for, 7374, 73t
causes of, 256 Attention, 152 in gynecologic disease, 79
formation of, 254 prefrontal network and, 152153 imaging in, 12t
Arthritis, 77 Audiogram, 204205 in inammatory bowel disease, 79
rheumatoid, 84 Audiometry local, 72
Arthrogryposis, 579 pure tone, 204 in lumbar adhesive arachnoiditis, 78
Ascending paresthesias, 2 speech, 205 lumbar disk disease and, 7576
Asendin, 665t AUDIT. See Alcohol Use Disorder Screening Test metabolic causes of, 78
Aseptic meningitis, 500, 500t Aura, 223 MRI for, 7374
Ashkenazi Jewish families, dystonia and, 338 Autoimmune autonomic neuropathy (AAN), 373 muscle spasm associated with, 72
Asimultanagnosia, 268 Automatisms, 224 neoplasms and, 7778
ASOs. See Antisense oligonucleotides Autonomic dysreexia, 372 from neoplastic spinal cord compression,
ASPD. See Advanced sleep phase disorder Autonomic failure, 375 389
Aspergillus, 178, 487t treatment of, 375376 nerve root injury causing, 7071
invasive sinonasal, MRI for, 626f627f patient education for, 375376 in osteoporosis, 78
MRI for CNS, 625f626f symptomatic, 376 in osteosclerosis, 78
Aspergillus species, 475 Autonomic nervous system (ANS), 366. See also ANS pain referred to, 72, 7879
Aspirin. See also Warfarin-Aspirin Symptomatic dysfunction postural, 79
Intracranial Disease BP regulation by, 366 in psychiatric disease, 79
adverse effects of, 44 functional consequences of normal activation of, radicular, 72
for pain, 4446, 45t 267t SLR for, 718, 732
recommendations for, 253, 254t inherited disorders of, 374 spina bida occulta and, 75
stroke prevention with, 260261 regulation of, 366 in spinal epidural abscess, 78, 390391
Association cortex, 140 schematic representation of, 367f spinal stenosis and, 7677, 77f
Astasia-abasia, 112 testing for, 370371, 370t of spine origin, 72
Asterixis, 134 heart rate variation with deep breathing in, from spondylolysis, 7475
Asthma, 162 370 in sprains/strains, 75
Astigmatism, 171 pharmacologic, 371 statistics of, 70
Astrocytic gliosis, 512 sudomotor function in, 371 tethered cord syndrome and, 75
Astrocytomas, 390, 411. See also Intramedullary valsalva response in, 371 traumatic vertebral fractures and, 75
astrocytoma Autonomic neuropathies, 368t, 546 treatment for, 8082
anaplastic, 411 Autonomic storm ALBP and, 8081, 81f
grading system for, 411 amitriptyline causing, 374 CLBP and, 8182
high-grade, 412413 from GBS, 375 types of, 72, 72t
glucocorticoids managing, 412 management of, 375 with unidentied cause, 7980
juvenile pilocytic, 411 Autoreactive T lymphocytes, 437 in urologic disease, 79
low-grade, 411412 Autoregulation, of CBF, 284, 284f in vertebral osteomyelitis, 78
malignant, 411f Autosomal dominant nocturnal frontal lobe epilepsy Baclofen, 339, 342, 522
model for pathogenesis of, 411f (ADNFLE), 227t Bacterial endocarditis, 254
oligodendrogliomas compared to, 413 Autosomal dominant partial epilepsy with auditory Bacterial meningitis. See Meningitis, bacterial
subependymal giant cell, 411, 417 features (ADPEAF), 227t BAEPs. See Brainstem auditory evoked
Asymptomatic Carotid Atherosclerosis Study (ACAS), Autosomal recessive ataxia, 354356 potentials
255 Autosomal recessive cardiomyopathy and BAERs. See Brainstem auditory evoked
