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Title: Blueprints neurology / Frank W. Drislane.
Other titles: Blueprints.
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 Contents

Preface
Acknowledgments
Abbreviations

PART I BASICS OF NEUROLOGY

1 The Neurologic Examination

2 Neurologic Investigations

PART II COMMON NEUROLOGIC SYMPTOMS

3 The Approach to Coma and Altered Consciousness

4 Neuro-Ophthalmology

5 The Approach to Weakness

6 The Sensory System

7 Dizziness, Vertigo, and Syncope

8 Ataxia and Gait Disorders

9 Urinary and Sexual Dysfunction

10 Headache and Facial Pain

PART III NEUROLOGIC DISORDERS

 11 Aphasia and Other Disorders of Higher Cortical Function

12 Dementia

13 Sleep Disorders

14 Vascular Disease

15 Seizures

16 Movement Disorders

17 Head Trauma

18 Systemic Conditions with Neurologic Manifestations

19 Central Nervous System Tumors

20 Demyelinating Diseases of the Central Nervous System

21 Infections of the Nervous System

22 Disorders of the Spinal Cord

23 Radiculopathy, Plexopathy, and Peripheral Neuropathy

24 Disorders of the Neuromuscular Junction and Skeletal Muscle

25 Pediatric Neurology

Questions
Answers
Appendix: Evidence-Based Resources
Index
 Preface

B lueprints Neurology was first published more than 15 years ago as one
of a series of books designed to help medical students prepare for
USMLE Steps 2 and 3. As the study and practice of Medicine and
Neurology and professional board examinations have evolved over the
years, so too has Blueprints Neurology changed to assist students to learn
Neurology in multiple evaluation and examination settings.
Examination preparation remains at the core of the series. To that end, the
authors review the subject matter of the examination before each edition.
The authors and editors work together to organize the most important,
current, and factually correct material into a complete but concise review
guide. Our goal remains integrating the depth of factual knowledge with the
breadth of practice information in order to optimize both understanding and
retention. We have been pleased to hear from our readers that the book is
utilized by many medical students during their clinical rotations, as well as
in preparation for shelf and board examinations. Residents in Internal
Medicine, Emergency Medicine, and Family Practice, as well as nurse
practitioners and physicians’ associates have found Blueprints helpful
during the Neurology portion of their training. We believe the book’s
applications have broadened with each edition due to the quality of our
authors’ experience and their dedication to highlighting and clarifying a
targeted range of basic but important topics that should be mastered.
Virtually all chapters are authored by experts in the content area,
including neurologists from both academic medicine and busy private
practice groups. They have incorporated suggestions received from medical
students, faculty, clinicians, and program directors with regard to content
and organization. Each chapter covers a single subject area for review; most
can be read in under an hour. “Key Points,” highlighted throughout,
facilitate quick review of the key concepts tested most frequently. Most
chapters have Vignettes with characteristic clinical presentations to test
one’s review of the chapter. The 100 Questions at the end of the book are
also written in the “Clinical Vignette” style used in USMLE and Board
examinations, as recommended by student reviewers of the Blueprints
series.
This fifth edition of Blueprints Neurology is the most thoroughly updated
edition to date, with several new authors (generally closer in stage of
education to the students for whom the book is written). It includes
important updates on areas such as Multiple Sclerosis, Stroke, Epilepsy,
Movement disorders and their genetic bases, Sleep disorders such as
narcolepsy and cataplexy, and new drug and other treatments for each. Each
chapter includes the most recent information and practice principles
available and accepted at the time of publication.
We hope that readers of Blueprints Neurology will come to see the
wonder of the human nervous system, how important it is to individuals in
health and when it fails, and how the study and practice of Neurology is
more helpful to patients than ever before.

Frank W. Drislane, MD
Aimee K. Boegle, MD, PhD
Alexandra Hovaguimian, MD
Courtney McIlduff, MD, MMSc
Andrew W. Tarulli, MD
Louis R. Caplan, MD
 Acknowledgments

W e thank our patients for the opportunity of working with them and
learning Neurology; our colleagues and teachers (and particularly,
upon his retirement, Michael Ronthal, MBBCh) at Beth Israel Deaconess
Medical Center Neurology department for teaching us more fascinating
concepts about the nervous system; and our families for tolerating the many
hours spent writing and revising this book.
 Abbreviations

A(β) amyloid-beta
ABP abductor pollicis brevis
Abs antibodies
AβPP amyloid–beta protein precursor
ACA anterior cerebral artery
ACE angiotensin-converting enzyme
AChR acetylcholine receptor
AD Alzheimer disease
ADEM acute disseminated encephalomyelitis
ADHD attention deficit–hyperactivity disorder
ADM abductor digiti minimi
AICA anteroinferior cerebellar artery
AIDP acute inflammatory demyelinating polyradiculoneuropathy
AIDS acquired immunodeficiency syndrome
AION anterior ischemic optic neuropathy
ALS amyotrophic lateral sclerosis
ANA antinuclear antibody
APP amyloid precursor protein
APS antiphospholipid syndrome
ASD anti-seizure drug
AVM arteriovenous malformation
AZT zidovudine
BMD Becker muscular dystrophy
BPPV benign positional paroxysmal vertigo
CBC complete blood count
GMP cyclic guanosine monophosphate
CIDP chronic inflammatory demyelinating polyradiculoneuropathy
CJD Creutzfeldt-Jakob disease
CK creatine kinase
CMAP compound muscle action potential
CMT Charcot-Marie-Tooth disease
CN cranial nerve
CNS central nervous system
COMT catechol O-methyl transferase
CP cerebral palsy
CPAP continuous positive airway pressure
CSF cerebrospinal fluid
CT computed tomography
DH detrusor hyperreflexia
DI detrusor instability
DLB dementia with Lewy bodies
DM dermatomyositis
DMD Duchenne muscular dystrophy
DSD detrusor sphincter dyssynergia
DTRs deep tendon reflexes
DWI diffusion-weighted imaging
EA episodic ataxia
ED erectile dysfunction
EEG electroencephalogram
EMG electromyography
ER emergency room
ESR erythrocyte sedimentation rate
ET essential tremor
EWN Edinger-Westphal nuclei
FDI first dorsal interosseus
FEV1 forced expiratory volume in 1 second
FLAIR fluid-attenuated inversion recovery
FTA fluorescent treponemal antibody
FTD frontotemporal dementia
FVC forced vital capacity
GAD glutamic acid decarboxylase
GBS Guillain-Barré syndrome
GCS Glasgow Coma Scale
GTC generalized tonic–clonic
HD Huntington’s disease
HIV human immunodeficiency virus
HNPP hereditary neuropathy with liability to pressure palsies
HS Horner’s syndrome
HSAN hereditary sensory and autonomic neuropathy
HSV herpes simplex virus
IBM inclusion body myositis
ICA internal cerebral artery
ICP intracranial pressure
ICU intensive care unit
IIH idiopathic intracranial hypertension
INO internuclear ophthalmoplegia
INR international normalized ratio
IVIg intravenous immunoglobulin
LEMS Lambert-Eaton myasthenic syndrome
LGN lateral geniculate nucleus
LMN lower motor neuron
LND light-near dissociation
LP lumbar puncture
MAG myelin-associated glycoprotein
MCA middle cerebral artery
MELAS mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke
MERRF myoclonic epilepsy with ragged red fibers
MFS Miller Fisher syndrome
MG myasthenia gravis
MLF medial longitudinal fasciculus
MMN multifocal motor neuropathy
MND motor neuron disease
MRA magnetic resonance angiography
MRC Medical Research Council
MRI magnetic resonance imaging
MRV magnetic resonance venography
MS multiple sclerosis
MSA multiple system atrophy
MSLT multiple sleep latency test
MuSK muscle-specific kinase
NCS nerve conduction studies
NCV nerve conduction velocity
NFTs neurofibrillary tangles
NIF negative inspiratory force
NMDA N-methyl-D-aspartate
NMJ neuromuscular junction
NMS neuroleptic malignant syndrome
NSAIDs nonsteroidal anti-inflammatory drug
OCD obsessive-compulsive disorder
ON optic neuritis
PANDAS pediatric autoimmune neurologic disorders associated with streptococcal
infection
PAS periodic acid–Schiff
PCA posterior cerebral arteries
PCD paraneoplastic cerebellar degeneration
PCNSL primary central nervous system lymphoma
PCR polymerase chain reaction
PD Parkinson’s disease
PDC paroxysmal (nonkinesigenic) dystonic choreoathetosis
PEO progressive external ophthalmoplegia
PET positron emission tomography
PICA posteroinferior cerebellar artery
PKC paroxysmal kinesigenic choreoathetosis
PM polymyositis
PML progressive multifocal leukoencephalopathy
PN peripheral neuropathy
PNS peripheral nervous system
POTS postural orthostatic tachycardia syndrome
PP periodic paralysis
PPD purified protein derivative
PPRF paramedian pontine reticular formation
PS1 presenilin 1
PS2 presenilin 2
PSP progressive supranuclear palsy
PT prothrombin time
PTT partial thromboplastin time
PVR postvoid residual
QSART quantitative sudomotor axon reflex test
RAPD relative afferent pupillary defect
REM rapid eye movement
RF radiofrequency
riMLF rostral interstitial nucleus of the MLF
RPR rapid plasma reagin
rt-PA recombinant tissue-type plasminogen activator
SAH subarachnoid hemorrhage
SCA spinocerebellar ataxia
SCA superior cerebellar artery
SE status epilepticus
SLE systemic lupus erythematosus
SMA spinal muscular atrophy
SNAP sensory nerve action potential
SPECT single-photon emission computed tomography
SSRI selective serotonin reuptake inhibitor
STT spinothalamic tract
TB tuberculosis
TCD transcranial Doppler
TE time to echo
TIA transient ischemic attack
TORCH toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex
TR time to repetition
TSC tuberous sclerosis complex
UMN upper motor neuron
VA visual acuity
VDRL Venereal Disease Research Laboratory
VOR vestibulo-ocular reflex
VP venous pulsation
VPL ventroposterolateral
WD Wilson’s disease
 PART I BASICS OF NEUROLOGY
1 The Neurologic Examination

The care of patients in all specialties has been enhanced by the use of an
increasingly sophisticated array of biomarkers, genetic tests, and imaging
modalities. Yet even in the setting of these critical advancements, the
physical examination remains of utmost importance in Neurology. We glean
valuable information from listening to the manner in which concerns are
expressed, observing how patients walk into the clinic or lie in a hospital
bed, and performing maneuvers designed to interrogate the functional
integrity of nervous system components. Ultimately, the examination is a
tool we use to pinpoint the nature and origin of abnormalities. The resultant
picture can narrow the list of possible diagnoses and guide further
investigation.

PRINCIPLES
1. It is useful to conduct a complete examination at least once for every
Neurology patient. The neurologic examination may be unique in its
length, but it is worthwhile to complete a thorough assessment at least
once with each Neurology patient for several reasons. First, that
examination provides a baseline assessment of neurologic status—which
can be particularly valuable in the hospital, where examinations can
evolve in important and sometimes unforeseen ways. Second, a full
examination may uncover unexpected abnormalities. One might be
tempted to skip a full mental status examination for a patient who can
exchange pleasantries normally—only to be surprised when the patient
identifies the year as 1962. Because neurologic problems can present
with discrete deficits, formal testing in each domain is sensible. Third,
abnormalities on basic tests can point out the need for more in-depth,
specialized evaluations. For example, the emergence of diplopia on
 testing extraocular movements might prompt a search for fatigable
eyelid weakness that can raise concern for myasthenia gravis. In this
way, the neurologic examination becomes tailored for each individual
patient. Fourth, the examination allows one to directly confirm or refute
hypotheses about contributory problems suggested by the history. Foot
drop is more likely to result from a lumbosacral radiculopathy if
accompanied by back pain; a positive straight leg raise test can help
corroborate this explanation. Finally, the examination can show a pattern
of abnormalities that provides a clue as to where in the nervous system
the problem lies.
2. The goal is to localize the problem. The nervous system is extensive.
Broadly, we can characterize elements as central or peripheral. The
central nervous system includes the brain and spinal cord. The peripheral
nervous system (PNS) incorporates nerve roots, plexi, peripheral nerves,
neuromuscular junctions, and muscles. Dysfunction originating from
each of these locations can translate into distinctive examination
findings (Table 1-1); recognizing characteristic patterns is often the key
to localizing a deficit. Using this approach, the exam can help determine
whether left hand weakness stems from carpal tunnel syndrome, a
brachial plexus injury, cervical radiculopathy, or a middle cerebral artery
stroke. These distinctions are important because the diagnostic steps,
prognoses, and therapies differ for each of these conditions.
3. Findings should be interpreted in the context of the history. In
performing a comprehensive neurologic examination, it is not
uncommon to detect incidental abnormalities. Particularly at the start of
one’s career, it can be difficult to discern whether certain abnormalities
are important. One should assign greater weight to findings related to the
presenting symptoms or a patient’s medical history. For instance,
abnormal sensation in a football-shaped region over the anterolateral
thigh may be a key finding in an obese person who developed burning in
this area after wearing tight-fitting pants, but an unimportant (or
untrustworthy) discovery in an individual who presents with an acute
change in mental status.

TABLE 1-1. Localizing Patterns of Sensorimotor Abnormalities

Location of Lesion Characteristic Distribution
Brain Right or left hemi-body (face, arm, and leg)
 Brainstem Crossed face and limbs (e.g., right face, left limbs)
Spinal cord At a sensory level on one or both sides of the posterior torso (at or
above the site of the lesion)
Nerve root Along an individual nerve root (i.e., a dermatome if a sensory
change, or a myotome if weakness)
Plexus Patchy in affected upper or lower extremity
Peripheral nerves Distal, symmetric sensorimotor changes
(polyneuropathy)
Neuromuscular junction Fatigable weakness
Muscle Proximal, symmetric weakness

KEY POINTS
● A complete neurologic examination is important to identify and characterize patterns of
abnormalities.
● The goal of the examination is to localize lesions in the nervous system.
● Findings should always be interpreted in the context of the clinical history.

ELEMENTS OF THE EXAMINATION

The details of the neurologic examination (Table 1-2) should be tailored to
fit the patient’s presenting symptoms and identified abnormalities on a basic
exam.

MENTAL STATUS
The mental status exam is performed to identify cognitive deficits related to
specific regions in the brain. The first step is to assess level of
consciousness, which can range from awake and alert to unarousable even
with noxious stimulation. Rather than using medical terms such as
stuporous or obtunded in the latter setting, it is more helpful to describe
what external stimuli are required to arouse a patient or maintain
wakefulness. The level of consciousness frames further testing of cognitive
function. Attention is tested, typically by asking patients to recite spans of
numbers, months, or words such as “world,” forward and backward. A
specific form of inattention is referred to as neglect. Patients with dense
neglect may fail to describe items on one side of a picture or of their
surroundings or fail to bisect a line properly. Subtle neglect may manifest as
extinction to double simultaneous stimulation; in this scenario, a patient can
sense a single visual or sensory stimulus on either side of the body but
reports it on the nonneglected side alone when bilateral stimuli are
presented. In some cases, it is not possible to perform formal tests of
attention because patients become focused on one detail or task and keep
repeating it (“perseveration”). Deficits in attention are important to
recognize because they can compromise the ability to complete other tasks
in the mental status examination. Orientation is tested by asking a patient
to identify his or her name and location as well as the day, date, month,
year, and current situation.
Memory is assessed by asking patients to repeat several words
immediately and again after intervals (e.g., 30 seconds and 3 minutes). The
examiner should make note of whether the patient is aware of current
events. Language is assessed in several ways: by listening to the fluency
and prosody of spontaneous speech, identifying word substitutions (i.e.,
paraphasic errors), and assessing the ability to repeat phrases, read, write,
and name common and uncommon objects. Furthermore, the examiner can
ask the patient to name as many words as possible starting with the letter
“F,” “A,” or “S” in 1 minute, paying attention not only to the number of
words generated but also to the manner in which they are named. For
example, does the patient recognize whether she or he repeated words?
Were words volunteered in identifiable categories? In addition to insight
into language function, these details provide insight into how well patients
can plan and organize information (i.e., frontal lobe executive function). To
assess verbal comprehension, check to see if patients can follow spoken
midline, appendicular, and cross-body commands.

TABLE 1-2. Commonly Performed Elements of the Neurologic

Examination
Mental Status
Attention Serial backward tasks (months of the year, digit span)
Language Fluency of speech, repetition, comprehension of commands, naming
objects, reading, writing
Memory Recall of words after 5 minutes
Visuospatial function Clock drawing; complex figure copying
Neglect Line bisection, double simultaneous stimulation
Frontal lobe function Generation of word lists; performance of learned motor sequence; test of
 inhibition
Cranial Nerves
II Visual acuity, fields, pupils, funduscopic exam
III, IV, VI Extraocular movements
V, VII Facial sensation and movement
IX, X, XII Palate and tongue movement
Motor
Bulk Inspection for atrophy
Tone Evaluation for rigidity, spasticity
Power Observational tests (pronator drift, rising from chair, walking on heels and
toes), direct confrontation strength testing
Reflexes
Muscle stretch reflexes Assessment at sites including biceps, brachioradialis, triceps, knee, ankle
Babinski sign Stroking lateral sole of foot
Sensory
Pinprick and Mapping of pinprick, cold sensation
temperature
Vibration and joint Timing appreciation of tuning fork stimulus at joints, assessing perception
position sense of location of limbs in space
Romberg sign Unsteady, when standing with feet together, then closing eyes
Coordination
Accuracy of targeting Finger-to-nose, heel-to-shin tests
Rhythm of movements Rapid alternating movements, rhythmic finger or heel tapping
Gait
Stance Evaluation of narrow or wide base
Stride and arm swing Assessment for shuffling, decreased arm swing
Ataxia Evaluation of ability to tandem walk

Calculation ability can be tested by asking patients to perform simple

arithmetic (e.g., the number of quarters in $1.50). One can check for
apraxia by asking patients to pantomime a learned motor task—optimally
one that requires use of both hands, for example, cutting a loaf of bread.
Visuospatial function and nonverbal learning can be tested in a variety of
ways. Patients can be asked to draw numbers in a circle to form a clock;
alternatively, they can be asked to copy a complex figure drawn by the
examiner (Fig. 1-1).
FIGURE 1-1. Example of a complex figure to be copied by the patient as test of visuospatial
function.

Other tests of frontal lobe function include learning and then repeating a
simple motor sequence of hand postures (i.e., the Luria manual sequencing
task). Another test of appropriate inhibition, the go/no go test, comprises
tapping the table when only one letter (e.g., “B”) is said aloud in a string of
letters. Perseveration is also considered a frontal deficit. If cognitive
impairment emerges as a concern, the examiner should consider looking for
the presence of primitive reflexes, which are signs of “frontal release” or
disinhibition. Examples include the palmo-mental, snout, and rooting
reflexes; of note, the examiner should be careful not to overinterpret these
reflexes, because they can occur in normal subjects with age or may not be
relevant to the presenting problem.

KEY POINTS
● The mental status exam should begin with assessment of level of consciousness and
attention because these can affect the interpretation of subsequent tests.
● Memory, language, calculation, praxis, visuospatial, and frontal lobe function are other
key elements of the mental status exam that can suggest focal brain lesions.
CRANIAL NERVES
One way to test cranial nerves is to start at eye level and move down the
face in approximate numerical order (Table 1-3).
Olfaction (I) is rarely tested. When patients report alterations in the
ability to smell, each nostril should be tested separately. A non-noxious
stimulus, such as coffee or vanilla, can be used.
Optic nerve (II) function is assessed in several ways. Visual acuity is
investigated with a near card. Visual fields are tested by having the patient
cover one eye and focus on the examiner’s nose; they are then asked to
signal when they can appreciate a small red object enter the field of view
from each of four quadrants when the object is held halfway between the
patient’s eye and the examiner’s (the limits of the patient’s visual fields
should correspond to those of the examiner’s). Direct visualization of the
optic nerve can be achieved by fundoscopy. The afferent limb of the
pupillary light reflex is also mediated by the optic nerve; the efferent limb is
subtended by CN III.
Extraocular movements (III, IV, and VI) are tested in three main ways: by
having the patient pursue a moving target (e.g., an examiner’s finger
drawing of the letter “H” in front of the face; i.e., pursuit); by directing the
patient’s gaze to various stationary targets or directions (saccades); and by
having the patient fixate on an object while the head is turned passively
(vestibulo-ocular movements). The presence of nystagmus should be noted.
Muscles of mastication (V) are tested by assessing the strength of jaw
opening and palpating the contraction of the masseter when the jaw is
clenched. Facial sensation can be tested to all modalities over the forehead
(V1), cheek (V2), and jaw (V3) regions. The afferent limb of the corneal
reflex is mediated by CN V; the efferent limb is controlled by CN VII.
Muscles of facial expression (VII) are tested by having patients raise the
eyebrows, squeeze the eyes shut, puff the cheeks, or show the teeth. Though
uncommonly tested, taste over the anterior two-thirds of the tongue is
mediated by this nerve and can be evaluated with sugar or another
nonnoxious stimulus.
Hearing (VIII) may be evaluated in each ear simply by whispering or
rubbing fingers; more detailed assessment of hearing loss may be
accomplished with the Weber and Rinne tuning fork (512 Hz) tests.
Vestibular function can be tested in many ways, including evaluation of eye
fixation while the patient’s head is turned rapidly or by observation for a
gradual rotation of gait direction while the patient is walking in place with
the eyes closed.

TABLE 1-3. The Cranial Nerves

Nerve Name Exit through the Function
Skull
I Olfactory Cribriform plate Olfaction (test using nonnoxious
substance)
II Optic Optic canal Vision (acuity, fields, color), afferent
limb of pupillary reflex
III Oculomotor Superior orbital fissure Superior rectus, inferior rectus, medial
rectus, inferior oblique, levator
palpebrae, efferent limb of pupillary
reflex
IV Trochlear Superior orbital fissure Superior oblique of contralateral eye
V Trigeminal Superior orbital fissure Muscles of mastication, tensor
(V1), foramen tympani, tensor veli palatini, facial
rotundum (V2), sensation, afferent limb of corneal
foramen ovale (V3) reflex
VI Abducens Superior orbital fissure Lateral rectus
VII Facial Internal auditory Muscles of facial expression,
meatus stapedius, taste on anterior two-thirds
of tongue, efferent limb of corneal
reflex
VIII Vestibulocochlear Internal auditory Hearing, vestibular function
meatus
IX Glossopharyngeal Jugular foramen Movement of palate, sensation over
palate and pharynx, taste over
posterior one-third of tongue, afferent
limb of gag reflex
X Vagus Jugular foramen Movement of palate; sensation over
pharynx, larynx, and epiglottis;
efferent limb of gag reflex;
parasympathetic function of viscera
XI Accessory Jugular foramen Sternocleidomastoid and trapezius
movement
XII Hypoglossal Hypoglossal foramen Tongue movement

Palate elevation should be symmetric, and the voice should not be hoarse
or nasal (IX and X). Failure of the right palate to elevate implies pathology
of the right glossopharyngeal nerve. The gag reflex is also mediated by
these nerves.
 Sternocleidomastoid strength is tested by having the patient turn the head
against resistance; weakness on turning to the left implies a right accessory
nerve (XI) problem. The trapezius muscle is tested by having patients shrug
the shoulders.
Tongue protrusion should be in the midline. If the tongue deviates toward
the right, the problem lies with the right hypoglossal nerve (XII).

KEY POINTS
● Cranial nerve testing is most easily performed and recorded in approximate numerical
order.
● Key elements of the cranial nerve exam include assessment of vision and eye movements,
facial movement and sensation, and movements of the palate and tongue.

MOTOR EXAM
First, bulk is assessed by observing and palpating the muscles and
comparing each side to the other and the patient’s overall muscle bulk to
that expected for age.
Tone is one of the most important parts of the motor exam. In the arms,
tone is checked by moving the patient’s arm, flexing and extending at the
elbow, moving the wrist in a circular fashion, and pronating and supinating
the forearm rapidly using a handshake grip. Abnormalities of tone such as
spasticity and rigidity are discussed in subsequent chapters. Tone in the legs
can be tested well only with the patient supine. The examiner lifts the leg up
suddenly under the knee; in the presence of increased tone, the heel comes
off the bed. Increased tone can be characterized further as rigid or spastic.
In rigid limbs, the examiner can sense increased resistance throughout the
passive movements, but spasticity is speed dependent, with abnormalities
emerging with quick movements (e.g., elbow extension).
Strength is assessed by both observation and direct confrontation (Fig. 1-
2). A pronator drift may be observed in an arm held supinated and extended
in front of the body. The patient may be asked to rise from a chair without
using the arms or to walk on the heels and toes. The power of individual
muscles as assessed by direct confrontation testing is most often graded
according to the Medical Research Council (MRC) scale (Table 1-4). In
some settings, such as the intensive care unit, it is not possible to perform
detailed motor assessments. In this case, the examiner can look to see if
there is symmetry to voluntary limb movements. Another approach is to
evaluate whether the patient can withdraw meaningfully (i.e., pull the
examined limb away from a mildly noxious stimulus such as a pinch).

FIGURE 1-2. Power testing of individual movements. For each movement, the predominant
muscle, peripheral nerve, and nerve root are given. (Reproduced with permission from Ginsberg L.
Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:40–41.)