Asymptomatic Carotid Surgery Trial (ACST), 255 ophthalmoplegia (ARCO), 588 responses
Ataxia. See also Spinocerebellar ataxia; specic ataxia Autosomal recessive spastic ataxia of Charlevoix- BAL. See British anti-Lewisite
acetazolamide for, 354 Saguenay (ARSACS), 351t Balamuthia, 469
autosomal recessive, 354356 AVM. See Arteriovenous malformation Balance disorders. See also Falls; Gait disorders
diagnosing, 347t Avonex, 447 age and, 109
episodic, 351t, 354 Awake coma, 130 characteristics of, 113
focal, 347 Axonal shearing lesions, 401 Parkinsons disease and, 321
gait and limb, 510 Axonotmesis, 548 vestibular system and, 113
symptoms of, 711, 725 Axons Blints syndrome, 148150, 191
inherited, 348 of corticospinal system, 104f causes of, 268
mitochondrial, 356 functional categories of, 41f Balloon angioplasty, 255256
MS and, 438439, 448 glaucoma destroying, 175 Balos concentric sclerosis, 644f654f
symmetric, 346347 nerve conduction in myelinated/demyelinated, Baltic myoclonus, 350t
symptoms/signs of, 346 436, 436f Barbiturates, 64, 535
treatment for, 356 primary afferent, 40, 41f for epilepsy, 240
with vitamin E deciency, 355 of pyramidal system, 104f overdoses of, 135
Ataxia telangiectasia, 352t spinothalamic tract, 43, 43f for sleep, 157
genetic considerations for, 356 Azathioprine, 447, 556, 607 Bartonella, 468
symptoms/signs of, 356 for MG, 565566 Basal ganglia
Ataxic disorders Azithromycin, 460, 504 infarction, 14f
approach to, 346347 Parkinsons disease and, 320
diagnosing, 347t Babinski signs, 386 Basal meningitis, 484
treatment for, 356 Back, physical examination of, 7273 Basic broblast growth factor (bFGF), 429
 742 Index

Basilar artery Blood pressure (BP) Brain tumor (Cont.):

migraine, 91 ANS regulating, 366 metastatic, 186, 379, 418
occlusion of, 272 OH, recordings of, 371 chemotherapy for, 419
stroke and, 268272 OH and drop in, 370 from known cancer, 418, 419f
syndrome, 269f OH from impaired, 366 without known primary tumor, 418419
TIA and, 270271 syncope and, 369 mechanisms of, 418, 418t
Basilar occlusion, impending, 271 Blood volume disorders, 8890, 88t treatment of, 419
Baylisascaris procyonis, 469, 488, 488t Blood-brain barrier (BBB), 282 neuroimaging for, 409
BBB. See Blood-brain barrier defects in, 13 seizures from, 408
BDNF. See Brain-derived neurotrophic factor MS disrupting, 435 syndromes of, 408
Beck Depression Inventory, 47 Blood-oxygen-level-dependent (BOLD), 220 treatment for, 409410
Becker muscular dystrophy, 575t, 577, 722, Bloody tap, LP and, 35 Brain-derived neurotrophic factor (BDNF), 215
736737 BOAA. See -N-oxalylaminoalanine Brainstem
clinical features of, 577578 BOLD. See Blood-oxygen-level-dependent accessory optic system, 171
laboratory features of, 578 Bone spicules, 185, 186f bilateral signs in, 271
treatment of, 578 Borrelia burgdorferi, 380, 394, 540 coma, examination of, 134, 135f
Bedwetting, 166 Bortezomib, 538 encephalomyelitis, 519
Beevors sign, 387 Botulinum toxin, 64, 340, 381382 migraine, pathways in, 53f
Behavior, 152 adverse effects of, 373 sensation, 121
prefrontal network and, 152153 pain from injection of, 374 Brainstem auditory evoked potentials (BAEPs), 27
Behavioral tolerance, 688 placebo trials for, 61 Brainstem auditory evoked responses (BAERs),
Behets syndrome, 485, 489t, 490 Botulism, 189 205206
MRI for, 627f ANS dysfunction and, 373 Breast-feeding, 245
Bells palsy, 380 MG and, 563 Brief intervention, for alcoholism, 692
clinical manifestations of, 380 Bouillon treatment, 376 British anti-Lewisite (BAL), 538
differential diagnosis of, 380381 Bound morphemes, 143 Brocas aphasia, 142t, 143
laboratory evaluation of, 381 Bournevilles disease, 417 Brocas area, 141
neuroimaging for, 641f Bovine spongiform encephalopathy (BSE), Bromocriptine, 328t
pathophysiology of, 380 508 Brown-Sequard hemicord syndrome, 388
treatment of, 381 vCJD caused by, 512 Brucella, 463, 485, 486t
Bells phenomenon, 380 Bowel incontinence, 439 Brudzinskis sign, 453
Bells reex, 335 BP. See Blood pressure Bruxism, 166
Benedikts syndrome, 189 BPPV. See Benign paroxysmal positional vertigo BSE. See Bovine spongiform encephalopathy
Benign familial neonatal convulsions (BFNC), Brachial neuritis, neck pain in, 85 Bubble-contrast echocardiography, 254
227t Brachial plexopathy, 546, 547f Buccofacial apraxia, 145
Benign forgetfulness of elderly, 299 lesions of, 547t Bulbospinal upper motor neuron pathways, 104f
Benign paroxysmal positional vertigo (BPPV), MRI for, 647f648f Bunyaviruses, 466
98, 98t Brachial plexus injury, 523 Buprenorphine, 700
Benzodiazepine, 126, 128, 699 neck pain in, 85 Bupropion, 665t
adverse effects of, 668 Bradyarrhythmia, syncope in, 90 side effects of, 675
for alcoholism, 693694 Bradykinesia, 102 BuSpar, 667t
for GAD, 666, 668 Bradykinin, 41 Buspirone, 345, 667t
for panic disorder, 664, 667t Brain abscess, 475. See also Epidural abscess for GAD, 668
withdrawal from, 668 clinical presentation of, 476 Butorphanol, 58
Beta blockers denition of, 475 for pain control, 45t
for migraine treatment, 60t diagnosis of, 476477, 477f
for phobic disorders, 669 differential diagnosis of, 477 Cabergoline, 328t
Betaseron, 447 epidemiology of, 475 CABG. See Coronary artery bypass grafting
Bextra, adverse effects of, 46 etiology of, 475476 Cachectic myopathy, 292
bFGF. See Basic broblast growth factor headache from, 476 CADASIL, 259, 311, 318
BFNC. See Benign familial neonatal convulsions hematogenous, 475476 MRI for, 634f635f
Biceps weakness, 712, 726 histopathology of, 476 Coenorhabditis elegans, 308
Bilateral brainstem signs, 271 MRI for, 476477, 477f Caf au lait spots, 417
Bilateral facial palsy, 108 pathogenesis of, 476 Caffeine, 162
Bilateral simultaneous stimulation, prognosis of, 478 wakefulness from, 168
120 treatment of, 477478 Calcinosis, 607
Binocular diplopia, 188 Brain biopsy Calcitonin gene-related peptide (CGRP), 53
Binswangers disease, 298299, 310311, stereotactic, 713, 726727 Calcium channel disorders of muscle, 589590,
311f in viral encephalitis, 468 591f
Bipolar disorder, 658f Brain death Calcium disturbances, 613614
clinical manifestations of, 676677 clinical evidence of, 138 Calculation ability, assessment of, 6
differential diagnosis of, 677 comas and, 138 Calf muscle hypertrophy, 576t, 579, 595
etiology/pathophysiology of, 677 diagnosis of, 717, 731 Calpain, 595
lithium and, 658, 677678 EEG and, 27 CAM. See Confusion Assessment Method