The presence of involuntary abnormal movements should be noted. For

instance, fasciculations appear as small twitches underneath the skin.
Myoclonus and asterixis can cause a limb to jump or transiently lose tone
from a given posture. Chorea has a writhing quality. Tremor can appear as
an alternating movement of the arm, leg, or head.

TABLE 1-4. Medical Research Council Grading of Muscle Power

0 No contraction of muscle visible
 1 Flicker or trace of contraction visible
2 Active movement at joint, with gravity eliminated
3 Active movement against gravity
4 Active movement against gravity and some resistance
5 Normal power

KEY POINTS
● The motor exam begins with assessment of bulk and tone (including an assessment for
spasticity and rigidity).
● Strength testing involves both functional observation and confrontation testing of
individual muscle power.
● Strength is graded on the MRC scale from 0 to 5.

REFLEXES
Muscle stretch (or “deep tendon”) reflexes can be useful aids in localizing
or diagnosing both central and PNS problems (Fig. 1-3).
FIGURE 1-3. Muscle stretch (“deep tendon”) reflexes. (Reproduced with permission from
Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:44.)

In the arms, the biceps, brachioradialis, and triceps reflexes are most
commonly tested. A pectoral reflex can be assessed by tapping the
pectoralis muscle and looking for adduction of the proximal arm. Thumb
flexion stimulated by flicking the distal phalanx of the middle finger is a
positive Hoffmann sign, an indication of hyperreflexia. In the legs, patellar
(knee jerk) and ankle reflexes are commonly tested. The adductor reflex can
also be tested by striking the medial thigh and looking for thigh adduction.
The Babinski sign is sought by stroking the lateral sole of the foot while
observing for extension of the great toe. Clonus, if present, can be elicited
by forcibly dorsiflexing the ankle when it is relaxed. In some cases, an
exaggerated jaw jerk can localize a problem above the level of the cervical
spine.
SENSORY EXAM
The sensory examination assesses small-fiber (pinprick, temperature) and
large-fiber (vibration, proprioception) function. Pinprick and temperature
information is carried in the spinothalamic tract. Vibration and
proprioception require dorsal column tract integrity. It is generally helpful
to start distally and move proximally when testing each modality because
polyneuropathy, one of the most common causes of sensory abnormality,
generally shows up first in the toes. Nevertheless, it makes sense to test
sensory function more extensively in any affected limb—even if more distal
function is normal—to look for other patterns of abnormality.
Pinprick: Using a sterile instrument (e.g., special pins designed for the
neurologic exam), the examiner starts to prick the toes and gradually
moves up the leg to assess if there is a gradient to sensation. The
process can be repeated starting in the fingers and moving up the arm. If
there is concern for a spinal cord lesion, it is important to perform
pinprick along the length of the torso to identify a “level” where
sensation transitions from abnormal to normal. If the patient reports
facial symptoms, the pin should be used to assess sensation in areas
representing each branch of the trigeminal nerve.
Temperature: Using a similar approach, a cold tuning fork can be used to
assess temperature sensation.
Vibration: After striking the 128-Hz tuning fork, the stem is placed against
a joint, and the duration for which the stimulus is appreciated is
recorded. In general, this great toe is tested first, with the examiner
testing increasingly proximal joints if the distal findings are abnormal.
Proprioception: Proprioception, or joint position sense, is tested in an order
similar to that used for vibration assessment. Usually, the examiner
starts by holding the sides of the great toe and asking the patient to
report when it is being moved upward and downward by a few
millimeters.
Light touch is often not useful to test in isolation because it relies on a
combination of pathways. By itself it is unlikely to provide clues to
localization or diagnosis.
 KEY POINTS
● Pinprick and temperature information is carried in the spinothalamic pathway, whereas
vibration and joint position sense are relayed in the dorsal columns.
● It is important to use an organized approach (e.g., always moving distal to proximal along
a limb) when testing sensory function.

COORDINATION
Coordination of the limbs and the trunk should be assessed. Finger-to-nose
testing can identify dysmetria (inaccuracy of targeting) or types of tremor in
the arms. Heel-to-shin testing can elicit incoordination in the legs. To test
axial abnormalities, the patient can be asked to sit upright and unsupported,
with the eyes closed.
Rapid alternating movements, rhythmic finger tapping, and heel tapping
are particularly sensitive to coordination problems. In some disorders, such
as Parkinson’s disease, there can be a hesitation, decremental slowing (i.e.,
damping), or increasingly small excursions with repetitive movements.
Patients may also have trouble with the timing, or cadence, of these
movements. Dysdiadochokinesis is the term used to describe difficulty with
rapid alternating movements.

GAIT
Ambulation is one of the most important elements of the neurologic
examination. Normal gait requires the proper functioning of many different
aspects of the nervous system, so it is one of the most sensitive ways to
detect an abnormality. Furthermore, some patterns of gait abnormality
herald the presence of specific disorders (e.g., parkinsonism). Routinely,
posture, base, initiation, stride length, turning, arm swing, and overall
balance are considered.
Posture should be upright. The patient with a normal base, or stance,
maintains the feet at about hip-width apart. In general, healthy individuals
start walking without any hesitation. Stride length should be full, with
clearance of the feet from the floor. Short-stepped and shuffling gaits are
characterized by decreased stride length and limited excursion of the feet
from the ground. The arms normally swing fully in the opposite direction
from their respective legs during ambulation. Decreased arm swing is often
a feature of extrapyramidal disorders. A normal turn can be executed in two
steps; patients with Parkinson’s disease may take multiple small steps to
turn “en bloc.”
Ataxia of gait results in an inability to walk in a straight line; patients
may stagger from one side to the other or list consistently toward one side.
Ataxia is typically associated with a wide-based stance. Ataxia can be
brought out most obviously by having the patient attempt to walk heel to
toe (tandem). A Romberg sign is present when the patient maintains a
steady stance with feet together and eyes open but sways and falls with feet
together and eyes closed; its presence usually implies a deficit of joint
position sense, not cerebellar dysfunction.

KEY POINTS
● Gait is one of the most important elements of the neurologic exam because it is sensitive
for many deficits, and certain diseases have characteristic gait disorders.
● Base, initiation, stride length, turning, arm swing, and the ability to perform tandem gait
should be assessed.
● A positive Romberg sign suggests a deficit in joint position sense.
 2 Neurologic Investigations

CEREBROSPINAL FLUID ANALYSIS

Cerebrospinal fluid (CSF) bathes the internal and external surface of the
brain and spinal cord. It is produced by the choroid plexus of the ventricles
and is absorbed through the villi of the arachnoid granulations that project
into the dural venous sinuses. CSF is produced continually at a rate of about
0.5 mL per minute; the total volume is approximately 150 mL. The entire
CSF volume is thus replaced about every 5 hours. Lumbar puncture (LP) at
the L3–L4 or L4–L5 interspace is the most commonly used means of
obtaining CSF for analysis. LP is contraindicated by the presence of a
space-occupying lesion that is causing mass effect in the central nervous
system (CNS), raised intracranial pressure, local infection or inflammation
at the planned puncture site, or a significant coagulopathy.

TECHNIQUE
Optimal positioning is the key to a successful and atraumatic LP. LP is best
performed with the patient in the lateral decubitus position with the legs
flexed up over the abdomen. Ideally, a pillow should be placed between the
legs, and the patient should lie on the edge of the bed where there is better
support to keep the back straight. The anterosuperior iliac spine is at the
level of the L3–L4 vertebral interspace. The LP may be performed at this
level, one interspace higher, or one to two interspaces lower. (Remember
that the spinal cord ends at the level of L1–L2.) The needle is inserted with
the bevel facing upward, so that it will enter parallel to the ligaments and
dura that it pierces rather than cutting them transversely. The needle is
directed slightly rostrally to coincide with the downward angulation of the
spinous processes. The needle is advanced gently until CSF is obtained. To
measure the opening pressure reliably, the patient’s legs should be extended
slightly and note should be made of fluctuation of the CSF meniscus within
the manometer with respiration.

INTERPRETATION OF RESULTS
CSF is a clear, colorless fluid. The glucose content is about two-thirds that
of blood, and it contains up to 40 to 50 mg/dL protein. Fewer than five cells
are present, and these are lymphocytes. The opening pressure measured by
LP in the lateral recumbent position is about 60 to 150 mm H2O.
Xanthochromia refers to the yellow discoloration of the supernatant of a
spun CSF sample. Its presence helps to distinguish an in vivo intrathecal
hemorrhage from a traumatic tap (in which red blood cells [RBCs] have not
lysed, so the supernatant is still colorless).
The implications of various CSF findings are summarized in Table 2-1.
CSF findings in a variety of common conditions are summarized in Table 2-
2. Special tests may be performed as indicated. Some examples include
cytology for suspected malignancy, oligoclonal banding for suspected
immune-mediated processes such as multiple sclerosis, 14-3-3 protein for
Creutzfeldt–Jakob disease, and a variety of polymerase chain reactions and
serologic tests to detect infections of the nervous system.

SAFETY, TOLERABILITY, AND COMPLICATIONS

Cerebral or cerebellar herniation may occur when LP is performed in the
presence of either a supratentorial or infratentorial mass lesion. A computed
tomography (CT) scan should be performed prior to an LP when there are
examination findings raising concern for increased intracranial pressure,
focal neurologic findings, or severe encephalopathy. Radiologic
contraindications to LP include closure of the fourth ventricle and
quadrigeminal cistern. Low-pressure headache is the most common
complication of LP. It is most effectively prevented by using smaller (higher
gauge) LP needles, inserting the bevel of the LP needle parallel rather than
perpendicular to the dural fibers, and replacing the stylet after obtaining
CSF. Should a post-LP headache develop, it is treated initially by having the
patient lie flat and increase his or her intake of liquids and caffeine. In
patients who do not respond to these conservative measures, it may be
necessary to administer an epidural blood patch (see Chapter 10).
TABLE 2-1. Interpretation of CSF Findings
Red Blood Cells
No xanthochromia Traumatic tap
Xanthochromia Subarachnoid hemorrhage; hemorrhagic encephalitis
White Blood Cells
Polymorphs Bacterial or early viral infection
Lymphocytes Infection (viral, fungal, mycobacterial); demyelination (MS,
ADEM); CNS lymphoma
Elevated protein Infection (fungal, mycobacterial); demyelination; tumor (e.g.,
meningioma, meningeal carcinomatosis); sarcoidosis; age
Low glucose Bacterial infection; mycobacterial infection
Oligoclonal bands Demyelination (MS); CNS infections (e.g., Lyme disease);
noninfectious inflammatory processes (e.g., SLE)
Angiotensin-converting May be elevated in neurosarcoidosis
enzyme
ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; CSF, cerebrospinal
fluid; MS, multiple sclerosis; SLE, systemic lupus erythematosus

TABLE 2-2. CSF Findings in Common Neurologic Diseases

Disease Cells Protein Glucose Other
(Pleocytosis)
Bacterial meningitis Polymorphs High Low Culture and Gram
stain may be positive
Viral Lymphocytes High Normal Viral PCR may be
meningitis/encephalitis positive
Tuberculous Lymphocytes High Very low Positive for acid-fast
meningitis bacilli
Guillain–Barré None High (degree Normal —
syndrome depends on
interval from
symptom onset)
Multiple sclerosis Several Slightly high Normal OCBs usually
lymphocytes present
ADEM Lymphocytes or Usually high Normal OCBs usually absent
polymorphs
Subarachnoid Lymphocytes May be high Normal Xanthochromia
hemorrhage and many RBCs
ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid; OCB, oligoclonal bands;
PCR, polymerase chain reaction; RBC, red blood cell.

KEY POINTS
 ● A CT scan should be performed prior to LP, especially when there is concern about
increased intracranial pressure or focal neurologic abnormalities.
● LP is performed at or below the L2–L3 interspace.
● Xanthochromia indicates recent intrathecal hemorrhage.

COMPUTED TOMOGRAPHY AND

MAGNETIC RESONANCE IMAGING
TECHNICAL CONSIDERATIONS
CT measures the degree of X-ray attenuation by tissue. Attenuation is
defined simply as the removal (by absorption or scatter) of X-ray photons
and is quantified on an arbitrary scale (in Hounsfield units) that is
represented in shades of gray. Differences in the shades directly reflect the
differences in the X-ray attenuation of different tissues, a property that
depends on their atomic number and physical density. Images are usually
obtained in either an axial or a coronal plane. Three-dimensional
reconstruction and angiography are possible with new-generation spiral CT
scanners.
Magnetic resonance imaging (MRI) is similar to CT in that radiant
energy is directed at the patient and detected as it emerges from the patient.
MRI differs, however, in its use of radiofrequency (RF) pulses rather than
X-rays. The images in MRI result from the varying intensity of radio-wave
signals emanating from the tissue in which hydrogen ions have been excited
by an RF pulse. A detailed understanding of magnetic resonance physics is
not necessary for the interpretation of routinely used MRI sequences. It is
sufficient to understand that the patient is placed in a magnet and that an RF
pulse is administered. Signal intensity is measured at a time interval, known
as time to echo (TE), following RF administration. The RF pulse is
administered many times in generating an image; the time to repetition
(TR) is the time between these RF pulses.
Two basic MRI sequences in common usage are T1-weighted (short TE
and TR) and T2-weighted (long TE and long TR) images. Fat is bright on a
T1-weighted image, which imparts a brighter signal to the myelin-
containing white matter. Water (including CSF) is dark on T1 and bright on
T2. T2 images are most useful in evaluating the spinal cord (Fig. 2-1).
Gadolinium is the contrast agent used in MRI, and gadolinium-enhanced
images are usually acquired with a T1-weighted sequence. Contrast-
enhanced images are invaluable in determining the presence of brain
tumors, abscesses, other areas of inflammation, and new multiple sclerosis
lesions (see Fig. 19-1).

FIGURE 2-1. T2-weighted MRI of the cervical spine. MRI, magnetic resonance imaging.

Other commonly used MRI sequences are fluid-attenuated inversion

recovery (FLAIR) and susceptibility- and diffusion-weighted imaging
(DWI). FLAIR is a strong T2-weighted image, but one in which the signal
from water/CSF has been inverted and is thus of low rather than high
intensity. FLAIR is the single best screening image sequence for most
pathologic processes of the CNS. It is very useful in assessing the chronic
lesion burden in multiple sclerosis (see Fig. 20-2). A susceptibility-
weighted sequence is one that is sensitive to the disruptive effect of a
substance on the local magnetic field. Examples of substances that exert
such a susceptibility effect are calcium, bone, and the blood breakdown
products ferritin and hemosiderin. Areas of increased susceptibility appear
black on these images.
 DWI demonstrates cellular toxicity with high sensitivity and is most
commonly employed in the diagnosis of acute stroke, where it can be
positive within half an hour of symptom onset. Areas of restricted diffusion
appear bright on DWI. Figure 2-2 provides examples of T1, T2, FLAIR,
and DWI images.

CLINICAL UTILITY
Head CT is often the initial investigation used in a variety of neurologic
disorders, including headache, trauma, seizures, subarachnoid hemorrhage,
and stroke. The sensitivity of a CT scan for detecting lesions depends on
many factors, including the nature and duration of the underlying disease
process. The sensitivity for detecting areas of inflammation, infection, or
tumor may be increased by the administration of intravenous contrast.
Contrast enhancement indicates local disruption of the blood–brain barrier.
CT is the investigation of choice for demonstrating fresh blood.
FIGURE 2-2. Normal T1, T2, FLAIR, and DWI images of the brain. DWI, diffusion-weighted
imaging; FLAIR, fluid-attenuated inversion recovery.

Apart from providing better anatomic definition, MRI is particularly

useful for imaging the contents of the posterior fossa and craniocervical
junction, which are seen poorly on CT because of artifact from surrounding
bone. DWI is the most sensitive technique available for demonstrating early
tissue ischemia and is therefore extremely useful in the evaluation of
patients with suspected stroke.

SAFETY, TOLERABILITY, AND COMPLICATIONS

CT scanning employs X-rays and is thus relatively contraindicated during
pregnancy. The use of RF waves in MRI makes this the imaging modality
of choice in pregnant women. There is no cross-reactivity between the
iodinated contrast agents used in CT and the gadolinium used as a contrast
agent in MRI. When contrasted imaging is required, MRI may therefore be
preferable when there is a history of allergy to intravenous contrast.
Similarly, gadolinium does not have the nephrotoxicity of iodinated
contrast. MRI is not safe when metal objects (foreign bodies, plates, and
screws) and pacemaker and defibrillator devices are present, unless those
materials have been made MRI compatible. Some people with
claustrophobia cannot tolerate MRI; under these circumstances, CT is
preferred.

KEY POINTS
● CT is the imaging modality of choice for demonstrating acute intracranial bleeding.
● MRI is required for adequate imaging of the posterior fossa and craniocervical junction.
● DWI is the most sensitive MRI sequence for demonstrating early cerebral ischemia or
infarction.

VASCULAR IMAGING STUDIES

Conventional angiography involves cannulation of the great vessels and
injection of contrast material to obtain an image of the vascular anatomy
(Fig. 2-3). This is the most sensitive and specific imaging study of the
intracranial and extracranial circulation. Risks of the procedure include
contrast reaction, stroke caused by plaque dislodged by the catheter, and
bleeding at the cannulation site. Although the risks of the procedure and
developments in magnetic resonance angiography (MRA) (below) have
decreased the use of conventional angiograms, it remains the “gold
standard” in vascular imaging.
MRA uses blood flow as a contrast agent and MR technique to define
vascular anatomy (Fig. 2-4). Compared with conventional angiography,
MRA is less invasive and can be performed more quickly and less
expensively, but it is not as sensitive or specific for cerebrovascular disease.
MRA is performed commonly on the intracranial circulation of stroke
patients to look for evidence of vascular narrowing or occlusion. “Fat-
suppressed” MRA of the neck is useful for determining the presence of
vertebral or carotid artery dissections. Magnetic resonance venography
(MRV) can be used to demonstrate venous sinus thrombosis and other
venous disease.

FIGURE 2-3. Conventional cerebral angiogram demonstrating aneurysm of the right middle
cerebral artery (arrow). ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle
cerebral artery. (Reproduced with permission from Yochum TR , Rowe LJ. Yochum and Rowe’s
Essentials of Skeletal Radiology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.)
FIGURE 2-4. MRA of the circle of Willis. MRA, magnetic resonance angiography.

CT angiography (CTA) of the head is most often used for patients with
acute stroke to determine whether there is a vascular occlusion that might
be amenable to mechanical thrombectomy or intra-arterial tPA (tissue
plasminogen activator) . CTA of the neck may identify carotid artery
stenosis or dissection of the carotid or vertebral arteries.
Extracranial Doppler sonography measures blood flow by determining
the difference between emitted and received ultrasound frequencies. It is
used commonly to detect stenosis or occlusion of the extracranial carotid
circulation, especially in the planning stages for carotid endarterectomy.
Transcranial Doppler (TCD) detects intracranial stenosis, emboli, and
vasospasm occurring after subarachnoid hemorrhage. Most of the
intracranial circulation, however, is inaccessible to TCD. Although
somewhat less accurate than MRA or conventional angiography, Doppler
studies are noninvasive and essentially without contraindication.

KEY POINTS
● Conventional angiography is the gold standard for evaluating cerebrovascular anatomy.
● CTA is useful in identifying acute vascular occlusions that may be treatable by mechanical
thrombectomy or intra-arterial tPA.
● MRA is less invasive but also less accurate than conventional angiography.
● MRV is useful for assessing the presence of venous sinus thrombosis.
OTHER IMAGING STUDIES
18-fluorodeoxyglucose positron emission tomography (FDG-PET)
scans measure regional brain metabolism. They are most often employed in
the presurgical evaluation of epilepsy patients. Hypermetabolism can be
demonstrated during seizures (although obtaining the scan during a seizure
is challenging), whereas hypometabolic regions may be evident interictally.
PET scans can also be useful in differentiating among the degenerative
dementias: Hypometabolism is more prominent in the temporal and parietal
lobes in Alzheimer disease patients, in the frontal and temporal regions in
frontotemporal dementia patients, and in the occipital region in dementia
with Lewy body patients. Amyloid PET imaging is a molecular imaging
technique which uses a radiotracer to detect elevated levels of β-amyloid in
the brain in patients with Alzheimer disease. It can be used to distinguish
between patients with Alzheimer disease, those with other dementias, and
normal subjects. Single-photon emission computed tomography
(SPECT) uses a radioactive isotope to demonstrate increased blood flow
during seizures or decreased blood flow in the degenerative dementias.
Dopamine transporter SPECT (DaT scan) is a special kind of SPECT
scan in which a radioisotope that binds to dopamine transporter in the
striatum is injected. It can be helpful to distinguish Parkinson disease from
other movement disorders. Magnetic resonance spectroscopy may be used
to demonstrate areas of neuronal damage or dysfunction and has been
studied in the assessment of brain tumors, demyelinating disease, and
infections of the CNS. Peripheral nerve ultrasound is being developed for
the evaluation of focal and general neuropathic symptoms.

ELECTROENCEPHALOGRAPHY
The electroencephalogram (EEG) provides a record of the electrical activity
of the cerebral cortex. EEG patterns are characterized by the frequency and
amplitude of the recorded electrical activity, and the patterns of activity
correlate with the degree of wakefulness or sleep. The normally observed
frequency patterns are divided into four groups: alpha (8–13 Hz), beta (14–
30 Hz), theta (4–7 Hz), and delta (0.5–4.0 Hz) (Fig. 2-5). Under normal
circumstances, alpha waves are observed over the posterior head regions in
the relaxed awake state with the eyes closed. Lower-amplitude beta activity
is more prominent over the frontal regions. Theta and delta activities are
normal during drowsiness and sleep, and the different stages of sleep are
defined by the relative proportions and amplitudes of theta and delta
activities (see Chapter 13).

FIGURE 2-5. Electroencephalogram frequencies.

TECHNIQUE
The standard EEG is recorded from electrodes attached to the scalp in a
symmetric array. The pattern in which these electrodes are connected to
each other is referred to as the montage, of which there are essentially two
types: bipolar and referential. In a bipolar montage, all electrodes are active
and a recording is made of the difference in electrical activity between two
adjacent electrodes. In a referential montage, the electrical activity is
recorded beneath the active electrode relative to a distant electrode or
common average signal. The signal recorded by an EEG is a sum of
excitatory and inhibitory postsynaptic potentials of cortical neurons.

CLINICAL UTILITY
Several common patterns of abnormal EEG activity are recognized. A
slower frequency background in all areas indicates a diffuse encephalopathy
(often caused by a systemic process). Focal slow activity in the theta or
delta range suggests local dysfunction in the underlying brain. The slowing
cannot specify the etiology, but vascular disease is a common cause of such
findings. Interictal epileptiform findings include sharp-and-spike-wave
discharges, with or without an accompanying slow wave. Electrographic
seizures may take various forms. The most common are rhythmic spike- or
sharp- and slow-wave discharges or rhythmic slow waves. They may be
focal or generalized. Activation procedures can be used to enhance the
likelihood of finding abnormal EEG patterns: Hyperventilation is useful for
provoking epileptiform discharges changes in patients with absence
seizures, whereas photic stimulation can induce epileptiform discharges in
patients with myoclonic seizures.
To appreciate the utility of the EEG, it is important to understand its
limitations. First, the patterns of electrical activity recorded by the EEG are
rarely specific to their cause. For example, widespread theta and delta
background slowing during the awake state suggests an encephalopathy but
does not indicate the etiology. Second, the EEG records the electrical
activity of cortical neurons. Although subcortical structures influence
cortical activity, the surface EEG may be insensitive to dysfunction of deep
structures. For example, seizures originating in the medial frontal or
temporal lobes may not be readily apparent on the surface EEG.
Furthermore, the EEG provides a measure of the electrical activity of the
cortex at the time of the recording and is therefore frequently normal in
paroxysmal conditions such as epilepsy. The interictal EEG, for example,
may be abnormal in only about 50% of adults with epilepsy. The frequency
of interictal EEG abnormalities may be higher in certain forms of epilepsy.

KEY POINTS
● EEG can be used in the evaluation of seizure disorders and encephalopathy.
● Epilepsy is a clinical diagnosis; interictal epileptiform findings are demonstrable in about
half of patients with epilepsy on routine EEG.

EVOKED POTENTIALS
Evoked potentials are electrical potentials or waveforms that are recorded
from the brain, spinal cord, or peripheral nervous system in response to a
stimulus. Visual-evoked potentials are used primarily in the diagnosis of
optic neuritis and multiple sclerosis. A visual target is presented to a patient,
and surface potentials are recorded over the occipital lobes. A delay in the
P100 potential suggests dysfunction of the optic nerve or its connections.
Somatosensory-evoked potentials (SSEPs) may be used to assess peripheral
nerve and spinal cord problems. They are also used in the evaluation of
patients with coma and brain death: Bilateral absence of the N20 potentials
indicates a very poor prognosis. SSEPs and motor-evoked potentials are
used to monitor neurologic function during several types of surgery,
especially spine surgery. Brainstem auditory–evoked potentials are useful to
assess brainstem dysfunction and are most often used in surgical planning
for patients with vestibular schwannomas and to assess hearing in infants.

NERVE CONDUCTION STUDIES AND

ELECTROMYOGRAPHY
Nerve conduction studies (NCS) and electromyography (EMG) are
electrophysiologic tools that may aid in the diagnosis of peripheral nervous
system disorders.