treatment of, 677678 Brain edema, 282 Campral, 694695
Bitemporal meningioma, 175 Brain germ-cell tumors, 430 Campylobacter jejuni, 551
Blackout, 688 Brain hemorrhages GBS and, 552553, 552f
Bladder areexia, 398 causes of, 401 Canal paresis, 100
Bladder dysfunction, 370, 372 CT scan of, 402f Cancer. See also Paraneoplastic neurologic syndromes;
causes of, 398 Brain injury. See also Secondary brain insults specic cancers
MS and, 439, 448 post-cardiac bypass, 611612 alcohol and, 689
Blastomyces dermatitidis, 487t post-solid organ transplant, 612 depression from, 671
Blepharitis, 175 Brain tumor. See also Metastatic brain tumors; Primary metastatic brain tumor from known, 418, 419f
Blepharoptosis, 187188 brain tumor systemic, 421
Blepharospasm, 277, 382 approach to, 408409 Cancer-associated retinopathy, 524
Blepharospasm dystonia, 339 benign, 416417 Candida, 178, 198, 487t
Blindness clinical features of, 408409 albicans, 650
color, 173 of CNS, 408 MRI for newborn, 624f
cortical, 268 headache and, 52 Candida species, 475
dening legal, 172 hemorrhage into, 278 Cannabis, 704
form herpes simplex, 177 hereditary syndromes associated with, 410t Capgras syndrome, 302
transient monocular, 178179 Karnofsky performance scale for, 409t Alzheimers disease and, 305
Blink reexes, 32 laboratory examination for, 409 Capillary telangiectasias, 280281
 Index 743

CAPRIE, 261 Cellular injury, 282284 Cerebrospinal uid (CSF) (Cont.):

Capsaicin creams, 529 Cellular tolerance, 688 dementia, levels of, 305
CARASIL, 259 Cellulitis, 127 HIV infection, analysis of, 497
Carbamazepine, 48, 378, 529 Central cord syndrome, 388 LP, leak of, 6566
dosage/adverse effects of, 238t Central core disease, 584 LP, normal values of, 36, 36t
for facial pain, 717, 732 Central fever, 134 LP and collection of, 3435
for glossopharyngeal neuralgia, 94 Central nervous system (CNS). See also Severe CNS MS and, 442
for mania, 678 dysfunction NPH and absorption of, 315
for pain control, 45t aspergillus, MRI for, 625f626f pathophysiology of, 284, 284f
for partial seizures, 239240 brain tumor of, 408 pleocytosis of, 442, 466
Carbidopa, 328t, 330 consultations regarding dysfunction of, PMNs in, 36
Carbon dioxide inhalation, 664 609612 post-LP headache and pressure drop in, 35
Carbon disulphide, 536t critical care disorders of, 287291 secondary NDPH with low volume, 6566
Carbon monoxide intoxication, 288 detecting abnormalities in, 5 secondary NDPH with raised pressure of, 66
treatment for, 289 disease, 100 skull fractures and leakage of, 402
Carcinomatous meningitis, 420f illness identied in, 2 viral encephalitis, culture from, 467
Cardiac cephalgia, 68 infections of, 316. See also Brain abscess; Encephalitis, viral encephalitis, examination of, 466
Cardiac ischemia, 162 chronic; Encephalitis, viral; Epidural viral encephalitis and PCR, 466467
Cardiac syncope, 9091 abscess; Meningitis, bacterial; Meningitis, suba- viral meningitis, examination of, 462
Cardioembolic stroke cute; Meningitis, viral; Subdural empyema; WBCs in, 455
atrial brillation and, 253, 254t, 718, 732 Thrombophlebitis, suppurative Cerebrovascular accidents (CVAs), 142
causes of, 252, 253t approach to, 452454, 452f453f at thalamus, 712, 726
Cardiovascular disease, 2 focal supportive, 458 Cerebrovascular disease
Cardiovascular system, alcohol and, 689690 LP for, 453454 approach to, 247, 247f
Caregiver burnout management of, 451 comas and, 138
Alzheimers disease and, 309, 319 nonbacterial causes of, 478479 syncope in, 91
FTD and, 313 isolated vasculitis of, 317 types of, 246
Carmustine, 412 MTDNA skeletal muscle syndromes of, 588589 Cervical cord, 386
Carney syndrome, 429 neoplasms of, 316 Cervical disk disease, neck pain in, 83
Carnitine palmitoyltransferase deciency, neurologic disorders in critical illness at, 283t Cervical dystonia, 339
586587 PNDs of, 517, 519 Cervical radiculopathy, 83t
Carotid artery toxoplasmosis, MRI of, 504, 504f Cervical spine trauma, neck pain in, 8283,
common, 267 tuberculosis, MRI for, 618f619f 83t
internal, 266267 vasculitis of Cervical spondylosis, 12t
Carotid atherosclerosis angiography for, 636f neck pain in, 83, 84f
artery-to-artery embolic stroke from, 254 CT/MRI for, 635f CES. See Cauda equina syndrome
risk factors for, 254, 255t Central pontine myelinolysis, 290, 290f CFS. See Chronic fatigue syndrome
treatment for, 254256 Central serous chorioretinopathy, 185 CGRP. See Calcitonin gene-related peptide
EC-IC bypass surgery in, 256 Central sleep apnea, 165 Chagas disease, 505
endovascular therapy in, 255256 Central transtentorial herniation, 131f, 132 Chalazion, 175
surgical therapy in, 254255 Central vertigo, 98, 98t99t, 714, 728 Channelopathies, 211, 212t, 589, 590t
Carotid cavernous stulas, 187 Centronuclear myopathy, 585 Charcot-Marie-Tooth disease, 528, 541
Carotid disease, 262 Cephalosporin, 477, 481482 autosomal recessive forms of, 544
Carotid sinus hypersensitivity, syncope in, 89, 92 Cerebellar artery, occlusion of, 271272 classication of, 541542
Carotid stenosis, 179, 263 Cerebellar degeneration clinical features of, 541
bilateral, 91 PND and, 521 CMT1, 541542, 542t
imaging in, 12t treatment for, 521 CMT1A, 542
treatment for, 255256 Cerebellar gait ataxia, 111, 112t CMT1B, 542543
Carpal tunnel syndrome, 531t Cerebellar hemorrhage, 277 CMT1X, 543
causes of, 722, 738 Cerebral abscess, fever and, 18f CMT2, 541542, 542t
CAST. See Chinese Acute Stroke Trial Cerebral amyloid angiopathy, 278 CMT2A to CMT2D, 543544
Catamenial epilepsy, 244 Cerebral amyloid angiopathy of aging, 310 CMT3. See Djerine-Roussy syndrome
Cataract, 184 Cerebral angiography, for stroke, 274275 CMT4, 543
Catatonia, 131 Cerebral artery. See also Middle cerebral artery family history and, 4
Catechol-O-methyltransferase inhibitors (COMT aneurysm of, 13f forms of, 542t
inhibitors), 331 occlusion of, 14f molecular testing for, 544, 544f
CATIE study, 683 Cerebral blood ow (CBF), 284, 284f rare forms of, 544546
Cauda equina syndrome (CES), 76, 387 Cerebral cortex transmission of, 720, 734
paraparesis from, 106 areas of, 140 type 1A, 211
Causalgia, 44 hemispheres of, 141f X-linked, 542543, 542t
ANS dysfunction and, 375 Cerebral dysfunction, higher, 153154 CHARISMA, 261
Cautious gait, 110 Cerebral hemisphere Chemotherapy, 535
Cavernous angiomas, 281 coma from damage to, 133 for CNS lymphoma, 414
Cavernous sinus syndrome, 384, 384f coronal section diagram of, 263f coasting and, 535