TECHNIQUE
In performing NCS, an electrical stimulus is applied over a nerve and
recordings are made from surface skin electrodes. For motor studies, the
recording electrodes are placed over the endplate of a muscle innervated by
the nerve being stimulated. The nerve is stimulated in at least two locations
(distal and proximal), and the distance between the two sites of stimulation
is measured carefully. The distal latency, compound muscle action potential
(CMAP), and conduction velocity are recorded. The CMAP is a recording
of the contraction of the underlying muscle. The distal latency is the time
interval between stimulation over the distal portion of the nerve and the
initiation of the CMAP. Conduction velocity is calculated by measuring the
difference in latency to CMAP initiation between proximal and distal sites
of stimulation. For sensory studies, the nerve is stimulated at one site and
the sensory nerve action potential is recorded either at a more proximal site
(orthodromic study) or at a more distal site (antidromic study). Repetitive
nerve stimulation studies are used to demonstrate either decremental or
incremental CMAP responses in disorders of the neuromuscular junction
(NMJ).
EMG involves the insertion of a needle into individual muscles.
Recordings are made of the muscle’s electrical activity upon insertion
(insertional activity), while the muscle is at rest (spontaneous activity), and
during contraction (volitional motor unit potentials). To increase the
strength of muscular contraction, motor units can fire more quickly
(activation) or more motor units can be added (recruitment). Reduced
activation is seen in CNS disease. Reduced recruitment suggests a
peripheral nervous system lesion, whereas early recruitment suggests
myopathic disease. For routine EMG studies, activity is recorded from a
group of muscle fibers simultaneously. Single-fiber EMG is the technique
used in the investigation of disorders of the NMJ: increased jitter and
blocking are the single-fiber EMG hallmarks of NMJ disease.

TABLE 2-3. Electromyography in Neurogenic and Myopathic Disorders

Neurogenic Myopathic
Insertional activity ↑ (active denervation) Usually normal (↑ in
inflammatory and necrotizing
myopathies)
Spontaneous activity ↑ (active denervation) Usually normal (↑ in
inflammatory and necrotizing
myopathies)
Volitional motor unit potentials Large amplitude; polyphasic Small amplitude; polyphasic
Recruitment Reduced Usually normal early

TABLE 2-4. Nerve Conduction Studies in Demyelinating and Axonal

Neuropathies
Demyelinating Axonal
Distal latency Markedly prolonged Normal or mildly prolonged
Conduction velocity Markedly reduced Normal; may be slightly slowed
CMAP amplitude Normal or mildly reduced Reduced
CMAP, compound muscle action potential

CLINICAL UTILITY
NCS and EMG are used primarily to assist in the localization of
dysfunction within the peripheral nervous system and to define
pathophysiology more clearly. For example, NCS and EMG may help to
differentiate a C8–T1 radiculopathy from a lower brachial plexopathy or an
ulnar neuropathy in the patient who presents with numbness of the fourth
and fifth fingers and weakness of the hand. Similarly, the combination of
motor NCS, repetitive nerve stimulation, and EMG may help to localize
motor dysfunction (i.e., weakness) to the peripheral nerve, the NMJ, or the
muscle (Table 2-3). In a patient with a polyneuropathy, NCS may help to
define the relative degree of motor and sensory involvement and to
distinguish primary demyelinating from axonal disease (Table 2-4).

KEY POINTS
● The goal of NCS and EMG is to localize the neurologic dysfunction within the peripheral
nervous system.
● Repetitive nerve stimulation and single-fiber EMG are useful in the diagnosis of disorders
of the NMJ.
 PART COMMON NEUROLOGIC
II SYMPTOMS

3 The Approach to Coma and

Altered Consciousness

The neurologic evaluation and management of a patient with coma or

altered consciousness can be intimidating for the student, because such
patients are usually critically ill and may require prompt intervention. The
fundamental principles behind the evaluation of a neurologic problem,
however, should not be discarded. On the contrary, an orderly and
hypothesis-based approach may be even more important in a comatose
patient than in others, given the need for timely diagnosis and the relative
limitations of history and examination.

DEFINITION
Coma is defined as a state of unarousable unresponsiveness. Typically, the
patient lies with eyes closed and does not open them even to vigorous
stimulation, such as sternal rub, nasal tickle, or nailbed pressure. Alterations
in consciousness short of coma are often described using terms such as
drowsiness, lethargy, obtundation, and stupor, but these terms tend to be
used imprecisely and it is generally best to describe simply how the patient
responded to various degrees of stimulation. The Glasgow Coma Scale
(GCS) assigns a numerical score to a patient’s level of responsiveness and
is commonly used by neurosurgeons in cases of head trauma (see Table 17-
1). Its utility lies in its ease of use by nurses and paramedics, its inter-rater
reproducibility, and its prognostic value following head injury. Although the
GCS describes a level of responsiveness, it does not assist in determining
the cause of coma.
 KEY POINTS
● Coma is a state of unarousable unresponsiveness.
● It is important to describe a patient’s responses to various degrees of stimulation.
● The GCS, which has prognostic value in patients with head trauma, is reproducible and
easy to use.

CLINICAL APPROACH
An algorithm for approaching patients with coma or altered consciousness
is presented in Figure 3-1. The initial steps of stabilization and evaluation
culminate in the neurologic exam, which is performed with two goals in
mind: to assess brainstem function and to look for focal signs. The
differential diagnosis and further investigations stem from this clinical
assessment.
1. Remember the ABCs. In any patient with altered consciousness, the
airway, breathing, and circulation (ABC) should be checked and
maintained according to usual protocols, including intubation and
mechanical ventilation if required.
2. Look for obvious clues to etiology. A brief history and general exam
should be performed to search for obvious clues. A history of medical
problems such as diabetes, hepatic failure, alcoholism, or a seizure
disorder may be provided by the family, noted on a medical alert
bracelet, or deduced from prescription labels. The circumstances in
which the patient was found can offer clues to the onset or etiology of
depressed consciousness. The general exam may yield telling signs, such
as an odor on the breath, needle tracks on the skin, or a tongue
laceration. It is important to check for meningeal signs in any
unconscious patient because both bacterial meningitis and subarachnoid
hemorrhage may lead to depressed consciousness.
FIGURE 3-1. The approach to coma and altered consciousness. [ABC: airway, breathing, and
circulation.]

3. Try reversing common reversible etiologies. Most emergency

departments make it standard practice to administer naloxone, thiamine,
and dextrose to any patient with depressed consciousness and no obvious
etiology. Note that thiamine should always be given before glucose
 because the latter can precipitate Wernicke encephalopathy if given
alone.
4. Check brainstem reflexes and look for focal signs. These are the two
primary goals of the neurologic exam in this setting, because the
subsequent diagnostic and therapeutic steps will depend on these clinical
findings.
5. Assess for all medication exposure. All comatose patients should have
a toxicology screen for substances of abuse and other drugs. It is also
important to remember what medications were administered in the
emergency setting, including for intubation, as they can impact the
findings of the neurologic exam. Remembering the half-life of the drug
and mechanisms of action will help inform the interpretation of the
exam.

KEY POINTS
● The clinical approach to the patient with altered consciousness begins with the ABCs:
airway, breathing, and circulation.
● Look for obvious clues to etiology.
● Try reversing common reversible etiologies.
● Use the neurologic exam to check brainstem reflexes and look for focal signs.

EXAMINATION
It is important to proceed with the neurologic exam of a comatose patient in
an orderly fashion—it is easy to be intimidated or distracted by the array of
attached tubes and lines or by the intensity and anxiety of other clinicians.
An appropriate way to begin is to progress systematically through the
sequence of the usual neurologic exam, making adjustments as necessary
for the patient’s altered level of responsiveness.
Mental status testing in these patients begins with assessing the level of
consciousness. An increasing gradient of stimulation should be applied and
the patient’s responses recorded. For example, does the patient lie with his
or her eyes closed but open them slowly when spoken to in a loud voice?
Does he or she groan but not open the eyes when sternal rub is applied? For
many patients, further cognitive testing may not be possible. For those who
can be aroused even briefly, however, a short evaluation of attention,
language, visuospatial function, and neglect is in order, because this may
reveal a gross focal finding such as an aphasia or dense neglect of the left
side.
Cranial nerves (CNs) should be examined in detail, because this is the
portion of the exam most relevant to the assessment of brainstem function.
In an arousable patient, most CNs can be tested in the usual manner. In a
patient who is not arousable enough to follow commands, several important
brainstem reflexes should be tested (Table 3-1), including the pupillary,
corneal, oculocephalic, and gag reflexes. In addition, a funduscopic
examination should always be performed. For many patients with altered
consciousness, testing for a blink to visual threat may be the only way to
judge visual fields. If the patient cannot move his or her face to command,
the examiner may be restricted to looking for an asymmetry at rest, such as
a flattened nasolabial fold on one side. Supraorbital pressure can be used to
assess for facial asymmetries, as well as response to noxious stimuli.
Bilateral nasal tickle also tests sensation in the trigeminal nerve (CN V)—
which prompts a response via CN VII. This is less painful than supraorbital
pressure. The presence of an endotracheal tube may make such testing
difficult.

TABLE 3-1. Brainstem Reflexes

Reflex Cranial Nerves How to Test
Involved
Pupillary II (afferent); III Shine light in each pupil and observe for direct
(efferent) (same side) and consensual (contralateral)
constriction
Oculocephalic (doll’s VIII (afferent); III, IV, Forcibly turn head horizontally and vertically
eyes) VI (efferent) and observe for conjugate eye movement in
opposite direction (contraindicated if cervical
spine injury has not been ruled out)
Caloric testing (if Same Inject 50 mL ice water into each ear and observe
necessary)a for conjugate eye deviation toward the ear
injected
Corneal V1 (afferent); VII Touch lateral cornea with cotton tip and observe
(efferent) for direct and consensual blink
Gag IX (afferent); X/XI Stimulate posterior pharynx with cotton tip and
(efferent) observe for gag
a
Caloric testing should be performed if turning the head is contraindicated or does not result in
eye movement. The external auditory canal should be examined first with an otoscope to exclude
tympanic perforation or obstruction by wax. Never assume the eyes are immobile unless caloric
testing has been done.
 Motor tone should be checked in all extremities. If the patient can
cooperate with some testing, a gross hemiparesis can be ruled out by having
the patient hold the arms extended or legs elevated and observing for a
downward drift. Otherwise, the examiner may be restricted to observing for
asymmetry of spontaneous movements (or to asking caretakers whether all
extremities have been seen to move symmetrically). Failing that, noxious
stimuli such as nailbed pressure or a pinch on a flexor surface can be
applied to each limb and the speed and strength of withdrawal noted,
although abnormalities here may result from sensory loss as well as motor
dysfunction. Decorticate and decerebrate posturing, signs of brainstem
dysfunction, may be seen either spontaneously or in response to noxious
stimuli (Fig. 3-2).
Muscle stretch reflexes can be tested in the usual manner, and a Babinski
sign should be sought.
Sensory testing in most patients with altered consciousness is limited to
testing of light touch or pain sensation. Noxious stimulation to each limb, as
described previously, may be useful in looking for gross sensory
abnormalities. In all cases in which noxious or invasive testing is needed, it
is important to explain to the family and others at the bedside what the
exam maneuvers and their purposes are before performing them, as noxious
stimuli can be distressing for loved ones to watch.
Coordination may be tested in patients who are arousable enough.

KEY POINTS
● The mental status exam in patients with altered consciousness primarily assesses the level
of responsiveness.
● The CN exam includes the testing of important brainstem reflexes, including the pupillary,
corneal, and oculocephalic reflexes.
● The remainder of the examination should be dedicated to looking for focal abnormalities.
FIGURE 3-2. Decorticate (above) and decerebrate (below) posturing. Both indicate brainstem
dysfunction, although decorticate posturing suggests dysfunction slightly more superior than
decerebrate posturing. (LifeART image Copyright © 2012 Lippincott Williams & Wilkins.)

DIFFERENTIAL DIAGNOSIS
In theory, there are two main ways in which consciousness can be
depressed: the brainstem can be dysfunctional or both cerebral hemispheres
can be dysfunctional simultaneously. As examples, acute disease in the
brainstem (e.g., pontine hemorrhage) can lead to coma, as can processes
affecting both cerebral hemispheres at once (e.g., hypoglycemia). Unilateral
cerebral hemispheric lesions, however, can also lead to coma if they are
large or severe enough to cause swelling and compression of the opposite
hemisphere or downward pressure on the brainstem.
Accordingly, most neurologists interpret the information obtained from
the exam of the comatose patient using the following principle: The
presence or absence of brainstem reflexes suggests how deep the coma is,
whereas the presence or absence of focal signs narrows the differential
diagnosis and guides the workup.
Thus, in milder cases of depressed consciousness, the pupillary, corneal,
and gag reflexes may all be preserved. In more severe cases, some or all of
these brainstem reflexes may be lost, no matter what the etiology. (Note that
if a brainstem reflex is abnormal in an asymmetric fashion, such as a
unilateral unreactive pupil, this would be interpreted as a focal sign and
suggests compression of, or primary disease in, the brainstem.)

BOX 3-1. Structural Causes of Depressed Consciousness

 Acute ischemic stroke
Brainstem
Unilateral cerebral hemisphere (with edema)
Acute intracranial hemorrhage
Intraparenchymal
Subdural
Epidural
Brain tumor (with edema or hemorrhage)
Primary
Metastatic
Brain abscess (with mass effect)

The presence of focal signs either on CN testing or in the remainder of

the examination—including such findings as hemiparesis, aphasia, reflex
asymmetry, facial droop, or a unilateral Babinski sign—suggests a
structural cause of depressed consciousness (Box 3-1). Examples include a
large unilateral stroke, abscess, tumor, or intracranial hemorrhage. The
absence of focal signs suggests a diffuse cause of depressed consciousness,
including metabolic, toxic, or hypoxic-ischemic etiologies (Box 3-2).
Examples include coma from fulminant hepatic failure, barbiturate
overdose, or anoxia following cardiac arrest. Remember to review
medications that were administered to the patient prior to the exam when
interpreting these findings because sedatives and paralytics can influence
the clinical findings and may mask brainstem functions transiently.

BOX 3-2. Diffuse Causes of Depressed Consciousness

Metabolic
Electrolyte abnormality
Hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia,
hypermagnesemia, hypophosphatemia
Glucose abnormality
Hypoglycemia, nonketotic hyperosmolar coma, diabetic ketoacidosis
Hepatic failure
Uremia
Thyroid dysfunction
Myxedema coma, thyrotoxicosis
Adrenal insufficiency
 Toxic
Alcohol
Sedatives
Narcotics
Psychotropic drugs
Other exogenous toxins (carbon monoxide, heavy metals)
Infectious
Meningitis (bacterial, viral, fungal)
Diffuse encephalitis
Hypoxic-ischemic
Respiratory failure
Cardiac arrest
Other
Subarachnoid hemorrhage
Carcinomatous meningitis
Seizures or postictal state

KEY POINTS
● In theory, consciousness can be depressed either by dysfunction of the brainstem or
dysfunction of both cerebral hemispheres simultaneously; in reality, large unilateral
hemispheric lesions (with pressure on the other side) qualify as well.
● The presence or absence of brainstem reflexes suggests how deep the coma is.
● The presence of focal signs suggests a structural cause of coma.
● The absence of focal signs suggests a diffuse cause of coma, such as metabolic, toxic,
infectious, or hypoxic-ischemic etiologies.
● Remember to review medications administered to the patient when interpreting the exam.

LABORATORY AND RADIOLOGIC STUDIES

The distinction between structural and diffuse causes of depressed
consciousness, arrived at by interpreting the findings on exam, suggests
different pathways of diagnostic workup.
The presence of focal findings on examination, suggesting a structural
cause, demands urgent head imaging, usually a noncontrast computed
tomography (CT) scan. One should look for signs of a large acute stroke, an
intracranial hemorrhage, or a mass lesion that may have enlarged rapidly or
had a hemorrhage within it. Contrast-enhanced CT should be avoided if an
acute hemorrhage is possible. Hemorrhages are readily evident on
noncontrast CT, but contrast enhancement can mimic hemorrhage when it is
used. Even in cases where focal brainstem signs are found, the initial choice
of head imaging may have to be a CT scan rather than magnetic resonance
imaging, despite the poor quality of the former in evaluating the brainstem,
because of the possibility of a large cerebral hemispheric lesion
compressing the brainstem and the usually more immediate availability of
CT.
The absence of focal findings on examination, suggesting a diffuse cause,
warrants an extensive workup for causes of metabolic, toxic, or infectious
etiologies. Blood testing, including complete blood count, electrolytes,
glucose, liver function tests, and toxicologic screen, is necessary. In women
of reproductive age, it is also prudent to obtain a pregnancy test, as this
impacts medication management. If infection is suspected, a chest X-ray,
urinalysis, and blood or urine cultures may be called for. There should be a
low threshold for obtaining a lumbar puncture (LP). If a basic workup is
unrevealing, one should search for more unusual causes (such as myxedema
coma, by checking thyroid function tests).
Head imaging is usually needed even in these cases of suspected diffuse
causes because it may demonstrate signs of global hypoxic-ischemic injury,
diffuse cerebral edema, or bilateral lesions mimicking a diffuse process,
although the urgency is not as high as for patients with focal findings.
Almost without exception, a head CT should be performed before obtaining
an LP in the evaluation of a patient with depressed consciousness, given the
risk of precipitating brain herniation if a large intracranial mass (particularly
in the posterior fossa) is present. If bacterial meningitis is suspected,
empiric antibiotic treatment can be started if CT scanning is delayed.
Frequently, an electroencephalogram (EEG) is ordered in patients with
coma or altered consciousness. Although many of its findings may be
nonspecific, the EEG can help to assess how deep a coma is based on the
degree of background slowing. In addition, there are occasionally more
specific patterns on EEG that suggest a particular diagnosis, such as hepatic
encephalopathy or anoxic brain injury. Finally, the EEG can help diagnose
nonconvulsive status epilepticus as a cause of coma in cases in which this is
(or is not) suspected clinically.

KEY POINTS
● If a structural cause of coma is suspected, urgent head imaging, usually with a noncontrast
head CT, should be performed.
● If a diffuse cause is suspected, an extensive workup for metabolic, toxic, or infectious
causes should be undertaken.
● Head imaging in suspected diffuse cases may demonstrate cerebral edema, signs of global
hypoxic-ischemic injury, or bilateral lesions mimicking a diffuse process.
● Almost without exception, head CT should be performed before LP.
● EEG can assess the depth of coma and can occasionally suggest a specific diagnosis.

TREATMENT AND PROGNOSIS

The treatment of coma and altered consciousness depends on the specific
diagnosis. Metabolic, infectious, or toxic etiologies require mostly medical
management, whereas some structural causes of coma may require
neurosurgical intervention. Specific treatments for particular conditions are
detailed in later chapters, in particular Chapter 14 for strokes and
hemorrhages, Chapter 17 for head trauma, Chapter 18 for systemic and
metabolic disorders, Chapter 19 for brain tumors, and Chapter 21 for central
nervous system (CNS) infections.
When increased intracranial pressure (ICP) is suspected clinically or
radiologically, treatments aimed at lowering ICP should be applied. These
include raising the head of the bed, hyperventilation, and the use of an
osmotic diuretic such as mannitol. Corticosteroids tend to be useful in cases
of edema associated with brain tumors. The lowering of ICP may be a
neurologic or neurosurgical emergency if the patient shows signs of brain
herniation, which is discussed in more detail in Chapter 17.
The prognosis of depressed consciousness is mostly dependent on
etiology. The patient with a barbiturate overdose may recover completely,
whereas one with a severe anoxic injury often does not. Age is an important
prognostic factor as well. One of the most frequent reasons for admission to
an intensive care unit or for neurologic consultation is to estimate the
prognosis of a patient in coma following cardiopulmonary arrest. Currently,
the standard of care for patients with cardiac arrest is usually to undergo
therapeutic hypothermia (aiming for a core body temperature between 32°C
and 34°C) in the acute phase—which has been demonstrated to lead to
better neurologic outcomes compared with normothermia or hyperthermia.
In these cases, the circumstances and duration of the cardiac arrest are
important, and published studies have correlated outcomes with findings on
neurologic examination performed at least 24 hours after the arrest.

KEY POINTS
● The treatment of coma or altered consciousness depends on the etiology.
● The lowering of ICP may be a neurologic emergency if the patient shows signs of brain
herniation.
● Therapeutic hypothermia is currently the standard of care in the acute phase for most post-
cardiac arrest patients.
● Prognostic factors for coma or altered consciousness include both etiology and patient age.

SPECIAL TOPICS

PERSISTENT VEGETATIVE STATE

Persistent vegetative state is a state in which patients have lost all
awareness and cognitive function but may remain with the eyes open,
exhibit sleep–wake cycles, and maintain respiration and other autonomic
functions. Patients may progress into this state after being in coma for a
prolonged period if their vital functions have been supported.

MINIMALLY CONSCIOUS STATE

The minimally conscious state (MCS) is defined by the Aspen Work Group
as “a condition of severely altered consciousness in which minimal, but
definite, behavioral evidence of self or environmental awareness is
demonstrated.” Patients can emerge from a vegetative state into an MCS.
The diagnosis of MCS is made by reproducible behaviors on exam as
outlined in Table 3-2 and includes following a simple command,
verbalization, and purposeful behaviors or responses that are
environmentally appropriate. The most common finding is sustained visual
fixation and pursuit. Patients in the MCS may have some limited awareness
of self or the environment—which differs from patients in a vegetative state
who do not have evidence of any awareness.

TABLE 3-2. Criteria for the Determination of the Minimally Conscious

State
A patient must demonstrate at least one of these features:
• Following simple instructions
• Can give a yes or no answer, either with a verbal response or a motor cue
• Can communicate verbally, and understandably
A patient must exhibit intentional or affective behavior in response to the immediate environment,
e.g.:
• Emotional responses (joyous or tearful) that are appropriate to verbal or visual stimuli (and that
are not elicited by neutral stimuli)
• Utterances or gesticulations in response to verbal questions
• Purposeful reaching for objects in which the intention of the movement toward the object is
clear
• Sustained gaze fixation on an external visual cue, visual pursuit, adjustment of grasp, or
movement in response to the shape of an object

Imaging modalities have also been used in hopes of identifying reliable

biomarkers to differentiate between the MCS and the persistent vegetative
state. Fluorodeoxyglucose positron emission tomography, functional
magnetic resonance imaging, and quantitative EEG have been shown in
some studies to demonstrate differences between these two conditions when
patients are given a cognitive challenge or instruction. Nevertheless, these
diagnostic techniques are not used routinely in most clinical practice as
controversies remain regarding their sensitivity and specificity.

LOCKED-IN SYNDROME
Although a locked-in syndrome can be confused with coma at first glance, a
patient with locked-in syndrome is awake and may be intact cognitively,
with no abnormality of consciousness. Usually a consequence of large
lesions in the base of the pons, the locked-in syndrome leaves patients
unable to move the extremities and most of the face. If all other motor
function is lost, patients may be limited to communicating by vertical eye
movements or blinks.
BRAIN DEATH
Death can be declared either when there has been irreversible cessation of
cardiopulmonary function or there has been irreversible cessation of all
functions of the entire brain, including the brainstem. A declaration of death
based on the latter criterion is commonly referred to as brain death. The
American Academy of Neurology has established evidence-based
guidelines on the diagnosis of brain death, and many institutions have
specific guidelines for how brain death must be determined based on these
guidelines. In general, the patient must be comatose, with a known and
presumed irreversible cause, have absent brainstem reflexes, and have no
spontaneous respirations even when the PCO2 has been allowed to rise (the
apnea test). Other causes of coma must be excluded, and confounding
factors such as hypothermia or CNS-depressant drugs must not be present.
The clinical diagnosis of brain death does not require ancillary testing
such as EEG or cerebral angiogram. These tests may be omitted when the
clinical diagnosis is clear, because they (very infrequently) give misleading
results. Ancillary testing may be used when there is uncertainty regarding
the diagnosis—because of the unreliability of the neurologic exam or when
an apnea test cannot be performed. In brain death, the EEG should
demonstrate an absence of reactivity to somatosensory or audiovisual
stimuli. Cerebral blood flow studies will demonstrate no intracerebral
filling above the carotid or vertebral arteries.

KEY POINTS
● A persistent vegetative state may follow prolonged coma and is characterized by preserved
sleep–wake cycles and maintenance of autonomic function, with the absence of awareness
and cognition.
● An MCS is a condition of impaired consciousness with retention of some environmental
awareness or self-awareness.
● Locked-in syndrome, in which awareness and cognitive function are preserved but almost
complete paralysis occurs, is often caused by large lesions in the base of the pons.
● Brain death is a declaration of death based on irreversible cessation of all brain function.
● Prognosis can also be aided using blood flow studies and EEG.

ACUTE CONFUSIONAL STATE

Definition
The terms confusion, delirium, and encephalopathy are often used
nonspecifically to indicate a disturbance of mental status in which the
patient is unable to carry out a coherent plan of thought or action. Most
neurologists employ the terms confusion or encephalopathy, whereas
delirium (commonly used by psychiatrists) often implies a state of
confusion characterized by a waxing and waning level of alertness and,
sometimes, agitation.
At its core, an acute confusional state results from a problem of attention.
Thus, a patient’s failure to answer questions in a coherent manner or to
carry out an intended series of actions in an expected way derives from an
inability to maintain attention for long enough to proceed through the
cognitive or motor steps required for the task. On formal mental status
testing, therefore, patients with confusion typically do poorly on standard
tests of attention, such as spelling the word “world” in reverse, reciting the
months of the year backward, or completing serial subtractions. Such
inattention may be significant enough to render impossible the performance
of more detailed mental status testing. These cognitive deficits may also
fluctuate, as do the levels of alertness. The term encephalopathy or
encephalopathic is therefore used frequently by neurologists to describe
patients who are unable to maintain attention because of a toxic or
metabolic derangement. This is different from patients with progressive
dementia syndromes or attention deficit disorder whose deficits are more
fixed. Depending on the underlying etiology of the acute confusional state,
other associated features on neurologic or general physical examination
might aid in the diagnosis—such as asterixis in a patient with hepatic (or
other) encephalopathy.

Differential Diagnosis
The differential diagnosis of acute confusion includes a number of different
disorders, such as aphasia (particularly Wernicke-type), psychosis, and
complex partial seizures. Patients with Wernicke aphasia may appear
“confused” but in fact are attentive and able to carry out coherent series of
actions; their deficit lies solely in their ability to communicate. Although
patients with psychosis may also behave as if they are acutely confused,
pure confusional states do not result in frank psychotic symptoms like
hallucinations or delusions. Complex partial seizures can be characterized
by behavior that appears “confused,” but seizures are typically self-limited
in duration and may be associated with clonic motor movements or
automatisms such as lip-smacking.

Diagnostic Evaluation
An acute confusional state is most commonly caused by an underlying
systemic or neurologic disorder, including infection, metabolic disturbance,
inflammatory condition, or hypoxic-ischemic state, among many
possibilities. Focal brain disorders, particularly acute right hemispheric
lesions, can also lead to confusion. The appropriate diagnostic workup in a
patient with confusion is therefore potentially quite extensive. Blood work
and urinalysis to search for infectious or metabolic disturbances are often
warranted. If there is clinical suspicion for a CNS infection, cerebrospinal
fluid (CSF) analysis should be performed. Neuroimaging should be
obtained if the neurologic history or examination suggests the possibility of
an acute focal lesion. An EEG can help to determine whether there is a
widespread dysfunction (encephalopathy), focal abnormalities, or ongoing
seizures. It is unlikely to demonstrate the precise cause of an acute
confusional state but can help to confirm a diagnosis, as characteristic
findings of an encephalopathy may be present, and in some cases the EEG
can help diagnose nonconvulsive status epilepticus.

Treatment and Prognosis

The treatment and prognosis of acute confusional states depend largely on
the underlying etiology. Most cases of confusion arise from a reversible
underlying cause and will resolve if the underlying disorder is treated
appropriately. Confusional states arising from structural neurologic lesions
or more chronic underlying disturbances may be less likely to improve
spontaneously.

KEY POINTS
● An acute confusional state, also sometimes called encephalopathy or delirium, is
characterized by an inability to carry out a coherent plan of thought or action.
● Acute confusion is primarily the result of a core problem with attention.
 Systemic infections and metabolic disturbances are common causes of an acute
● confusional state, although many possible etiologies exist.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old homeless man is brought into the emergency room (ER)
by police after he was found unresponsive on a sidewalk in the middle
of the night. The police indicate that with vigorous shaking, they were
able to get him to open his eyes briefly, but then he began speaking
“nonsense” and fell back asleep quickly. On arrival to the ER, the
patient is afebrile, heart rate is 120, blood pressure is 90/50 mm Hg, and
respiratory rate is 12.
1. Which of the following assessments or interventions for an
unresponsive patient should not be done immediately upon arrival
to the ER?
a. Fingerstick blood glucose check
b. Maintenance of airway, breathing, and circulation
c. Evaluation of pupillary and other brainstem reflexes
d. LP for CSF analysis
e. Administration of thiamine
2. Initial screening neurologic exam shows that the patient can only
sustain attention for 10 to 20 seconds after vigorous stimulation
before closing his eyes again and becoming unresponsive. He
cannot perform any serial tasks forward or backward, and only
follows a single simple command at a time. He has prominent
horizontal nystagmus when he keeps his eyes open, and wobbles
noticeably when trying to sit up straight. There are no other focal
findings. A social worker who knows the patient from a nearby
shelter reports that he has problems with chronic alcohol abuse.
What is the most likely diagnosis?
a. Wernicke encephalopathy
b. Korsakoff syndrome
c. Hepatic encephalopathy from alcoholic cirrhosis
d. Cerebellar degeneration
 e. Carcinomatous meningitis (leptomeningeal metastasis)

ANSWERS

VIGNETTE 1 QUESTION 1
Answer D:
Although LP for CSF analysis may be necessary to rule out infectious
meningitis, it should only be performed after the clinician is certain that
there is no intracranial mass, particularly in the posterior fossa. Whereas
in certain circumstances, an LP could be performed after a careful
funduscopic examination rules out raised ICP (e.g., by confirming the
presence of venous pulsations), in most situations a noncontrast head
CT should be performed first to rule out a mass or bleeding.
Maintenance of the ABCs, fingerstick blood glucose check, a
screening neurologic exam focused on brainstem reflexes, the
identification of clear focal neurologic deficits, and administration of
thiamine are all standard assessments or interventions that can (and
should) be performed immediately for an unresponsive patient.

VIGNETTE 1 QUESTION 2
2. Answer A:
Wernicke encephalopathy, commonly seen in the setting of thiamine
deficiency in chronic alcoholism, is characterized by an acute
confusional state, sometimes progressing to frank coma, eye movement
abnormalities (often nystagmus or horizontal gaze deficits), and ataxia
(in this case an inability to maintain midline posture). Autonomic signs
are frequent. Treatment with parenteral thiamine can reverse or improve
the neurologic impairment to varying degrees.
Korsakoff syndrome is a long-term memory disorder, characterized
by anterograde amnesia and confabulation, that can arise after acute
Wernicke encephalopathy has resolved. Although an alcoholic patient
may be at risk for hepatic encephalopathy or cerebellar degeneration,
and carcinomatous meningitis can cause an acute confusional state,
those are not the most likely causes of this patient’s current clinical
presentation.
 4 Neuro-Ophthalmology

Neuro-ophthalmology is a field that helps elucidate the causes of visual

symptoms, such as double vision (diplopia), and signs including pupillary
dysfunction and eye movement abnormalities. Because these symptoms and
signs can reflect lesions at multiple points along a complex path from the
eye to the brain, or even more generalized systemic illnesses, it is important
to take a careful history. The presenting details narrow the differential and
guide the choice of specialized tests during the neuro-ophthalmologic
examination. This examination focuses on factors including visual acuity,
visual fields, the optic disc, pupillary function, eye movements, and eyelid
elevation. Sometimes, a combination of findings forms a pattern that
reflects a well-recognized syndrome.
The ability to localize lesions and identify syndromes to generate a plan
for investigation and management depends on understanding the structures
that play a role in visual systems. It is also important to comprehend how
they interact with the external environment. The more anterior parts of the
visual system (i.e., the eyes and optic nerves) allow exploration of visual
space. The posterior cerebral hemispheres are involved in the integration
and perception of visual information through higher cortical function—as
discussed in Chapter 11.

ANATOMY OF VISUAL PATHS, PUPILS, AND

OCULOMOTOR NERVES
Light enters the cornea and stimulates the rods and cones in the retina,
generating electrical signals that are transmitted through the optic nerve.
Fibers from the nerve of each eye cross at the optic chiasm before forming
the optic tracts. Ninety percent of retinal axons in these tracts terminate in
the lateral geniculate nucleus of the thalamus, the principal subcortical
structure that carries visual information to the cerebral cortex through the
optic radiations. The primary visual cortex is visual area 1, corresponding to
Brodmann area 17 (striate cortex), which receives information from the
contralateral visual hemi-field. This information is then transferred to the
associative visual cortex, including areas 18 and 19, and to higher order
centers in the posterior parietal and inferior temporal cortices, where the
perception of motion, depth, color, location, and form takes place. The
visual pathway and associated visual field defects are shown in Figure 4-1.
Pupil size is determined by parasympathetic and sympathetic influences.
The pupil controls light transmission through the initial part of the visual
pathway, including the optic tract. The optic tract synapses with the
Edinger–Westphal nucleus (EWN) in the rostral aspect of the third nerve
nucleus. Efferent parasympathetic fibers from the EWN travel with the third
cranial nerve (CN III). In the cavernous sinus, they run with the inferior
division of CN III and synapse in the parasympathetic ciliary ganglion in
the posterior orbit. Parasympathetic fibers ultimately innervate
pupilloconstrictor muscles in the iris (Fig. 4-2).
Sympathetic fibers effect pupil dilation via a three-neuron route. First-
order neurons project down from the hypothalamus to an initial synapse in
the intermediolateral cell column from C8 to T2 spinal levels (the
“ciliospinal center of Budge”). Second-order neurons then travel from the
sympathetic trunk to the superior cervical ganglion located near the
bifurcation of the common carotid artery. Third-order neurons then travel in
the adventitia of the internal carotid artery to join the first division of the
trigeminal nerve to innervate elements of the orbit and eye, including the
pupillodilator muscles (Fig. 4-3).
FIGURE 4-1. Visual pathways (figure, left; Note: this diagram is as if from an MRI scan: right
side of brain on the left and left side of the brain on the right.) and visual field defects associated with
lesions along the visual pathway (table, right). Light entering from the nasal visual field stimulates
photoreceptors of the temporal retina, and vice versa. Photoreceptors transmit signals to bipolar cells
and then retinal ganglion cells. Ganglion cell axons form the nerve fiber layer of the retina and enter
the optic nerve (1 and 2). Each optic nerve carries visual information from one eye. (Arteritic and
nonarteritic anterior ischemic optic neuropathy may be associated with altitudinal deficits.) The two
optic nerves form the optic chiasm (3). Fibers from nasal halves of the retina (carrying information
from the temporal visual fields) decussate at the optic chiasm and join temporal fibers (carrying
information from the nasal visual fields) from the contralateral eye to form the optic tracts (4). Each
optic tract carries visual information from the contralateral visual field. Each optic tract synapses
with neurons at the lateral geniculate nucleus (LGN) on the same side (some fibers involved in the
light reflex do not reach the LGN but go instead to the pretectal nucleus as part of the pupillary light
reflex). From the LGNs, signals are transmitted through the geniculocalcarine tract (5, 6, and 7).
Fibers that carry visual information from the upper contralateral visual fields travel through Meyer’s
loop in the temporal lobes; fibers carrying visual information from the lower contralateral visual field
travel through the parietal lobes. Visual information from the contralateral visual field reaches the
occipital (calcarine) cortex (8). Strokes affecting the PCA may be associated with macular sparing
because the macula is also supplied by the MCA. AMD, age-related macular degeneration; CRAO,
central retinal artery occlusion; CRVO, central retinal vein occlusion; MCA, middle cerebral artery;
PCA, posterior cerebral artery. Reprinted with permission from Chowdhury SH, Chowdhury JH,
Cozma AI. Essentials for the Canadian Medical Licensing Exam: Review and Prep for MCCQE. 2nd
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2016. Figure 15-5.

FIGURE 4-2. Eye movement abnormalities related to brainstem lesions of the abducens nerve
or nucleus or both, and of the medial longitudinal fasciculus (MLF), causing deficits of eye
movements in the horizontal plane. (The diagram depicts a coronal view of the brainstem, with
midbrain structures above and pontine structures below.) (1) Lesion of the abducens nerve root:
Motor neurons in the abducens nucleus innervate the ipsilateral lateral rectus muscle, so a patient
with a lesion of the abducens root external to the pons has a loss of voluntary lateral gaze in the eye
on the side of the lesion, with paralysis of the lateral rectus muscle. Other movements in the affected
eye, and all movements in the contralateral eye, are normal. The patient will have diplopia. When
looking straight ahead, the eye on the lesioned side will deviate slightly toward the midline (given the
unopposed action of the medial rectus in the same eye). The diplopia is made worse when attempting
to look toward the lesioned side in a horizontal plane. (2) Caudal basilar pontine lesion: Because
axons arising from abducens motor neurons pass through the basilar pons, they are located laterally
adjacent to corticospinal fibers. A lesion in this portion of the pons may simultaneously damage the
exiting abducens fibers and corticospinal axons. A patient with this lesion may have a crossed
hemiplegia, paralysis of the lateral rectus muscle on the side of the lesion (with loss of voluntary
lateral gaze to that side, and diplopia), and a paralysis of the arm and leg on the opposite side of the
body. (3) Internuclear ophthalmoplegia (INO): In addition to abducens motor neurons that
innervate the ipsilateral lateral rectus muscle, the abducens nucleus also contains interneurons. The
axons of these interneurons cross the midline, enter the MLF, and ascend to terminate on motor
neurons in the oculomotor nucleus that innervate the medial rectus muscle on that side. A lesion in
the MLF interrupts these axons and results in a loss of medial gaze (medial rectus paralysis) in the
eye on the side of the lesion during attempted conjugate eye movements. Other movements in the
affected eye and all movements in the contralateral eye are normal. (Thus, a right INO specifies a
lesion in the right MLF and paralysis of the right medial rectus muscle.) (4) A lesion of the abducens
nucleus damages α motor neurons innervating the ipsilateral lateral rectus muscle and the
interneurons that terminate on medial rectus α motor neurons in the contralateral oculomotor nucleus.
A patient with this lesion has loss of horizontal gaze in both eyes during attempted voluntary eye
movement toward the side of the lesion; horizontal gaze toward the contralateral side is normal. (This
is basically an abducens root lesion plus an INO.) (5) The one-and-a-half syndrome is so named
because a unilateral pontine lesion may result in a loss of medial and lateral voluntary eye movement
on the side of the lesion (the “one”) and a loss of medial horizontal eye movement on the
contralateral side (the “one-half”). This lesion involves the abducens nucleus on one side (deficits =
lateral rectus paralysis on the side of the lesion, medial rectus paralysis on the contralateral side) and
the immediately adjacent MLF conveying the axons of abducens interneurons originating in the
opposite abducens nucleus (deficit = medial rectus paralysis on the side of the lesion). These lesions
are usually large and involve portions of the paramedian pontine reticular formation, commonly
called the horizontal gaze center. Reprinted with permission from Haines DE. Neuroanatomy: An
Atlas of Structures, Sections, and Systems. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2011.
FIGURE 4-3. Parasympathetic pathway mediating pupillary constriction to light. The axons of
the retinal ganglion cells project to the pretectal area. The neurons in the pretectal area send
projections to the preganglionic parasympathetic neurons of the ipsilateral and contralateral Edinger–
Westphal nuclei (EWN). The axons of the neurons in each EWN exit through the ipsilateral
oculomotor nerve and project to the corresponding ciliary ganglion. The postganglionic fibers of the
ciliary ganglion innervate the ciliary muscle. CN, cranial nerve.

Eye movements are facilitated by the oculomotor (III), trochlear (IV),

and abducens (VI) CNs. CN III innervates the contralateral superior rectus
and ipsilateral medial rectus, inferior rectus, levator palpebrae, pupil
constrictors, and inferior oblique muscles. CN IV innervates the superior
oblique muscle that intorts and depresses the adducted eye. CN VI
innervates the lateral rectus muscle, which abducts the eye. The medial
longitudinal fasciculus (MLF) connects the contralateral abducens nucleus
and paramedian pontine reticular formation (PPRF) with the ipsilateral third
nerve nucleus; it effectively yokes the eyes for coordinated horizontal
movements. Vertical eye movements are controlled by the rostral interstitial
nucleus of the MLF (riMLF), which resides in the midbrain near the CN III
nucleus. Fibers controlling upgaze cross in the posterior commissure to
communicate with the contralateral inferior oblique and superior rectus
subnuclei of the CN III complex.

KEY POINTS
● Visual perception depends on the transmission of signals that travel through a multi-step
pathway including the retina, optic nerve, optic chiasm, optic tracts, lateral geniculate
nucleus, and optic radiations on their way to the visual cortex.
● The primary visual cortex receives information from the contralateral visual hemi-field.
● Parasympathetic fibers from the Edinger–Westphal nucleus play an important role in pupil
constriction.
● Sympathetic fibers travel in a three-neuron path from the hypothalamus to the
intermediolateral cell column/ciliospinal center and then to the superior cervical ganglion
before joining the first division of the trigeminal nerve to innervate pupil dilators.
● Extra-ocular movements are governed by six muscles served by CNs III, IV, and IV.

HISTORY
As in all branches of medicine, the history is key in characterizing
symptoms such as eye pain, eyelid droop, and visual disturbance. It is
important to ask about antecedent trauma. If there is no identifiable trigger,
inquiring about the timing of symptom onset can be helpful. For example,
the sudden onset of visual symptoms makes vascular causes more likely.
Diurnal variations in symptoms can also provide a clue: Patients with
myasthenia gravis often experience worsening double vision and eyelid
droop at the end of the day. Exploring associated symptoms is important:
Does the patient have concomitant limb weakness that could point to a
stroke? Review of systems can uncover diagnostic hints such as prior
transient neurologic deficits, which could point to vascular cause or
multiple sclerosis. Similarly, medical and surgical history can be
informative (e.g., diabetes can predispose to sudden, painful dysfunction of
CN III, or less frequently, CN IV or VI). Prior cataract surgery can change
pupillary reactivity and be associated with an eyelid droop. A review of
recently used medications is essential because oral antiseizure drugs, topical
agents such as apraclonidine (used for glaucoma), transdermal scopolamine,
inhaled ipratropium, and injected botulinum toxin can cause symptoms and
signs on exam. Habits such as alcohol ingestion are important to ask about
because intoxication and vitamin deficiencies may be relevant. Finally, a
family history of neurologic symptoms (e.g., gait imbalance or
incoordination) raises the possibility of genetic disorders (e.g.,
spinocerebellar ataxia) that can be accompanied by visual deficits.

CHARACTERIZING COMMON CHIEF

CONCERNS
DIPLOPIA
Neurologists and ophthalmologists commonly evaluate patients who report
blurred or frankly double vision. Double vision results from a misalignment
of the eyes, either as a decompensation of a previous strabismus or more
commonly as a symptom of one of many neurologic disorders. To help
narrow the differential, a pertinent history is important. Four questions are
particularly worthwhile: (1) Does the double vision improve with closure of
one eye? The aim is to determine if the lesion is monocular (involves one
eye) or binocular (involves both eyes). Monocular visual loss implies a
problem in the eye, optic nerve, or chiasm. Binocular visual loss reflects a
chiasmal or retrochiasmal lesion. (2) Does the double vision emerge when
looking in a particular direction (e.g., up, down, left, or right)? Answers
help determine which extra-ocular muscles could be weak, as does the next
query. (3) Do the two images appear side by side, one directly above the
other, or with a skew? Finally, (4) Does the double vision worsen when
looking at objects up close or far away? Whereas intact medial rectus (CN
III) function is needed for near gaze, CN VI is needed for far gaze.
POSITIVE AND NEGATIVE VISUAL PHENOMENA
Visual disturbances, as with other sensory symptoms, can be described as
negative or positive phenomena. Negative visual phenomena can be
described as blackness, grayness, dimness, or a shade that obscures vision
(i.e., amaurosis fugax), as seen in patients with strokes or transient ischemic
attacks. When decreased vision is unilateral and associated with eye pain
that worsens with movement, optic neuritis is an important consideration.
Positive visual phenomena include brightness, shimmering, sparkling,
shining, flickering, or colors, often suggesting migraine or seizures. In the
Charles Bonnet syndrome, simple and complex, nonstereotyped
hallucinations (including of scenes and people) occur in the setting of
acquired visual loss. A “release phenomenon,” it is most common with
chronic disease, impaired visual acuity, and known binocular disease (e.g.,
glaucoma). Altered perception of the external environment can also
manifest as the illusion of movement (oscillopsia).

KEY POINTS
● Determine if an eyelid abnormality is congenital or acquired using the history and
photographs.
● If there is diurnal variation, determine if the application of ice decreases the degree of
ptosis, as can be seen in myasthenia gravis.
● Assess for other historical and clinical signs to characterize the ptosis.

SPECIALIZED EXAMINATION
TECHNIQUES: LOOKING FOR SIGNS AND
SYNDROMES
Building on the examination outlined in Chapter 1, more in-depth testing is
required to define neuro-ophthalmologic deficits. Of particular note are
structures and function related to the eyelid, pupil, optic disc, vision, and
extra-ocular movements. At least some elements of the neuro-
ophthalmologic examination can be performed in all patients, whether they
are assessed in the intensive care unit or outpatient clinic.
EYELID
Eyelid abnormalities may be the first feature noted when evaluating
patients. The palpebral fissure (the distance between the upper and lower
eyelid margins in line with the pupil) measures 9 to 12 mm in healthy
adults. The upper lid comes about 1 mm down over the cornea and the
lower lid up to the intersection of the cornea and sclera. “Ptosis” generally
refers to an abnormal droop of the upper eyelid, such that it covers at least
part of the pupil. Conversely, “upside-down ptosis” refers to elevation of
the lower lid. In addition to abnormal lid closure, one can detect lid
retraction with ptosis.
As an initial step, it is important to distinguish whether an eyelid
abnormality is congenital or acquired. Looking at photographs or driver’s
licenses can help establish chronicity. Improvement in acquired forms of
ptosis after the application of ice for 2 minutes suggests a neuromuscular
junction disorder (myasthenia gravis), although ptosis can also stem from a
primary muscle disease (e.g., myotonic or oculopharyngeal muscular
dystrophy), CN dysfunction (CN III lesion), or a central process. Beyond
the neurologic system, structural changes can involve the eyelid; for
example, eyelid infections can alter lid appearance. Contact lens use and
natural aging can lead to the spontaneous dehiscence of the levator
aponeurosis—mimicking ptosis. Lid retraction, on the other hand, might
reflect a CN VII lesion (as can be seen with a Bell’s palsy) or
hyperthyroidism. The latter possibility should prompt assessment of the
globe for signs of concomitant proptosis.

KEY POINTS
● Determining if double vision is worse with both eyes open (i.e., binocular), elicited by a
particular direction or distance of gaze, or associated with images in a particular
orientation can help localize the lesion.
● Negative visual phenomena include loss of vision, often due to a vascular cause or
inflammation.
● Positive visual phenomena include lights, colors, and hallucinations; potential causes
include migraine, seizure, and the Charles Bonnet syndrome.

PUPIL
Examination of the pupil requires attention to size and reactivity to light
and near objects.
Size: factors affecting resting pupil size include emotional state, age, and
intraocular pressure. When conducting an examination of asymptomatic
individuals, one can encounter a difference in right and left pupil size
(anisocoria). Side-to-side asymmetries can be benign, or “physiologic.” In
general, physiologic asymmetries are within 0.4 mm.
Asymmetries can also become apparent when one pupil becomes
abnormally small (miosis) or large (mydriasis). Distinguishing which pupil
is abnormal can be determined preliminarily by assessing the degree of
asymmetry in the light and dark. If the anisocoria is most pronounced in the
light, the abnormal pupil is the larger one; it is pathologically dilated
(mydriatic). Mydriasis can be a function of problems anywhere along the
path from the CN III nucleus in the midbrain, along the CN III, to the iris.
With midbrain lesions, the mydriasis is often associated with other signs
including weakness, nystagmus, and loss of consciousness. Drugs (e.g.,
topical apraclonidine) are also commonly associated with asymmetric
pupillary dilation—if administered unilaterally. In this case, there is no
associated pain, ptosis, or diplopia.
If the anisocoria is more apparent in the dark, the abnormal pupil is the
smaller one; it is pathologically constricted (miotic). It may demonstrate a
lag of seconds before starting to dilate in dark conditions. When this occurs,
there is a sympathetic system defect. Miosis should always prompt a full
evaluation for Horner’s syndrome (HS), which is characterized by
unilateral miosis, ptosis, and (depending on the level of the lesion) impaired
ipsilateral facial flushing and sweating (anhidrosis). There are many
different causes of HS (Box 4-1). In each case, the syndrome can be
confirmed by the absence of dilation in response to cocaine eye drops.
Hydroxyamphetamine eye drops can then help to distinguish a
preganglionic from a postganglionic third-order neuron HS (the pupil with a
postganglionic HS fails to dilate with hydroxyamphetamine).
Reactivity: To test pupil reactivity, a bright light is flashed alternately for
2 to 3 seconds in each eye. If one pupil appears to dilate when the light is
directed toward that eye, but it constricts appropriately when light is
directed toward the other eye, there is a relative afferent pupillary defect
(RAPD). The affected pupil is also known as a Marcus Gunn pupil. A
normal pupil constricts reflexively not only to adjust to light but also to
view objects held at reading distance. A pattern of “light near dissociation”
(LND) occurs when an individual has impaired pupil constriction to light
but intact pupil constriction to objects placed close to the eye. This pattern
of “accommodation without reaction” is commonly affiliated with an
Argyll Robertson pupil, which can be a sequela of syphilis. LND can also
be a sign of a tonic (Adie) pupil. A tonically dilated pupil results from the
interruption of the parasympathetic supply from the ciliary ganglion and
can be seen in the setting of problems with the retina, optic nerve, chiasm,
or optic tract. Enhanced contraction of the affected pupil to 0.1%
pilocarpine supports the diagnosis of a tonic pupil.