CBD. See Cortical basal degeneration lateral aspect diagram of, 264f for metastatic brain tumor, 419
CBF. See Cerebral blood ow medial aspect diagram of, 265f toxicities of, 422
CCK-4. See Cholecystokinin tetrapeptide Cerebral herniation Cheyne-Stokes respiration, 136
CD4 molecule, 494, 496f central transtentorial, 131f, 132 Chiari malformation, 52, 67, 347, 396
CDH. See Chronic daily headache coma from, 131132 syringomyelia and, 713, 727
CDR. See Clinical Dementia Rating foraminal transtentorial, 131f, 132 Chiari tonsillar herniation, 396
Cefepime, 460 transfalcial, 131f, 132 Chiasmal tumors, 186
Cefotaxime, 477, 481 transtentorial, 132 Childhood, epilepsy and, 229
Ceftazidime, 460, 477, 482 types of, 131f Chinese Acute Stroke Trial (CAST),
Ceftriaxone, 477, 481 uncal transtentorial, 131f, 132 250251
Celebrex, 46 Cerebral ischemia, 246 Chlamydia pneumoniae, 436
Celecoxib major steps in cascade of, 248, 248f Chlorambucil, 230, 523, 557
adverse effects of, 46 Cerebral mass lesions, 131132 Chloramphenicol, 536t
for pain control, 45t Cerebral perfusion, 284 Chlordiazepoxide, 667t, 668, 693
Cell death, 217 Cerebral perfusion pressure (CPP), 284 Chloride channel disorders, 592
apoptosis and, 218219 Cerebritis. See Brain abscess Chloroquine, 535
dopamine, Parkinsons disease and, 323, 324f Cerebrospinal uid (CSF) Cholecystokinin tetrapeptide (CCK-4), 664
excitotoxicity and, 217218 bacterial meningitis, analysis of, 455458, 455t, 457t Cholesteatoma, 202, 475
mitochondria in, 216f chronic meningitis, analysis of, 490491 Cholinesterase inhibitors, 319
 744 Index

Chorea, 340. See also Hemiballismus; Huntingtons Clonazepam, 529, 667t, 668 Comas (Cont.):
disease; Levodopa-induced dyskinesia dosage/adverse effects of, 239t LP for, 137
hyperthyroidism and, 342 Clonidine, 372 metabolic disorders causing, 132133
movement characteristics of, 338t Clostridium botulinum, 563 MRI for, 136
Sydenhams, 341 Clozapine, 331 neurologic examination for, 134
treatment for, 342 for schizophrenia, 657, 682t, 683 ocular movements in, 135136
in various disorders, 341342 side effects of, 683 physician examination, general, for, 134
Choriocarcinoma, 278, 430 Clumsy hand, 257 physiology of, 131133
Chorioretinopathy, central serous, 185 Cluster headache prognosis for, 139
Chronic alcoholism, 161 acute attack treatment of, 62, 62t pupillary reaction assessment for, 135
dementia and, 315316 clinical features of, 6162, 61t respiratory patterns in, 136
Chronic benign lymphocytic meningitis, 489t diagnosis of, 717, 731732 toxic drug-induced, 133
Chronic childhood SMA, 363 neurostimulation therapy for, 62 treatment for, 138139
Chronic daily headache (CDH) periodicity of, 61 Common carotid artery, 267
classication of, 64t posterior hypothalamic gray matter in, Comorbid insomnia, 161162
diagnosis of, 6364 54, 54f Complex partial status epilepticus, 316
management of medically disabling, 64 preventative treatments of, 62, 62t Complex regional pain syndrome (CRPS), 375
preventive treatments for, 64 sumatriptan for, 62 Comprehension, 142
Chronic drug use, 318 treatment of, 62 Comprehensive stroke centers, 275
Chronic fatigue syndrome (CFS), 164, 604, 650 sumatriptan for, 709, 723 Compressive myelopathy