BOX 4-1. Etiology of Horner’s Syndrome

First-order (or central):
Hypothalamic infarcts, tumor
Mesencephalic stroke
Brainstem: ischemia (Wallenberg syndrome), tumor, hemorrhage
Spinal cord: syringomyelia, trauma
Second-order (or preganglionic):

Cervicothoracic cord/spinal root trauma

Cervical spondylosis
Pulmonary apical tumor: Pancoast tumor
Third-order (or postganglionic):
Superior cervical ganglion (tumor, iatrogenic)
Internal carotid artery: dissection, trauma, thrombosis, tumor
Base of skull: tumor, trauma
Middle ear problems
Cavernous sinus: tumor, inflammation (Tolosa–Hunt syndrome), aneurysm, thrombosis,
fistula

KEY POINTS
● If anisocoria is more apparent in the dark, the abnormal pupil is the smaller (miotic) one.
Consider a HS when miosis is accompanied by a mild ptosis and, possibly, facial
anhidrosis.
● If the anisocoria is more apparent in the light, the abnormal pupil is the larger (mydriatic)
one; consider a CN III lesion.
 ● An RAPD is dilation of a pupil on direct stimulation of light, with preserved consensual
constriction with light stimulation of the contralateral pupil; the finding raises the
possibility of an optic nerve lesion.
● LND occurs when an individual has impaired pupil constriction to direct stimulation by
light but intact constriction to objects placed close to the eye, as can be seen in Adie or
Argyll Robertson pupillary defects.

OPTIC DISC
Examination with an ophthalmoscope is essential to assess for disc
abnormalities including pallor, loss of nearby venous pulsations, and
blurring of disc margins, as can be seen with swelling of the optic disc. The
term papilledema implies optic disc swelling from blockage of axoplasmic
transport in the optic nerve resulting from increased intracranial pressure
(ICP); it is often painless and bilateral. Papilledema is unilateral in the
Foster–Kennedy syndrome, which refers to ipsilateral optic disc atrophy
(due to compression of the optic nerve by a mass lesion in the frontal lobe)
and papilledema in the contralateral optic disc (due to increased ICP). The
term papillitis refers to swelling of the optic disc from other local or
systemic causes such as viruses and rheumatologic disorders. It can be
associated with painful eye movements and is generally unilateral. Another
cause of unilateral optic disc swelling is anterior ischemic optic neuropathy
(AION), which is painless and further classified as nonarteritic or arteritic.
The nonarteritic form is associated with atherosclerotic risk factors. The
arteritic form is often seen in the setting of giant cell arteritis (GCA).

KEY POINTS
● Papilledema is optic disc swelling from increased ICP; it is often bilateral.
● Papillitis refers to swelling of the optic disc from other local or systemic causes; it is often
unilateral.
● Foster–Kennedy syndrome refers to ipsilateral optic disc atrophy and contralateral
papilledema, due to a frontal lobe mass.
● AION is a painless, unilateral condition associated with atherosclerotic risk factors
(nonarteritic) or GCA (arteritic).

VISION
In the very ill patient, it may only be possible to evaluate vision by learning
if there is a preserved ability to “blink to threat.” This phenomenon
describes when a patient closes an eye when an object, such as the
examiner’s finger, is presented quickly to a given visual field. Each eye
should be tested for a response.
In a fully conscious patient, visual acuity (VA) can be checked one eye at
a time using a distance chart (e.g., a handheld Snellen chart) with good
illumination. If VA is poor, have the patient read through a pinhole. If the
use of the pinhole improves VA, a problem with refraction has been
identified. If the patient is unable to read letters, try counting fingers,
followed by perception of movement, and finally perception of a bright
light. Impairment of VA usually represents a defect in the refractive
apparatus of the eye, in the optic nerve, or both. Rarely, chiasmal or
retrochiasmal lesions cause diminished VA. Color vision can also be tested
by using Ishihara plates. Another method is looking for red desaturation
(decreased perception of red color or its intensity), which often suggests an
optic neuropathy or neuritis. Visual field testing at the bedside is done by
confrontation, evaluating each eye individually. While the patient looks at a
fixed target near your own center of visual field (such as your nose), move
your fingers or a small object in the different quadrants and compare the
patient’s visual field to yours.
Vision loss with eye pain that worsens with movement raises concern for
optic neuritis. A loss of color vision out of proportion to the VA loss
supports this diagnosis. Particularly in young patients, these findings
suggest demyelinating disorders such as multiple sclerosis and
neuromyelitis optica. In patients older than 50 years, ischemic optic
neuropathies (e.g., as with GCA) are more likely. In immunocompromised
patients, unilateral eye pain and visual loss in the context of sensory change
on the ipsilateral forehead, headache, malaise, and fever should raise the
possibility of zoster ophthalmicus—even before the appearance of
characteristic lesions; suspicion for this diagnosis should be even higher if
vesicular lesions are noted on the nose (Hutchinson’s sign) because the
globe is also innervated by the nasociliary branch of the trigeminal nerve.
Box 4-2 shows some causes of visual loss categorized by lesion location.
 KEY POINTS
● Test VA and fields one eye at a time.
● Ocular and refractory, rather than neurologic, problems are suggested by improvement in
VA when using a pinhole.
● The combination of vision loss, abnormal color vision, and pain with eye movements in a
young patient raises concern for a demyelinating disorder such as multiple sclerosis or
neuromyelitis optica.

EYE ALIGNMENT AND MOVEMENTS: CRANIAL

NERVES III, IV, AND VI
Abnormal eye position and movements can result from lesions in individual
extra-ocular muscles, abnormalities of the neuromuscular junction, or
dysfunction of the oculomotor nerves, their central nuclei, or central
connections. The most common cause of oculomotor nerve dysfunction in
older adults is brainstem microvascular ischemia, commonly associated
with hypertension, diabetes mellitus, and atherosclerosis. Resultant lesions
can occur in isolation or in the setting of more serious systemic illness.

BOX 4-2. Causes of Visual Loss

Retina
Detachment
Infectious: CMV, toxoplasmosis
Toxic: ethambutol
Degenerative: macular degeneration, retinitis pigmentosa
Ischemic: embolic
Optic disc
AION: nonarteritic and arteritic
Optic neuritis
Glaucoma
Papilledema (late)
Sarcoidosis
Tumor
Optic nerve
Demyelination, including multiple sclerosis and neuromyelitis optica
Tumor, including meningioma, glioma, etc.
Thyroid ophthalmopathy
Trauma
Optic chiasm
 Tumor: pituitary tumors such as adenoma, craniopharyngioma, and glioma
Sphenoid mucocele
Internal carotid artery aneurysm
Trauma
Demyelination
Vascular
Toxic
Retrochiasmal
Tumor: glioma, meningioma, metastasis
Stroke involving the visual pathway
Demyelination
Degenerative diseases

AION, anterior ischemic optic neuropathy; CMV, cytomegalovirus.

In very sick patients, the examination often consists of observation

without the patient’s active involvement. In this scenario, the examiner can
comment on lid position and pupillary responses and on the direction of
gaze at rest and alignment of the eyes in the primary position. Some helpful
terms used to describe eye misalignment are detailed in Table 4-1. A patient
with a decreased level of consciousness may not be able to follow
directions (e.g., to track the examiner’s finger in the shape of an “H”). It is
still possible, however, to gain insight into how the eyes move through the
oculocephalic maneuver (doll’s eye test). This is performed by making
rapid horizontal and vertical movements of the head. A normal response is
for the eyes to remain “looking” forward (i.e., by rotating in a direction
opposite to that of the head movement). The vestibulo-ocular reflex (VOR)
coordinates eye movements with head movement, preventing the visual
image from slipping during movements of the head. Slow, passive head
movements can elicit it. Information from the semicircular canals (rotation)
and otoliths (linear acceleration) travels to the vestibular nuclei. From there,
it proceeds to the abducens (CN VI) nuclei and then through the MLF to
CNs III and IV. Abnormalities of the VOR can result in nystagmus (which
is discussed later in this chapter).
In the interactive patient, extra-ocular movements are tested by having
him or her follow a target moving in the shape of an H (as outlined in
Chapter 1). If double vision is a concern, it is important to note if and when
the diplopia emerges in the course of this maneuver. Extra-ocular testing
can demonstrate a myriad of lesions that occur in isolation or in
combinations.
CN III Deficit
An oculomotor nerve lesion can cause ophthalmoparesis, pupil dilation,
ptosis, or a combination of these findings. Because parasympathetic fibers
run in the outer part of CN III and the motor fibers are more internal,
compression of the nerve initially produces a dilated pupil without
compromising eye movements. Particularly when there is pain, this finding
should raise concern for a posterior communicating artery aneurysm. On the
other hand, vascular problems producing CN III ischemia (e.g., diabetes)
produce a pupil-sparing third nerve lesion in which the pupil is normal and
reactive but there is a deficit of the ocular movements innervated by CN III;
pain is common, except in midbrain lesions. A lesion in the nucleus of the
CN III causes bilateral ptosis and weakness of the contralateral superior
rectus, with failure of upward gaze.

TABLE 4-1. Some Terms Used to Define Eye Misalignment

Strabismus Misalignment of the Eyes
Comitant strabismus Misalignment constant in all directions of gaze; each eye has full
range of movement (usually an ophthalmologic problem)
Incomitant strabismus Degree of misalignment varies with the direction of gaze (usually a
neurologic problem)
Phoria Misalignment of the eyes when binocular vision is absent (cover–
(esophoria, exophoria) uncover one eye)
Tropia Misalignment of the eyes when both eyes are opened and binocular
(esotropia, exotropia) vision is possible

CN IV Deficit
A trochlear nerve lesion leads to a lack of intorsion on downgaze,
producing an oblique diplopia, worse on downgaze when the affected eye is
adducted. Patients may report diplopia when reading or going down stairs.
They may discover that tilting the head away from the side of the lesion
decreases the double vision. Trauma is a relatively common cause.

CN VI Deficit
An abducens lesion is associated with inward deviation of the affected eye
at rest. This is because there is a deficit in lateral gaze on the affected side
even in primary position. Raised ICP, for instance, in the setting of
pseudotumor cerebri, can be the culprit.
 CNs III, IV, and VI travel together through the cavernous sinus along
with the first and second divisions of CN V. Accordingly, conditions such as
a carotid-cavernous fistula are important considerations when pain and
altered sensation of the upper face occur along with impaired eye
movements. Chemosis, proptosis, and ecchymosis can be accompanying
features.
As discussed, some extra-ocular movement and alignment abnormalities
stem from primary central nervous system processes. For instance, lesions
of the MLF produce an internuclear ophthalmoplegia (INO) (Fig. 4-4).
Adduction during convergence is preserved because convergence does not
depend on the MLF. Bilateral INOs can be seen in brainstem strokes and
demyelination. In the “one-and-a-half syndrome” (caused by a lesion in the
PPRF or CN VI nerve nucleus, also involving the adjacent ipsilateral MLF;
Fig. 4-4), the only possible eye movement in the lateral plane is abduction
of the contralateral eye. Convergence is spared, as well. These syndromes
are relatively common in multiple sclerosis and can also occur because of
stroke, in which case there is often accompanying dysarthria, facial
weakness, and ataxia.
FIGURE 4-4. Sympathetic pathway mediating pupillary dilation (oculosympathetic pathway).
Hypothalamic fibers (right side of the diagram) project to the ipsilateral ciliospinal center of the
intermediolateral cell column from C8 to T1 spinal levels, which projects “preganglionic”
sympathetic fibers to the superior cervical ganglion (left side of diagram), which in turn projects
perivascular “postganglionic” sympathetic fibers via the tympanic cavity, cavernous sinus, and
superior orbital fissure to the dilator pupillae. Interruption of this pathway at any level results in a
Horner’s syndrome. Modified from Fix JD. High-Yield Neuroanatomy. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2005:67.

A brainstem or cerebellar lesion can also result in a skew deviation. This

term describes when one eye appears higher than the other (i.e., a vertical
tropia). The hypotropic (lower) eye is often on the side of the lesion.
Parinaud syndrome is characterized by an upgaze disturbance,
convergence-retraction nystagmus on attempted upgaze, and LND. It can be
produced by dorsal midbrain compression (e.g., by hydrocephalus or a
pineal tumor). Abnormal vertical gaze movements can also be found in
other dorsal midbrain syndromes.
Other eye movements include saccades and nystagmus. Both findings
can be normal or abnormal. Accordingly, clinical context is important for
interpretation. Saccades are normal rapid eye movements that redirect the
eyes to a new fixation object. To test saccades, an examiner asks the patient
to fix the eyes on one target and then to another located along the horizontal
or vertical plane. Abnormal voluntary saccades involve either multiple
jumps to reach the visual target (undershoot, hypometric) or jumps beyond
the target (overshoot, hypermetric). One can also look for involuntary
saccadic intrusions (quick jumps rather than a continuous movement)
during tests of smooth pursuit. Inability to produce saccades is called
oculomotor apraxia. Abnormal saccades have limited localizing value and
can be seen in conditions including Parkinson disease. In general, they are
associated with supranuclear abnormalities.

TABLE 4-2. Nystagmus: Categories, Characteristics, and Causes

Physiologic (Nonpathologic) Characteristics
Nystagmus
Optokinetic Normal response to a continuously moving object
Vestibulo-ocular Elicited by rotations of the patient’s head
Endpoint Few beats elicited by eccentric gaze
Congenital Jerk or pendular; present after birth; remains throughout life
Pathologic or Acquired Characteristics Possible Causes
Nystagmus
Periodic alternating Horizontal jerk nystagmus that Craniocervical junction
changes direction every 2 to 3 disorders, multiple sclerosis,
min bilateral blindness, toxicity
from anticonvulsants
Downbeat Present in primary position Craniocervical junction
disorders (Chiari
malformation), spinocerebellar
degeneration, multiple
sclerosis, familial periodic
ataxia, drug intoxication
Upbeating Present in primary position Anterior cerebellar vermis and
lower brainstem lesions, drug
intoxication, Wernicke
encephalopathy
See–saw One eye elevates and intorts, Trauma, brainstem vascular
whereas the other depresses and disease, multiple sclerosis, third
extorts ventricle tumors (in which case
the nystagmus is associated
with bitemporal hemianopia
reflecting chiasmal
involvement)
Gaze-evoked Similar to endpoint nystagmus, Drug intoxication, cerebellar
but amplitude is greater and it disease, brainstem or
occurs in a less eccentric hemisphere lesions
position of the eyes
Rebound Transient, rapid, horizontal jerk Cerebellar or posterior fossa
when the eyes are moving to or lesions
from an eccentric position
Vestibular Usually horizontal, with a Peripheral inner ear disorders,
rotatory component Ménière disease, vascular
disorder, drug toxicity

TABLE 4-3. Tips for Differentiating Central from Peripheral Nystagmus

Peripheral (Vestibular) Central (Brainstem)
Direction Unidirectional; fast phase away Bidirectional or unidirectional
from the lesion
Purely horizontal without Uncommon Common
rotatory component
Vertical nystagmus Never present May be present
Visual fixation Inhibits nystagmus and vertigo Has no effect
Tinnitus or deafness Often present Rarely present
Vertigo Severe Mild
Duration Short, but recurrent May be chronic
Causes Vascular disorders, trauma, Vascular, demyelination, and
toxicity, Ménière disease, neoplastic/paraneoplastic
vestibular neuronitis disorders
 Nystagmus is a rhythmic to-and-fro movement of the eyes. It can be
congenital, physiologic, or a sign of visual or neurologic dysfunction. It can
be slow and continuous, with movements of equal speed in any direction
(pendular), or consists of a slow drift and quick corrective jerk in the
opposite direction (jerk). Jerk nystagmus is common and is described by the
direction and trajectory of the quick movement. Table 4-2 gives a brief
description of different forms of nystagmus and possible causes. Table 4-3
describes a few characteristics to help differentiate central from peripheral
sources of nystagmus.

KEY POINTS
● Deficits in extra-ocular movements can help identify lesions of CNs III, IV, and VI.
● A left INO (affecting the left MLF) includes the inability to adduct the left eye in right
lateral gaze, plus nystagmus of the abducting right eye.
● With a one-and-a-half syndrome, the only eye movement in the lateral plane is abduction
of the eye contralateral to the affected PPRF, CN VI nucleus, and MLF.
● Parinaud syndrome includes limited upgaze and can be seen with hydrocephalus and
pineal tumors.
● Saccades are rapid eye movements that redirect the eyes to a new fixation object.
● Jerk nystagmus is described according to the direction of the quick, corrective “jerk.”
 5 The Approach to Weakness

Weakness is one of the most common presenting neurologic complaints.

Many patients may tolerate some degree of numbness, tingling, or even
pain, but often it is when weakness sets in that medical attention is finally
sought. Similarly, friends or family members will not notice a patient’s
sensory problems, but significant weakness will be obvious to all.
At the same time, weakness can be one of the most difficult neurologic
problems to sort out, because the pathways that control motor function span
the entire axis of the nervous system. Left leg weakness can arise from a
peripheral nerve lesion, a lumbosacral plexus problem, or a stroke in the
right cerebral hemisphere. Each of these has a different workup, prognosis,
and treatment, and it is the job of the physician to use the history and
examination to distinguish among them.

PRINCIPLES
Figure 5-1 presents a flowchart to aid in the diagnosis of weakness. The key
steps in the clinical approach are outlined below.
1. Make sure that true weakness is the complaint. Sometimes patients
will use the term weak to mean a general sense of fatigue; others will say
a limb is “weak” when it is clumsy or numb. Having the patient confirm
that decreased strength is the symptom may be useful. Likewise, a limb
that is painful to move may seem “weak” because of effort; whether
there is true underlying weakness may be difficult to discern. Weakness
should be characterized as objectively as possible, representing the
patient’s understanding of the reported symptom in conjunction with the
findings on a detailed physical exam. It is therefore important that
patients undergo a systematic motor exam that quantifies the severity of
 the weakness and discerns whenever possible if the weakness is effort
dependent or pain limited.
The history of the onset and pattern of progression of the symptoms is
also very important. If the weakness was preceded by a seizure, it may
be due to a Todd paralysis (a transient unilateral weakness that resolves
typically within several hours after a seizure). If the weakness occurred
abruptly and is unilateral, this may be more suggestive of a vascular
cause, whereas if the weakness occurred insidiously and is progressive,
other etiologies should be considered.
2. Identify which muscles are weak. This seems like an obvious point but
must be emphasized. It is not sufficient to know that a patient has left leg
weakness. Testing must be done in enough detail to know which muscles
in the left leg are weak or, if they are all weak, which are weaker than
others.
3. Determine the pattern of weakness. This is frequently the crux of the
entire diagnosis. It is the pattern of weakness that will indicate the
underlying lesion—whether left leg weakness is due to a peroneal nerve
problem or a right hemispheric stroke. One must be familiar with the
different patterns of weakness and their implications.
4. Look for associated signs and symptoms. If a leg is weak, determine
whether it is also numb, tingling, or painful. Check the reflexes
carefully. Examine the muscles themselves looking for atrophy and
fasciculations. Tone is also important in helping assess if the problem is
peripheral or central. Often the motor deficit overshadows other
problems, whose presence may be helpful in supporting or excluding
certain diagnoses. Patients may also have an acute cause of weakness
superimposed upon a more chronic underlying condition.
FIGURE 5-1. The approach to weakness. EMG/NCS, electromyography/nerve conduction
studies; NMJ, neuromuscular junction.

5. Use laboratory and electrophysiologic tests wisely. Blood tests or

neuroimaging studies can be useful in the appropriate settings, and
electromyography/nerve conduction studies (EMG/NCS) can act as an
extension of the clinical exam in localizing the problem to a particular
segment of the peripheral nervous system. Lumbar puncture (LP) may
also be necessary in patients with suspected Guillain–Barré syndrome.
 Tests are most useful, however, in the setting of a complete clinical
evaluation and formed diagnostic hypothesis.

KEY POINTS
● Weakness can be caused by lesions along the entire neuraxis, from brain to muscle.
● The diagnosis rests on determining what the pattern of weakness is, searching for
associated signs and symptoms, and using laboratory tests and EMG/NCS to confirm
clinical hypotheses.

DIFFERENTIAL DIAGNOSIS
It is useful to consider the disorders that cause weakness in an anatomic
order, from most distal in the nervous system (primary muscle disorders) to
most proximal (disorders of the cerebral hemispheres). Below, each
anatomic category is presented with the clues that might lead a clinician to
suspect a disorder in that location. Individual diseases in each category are
discussed in the later chapters covering specific neurologic disorders.

PRIMARY MUSCLE DISORDERS

Pattern of Weakness
Primary muscle problems tend to cause weakness predominantly in
proximal muscles, in a symmetric fashion. Distal muscles are affected later
or not as severely. In addition, neck flexors and extensors, which are not
affected in most nerve or brain lesions, may be weak in a muscle disorder.

Associated Signs and Symptoms

Associated signs and symptoms may occasionally include muscle pain if
the muscle disorder is inflammatory, such as polymyositis. By their nature,
primary disorders of muscle should not cause sensory signs or other
symptoms. Reflexes are characteristically preserved unless the process is so
severe that the muscles are nearly paralyzed.
Laboratory Studies
Some disorders of muscle are characterized by an elevated serum creatine
kinase (CK) level. The demonstration of characteristic “myopathic”
changes on an EMG can help confirm a primary muscle disorder.

Differential Diagnosis
Primary muscle disorders, discussed in Chapter 24, include both acquired
problems (myopathies), which can result from inflammatory or toxic
etiologies among other causes, and congenital problems (muscular
dystrophies).

KEY POINTS
● Primary muscle disorders typically cause symmetric proximal weakness and can affect
neck muscles.
● Sensory signs and symptoms are typically not present in primary muscle disorders.
● Serum CK level is elevated in some muscle disorders, and EMG may show a characteristic
“myopathic” pattern.

NEUROMUSCULAR JUNCTION DISORDERS

Pattern of Weakness
Neuromuscular junction (NMJ) problems can vary in the pattern of
weakness they cause, though most affect proximal limb muscles. Some
NMJ disorders can lead to ptosis as well as weakness of extraocular, bulbar,
and neck muscles. The characteristic feature of NMJ disorders is not the
location of weakness, however, but the fluctuation. The degree of weakness
may change from hour to hour. Depending on the specific disease, strength
may be worse after using the muscles or toward the end of the day; it may
improve after resting or in the morning (fatigability). Alternatively, strength
may improve paradoxically after exercise in other conditions.

Associated Signs and Symptoms

By their nature, NMJ problems, which affect only the junction between the
motor axon terminal and the muscle, should not lead to sensory signs or
symptoms. Some NMJ disorders may have associated autonomic features
and can also be associated with malignancies. A detailed review of systems
can help identify these features.

Laboratory Studies
EMG/NCS can demonstrate nearly pathognomonic findings for certain
NMJ disorders on specialized testing. Some of the diseases in this category
have specific serum markers, such as anti-acetylcholine receptor antibodies
and muscle specific kinase in myasthenia gravis. These are discussed in
further detail in Chapter 24.

Differential Diagnosis
NMJ disorders are discussed in Chapter 24; they include myasthenia gravis
and Lambert–Eaton myasthenic syndrome, among others.

KEY POINTS
● NMJ disorders can cause weakness of proximal muscles; some characteristically affect
extraocular and bulbar muscles.
● The key to diagnosing NMJ disorders is fluctuation in the degree of weakness.
● Sensory signs and symptoms are not generally present in NMJ disorders.
● EMG/NCS can be nearly pathognomonic in some cases of NMJ disorders.

PERIPHERAL NERVE DISORDERS

Pattern of Weakness
Each muscle in the upper or lower limbs is innervated by an individual
peripheral nerve (Table 5-1). A lesion involving a particular peripheral
nerve will lead to weakness in the muscles innervated by that nerve while
sparing other, often neighboring muscles.
Disorders affecting a single peripheral nerve are known as
mononeuropathies. Certain systemic conditions can lead to dysfunction of
multiple peripheral nerves in succession, a disorder known as
mononeuropathy multiplex. Finally, when peripheral nerves are all
affected diffusely, in a polyneuropathy, dysfunction typically occurs in the
longest nerves first. Thus, weakness from a polyneuropathy usually appears
first in the distal muscles, symmetrically.

Associated Signs and Symptoms

Mononeuropathies may cause sensory symptoms—such as numbness,
tingling, or pain—in the distribution of the relevant peripheral nerve.
Mononeuropathy multiplex is characteristically associated with pain.
Polyneuropathies, depending on etiology, usually have associated sensory
loss and depressed or absent reflexes, particularly in the distal extremities.

Laboratory Studies
EMG/NCS can confirm the clinical suspicion of a problem localized to the
peripheral nerves. NCS can identify whether the pathologic process affects
primarily the axons or the myelin of the nerve, an essential step in
formulating a differential diagnosis. EMG may yield insight into the
relative acuity or chronicity of a nerve disorder.

Differential Diagnosis
Mononeuropathies most commonly occur as a result of entrapment (as in
carpal tunnel syndrome). Mononeuropathy multiplex is associated with
systemic vasculitis and other metabolic or rheumatologic diseases.
Demyelinating polyneuropathies can be hereditary (such as Charcot–Marie–
Tooth disease) or acquired (as in Guillain–Barré syndrome), whereas axonal
polyneuropathies have many potential underlying causes from systemic
conditions or ingestions (e.g., alcohol or toxins). Peripheral nerve disorders
are discussed in Chapter 23.

TABLE 5-1. Commonly Tested Movements

Movement Muscle Nerve Root
Shoulder abduction Deltoid Axillary C5
Elbow flexion Biceps Musculocutaneous C5/C6
Elbow extension Triceps Radial C7
Wrist extension Wrist extensors Radial C7
Finger flexion Finger flexors Median, ulnar C8/T1
Finger extension Finger extensors Radial C7
Finger abduction Interossei Ulnar C8/T1
Hip flexion Iliopsoas Nerve to iliopsoas L1/L2/L3
 Hip abduction Gluteus medius, Superior gluteal L5
minimus
Hip adduction Hip adductors Obturator L3
Hip extension Gluteus maximus Sciatic S1
Knee flexion Hamstrings Sciatic L5/S1
Knee extension Quadriceps Femoral L3/L4
Plantar flexion Gastrocnemius, soleus Tibial S1
Dorsiflexion Tibialis anterior Peroneal L5
Foot eversion Peroneus muscles Peroneal S1
Foot inversion Tibialis posterior Tibial L5
Great toe extension Extensor hallucis Peroneal L5
longus

KEY POINTS
● Mononeuropathies lead to weakness in muscles innervated by a single peripheral nerve.
● Polyneuropathies first affect the muscles of the distal extremities symmetrically.
● EMG/NCS can confirm peripheral nerve involvement, identify axonal or demyelinating
features, and evaluate the relative chronicity of a nerve disorder.

NERVE ROOT DISORDERS

Pattern of Weakness
Each nerve root relevant to the upper or lower limbs exits the spinal cord
and eventually traverses a plexus (either brachial or lumbosacral) in which
its fibers separate and become part of multiple different peripheral nerves,
which then go on to innervate multiple different muscles. The result is that
most muscles are innervated by fibers that originate from more than one
nerve root, although some muscles are predominantly innervated by fibers
from one nerve root (Table 5-1). In any case, a lesion of a single nerve root
will cause weakness in the muscles innervated predominantly by fibers
from that root, while leaving other, often neighboring muscles unaffected.
A problem involving a single nerve root is termed a radiculopathy.
Some processes lead to dysfunction of multiple nerve roots at once
(polyradiculopathy), leaving a pattern of weakness that may be more
diffuse and difficult to sort out because multiple muscles related to multiple
nerve roots can be weak bilaterally.
Associated Signs and Symptoms
Radiculopathies often have associated tingling or pain, frequently radiating
out from the neck or back. Objective sensory loss is rare in disorders
affecting a single nerve root because there is overlap from neighboring
roots. If the nerve root is one that subserves a particular muscle stretch
reflex (Table 5-2), that reflex may be depressed or absent. Cervical
radiculopathies (causing symptoms in the arms) and lumbar radiculopathies
(causing symptoms in the legs) are the most common radiculopathies.
Symptoms from thoracic nerve roots are uncommon.

Laboratory Studies
EMG/NCS can confirm that nerve roots are the culprit in a weak patient and
can be particularly useful for cases where clinical differentiation between a
root problem and a peripheral nerve problem is murky. Single
radiculopathies may require magnetic resonance imaging (MRI) of the
spine to rule out structural causes, whereas polyradiculopathies may require
LP to look for infectious or inflammatory conditions.

TABLE 5-2. Commonly Tested Muscle Stretch Reflexes

Reflex Root
Biceps C5
Brachioradialis C6
Triceps C7
Finger flexor C8/T1
Patellar (knee jerk) L4
Hip adductor L3
Ankle jerk S1

Differential Diagnosis
Single radiculopathies can be caused by herniated disks or by reactivation
of varicella zoster virus (shingles), for example. Polyradiculopathies are
often inflammatory or infectious. These disorders are discussed in Chapter
23.

KEY POINTS
 ● A radiculopathy causes weakness in the muscles innervated predominantly by fibers from
one nerve root.
● Radiating pain and tingling are common symptoms.
● If the nerve root subserves a particular muscle stretch reflex, that reflex may be depressed
or absent.
● A polyradiculopathy may lead to weakness of multiple muscles related to multiple nerve
roots bilaterally.

PLEXUS DISORDERS

Pattern of Weakness
The intricacies of brachial and lumbosacral plexus anatomy (Fig. 5-2) are
often quite intimidating for students, but they need not be, because—
ironically—it is their complex anatomy that makes localizing lesions to a
plexus more straightforward than expected. Put simply, if multiple muscles
in a limb are weak and do not conform to the pattern of a particular nerve
root or peripheral nerve, a plexus problem should be suspected. In the leg,
for example, weakness in both hip flexors and hip adductors would have to
involve the L1, L2, and L3 roots or both the nerve to the iliopsoas and the
obturator nerve (Table 5-1); a much more likely explanation is a lesion in
the upper part of the lumbosacral plexus.
FIGURE 5-2. Brachial plexus anatomy. (Reprinted with permission from Moore KL, Dalley
AF. Clinically Oriented Anatomy. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006:776.
Figure 6.5.)

Associated Signs and Symptoms

Because the plexus is where multiple nerve roots intermingle their fibers to
form multiple peripheral nerves, it is unsurprising that plexus disorders can
have associated sensory findings (in the distribution of one or more roots or
nerves) or dropped reflexes (subserved by one or more roots).

Laboratory Studies
EMG/NCS is frequently ordered in cases of clinically suspected
plexopathies to help confirm the localization to the plexus, given the less-
than-straightforward anatomy. MRI of the brachial plexus or pelvis (or
lumbosacral plexus) may be necessary to rule out mass lesions.
Differential Diagnosis
Plexopathies can be caused by idiopathic inflammation, radiation,
infiltration by metastases, hemorrhage, or trauma, and are discussed in
Chapter 23. Diabetic patients are prone to develop a characteristic
lumbosacral plexopathy known as diabetic amyotrophy.

KEY POINTS
● A plexus problem should be suspected when multiple muscles in a limb are weak and do
not conform to a particular nerve root or peripheral nerve pattern.
● There may be associated sensory signs or reflex loss in plexus disorders.
● Plexopathies can be confirmed by EMG/NCS and have many potential causes.

SPINAL CORD DISORDERS

Pattern of Weakness
Spinal cord disorders cause weakness in two ways. First, the anterior horn
cells located at the level of the lesion are affected, leading to weakness of
the muscles innervated by the nerve root at that level. This mimics a
radiculopathy, with weakness in a particular nerve root pattern. Second,
there is weakness below the level of the lesion because of the interruption
of the descending corticospinal tracts. This weakness occurs in an upper
motor neuron (UMN) pattern (Fig. 5-3).
FIGURE 5-3. Upper motor neuron (UMN) versus lower motor neuron (LMN).

Associated Signs and Symptoms

Depending on the extent of the lesion, there may be sensory findings
because of the interruption of the ascending tracts. There may be a sensory
level (loss of sensation below a particular dermatomal level) on the torso.
Bladder and bowel incontinence may occur.
 The findings in patients with a spinal cord lesion may also vary
depending on the mechanism and acuity of the lesion. Patients with acute
spinal cord injuries may also have spinal shock which is manifested by loss
of reflexes, flaccid paralysis, and loss of sensory functions below the level
of the injury. They may also have neurogenic shock because of the impaired
autonomic function resulting in hypotension, bradycardia, and hypothermia.
In the later phases of a spinal cord injury, the neurologic findings change
significantly. Muscle stretch (“deep tendon”) reflexes below the level of a
spinal cord lesion are increased, and there may be Babinski signs. Spasticity
ensues, and patients with lesions above T6 may develop autonomic
dysreflexia after the first month from the onset of the injury. This condition
is characterized by paroxysmal profound hypertension, bradycardia,
flushing, and headache. It can be triggered by almost any physical or
metabolic stimuli and results in significant morbidity and cardiovascular
mortality for patients with spinal cord injuries.

Laboratory Studies
MRI of the spine can rule out structural etiologies or demonstrate intrinsic
inflammation within the cord. LP may be needed to evaluate infectious,
inflammatory, or neoplastic causes of cord dysfunction.

Differential Diagnosis
Spinal cord disorders are discussed in Chapter 22; they may stem from
inflammation (transverse myelitis), infarction, compression, or other causes.
Amyotrophic lateral sclerosis causes degeneration of both the corticospinal
tracts and anterior horn cells.

KEY POINTS
● Spinal cord disorders lead to weakness in a UMN pattern below the lesion and weakness
in a nerve root pattern at the level of the lesion.
● The pattern of weakness and associated findings such as tone and reflexes may vary
depending on the acuity and mechanism of the spinal cord lesion.
● There may be sensory loss below the level of the lesion because of the interruption of
ascending tracts.
● Reflexes below the level of the lesion are typically increased, and Babinski signs may be
present.
 ● Autonomic dysreflexia may develop in patients with lesions above T6 about a month after
the initial spinal cord trauma.
● Bladder and bowel incontinence may occur.

DISORDERS OF THE CEREBRAL HEMISPHERES AND

BRAINSTEM

Pattern of Weakness
Lesions in the cerebral hemispheres lead to weakness of the contralateral
body in a UMN pattern (Fig. 5-3). Knowledge of the homunculus of the
motor strip (Fig. 5-4) explains why lesions in the parasagittal part of the
cerebral hemisphere cause weakness primarily in the leg, whereas lesions
more laterally in the hemisphere cause weakness primarily in the face and
arm. Deep hemispheric lesions, as in the internal capsule, may lead to
weakness of all three parts of the contralateral body (face, arm, and leg),
because motor fibers from all areas of the motor strip join together as they
travel toward the brainstem.
Lesions in the base of the pons may lead to weakness of the ipsilateral
face and contralateral arm and leg (crossed signs), because descending
motor fibers to the face have crossed at that level but those to the body have
not.
FIGURE 5-4. The homunculus of the motor strip.

Associated Signs and Symptoms

Lesions of the cerebral hemispheres frequently have associated cognitive
signs, such as those described in Chapter 11. Left hemisphere lesions may
cause aphasia or apraxia, whereas right hemisphere lesions may cause
neglect or visuospatial dysfunction. Lesions of the brainstem may cause
cranial nerve problems, such as extraocular movement disorders.

Imaging Studies
Imaging of the brain is important to evaluate almost all of the potential
etiologies in this category. The choice of MRI or computed tomography
depends on the suspected etiology and relative acuity.

Differential Diagnosis
The differential diagnosis includes such diverse etiologies as stroke
(Chapter 14), demyelinating disease (Chapter 20), traumatic injury (Chapter
17), brain tumor (Chapter 19), and infection (Chapter 21).

KEY POINTS
● Cerebral hemisphere lesions lead to weakness of the contralateral side in a UMN pattern.
● Parasagittal lesions lead primarily to leg weakness, more lateral lesions lead primarily to
face and arm weakness, and deep lesions may lead to weakness of all three parts.
● Cerebral hemisphere lesions may have accompanying cognitive signs, such as aphasia or
neglect.
● Brainstem lesions may have accompanying cranial nerve findings.
 6 The Sensory System

The sensory system is that part of the nervous system responsible for
processing sensory information, including the somatosensory and special
senses: smell, vision, taste, hearing, and vestibular sensation. Abnormalities
of sensation can be characterized by an increase, decrease, impairment, or
loss of feeling. The diagnosis of sensory problems requires an
understanding of the anatomy and an analysis of the presentation, location,
characteristics, and distribution of symptoms.

ANATOMY OF THE SENSORY PATHWAYS

The first step in any sensory pathway is activation of a sensory receptor by
a specific stimulus. Information from the receptor is then carried to the
central nervous system (CNS) by the afferent nerves (peripheral or cranial)
known as first-order neurons. Pain and temperature sensation is carried by
thinly myelinated (A-δ) and unmyelinated slowly conducting (C) fibers that
synapse as they enter the dorsal horn of the spinal cord. From there, axons
from the second-order neurons cross and travel contralaterally in the
spinothalamic tract (STT), also called the anterolateral system (Fig. 6-1).
Proprioception, vibration, and light touch run ipsilaterally in heavily
myelinated (A-α and A-β) fibers in the dorsal column system, reaching the
second-order neuron at the level of the medulla in the nuclei gracilis and
cuneatus. Axons from these nuclei cross in the lower medulla to form the
medial lemniscus (Fig. 6-2).
There is a somatotopic arrangement of fibers in these tracts.
• STT: At the level of the spinal cord, sacral segments are located laterally
and cervical segments medially.
• The dorsal columns: The most medial fibers convey input from sacral
areas, whereas lateral fibers convey information from the arms. At the
 level of the medial lemniscus, the upper body fibers become medial and
those of the lower body lateral.
Facial sensation is carried to the brainstem by the trigeminal nerve. The
STT and the trigeminal tract terminate in the thalamus, ventroposterolateral
and ventroposteromedial, respectively, with further cortical projections
through the third-order neurons to the postcentral cortex in a somatotopic
arrangement similar to that seen in the motor cortex, with the face in the
lowest area of the parietal lobe and the leg in the parasagittal parietal area.
Fine sensory discrimination and localization of pain, temperature, touch,
and pressure require normal functioning of the sensory cortex (Fig. 6-3).

EXAMINATION OF THE SENSORY SYSTEM

The sensory examination is the most subjective, and sometimes the most
difficult, component of the neurologic examination; it requires the patient’s
cooperation. Inattention or aphasia may complicate interpretation of the
sensory examination. The evaluation of different primary sensory
modalities, including temperature, pain (or pinprick), light touch, vibration,
and proprioception, is necessary to characterize sensory loss and its extent.
In some instances, it is difficult to demonstrate sensory abnormalities in a
patient with sensory symptoms. In others, the examination may show
sensory findings in an asymptomatic patient. Whatever the situation, the
sensory examination must be organized and methodical.
Touch sensation is tested using a very soft stimulus, such as a wisp of
cotton. Pain sensation is tested with a pin. Thermal modalities are tested
using objects with a temperature range between 10°C and 50°C because
beyond those limits the stimulus becomes painful. Moving the great toe (or
a finger) up and down, by just a few millimeters, and asking the patient to
indicate the direction of movement (with the eyes closed) tests
proprioception or joint position sense. Vibration sense requires a tuning fork
(128 Hz) to be applied to the toes and other bony prominences.
FIGURE 6-1. The anterolateral system. VPL, ventroposterolateral.

The next step is to record the sensory symptoms and findings using
accepted definitions. It is best to record the patient’s own words when
possible. Not only the presence or absence of sensation but also slight
differences and gradations should be recorded. The following list defines
some of the terminology used to describe sensory abnormalities:
FIGURE 6-2. The posterior column—medial lemniscal system. VPL, ventroposterolateral.

• Paresthesias are abnormal sensations described by the patient as

tingling, prickling, pins, and needles, and so on.
• Dysesthesias are abnormal and often unpleasant sensations in response
to touch.
• Hyperesthesia is increased sensitivity to sensory stimuli. The opposite
is hypoesthesia.
• Allodynia is pain provoked by normally innocuous stimuli.
• Dissociated sensory loss is a pattern of neurologic dysfunction of a
single sensory tract (either posterior columns or STTs) in which the loss
of proprioception and fine touch is not associated with loss of pain and
temperature, or vice versa. For example, in syringomyelia, a condition in
which the central canal of the spinal cord expands, the STT is
compromised early. This leads to loss of pain and temperature sensation
in the dermatomes involved but preservation of posterior column
function and, therefore, a normal response to light touch and normal
proprioception. Such dissociated sensory loss occurs frequently with
central cord syndromes (see Chapter 22).

FIGURE 6-3. Somatotopic map (“homunculus”) of the sensory cortex. Reprinted with
permission from Jensen S. Nursing Health Assessment. 1st ed. Baltimore, MD: Lippincott Williams
& Wilkins; 2010. Figure 24.3.
APPROACH TO THE PATIENT WITH
SENSORY LOSS
As with any aspect of the neurologic examination, the approach to sensory
symptoms begins with a careful history. Patients complaining of sensory
dysfunction can report negative symptoms, positive symptoms, or both.
Negative symptoms include numbness, loss of cold or warm sensation,
blindness, and deafness. Positive symptoms include pain, paresthesias
(tingling, pins, and needles), visual sparkles, and tinnitus. Listening to the
patient’s experience will help guide the physical examination and may even
provide insight into potential causes. For example, negative symptoms
usually imply disruption of nerve excitation (such as in a stroke), whereas
positive symptoms refer in general to excitation or disinhibition (as seen
with seizures or migraine).
Once the history is obtained, the next task is to establish the presence or
absence of a neurologic lesion or deficit. If a lesion is identified, the extent
or location of the lesion and its effect on different sensory modalities should
be mapped out by a careful and detailed sensory examination. This is
important because different pathologic processes can affect different
sensory symptoms and lead to specific patterns of sensory loss.
Although in theory it is easy to distinguish peripheral nerve injury from
disease in other locations, this is often not possible or at best imprecise in
practice. Nevertheless, the history and complete physical examination
together may help the clinician more definitively determine the
neuroanatomic level at which the symptoms are produced, that is, at nerve,
plexus, root, cord, or other CNS locations. In general, compression of a
peripheral nerve causes sensory loss in the territory of that specific nerve.
Root problems produce a dermatomal pattern of sensory loss (Fig. 6-4).
Spinal cord disease leads to a characteristic loss of sensation below a
certain spinal level (sensory level). With brainstem lesions, the sensory
abnormalities may occur on the ipsilateral side of the face and contralateral
side of the body. Central sensory loss involving the thalamus or sensory
cortex will generally affect the contralateral face, arm, and leg.
Because there are many primary neurologic diseases as well as systemic
illnesses that can present with sensory symptoms, putting the sensory
examination into the context of the remainder of the physical examination
may make potential etiologies more obvious. Sometimes, the sensory
problems are accompanied by other signs such as weakness, neglect, visual
field cuts, cognitive or behavioral problems, or seizures that may help to
determine the location of the lesion.

FIGURE 6-4. Sensory dermatomes. Reprinted with permission from Hoppenfeld JD.
Fundamentals of Pain Medicine: How to Diagnose and Treat your Patients. 1st ed. Baltimore, MD:
Lippincott Williams & Wilkins; 2014. Figure 2.12.

Examples of different patterns of sensory loss and the location of the

respective neurologic problem are shown in Table 6-1. This table serves as
a guide to the process of localization and diagnosis based on clinical
symptoms and the neurologic examination, without the need for further
technologic resources.

TABLE 6-1. Patterns of Sensory Loss According to Localization

Site of the Sensory Findings Other Neurologic Examples
Lesion Abnormalities
Peripheral Loss of LT, T, PP, and Distal muscle Peroneal neuropathy;
nerve proprioception in the weakness, muscle median neuropathy (carpal
affected area; associated atrophy, areflexia tunnel syndrome); ulnar
weakness in muscles neuropathy
innervated by that nerve
Root Variable loss of all sensory Weakness in a L5 radiculopathy; C6
modalities in a dermatomal myotomal distribution, radiculopathy
distribution atrophy, segmental
hyporeflexia
Plexus Sensory loss in the Weakness and atrophy Brachial plexopathy due to
distribution of two or more that cannot be localized trauma, inflammation,
peripheral nerves to a single nerve or tumor infiltration
root, areflexia
Spinal cord • Sensory level: bilateral Paraplegia, tetraplegia. Myelopathy; central cord
loss of all sensory Initially areflexia, then syndromes; Brown-Sequard
modalities hyperreflexia below the syndrome; vitamin B12
• Sensory dissociation lesion; Babinski sign deficiency (subacute
• Contralateral combined degeneration)
hypoesthesia and
ipsilateral loss of
proprioception (Brown-
Sequard syndrome)
• Proprioceptive loss and
corticospinal tract
involvement
Brainstem Ipsilateral facial numbness Alternating Posterior circulation strokes;
and contralateral body hemiplegia; cranial brainstem tumor
numbness nerve findings; ataxia
Thalamus Hemibody anesthesia May have motor Lacunar stroke; hemorrhage
findings
Posterior Hemibody anesthesia Hemiplegia Lacunar stroke;
limb of hemorrhage; tumor
internal
capsule
Cortex All modalities affected on Sensory neglect; Parietal stroke; hemorrhage;
the contralateral side agraphesthesia AVM
Psychogenic Hyperesthesia for one Any Psychogenic (this is a
modality in one area with diagnosis of exclusion)
anesthesia for another
modality in the same area;
changing sensory findings;
 nonphysiologic sensory
level changes (abrupt
midline changes, vibration
asymmetry over the
forehead, etc.)
AVM, arteriovenous malformation; LT, light touch; PP, pinprick; T, temperature.

The last step in evaluating these sensory abnormalities is to determine the

cause. There are many primary neurologic diseases as well as systemic
diseases that can present with sensory symptoms; many are explored in
more detail in Chapter 23 on peripheral neuropathies.

KEY POINTS
● STT is the pathway for pain, temperature, and light (poorly localized) touch. Mnemonic:
STT (sting, temperature, touch).
● The dorsal columns carry well-localized touch, pressure, vibration, and conscious
proprioception.
● Nonconscious proprioception is conveyed by the spinocerebellar tracts.
● Damage to a peripheral nerve produces a sensory deficit in the territory innervated by that
nerve. Damage to a nerve root may produce a dermatomal loss of sensation. Damage to the
brachial or lumbar plexus produces sensory loss in multiple nerve territories.
● Spinal cord lesions often produce an identifiable sensory level on examination. Brainstem
lesions cause crossed sensory loss. Thalamic and cortical lesions produce contralateral
hypoesthesia or anesthesia.
● Examples of sensory dissociation include syringomyelia (loss of pain and temperature
sensation, with preserved proprioception); Brown-Sequard syndrome (loss of
proprioception on the side ipsilateral to the lesion, and loss of pain and temperature
sensation on the contralateral side); and subacute combined degeneration (loss of
proprioception, but preserved pain and temperature sensation).
 7 Dizziness, Vertigo, and Syncope

The word dizziness is used by patients and sometimes clinicians to describe

many different symptoms ranging from room spinning and light-headedness
to disorientation, complex partial seizures, and anxiety. As a result, the
differential diagnosis for self-reported “dizziness” is very broad. As with all
of medicine, obtaining a clear history of what “dizziness” really means to
the patient, followed by a careful neurologic examination, is vital to
establish the diagnosis and avoid unwarranted testing. The following
sections detail different types of dizziness, including the key features and
underlying etiologies.

VERTIGO
Vertigo is a type of dizziness in which a patient perceives motion when
there is no actual motion. This is most commonly a sensation of the room
spinning in a clockwise or counterclockwise direction. Vertigo can also be a
sensation of motion, as if on a boat. Some patients also experience a
sensation of propulsion, as if they are being pulled or pushed in a direction.
Vertigo is a descriptive term, not a diagnosis. Stating that a patient has
vertigo is no more specific than saying that a patient has fever or chest pain.
The specific cause of the vertigo must be established in order to establish a
diagnosis.
Vertigo is caused by an asymmetric impairment in the vestibular system.
This can occur at any point along the vestibular pathway from the vestibular
nerve or labyrinth to the central vestibular structures. Vestibular disorders
can therefore be divided into peripheral and central categories, based on
the cause.
The specific details of the onset, quality, duration, triggers, and
associated symptoms, as well as the patient’s medical history, aid in guiding
the differential diagnosis.
Vertigo is often associated with nausea. Patients may describe a
staggering gait or that they must hold on to nearby objects to avoid falling.
Depending on the etiology, patients may also have symptoms of diplopia
(double vision). Vertigo may be constant or intermittent, depending on the
cause. The duration of symptoms and associated features aid in narrowing
the diagnostic possibilities. The examination is used to evaluate further and
establish the diagnosis. These are critical steps that allow a clinician to
triage or distinguish an emergency cause of vertigo such as a brainstem
stroke from a benign etiology, for example, benign paroxysmal positional
vertigo (BPPV).

PERIPHERAL VERTIGO
There are many causes of peripheral vertigo, each with key features that
allow the clinician to determine it.
BPPV is a common form of vertigo. It is caused by an otolith (also called
a canalith) of calcium carbonate debris in the semicircular canal. The
semicircular canals are within each inner ear and are lined with cilia and
endolymph. Each time the head moves, the endolymph moves, which in
turn causes the cilia to move and send signals to the central vestibular
structures. When an otolith is in the semicircular canal, it disrupts the
movement of the endolymph and creates a sensation of spinning. The
vertigo occurs only when the person moves the head. The spinning
sensation resolves, usually in under a minute, if the patient is perfectly still.
Bending over, looking up, or rolling over in bed are common triggers. The
vertigo may be accompanied by nausea and sometimes emesis. Importantly,
BPPV is not associated with diplopia, weakness, sensory symptoms, or
hearing loss.
Otoliths can form in the horizontal and anterior (superior) semicircular
canals but are most common in the posterior canal. The orientation and
position with which the nystagmus is elicited are slightly different
depending on the location of the otolith. Episodes of BPPV often occur in
bouts; patients may have recurrent episodes for several days in a row which
then resolve, but BPPV may recur frequently if untreated.
BPPV patients have normal neurologic examinations, without evidence
of ataxia or sustained nystagmus. The gait remains normal. The diagnosis
may be corroborated by doing the Dix–Hallpike maneuver (Fig. 7-1). The
maneuver is 50% to 80% sensitive, but some patients are unable to
cooperate. During the test, the patient should be observed in each position
for 30 to 45 seconds. Nystagmus usually appears within a few seconds and
extinguishes after less than 1 minute. The nystagmus is typically upbeating
and torsional. When the patient is repositioned in the upright position, the
nystagmus recurs with the same cadence. The maneuver is performed with
each side of the head turned downward; the side tested which provokes the
nystagmus is the one with the otolith. With each repetition of the maneuver,
the clinical response becomes less intense. During the maneuver, nystagmus
is not always visible to the examiner, but the patient may still experience
vertigo. This is referred to as “subjective BPPV” and still responds to
treatment.
BPPV is treated with vestibular therapy aimed at repositioning the
otolith, usually by doing the Epley maneuver (Fig. 7-2). Of note, patients
with otoliths in the horizontal and anterior canals may require different
repositioning maneuvers.
FIGURE 7-1. Dix–Hallpike maneuver. This bedside maneuver helps to diagnose BPPV. From
Furman JM, Cass SP. Benign paroxysmal positional vertigo. N Engl J Med. 1999;341(21):1590–
1596. Copyright © 1999 Massachusetts Medical Society. Reprinted with permission from
Massachusetts Medical Society.
FIGURE 7-2. The Epley maneuver. Reprinted with permission from Krebs C, Weinberg J,
Akesson E. Lippincott’s Illustrated Review of Neurscience. 1st ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2012.