diagnosis of, 651t, 652 verapamil for, 62 noncompressive compared to, 388389
epidemiology of, 650 CMD. See Congenital muscular dystrophy types of, 389392
manifestations of, 651652, 651t CMV. See Cytomegalovirus Computed tomography (CT), 11. See also Single
pathogenesis of, 650651 CNS. See Central nervous system photon emission computed tomography
prevalence of, 650 CNS lymphoma axial noncontrast, 14f
symptoms of, 651t chemotherapy for, 414 for back pain, 73
treatment of, 652 in HIV infection, 502503, 503f of brain hemorrhages, 402f
Chronic hemiparesis, 105 MRI of, 415f for brain tumor, 409
Chronic inammatory demyelinating polyneuropathy primary, 414, 502 for CNS vasculitis, 635f
(CIDP), 501, 555 AIDS and, 414 for coccidiomycosis meningitis, 623f
clinical manifestations of, 555 secondary, 414415 comas and, 136
diagnosis of, 555556 systemic, 502503 complications of, 13, 15
GBS compared to, 555 CNTF. See Ciliary neurotrophic factor of contusion, 401f
pathogenesis of, 556 Coasting, 535 delirium detected with, 127
treatment for, 556 Coats disease, 582 guidelines for use of, 12t
Chronic lead poisoning, 362, 536t Cobalamin, 538539. See also Vitamin B12 deciency helical, 12
Chronic low back pain (CLBP), 79 Cocaine, 699, 702 for Huntingtons disease, 640f
back pain treatment for, 8182 acute/chronic intoxication of, 703 of hypertensive hemorrhage, 277f
NSAIDS for, 82 crack, 374, 703 indications for, 12t, 13
risk factors for, 8182 drug use/abuse of, 702704 for lacunar infarction, 633f
Chronic meningitis. See Meningitis, chronic prevalence of use of, 702703 MRI compared to, 11, 18, 715, 728
Chronic metal exposure, 317 stroke from, 278 multidetector, 1213
Chronic monoparesis, 107 treatment for use/abuse of, 703704 myelography, 2122
Chronic myelopathy, 394 Coccidioides immitis, 487t low-dose, 21
of MS, 396 Coccidiomycosis meningitis, 623f of oligodendrogliomas, 413f
types of, 394397 Cochlear otosclerosis, 202 radiation exposure from, 13
Chronic pain, 47 Codeine, 696 for stroke, 273, 274f
myofascial, 47 for pain control, 45t of superior sagittal sinus thrombosis, 636f
opioids for, 48 pharmacology of, 696697 techniques in, 1113
treatment of, 4749 Coenzyme Q10, 332 for viral encephalitis, 467468
Chronic paraparesis, 106 Cognitive dysfunction, 439, 448, 688 xenon, 275
Chronic progressive external ophthalmoplegia HIV infection and, 498500 Computed tomography angiography (CTA), 11, 13f14f
(CPEO), 587 Cognitive-behavioral psychotherapy. See also Dialectical stroke and, 273
Chronic quadriparesis, 107 behavior therapy COMT. See Catechol-O-methyltransferase inhibitors
Chronic subdural hematoma, 404 for depression, 660 Concussion, 400
bilateral, 404, 404f for suicide risk, 661 amnesia with, 400401
diagnosis of, 713714, 728 Cogwheeling sensation, 321 mechanics of, 400
Chronic visual loss, 184 Colchicine, 536t postconcussive syndrome and, 408
Chronic wasting disease (CWD), 508 Collapsing falls, 114 in sports, 405406, 405t
Churg-Strauss syndrome, 528 Color blindness, 173 treatment for, 408
Cidofovir, 394, 471, 474, 505 Color vision, 173 Conduction aphasia, 142t, 144
CIDP. See Chronic inammatory demyelinating Comas Conduction block, 30