Vestibular Neuritis and Labyrinthitis

Vestibular neuritis (aka vestibular neuronitis) is believed to be caused by
an infectious or autoimmune injury to the vestibular portion of the VIIIth
cranial nerve (although there is no clear evidence of inflammation, and the
exact etiology remains unknown). Patients present with acute-onset vertigo,
often associated with nausea, emesis, and mild gait ataxia. When the patient
also has acute hearing loss, the syndrome is called labyrinthitis. Patients
should not have additional symptoms of focal weakness or sensory changes.
Rarely, patients may report diplopia, but this symptom is more concerning
for a brainstem infarct or hemorrhage.
On examination, patients have spontaneous unilateral horizontal or
torsional nystagmus. The nystagmus can be suppressed with gaze fixation
(having the patient fixate on a target). Patients may also have some gait
ataxia and typically fall away from the side of the lesion. The head impulse
test (HIT) (Fig. 7-3) is used to identify whether there is vestibular
impairment, but it does not definitely exclude a central cause.
Vestibular neuritis can mimic a brainstem infarct or, less commonly, a
demyelinating lesion (described later). The decision to proceed with a
stroke workup is often based on the age and vascular comorbidities of the
patient. A magnetic resonance imaging (MRI) of the brain with thin cuts
through the brainstem is often warranted in patients with a high risk of
stroke.
In patients with an acute onset of symptoms, treatment with a
corticosteroid taper can reduce the duration of symptoms. Additional
symptomatic treatment with antiemetics and antihistamines may also be
helpful.

Ménière disease
Ménière disease is a constellation of symptoms of vertigo, sensorineural
hearing loss, and tinnitus. It is believed to be caused by surplus endolymph.
The exact cause is unknown, but there are theories that endolymph
homeostasis is impaired. It is most common in adults between the ages of
20 and 40 years. Patients may also report gait unsteadiness and nausea,
vomiting, or both. Patients typically have phases of exacerbation and
remission of the vertigo. Hearing loss remains and often progresses to
deafness.
FIGURE 7-3. Head impulse test (HIT) (sometimes referred to as the head thrust test) is a test of
vestibular function that can be easily done in bedside examination. It tests the vestibulo-ocular reflex
(VOR) and can help to distinguish a peripheral process (e.g., vestibular “neuritis”) from a central one
(e.g., a cerebellar stroke). With the patient sitting, the physician instructs him to maintain his gaze on
the examiner’s nose. The physician holds the patient’s head steady in the midline (Panel 1) and then
turns the head rapidly to about 20 degrees from the midline. The normal response (intact VOR) is for
the eyes to stay locked on the examiner’s nose. The abnormal response (impaired VOR) is for the
eyes to move with the head (Panel 2) and then to snap back in one corrective saccade to the
examiner’s nose (Panel 3). The HIT is usually “positive” (i.e., a corrective saccade is visible) with a
peripheral lesion and “normal” (no corrective saccade) with a central lesion (because the VOR
pathway does not pass through the cerebellum). Occasionally, patients with small brainstem strokes
have a positive test because the VOR pathway does pass through the brainstem.
Because it is the “positive” HIT that is reassuring and the “negative” test worrisome, it is
important to use the test only in patients with an acute vestibular syndrome (AVS). If one were to use
the HIT in patients with pneumonia or a fractured wrist, it might be “negative” (or worrisome for a
central nervous system event). Therefore, it is critical that it be applied only to patients presenting
with an AVS. Reprinted with permission from Wolfson AB. Harwood-Nuss’ Clinical Practice of
Emergency Medicine. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. Figure 14.1.
Ménière disease is diagnosed by the history, while excluding other
causes, especially central causes of vertigo (see below). Treatment
addresses the symptoms. Patients are counseled to avoid triggers and to
have a diet low in sodium and caffeine.

Acoustic Neuroma
An acoustic neuroma (vestibular schwannoma) is a tumor that grows in the
vestibular portion of the vestibulocochlear nerves (cranial nerve VIII). Its
cells are derived from Schwann cells, usually in the internal auditory canal.
The tumor can extend into the posterior fossa and can even cause mass
effect on the brainstem. Acoustic neuromas are among the most common
tumors in the cerebellopontine angle. They are most common in adulthood
and are usually unilateral. They are also common in patients with
neurofibromatosis type 2, occurring bilaterally in this condition.
Acoustic neuromas may be asymptomatic and identified as incidental
findings on neuroimaging. When patients are symptomatic, they often
present with hearing loss and tinnitus. Frank vertigo (i.e., room spinning) is
not a common symptom, but feelings of unsteadiness and imbalance are
often reported. If there is significant mass effect, the tumor may compress
adjacent cranial nerves, and patients may report symptoms of trigeminal
neuralgia, a facial nerve palsy, or both.
On examination, patients typically have sensorineural hearing loss on the
affected side, but the remainder of the examination is typically normal
unless there is significant mass effect impacting other cranial nerves.
Patients have hearing impairment on audiometry. The diagnosis is
established with an MRI (Fig. 7-4). Treatment is usually surgical resection.
In patients who are not surgical candidates, stereotactic radiotherapy may
be attempted to reduce the tumor burden. Tumor recurrence is uncommon.

FIGURE 7-4. Magnetic resonance imaging (MRI) of vestibular schwannoma. (A) T1-weighted
axial MRI before contrast shows large hypointense mass within the cerebellopontine angle exerting
mass effect on the brainstem. (B) T1-weighted axial MRI postcontrast shows a vestibular
schwannoma with expansion of the internal auditory meatus. Reprinted with permission from Louis
ED, Mayer SA, Rowland LP. Merritt’s Neurology. 13th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2015. Figure 102.1.

Medications
There are numerous medications that cause dizziness as a side effect. Frank
vertigo from medications is uncommon, but aminoglycosides are the
exception and can cause both cochlear and vestibular toxicity. Patients who
develop this side effect have hearing loss from cochlear involvement and
vertigo and disequilibrium from the vestibular nerve damage. These side
effects are most common in patients on long-term therapy. The exact
incidence of ototoxicity from aminoglycosides is not known.
 KEY POINTS
● Peripheral vertigo can be due to several different etiologies.
● Careful history and examination are needed to narrow the differential.
● Focal neurologic deficits such as involvement of other cranial nerves, sensory deficits, or
weakness are atypical and warrant workup for a central cause.

CENTRAL VERTIGO
Central vertigo is a category of vertigo that is caused by a lesion in the
brainstem or cerebellum. Patients with central vertigo develop abrupt onset
sustained vertigo. It is not positional and is typically sustained during the
acute phase. Central vertigo is most commonly due to cerebellar infarcts or
hemorrhages, but in younger patients, central vertigo may be due to a
demyelinating lesion such as from multiple sclerosis. Migraine may also
cause vertigo but are a diagnosis of exclusion.
Central vertigo is often associated with focal symptoms and findings on
examination. The patient’s eye movements should be examined carefully
for spontaneous or gaze-evoked nystagmus. In addition, a horizontal or
vertical misalignment (skew deviation) may be seen. Patients may have a
head tilt if they have a IVth nerve (trochlear nerve) palsy, and ptosis may be
present. Other cranial nerve deficits as well as focal weakness and sensory
changes suggest a central etiology. Hearing loss (as tested with Weber and
Rinne tests) is more suggestive of a peripheral etiology but does not
exclude a central cause.

Cerebral Infarct or Hemorrhage

When vertigo is due to a cerebellar infarct or hemorrhage, the patient
typically reports abrupt onset vertigo and may report a headache. The
brainstem is a dense structure with many nuclei and nerves abutting one
another, so most brainstem strokes are associated with symptoms in
addition to vertigo—often referred to as “neighborhood signs.” Patients
may report nausea, vomiting, ataxia, dysphagia, dysarthria, dysmetria, or
combinations of these.
A classic example of a stroke syndrome that causes vertigo is the
Wallenberg (or lateral medullary) syndrome caused by a stroke in the
lateral medulla due to a vertebral or posterior inferior cerebellar artery
occlusion. The stroke not only causes vertigo but is also associated with
diplopia and multidirectional nystagmus. Patients with a Wallenberg
syndrome may also have
• Ipsilateral Horner syndrome
• Dissociated sensory loss, that is,
• ipsilateral loss of pain and temperature sensation over the face, with
• contralateral loss of pain and temperature over the limbs and trunk
• Nystagmus: sometimes, direction changing, and not suppressible with
visual fixation
• Ipsilateral loss of the corneal reflex
• Hoarseness and dysphagia
• Ipsilateral limb ataxia
• Dysmetria and dysarthria (sometimes)
Abrupt onset of sustained vertigo from vestibulitis can mimic a brainstem
or cerebellar stroke. Brief vertiginous episodes from a transient ischemic
attack (TIA) can also mimic BPPV, at least by history. The additional
associated symptoms and findings on examination help localize the lesion.
In addition, the patient’s medical history, including vascular risk factors,
age, and trauma history, is vital in formulating a differential diagnosis.
Isolated vertigo without other symptoms or findings on examination is
rarely due to a stroke. If there is any concern for a central cause of vertigo,
imaging with MRI of the brain should be obtained. If there is specific
concern for a stroke, blood vessel imaging with a magnetic resonance
angiography (MRA) or computed tomography angiography (CTA) should
also be ordered. Treatment is based on management of risk factors for
stroke. Symptomatic treatment with antihistamines and antiemetics may
also help.

Demyelinating Lesions
Demyelination in the cerebellum and brainstem can cause acute vertigo.
Possible neighborhood signs depend on the location of the lesion. Patients
with central vertigo from multiple sclerosis or other demyelinating diseases
usually have central oculomotor signs, as described earlier. The diagnosis is
established with an MRI of the brain with and without contrast. The
treatment is usually immune therapy for multiple sclerosis. Symptomatic
treatment with antihistamines and antiemetics may also be required.

Migraine
Patients with migraine may experience vertigo with a migraine attack or as
an aura preceding a migraine. There are two specific types of vertigo
associated with migraine.
Vestibular migraine (previously called migraine-associated vertigo) is
defined as a headache that meets criteria for a migraine (with or without
aura) associated with symptoms of vertigo. The vertiginous symptoms
range from vertigo triggered by head movement to feelings of motion—
either internally or feeling that the external space is spinning. Symptoms
can last for minutes to hours but rarely last weeks.
Migraine with brainstem aura (previously called basilar migraine) is
defined as a fully reversible aura involving at least two brainstem
symptoms, including vertigo, tinnitus, hyperacusis, diplopia, dysarthria,
ataxia, decreased level of consciousness, or combinations of these.
Symptoms evolve gradually over 5 to 60 minutes. The auras must be
accompanied or followed by a headache that meets criteria for migraine.
Importantly, patients do not have focal weakness during these auras.
Vertigo because of migraine is generally a diagnosis of exclusion and
usually warrants neuroimaging to exclude other central causes of vertigo.
Treatment is focused on aborting the migraine with typical regimens and
treating associated symptoms of nausea and emesis as needed.

KEY POINTS
● Central causes of vertigo should be evaluated as an emergency with neuroimaging.
● The history and associated focal neurologic deficits will aid in localization and
differentiation from a peripheral cause of vertigo.
● Treatment is based on symptomatic management and addressing the structural cause.
● Table 7-1 outlines key features of both peripheral and central vertigo.

TABLE 7-1. Characteristics of Causes of Vertigo

Causes Duration Triggers Hearing Neurologic Diagnostic
Symptoms Symptoms Workup
BPPV Seconds Head None None Dix–Hallpike
 movements
Vestibular Days–weeks May be Labyrinthitis + No cranial HIT test
neuritis and preceded by an hearing loss nerve deficits
labyrinthitis upper
respiratory
infection
Ménière Minutes–hours Unknown + Hearing loss None Audiometry:
disease + Tinnitus sensorineural
hearing loss
Acoustic Does not None + Hearing loss May be present MRI of the
neuroma typically cause + Tinnitus if there is mass internal
vertigo effect on the auditory canal
brainstem
Brainstem Hours–days; Stroke risk Variable Typically MRI of the
infarct, may be factors present brain
hemorrhage, intractable (excluding MS
or lesion)
demyelinating
lesion
Migraine with Hours–days Migraine ± Tinnitus Headache MRI of the
brainstem aura triggers meeting brain is normal
criteria for
migraine and
reversible
brainstem
symptoms
Vestibular Hours–days Migraine ± Tinnitus Headache None
migraine triggers meeting
criteria for
migraine
BPPV, benign paroxysmal positional vertigo; HIT, head impulse test; MRI, magnetic resonance
imaging; MS, multiple sclerosis.

LIGHTHEADED
Lightheadedness is a sensation of feeling faint and is essentially
synonymous with presyncope. It may precede syncope. Lightheadedness is
often associated with diaphoresis, flushing, pallor, or combinations of these.
Patients may also have symptoms of tunnel vision or palpitations. The most
concerning acute cause of presyncope is cerebral hypoperfusion. This can
be due to significant hypovolemia, or cardiac or autonomic etiologies.
Unlike with seizures, patients with syncope do not have alteration of
awareness when they regain consciousness (i.e., there is no postictal
confusion). Patients are generally aware of their circumstances and are able
to respond appropriately within seconds of regaining consciousness
(although they may be bewildered by what has happened).

HYPOVOLEMIA
Hypovolemia can be due to severe dehydration, but the most concerning
etiology is severe internal hemorrhage. Acute blood loss is typically
identified as the patient remains hypotensive in all positions and is typically
tachycardic. The hemoglobin and hematocrit levels are very low. Treatment
is based on volume repletion while simultaneously identifying and
resolving the cause of the bleeding.

CARDIAC ARRHYTHMIAS
Malignant cardiac dysrhythmias can also cause Lightheadedness. These can
be either tachy- or bradyarrhythmias. Patients may have symptoms of
palpitations or chest pain, but these may be absent. The symptoms are
typically not posturally induced (i.e., patients feel light-headed in any
position) but patients may report feeling worse when standing. The
diagnosis is made by capturing an event on electrocardiogram (ECG) or
longer cardiac telemetry. This may require brief cardiac monitoring, but if
the symptoms are very infrequent, implantable cardiac monitoring may be
warranted. Treatment is based on addressing the underlying dysrhythmia.

AUTONOMIC CAUSES
There are both normal variants and pathologic causes of autonomic
presyncope. Autonomic causes are distinctive from the other causes of
presyncope and syncope, as they generally do not cause symptoms unless
the patient is standing.
Neurally mediated syncope (also called vasovagal syncope) is a normal
variant where patients activate an autonomic reflex in which generally
parasympathetic activity is preserved but sympathetic activity is
insufficient. Patients therefore typically have simultaneous bradycardia and
hypotension, resulting in cerebral hypoperfusion and presyncope, syncope,
or both. There is typically a prodrome of rapid onset Lightheadedness,
flushing, diaphoresis, and pallor. Some patients also feel nauseated and
have tunnel vision. Sitting or lying down with legs elevated helps
ameliorate the symptoms, but the event is typically self-limited and resolves
within a few minutes. Symptoms are most commonly triggered by postural
changes from supine to standing, especially after prolonged recumbency.
Pain, seeing blood, venipuncture, and micturition are common triggers.
People who develop neurally mediated syncope from pain or blood drawing
can develop symptoms even when supine but do not typically have a full
syncopal event when supine. Episodes of presyncope and syncope from
neurally mediated syncope are intermittent and typically triggered. They are
self-resolving and brief. Carotid hypersensitivity is another cause of
syncope and presyncope, triggered by stimulation of the baroreceptors in
the carotid sinus, resulting in bradycardia and hypotension.
The diagnosis can often be made based on history alone, but if there are
atypical features or other factors that warrant additional evaluation, a head-
up tilt table test may be helpful. In this test, the patient’s supine blood
pressure and heart rate are measured when the patient is at rest. The patient
is then tilted in reverse Trendelenburg with the head elevated at a 60-degree
angle or higher. The blood pressure and heart rate are monitored
continuously, and the pattern of the blood pressure, heart rate, and patient’s
symptoms is used to identify neurally mediated syncope, orthostatic
hypotension, and a postural tachycardia. Patients who have a normal tilt
table test may still have neurally mediated syncope if their symptoms are
intermittent and not captured during the monitoring.
Orthostatic hypotension is another autonomic cause of presyncope. It is
defined as a drop in the blood pressure within 3 minutes of standing when
transitioning from supine to standing. Criteria include a drop in systolic
blood pressure by ≥ 20 mm Hg and in diastolic blood pressure by ≥ 10 mm
Hg. The diagnosis can be established at the bedside by performing
orthostatic vital signs. A head-up tilt table test may also be used. Some
patients have delayed orthostatic hypotension, where the blood pressure
drops after more than 3 minutes of standing.
Orthostatic hypotension can be caused by endocrinopathies, so screening
for adrenal insufficiency may be warranted. Aortic stenosis, pericarditis,
and myocarditis can also cause orthostatic hypotension; an echocardiogram
may be needed to assess for structural cardiac etiologies. There are also
many systemic disorders that can cause an autonomic neuropathy. Diabetic
autonomic neuropathy is common, especially in patients with long-standing
or poorly controlled diabetes. This can result in orthostatic hypotension, in
addition to other autonomic impairments. Neurodegenerative conditions
such as Parkinson disease can also cause orthostatic hypotension. There are
no tests to identify the underlying cause, so a detailed history, neurologic
examination, and screening for comorbidities are necessary.
Treatment of orthostatic hypotension is directed at removing any
medications that contribute to the problem, as well as preventing
progression of any comorbidity such as diabetes or cardiac valvular disease
that can exacerbate it. Symptomatic management is based on increasing the
volume through a high-fluid and sodium intake, if appropriate for the
patient’s other medical management. Compression stockings may be
helpful. In patients with persistent symptoms despite these strategies,
medications such as fludrocortisones, midodrine, or droxidopa may be
helpful as they raise the blood pressure. When patients are treated with
these medications, they must be monitored carefully for supine
hypertension.

POSTURAL TACHYCARDIA
Postural tachycardia is defined as a sustained increase in the heart rate by ≥
30 bpm within 10 minutes of standing. It may be caused by hypovolemia or
medication side effects. Some patients with postural tachycardia have a
syndrome known as postural tachycardia syndrome (POTS) and have
symptoms of presyncope, as well as fatigue and cognitive concerns. The
cause of POTS is unknown, but it has been associated with systemic and
inflammatory conditions that cause small fiber neuropathies. Treatment is
similar to that of orthostatic hypotension, and patients are counseled to
increase their oral fluid and sodium intake. If behavioral measures are not
sufficient, pressure support with midodrine, fludrocortisones, or beta-
blockers may be helpful. Cardiovascular conditioning is very important to
help patients improve their orthostatic tolerance.

METABOLIC CAUSES
There are numerous metabolic derangements that can also cause
nonspecific light-headedness. Hypoglycemia is a common cause in patients
with diabetes, especially in those using insulin. The diagnosis can be
established by having the patient check the blood glucose during the event.
 Many medications cause side effects of light-headedness. This may be a
nonspecific symptom, but there are also numerous medications that cause
hypotension (not only antihypertensives) and may cause light-headedness.
It is important to review carefully all the patient’s medications, including
over-the-counter remedies and herbal treatments, to assess for such
potential triggers.
Some patients have symptoms of orthostatic intolerance (i.e., feeling
light-headed or presyncope) without significant changes in blood pressure
or heart rate. These symptoms can be due to focal stenosis of the basilar
artery or bilateral vertebral arteries, or even less commonly the carotid
arteries bilaterally, but vascular stenosis alone is a very uncommon cause of
symptoms of orthostatic intolerance.

KEY POINTS
● Light-headedness is a term used to describe feelings like presyncope.
● There are numerous etiologies. Cardiac causes are the most important to consider.
● Management of the symptom is based on identifying and treating the underlying cause
when possible.
● Increased oral volume, cardiac conditioning, and, sometimes, medications are warranted
for management of orthostatic hypotension.

CONCLUSION
Dizziness and light-headedness are terms that patients may use to describe
many different symptoms. The quality of the symptoms, the history, and
examination are vital in clarifying the etiology. The most urgent concern is
for cardiovascular etiologies such as stroke, TIA, or dysrhythmia. If the
dizziness or light-headedness is not consistent with vertigo or presyncope,
other causes including metabolic derangement, medication effect, seizures,
and anxiety should be considered.

CLINICAL VIGNETTES

VIGNETTE 1
A 54-year-old woman is seen in the emergency room (ER) for
evaluation of new-onset dizziness. She describes severe but short-lived
paroxysms of dizziness, sometimes accompanied by nausea. The
episodes occur in both the upright and recumbent positions. Movement
exacerbates the dizziness. She reports no other neurologic symptoms
other than long-standing headaches that have not changed in character
or frequency. She recalls that, years ago, she may have had similar
symptoms that resolved spontaneously after her doctors were unable to
find a clear cause. The ER physician reports a normal neurologic
examination and requests a neurology consultation because he is
concerned about the possibility of “vertebrobasilar ischemia.”
1. The best first thing to do is:
a. Reassure the ER physician that isolated dizziness is almost never
caused by vertebrobasilar ischemia and advise him that the
patient may be discharged from the ER.
b. Ask the ER physician to order a stat head computed tomography
(CT) scan to exclude a cerebral hemorrhage.
c. Order a brain MRI with magnetic resonance angiography to
evaluate for a posterior circulation stroke.
d. Carefully review the history of symptoms with the patient and
perform a detailed neurologic examination, including the Dix–
Hallpike maneuver.
e. Perform the Epley maneuver to aid with the diagnosis of
vestibular neuronitis.
2. You review the patient’s history and determine that she is
describing a hallucination of movement (i.e., vertigo). You concur
that there are no other symptoms. You perform the Dix–Hallpike
maneuver. Which of the following descriptions is most typical of
the nystagmus you would expect if the patient has benign positional
paroxysmal vertigo?
a. A combined vertical and torsional nystagmus
b. A combined horizontal and torsional nystagmus
c. A purely vertical nystagmus
d. A purely torsional nystagmus
e. A purely horizontal nystagmus
 3. You confirm the diagnosis of posterior canal BPPV based on a
history of vertigo provoked by changes in head position relative to
gravity and demonstration of the characteristic nystagmus on the
Dix–Hallpike maneuver. You decide to treat the patient using which
of the following?
a. Meclizine
b. The Epley maneuver
c. “Tincture of time”
d. Physical therapy
e. Lorazepam

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D
The first step in evaluating a patient with dizziness is to clarify what is
meant by “dizzy,” as different people mean very different symptoms
when using this term. Although vertebrobasilar ischemia may rarely
cause isolated vertigo (i.e., with no other symptoms to suggest
brainstem dysfunction), you should review the history with the patient
and ask specifically about symptoms such as dysarthria, dysphagia,
diplopia, and facial sensory symptoms. A careful neurologic
examination is important, paying specific attention to the presence of
any neurologic deficit—including nystagmus, other cranial nerve
deficits, ataxia, or focal sensory findings. The Dix–Hallpike maneuver
should also be performed because, in the context of an appropriate
history, it can be highly diagnostic. Head CT or brain MRI is not
appropriate without a clear clinical differential diagnosis that warrants
such scans; they may or may not be appropriate once the clinical
evaluation has been completed. The Epley maneuver is a therapeutic
(not diagnostic) procedure.

VIGNETTE 1 QUESTION 2
2. Answer A
The nystagmus produced by the Dix–Hallpike maneuver, with BPPV
based in the posterior canal, typically includes two important features:
(1) a short latency (usually 5 to 20 seconds) between completion of the
maneuver and the onset of a subjective rotational vertigo along with
objective nystagmus and (2) a provoked subjective vertigo and
nystagmus, first increasing in severity and then resolving within about
60 seconds of the onset of symptoms. The fast component of the
nystagmus is characteristically mixed vertical and torsional. The
nystagmus may be observed again after the patient sits up and the head
is in an upright position.