polyneuropathy acutely appearing masses and, 132 Conduction velocity, 30
Ciliary neurotrophic factor (CNTF), 215 anatomy of, 131133 Conductive hearing loss, 201202
Cingulate cortex, 147 approach to, 133136 Cones, 170, 173
Circadian rhythm, 167 arousal level testing for, 134 Confabulation, 151
medical implications of, 169 awake, 130 Confusion
molecular feedback loop in, 157f brain death and, 138 denition of, 122
physiology of, 157158 brainstem examination for, 134, 135f right-left, 145
sleep disorders, 167169 cerebral hemisphere damage causing, 133 Confusion Assessment Method (CAM), 124, 124t
Circle of Willis, 14f cerebral mass lesions/cerebral herniations causing, Congenital hypomyelination, 542, 542t
Cisplatin, 422, 535 131132 Djerine-Roussy syndrome compared to, 543
composition of, 535, 537 cerebrovascular disease and, 138 Congenital muscular dystrophy (CMD), 575t
peripheral neuropathy and, 537 CT scans and, 136 clinical features of, 579
Citalopram, 675 denition of, 130 laboratory features of, 579
CJD. See Creutzfeldt-Jakob disease differential diagnosis of, 137138, 137t treatment of, 579
Claudes syndrome, 189 EEG and, 2627, 136137 types of, 580t
Claustrophobia, 668 epileptic, 133 Congenital myopathy, 584585
CLBP. See Chronic low back pain eyes and, 135136 Conjunctivitis, 175
Clindamycin, 479 history of patient with, 133134 allergic, 175
Clinical Dementia Rating (CDR), 125 hypotension from, 134 atopic, 176
Clinical practice guidelines (CPGs), 80, 81f laboratory studies/imaging for, 136137 Connexins, 213
Clomipramine, 670 locked-in syndrome and, 131 Conns syndrome, 593
 Index 745

Consciousness, level of, 5 Creutzfeldt-Jakob disease (CJD) (Cont.): Defecation syncope, 89

Constipation, 439, 448 impact of, 507 Deglutition syncope, 89
Construction apraxia, 150 laboratory tests for, 514 Djerine-Roussy syndrome, 121
Contraception, 245 molecular basis for, 301t congenital hypomyelination compared to, 543
Contralateral hemiparesis, 277 MRI for, 514, 514f forms of, 542t
Contrast media myoclonus and, 513 Delayed postanoxic encephalopathy, 289
adverse effects to, 13, 15, 17 neuropathology of, 512 Delayed sleep phase disorder, 168
allergic reactions to, 15, 15t pathogenesis of, 508511 Delirium
angiography and, 23 patient care for, 514 ACh deciency and, 124
gadolinium and, 1617 prevention for, 515 alcohol withdrawal causing, 126
ionic, 13, 15, 15t rapid progression of, 314 anticholinergics and, 124
MRA, 1920 sporadic, 507 approach to, 124125
MRI, 1617, 18f variant, 508, 512 CAM for, 124, 124t
nonionic, 13, 15, 15t BSE causing, 512 clinical features of, 122123
in patient with kidney failure, 15t CRH. See Corticotropin-releasing hormone CT for, 127
Contrast nephropathy, 13, 15 Critical care disorders, 287 denition of, 122
Contrecoup lesion, 401 approach to, 285287 dementias relationship with, 123
Contusion of CNS, 287291 diagnosing, 127128, 128t
causes of, 401 pathophysiology of, 282284 epidemiology of, 123
CT scan of, 401f of PNS, 291292 etiologies of, 126127, 126t
Conus medullaris, 387 neuropathy of, 291292 history with, 125
Convergence-projection hypothesis, of referred pain, Critical illness, sensory neuropathy and, 715, 728 in ICU, 122123
42, 42f Critical i