VIGNETTE 1 QUESTION 3
3. Answer B
The Epley maneuver is appropriate for patients with posterior canal
BPPV, the most common form of this illness. The key elements of the
Epley maneuver include starting with the head turned 45 degrees toward
the affected side; moving the patient swiftly to a supine position with
the head tilted 30 degrees backward off the edge of the bed; followed by
subsequent progressive rotation of the head and body toward the
unaffected side, before sitting upright (Fig. 7-2); each positioning
movement is separated by a 30-second pause. The goal of the Epley
maneuver (or any other canalith repositioning procedure) is to move
canaliths from the posterior semicircular canal to the vestibule, thereby
relieving the stimulus in the semicircular canal responsible for the
vertigo. Ideally, symptoms are at least partially reproduced with each
successive position and then finally resolve.
 8 Ataxia and Gait Disorders

The staggering steps of a young child learning to walk are a classic example
of ataxia, a condition in which the control of motor movements is impaired
in the absence of muscle weakness. The term ataxia is of Greek origin, with
“a taxis” meaning “without order or arrangement.” The precision of
movement is controlled by an intricate sensory and motor feedback system,
with key processing of this information occurring in the cerebellum. As
such, disorders affecting the modulation of information entering or leaving
the cerebellum may affect the specific components of movement including
rate, direction, force, and rhythm. Depending on the pathologic cause,
ataxia can be diffuse, unilateral, or bilateral. It can affect the upper limb,
lower limb, and truncal, ocular, or bulbar muscles. Although ataxia can
cause significant difficulties with walking, it is not the only type of gait
abnormality. This chapter will review common causes of ataxia and gait
disorders.

ATAXIA
DIAGNOSTIC APPROACH
Ataxia is not a diagnosis, but rather a neurologic examination finding.
There are many ways in which ataxia may manifest clinically. Patients may
complain of clumsiness, gait difficulties, speech or swallowing difficulties,
or other problems. Because of the diverse array of symptoms, several terms
are used to describe specific aspects of ataxic movements. They include the
following:
1. Dysarthria: speech characterized by poor articulation. Although not
specific for ataxic disorders, ataxic disorders can lead to slurred, slow,
 hesitating, and effortful speech.
2. Dysmetria: incoordination of movement characterized by under- or
overshooting the intended position of the limb or eyes. Dysmetric
movements appear jerky and erratic.
3. Dysdiadochokinesia: impaired ability to perform movements that require
a rapid change of motion, leading to an inability to keep a steady rate or
rhythm.
4. Gait ataxia: broad-based and staggering steps because of incoordination
of the legs.
5. Intention tremor: a tremor with an increasing amplitude at the end of a
voluntary movement, due to impaired control of the proximal limb
muscles.
6. Nystagmus: periodic, rhythmic oscillation of the eyes. Nystagmus can
vary significantly based on the underlying cause. It can be present in
primary gaze or in specific directions of gaze.
7. Truncal ataxia: instability of the truncal muscles, often manifested by
oscillatory movements of the trunk when sitting or standing.
8. Pseudoathetosis: involuntary, slow, writhing movements of the digits or
distal limbs when the eyes are closed; this results from loss of
proprioception.
Given the number of disorders that cause ataxia, the presence and
distribution (focal, diffuse, unilateral, etc.) of the physical examination
findings are key to making a clinical diagnosis. These findings, however,
remain tied to the patient’s history. By understanding the nature of the
ataxia (temporary, progressive, or episodic), the acuity and age of onset, and
family history, the differential diagnosis can be pared down significantly.

ATAXIC DISORDERS
Ataxia is a hallmark of cerebellar disease. As there are many disorders that
affect the cerebellum, it is often the nonataxia-associated symptoms and
examination findings that help differentiate the origin of the ataxia (Table 8-
1). Similarly, the time course of symptom onset and progression aids
substantially in diagnosis. Differentiated by time course, several common
causes of ataxia are summarized here and in Box 8-1.
 TABLE 8-1. Associated Symptoms and Signs in Cerebellar Ataxia
Associated Symptom or Diagnostic Possibilities
Sign
Vomiting Cerebellar stroke, posterior fossa mass
Fever Viral cerebellitis, infection, abscess
Malnutrition Alcoholic cerebellar degeneration, vitamin E deficiency
Depressed consciousness Cerebellar stroke, childhood metabolic disorders
Dementia Creutzfeldt–Jakob disease, inherited SCA
Optic neuritis Multiple sclerosis
Ophthalmoplegia Wernicke encephalopathy, MFS, multiple sclerosis, cerebellar stroke,
posterior fossa mass
Extrapyramidal signs Wilson disease, Creutzfeldt–Jakob disease, olivopontocerebellar
atrophy
Hyporeflexia or areflexia MFS, Friedreich ataxia, alcoholic cerebellar degeneration,
hypothyroidism
Downbeat nystagmus Foramen magnum lesion, posterior fossa mass
MFS, Miller Fisher syndrome; SCA, spinocerebellar ataxia.

ACUTE ONSET ATAXIA

Cerebellar strokes, either with infarction or hemorrhage, typically present
as acute onset ataxia. Depending on where in the cerebellum the infarct has
occurred, clinical symptoms may include truncal ataxia (seen with lesions
of the cerebellar vermis) or ipsilateral limb ataxia (with cerebellar
hemisphere lesions). In many cases, there is associated vomiting, vertigo,
nystagmus, and dysarthria. In cases where hemorrhage or postinfarction
swelling leads to compression of the brainstem, impaired levels of
consciousness may occur. Because of this potential complication, cerebellar
strokes are considered medical emergencies.

BOX 8-1. Differential Diagnosis of Ataxias

Acute or subacute onset

Cerebellar hemorrhage or infarction
Postinfectious or infectious cerebellitis
Toxic (phenytoin, barbiturates, alcohol)
Multiple sclerosis
Episodic ataxia
Acute or subacute with progressive course
 Paraneoplastic cerebellar degeneration
Alcoholic or nutritional degeneration
Posterior fossa mass
Chronic onset and progressive course
Autosomal dominant spinocerebellar degeneration
Autosomal recessive cerebellar degenerative disorders
Creutzfeldt–Jakob disease
Hypothyroidism
Wilson disease
Ataxia telangiectasia
Friedreich ataxia

Postinfectious cerebellitis is another acute-to-subacute ataxic syndrome

typically affecting young children between the ages of 2 and 7 years.
Symptoms often follow a viral infection, and there is a strong association
with varicella. Symptoms of dysmetria, gait ataxia, and dysarthria often
accompany fever, headache, and vomiting. Fortunately, symptoms typically
resolve over the course of weeks with supportive therapy. Often, antivirals
and steroids are used for treatment.
The clinical triad of ataxia, areflexia, and ophthalmoplegia is the
hallmark feature of Miller Fisher syndrome (MFS). This, too, is often a
postinfectious process. It is thought that MFS is mediated by anti-GQ1b
antibodies, which are found in the serum of more than 90% of patients with
this disorder. Typically classified as a variant of Guillain–Barré syndrome,
the illness is responsive to treatment with intravenous immunoglobulin
(IVIG).
Paraneoplastic cerebellar degeneration (PCD) is a disorder caused by the
development of autoantibodies. Pancerebellar symptoms of nystagmus,
dysarthria, gait, limb, and truncal ataxia often present acutely to subacutely,
with progression in their intensity over weeks. The disorder can lead to
severe disability and often precedes the diagnosis of malignancy.
Associated with several cancer types (most notably ovarian and small cell
lung cancer), PCD is treated both by treatment of the underlying cancer and
by treatment with immunomodulatory therapies such as IVIG or rituximab.
There are at least nine autoantibodies associated with PCD, although only
60% to 70% of patients have antibody positivity. Anti-Yo antibody, also
known as Purkinje cell cytoplasmic antibody type 1 (PCA-1), is the most
common autoantibody in PCA.

SLOWLY PROGRESSIVE ATAXIC SYNDROMES

Alcoholic Cerebellar Degeneration

Chronic, long-term alcohol consumption is the most common cause of
acquired cerebellar degeneration. Alcohol abuse disproportionately affects
the cerebellum and, in particular, the vermis. This leads to gait and truncal
ataxia that progresses over the course of months to years. As similar
syndromes and cerebellar pathology have been seen in severe malnutrition,
it is felt that alcoholic cerebellar degeneration may be due, in part, to
thiamine deficiency. In addition to abstinence from alcohol, treatment is
often focused on vitamin supplementation.

Friedreich Ataxia
Friedreich ataxia (FRDA) is a multisystem disorder and the most common
hereditary ataxia, affecting approximately 1:50,000 individuals worldwide.
It is caused by a trinucleotide repeat expansion in the gene that encodes a
protein called frataxin. The disease typically presents in childhood with gait
ataxia, which slowly spreads to involve the trunk and arms. In addition to
the ataxia, the physical examination is often notable for the distinct
combination of absent reflexes, neuropathy, and upgoing toes. Patients with
FRDA are also susceptible to cardiomyopathy, diabetes, and hearing loss.
The disorder is progressive, and there is currently no treatment.

Autosomal Dominant Spinocerebellar Ataxia

The spinocerebellar ataxias (SCAs) are a diverse group of inherited ataxic
disorders, with nearly 40 genetically distinct disorders identified to date.
These syndromes are dominantly inherited and vary significantly in their
age of onset. The classic presentation is that of frequent falls and slurred
speech in early adulthood. Depending on the genetic subtype, patients may
also have extrapyramidal, pyramidal, cranial nerve, or cognitive symptoms.
As for the underlying genetic etiologies, the most common forms of SCA
are due to polyglutamine repeats in causative genes. Machado–Joseph
disease, also known as SCA3, is the most common SCA worldwide. Less
common forms of SCA are related to ion-channel genes and genes involved
in signal transduction. Treatment is currently supportive.

Episodic Ataxia
Recurrent, brief episodes of ataxia, vertigo, nausea, and vomiting are the
features of inherited episodic ataxia (EA) syndromes. These disorders
typically present in childhood. Although some forms of EA have complete
resolution of symptoms between spells, these disorders can be associated
with interictal symptoms as well as progressive weakness and ataxia. The
two most common forms of EA are EA-1 and EA-2. The attacks of EA-1
are brief (seconds to minutes) but can occur as frequently as 30 times per
day. Myokymia (muscle twitching) is common between events. EA-1 is
caused by mutations in the voltage-gated potassium channel gene KCNA1.
EA-2 is the most common EA syndrome. Caused by mutations in the
calcium channel gene CACNA1A, EA-2 is characterized by longer episodes
of ataxia (lasting hours) with interictal nystagmus and mildly progressive
baseline ataxia. Treatment with acetazolamide can significantly reduce
attacks of ataxia.

KEY POINTS
● Sudden onset ataxia occurring with vomiting and depressed consciousness suggests a
cerebellar stroke.
● Postinfectious cerebellitis is a common cause of ataxia in children.
● PCD is a pancerebellar syndrome and is most often associated with small cell lung cancer
and gynecologic malignancies.
● Alcoholic cerebellar degeneration typically affects the vermis and is manifested in gait and
truncal ataxia.
● The inherited EAs are caused by mutations in calcium and potassium channel genes.
● The autosomal dominant SCAs are a heterogeneous group of slowly progressive
degenerative disorders with nearly 40 different genetic causes.

OTHER GAIT DISORDERS

The prevalence of gait difficulties increases with age, with more than 60%
of patients over the age of 80 having some degree of gait impairment.
Because successful ambulation is dependent on a number of factors
including muscle tone and strength, sensation, and healthy joint mechanics,
nonneurologic disorders such as osteoarthritis and impaired vision can also
lead to gait disorders. When ambulatory difficulties are present, direct
observation of the gait is key to understanding potential contributors. There
are some aspects of gait that, when impaired, may yield enough information
on physical examination to diagnose particular neurologic causes (Table 8-
2). Below are pathologic gaits attributed to specific neurologic conditions or
locations within the nervous system.

TABLE 8-2. Etiology of Various Abnormal Gaits

Gait Disorder Anatomic Pathology
Location
Hemiplegic Brainstem, Stroke, tumor, trauma
cerebral
hemisphere
Paraplegic Spinal cord Demyelination (e.g., with multiple sclerosis), transverse
myelitis, compressive myelopathy
Bihemispheric Diffuse anoxic injury
Akinetic-rigid Basal ganglia Parkinson disease; other parkinsonian syndromes
Frontal Frontal lobes Hydrocephalus, tumor, stroke, neurodegenerative disease
Waddling Hip-girdle Hereditary and acquired myopathies, muscular dystrophies
weakness
Slapping Large fiber Vitamin B12 deficiency, tabes dorsalis
neuropathy, dorsal
columns

SPASTIC GAIT
Impairment of upper motor neurons leads to spasticity of the muscles,
limiting leg flexion at the ankle, knee, and hip. The increased tone leads to a
narrow base, circumduction of the legs, with dragging of the toes. Tightness
of hip adductors causes “scissoring,” where the legs cross the midline with
each step. Depending on the location of the lesion, one or both legs can be
affected.

AKINETIC-RIGID GAIT
This gait is characterized by a stooped posture, with the head and neck
forward, and slow, shortened steps (“marche à petits pas”). Initiating steps
may be difficult, but once the patient starts walking, there may be a
quickening of the steps, known as festination. Typical of Parkinson disease,
this gait may also be seen in other parkinsonian syndromes or conditions.

FRONTAL GAIT
Described as “magnetic,” a frontal gait is recognized by the impairment in
lifting the feet off the ground despite having normal strength and ability to
move the limbs appropriately when sitting or lying down. Other features of
a frontal gait disorder include a slightly wide base and impaired gait
initiation. Frontal gait disorders are related to impaired communication
between the frontal cortex and the deeper structures required for gait (basal
ganglia, brainstem, etc.). This type of gait abnormality may be due to a
number of conditions, including vascular disease and hydrocephalus.

WADDLING GAIT
A normal gait requires the ability to stabilize the hips with each step. This is
accomplished by contracting the hip abductors on the weight-bearing leg
while the other leg rises from the ground. Failure of these muscles to
contract effectively leads to a tilt of the hip-girdle toward the nonweight-
bearing leg during ambulation. A waddling gait is characteristic of many
myopathies that tend to disproportionately affect proximal muscles.

SENSORY ATAXIA
Key to normal walking is the ability for the brain to know where the feet are
in space. Impairment in this sense of proprioception leads to a wide base—
to compensate for the loss of balance. In addition, the foot tends to hit the
ground with the heel, with a subsequent “slapping” of the forefoot leading
to a characteristic “slapping” sound. Limiting other sensory input (dark
environment) or uneven surfaces tends to exacerbate sensory ataxia.

PSYCHOGENIC GAIT
As with many organ systems, the nervous system can be a site of symptoms
reflective of a psychogenic process. When somatization affects gait, the
abnormalities seen on examination rarely fit a traditional or specific gait
disorder. Often, the gait demonstrates variable or inconsistent features. The
legs and arms may move in an exaggerated fashion when walking is
attempted, with a tendency to “nearly fall” but without actually falling. This
type of gait is often referred to as astasia-abasia.

KEY POINTS
● Hemiparetic gait suggests hemispheric dysfunction, such as with a stroke.
● Diplegic gait is seen with a myelopathy and bilateral periventricular lesions, as in cerebral
palsy.
● Paraparetic gait typically suggests spinal cord disease.
● Akinetic-rigid gait is a feature of parkinsonian syndromes.
● Frontal gait suggests hydrocephalus, neurodegenerative processes, or subcortical disease.
● Waddling gait suggests proximal muscle (hip-girdle) weakness.
● Slapping gait indicates large fiber sensory or dorsal column dysfunction.
● Gait that worsens with eyes closed is often indicative of a sensory or vestibular component
to the gait disorder.
● Astasia-abasia is the term for dramatically impaired gait due to psychogenic causes.

CLINICAL VIGNETTES

VIGNETTE 1
A 14-year-old girl is seen in the outpatient Neurology clinic for
evaluation. She describes a 3-year history of slowly progressive gait
ataxia and slurred speech. There is no family history of a similar
disorder. Examination shows limb and gait ataxia, slurred speech,
nystagmus, absent ankle reflexes, hammering of the toes and high
arched feet, and diminished vibration sense in the toes.
1. The most likely cause in this child is:
a. Wilson disease
b. Postinfectious cerebellitis
c. FRDA
d. EA-2
e. MFS
2. Which inheritance pattern is most consistent with FRDA?
a. Autosomal dominant
b. Autosomal recessive
 c. X-linked recessive
d. X-linked dominant
e. Maternal (mitochondria)
3. Which of the following systemic problems is not encountered in
FRDA?
a. Hearing loss
b. Glucose intolerance and diabetes
c. Hypertrophic cardiomyopathy
d. Cardiac arrhythmias
e. Infertility

ANSWERS

VIGNETTE 1 QUESTION 1
Answer C:
FRDA is a debilitating neurologic disorder characterized by damage to
the cerebellum and the peripheral nerves. Onset is typically between the
ages of 10 and 15 years. Characteristic findings include ataxia, slurred
speech, dysphagia, weakness, spasticity, loss of sensation, and skeletal
deformities. Wilson disease may also cause childhood onset ataxia, but
is less likely here, given the evidence for a polyneuropathy (absent
ankle reflexes, diminished vibration sense, and foot deformities
indicative of a chronic process); there are isolated reports of
polyneuropathy in Wilson disease, but this is unusual. The slowly
progressive symptoms argue against a postinfectious cerebellitis
(usually acute or subacute in onset). EA is unlikely in view of the
temporal course of symptoms. MFS may include ataxia and evidence of
neuropathy, but is typically acute or subacute in onset, and it is usually
characterized by ophthalmoplegia, which was not present in this child.

VIGNETTE 1 QUESTION 2
Answer B
FRDA is an autosomal recessive disorder caused by a mutation in the
FXN gene. The inheritance is autosomal (rather than X-linked) recessive
because the FXN gene lies on chromosome 9, not on the X-
chromosome. FXN produces a protein called frataxin. The most
common mutation is an expanded GAA trinucleotide repeat. Normally,
there are 5 to 33 GAA repeat units; in people with FRDA, the GAA
trinucleotide repeat is expanded to at least 66 units. The abnormally
long trinucleotide repeat disrupts the production of frataxin, severely
reducing the amount of this protein in cells.
Having made a presumptive diagnosis of FRDA, you recognize the
multisystem nature of this disease and the need to screen for systemic
manifestations of the disease.

VIGNETTE 1 QUESTION 3
Answer E:
Sensorineural hearing loss occurs in 13% of individuals with FRDA.
Diabetes mellitus occurs in up to 30%; patients without diabetes may
have impaired glucose tolerance. Hypertrophic cardiomyopathy is found
in about two-thirds of patients with FRDA; the electrocardiogram is
abnormal in the majority. Infertility is not a feature of FRDA.
 9 Urinary and Sexual Dysfunction

The complex neural mechanisms involved in bladder regulation make this

process sensitive to a wide variety of neurologic diseases affecting the
central and peripheral nervous systems, including but not limited to stroke,
dementia, Parkinson disease, multiple sclerosis (MS), and diabetes.
Understanding the anatomy and physiology of the normal bladder is
important for both diagnosis and management of impaired bladder control.

BLADDER CONTINENCE
ANATOMY AND PHYSIOLOGY
Bladder control is maintained at different levels of the nervous system and
involves sensory pathways as well as voluntary and involuntary motor
pathways. Several neuroanatomic connections important for bladder control
create “circuits” with key components located in the brain, spinal cord, and
peripheral nerve ganglia. These neural circuits coordinate the activity of
smooth muscle (involuntary control of the bladder and urethra) and striated
muscle (voluntary control of the external urethral sphincter) leading to
urinary storage or micturition (voiding) (Fig. 9-1).
Voluntary micturition is controlled by a circuit connecting the
dorsomedial frontal lobes to the medial (M) region of the pontine
micturition center (PMC). Through learned behavior, the frontal lobes
provide volitional control of micturition by initiating a decrease in urethral
pressure. This is followed by increased contraction of the detrusor muscle,
leading to voiding. The nearby lateral (L) region of the PMC, on the other
hand, produces a powerful contraction of the urethral sphincter (promoting
storage).
 Urinary storage and voiding is also controlled by reflexes at the spinal
level, which affect the PMC signaling. For example, afferent signals of
bladder distention trigger sympathetic outflow in the hypogastric and
pudendal nerves to promote urethral constriction and continence. During
elimination of urine, efferent firing in the pelvic nerves triggers the
spinobulbospinal reflex that passes through the PMC and promotes
parasympathetic outflow to the bladder and urethra, allowing for bladder
emptying (Fig. 9-1).
Lesions affecting the coordinated effort of the PMC produce a loss of
inhibitory control over spinal reflexes. Then, when the bladder becomes
distended, the micturition reflex is automatically activated at the spinal
level, without the patient’s awareness or control, and detrusor hyperreflexia
(DH) and incontinence occur. Likewise, lesions affecting the peripheral
input and spinal reflexes can lead to a variety of urinary symptoms
including urinary retention, incontinence, hesitancy, and overflow urinary
incontinence.

DIAGNOSTIC EVALUATION
The first objective in the evaluation of bladder dysfunction is to determine
if the problem is neurologic or not and, if it is, localize the lesion causing
the urinary difficulties. A detailed history is essential. It is important to
obtain information about initiation; voiding problems such as frequency,
stream characteristics, urine volume, fullness, and urgency; effects of
posture, cough, Valsalva maneuver, and medications; and associated bowel
and sexual dysfunction.
Thorough physical and neurologic examinations are necessary. The
examiner seeks signs of frontal lobe dysfunction, parkinsonian features, a
sensory level, myelopathy, and so forth. Laboratory evaluation includes
urinalysis to rule out infection. Measurement of the post-void residual
(PVR) by bladder ultrasound or catheterization is important in the
characterization of bladder dysfunction. The PVR is the residual volume in
the bladder after voiding. A normal PVR is less than 50 mL. Urodynamic
studies can clarify the characteristics of incontinence, determine the
underlying neurologic abnormality, categorize vesicourethral dysfunction,
and provide a basis for appropriate therapy.
FIGURE 9-1. The control of bladder function. (Copyright © 2012 Dr. Juan Acosta, MD.)

Some urodynamic studies include the following:

• Cystometry: Provides information about bladder compliance, capacity,
and volume at first sensation and at urge to void; voiding pressure; and
the presence of uninhibited detrusor contractions.
• Cystourethroscopy: Assesses the integrity of the lower urinary system
and identifies important urethral and bladder lesions.
• Neurophysiologic studies: These include electromyography (EMG) of
the sphincter and pelvic floor muscles. Urodynamic findings in various
types of neurogenic bladder dysfunctions are listed in Table 9-1.
 KEY POINTS
● The M region in the pons is the site of activation of micturition.
● History and a complete neurologic examination are important in the evaluation of bladder
incontinence.
● PVR should be less than 50 mL. Increased PVR implies poor bladder emptying. Sphincter
dyssynergia and atonic bladder are common neurogenic causes of elevated PVR.

TABLE 9-1. Urodynamic Findings in Neurogenic Bladder

Type Capacity Compliance Others
Spastic bladder Decreased Reduced Uninhibited detrusor
contractions
Atonic bladder Increased Increased Low voiding pressure
and flow rate

CLASSIFICATION
Based on the patient’s symptoms, urinary incontinence can be classified as
follows:
Urge incontinence is an involuntary loss of urine associated with a strong
desire to void (urgency), usually associated with detrusor instability
(DI). When the DI is the result of a neurologic problem, the term
detrusor hyperreflexia is used and its clinical expression is a spastic
bladder. DH is common in patients with strokes, frontal lobe
dysfunction, suprasacral spinal cord lesions, and MS. It is usually
accompanied by detrusor-sphincter dyssynergia (DSD), which is
inappropriate contraction of the external sphincter with detrusor
contraction. This can result in urinary retention, vesicoureteral reflux,
and subsequent renal damage.
Stress incontinence is an involuntary loss of urine during coughing,
sneezing, laughing, or other physical activities that increase
intraabdominal pressure (in the absence of detrusor contraction or an
overdistended bladder). This is common in multiparous women who
have cystoceles or weakened muscles of the pelvic floor. Other causes
include urethral hypermobility, significant displacement of the urethra
and bladder neck, and intrinsic urethral sphincter deficiency caused by
congenital weakness in patients with myelomeningocele or epispadias.
 This can also be seen in patients who have had prostatectomy, local
trauma, or radiation.
Mixed incontinence is a combination of urge and stress incontinence.
Overflow incontinence is an involuntary loss of urine associated with
overdistention of the bladder, typically reflecting a lower motor neuron
problem. Patients report constant dribbling and urge or stress
incontinence symptoms. Causes of overflow incontinence include an
underactive or acontractile (atonic) detrusor because of drugs, diabetic
neuropathy, lower spinal cord injury or radical pelvic surgery
(interrupting innervation to the detrusor muscle), or urethral or bladder
outlet obstruction, leading to overdistention and overflow.

KEY POINTS
● Spastic bladder implies an upper motor neuron problem caused by lesions involving the
frontal lobes, pons, or suprasacral spinal cord. Symptoms include incontinence with
urgency and frequency. Urodynamics show decreased capacity and reduced compliance.
● Stress incontinence is rarely a neurologic problem.
● Atonic bladder implies a lower motor neuron lesion at the level of the conus medullaris,
cauda equina, or sacral plexus; or it may reflect peripheral nerve dysfunction. It is
characterized by overflow incontinence and increased capacity and compliance.
● Sphincter dyssynergia produces an increased PVR, with fluctuating voiding pressures and
varying flow rate.
● A small PVR is good; a large PVR with a spastic or atonic bladder is not. It can cause
increased intrabladder pressure with deleterious effects on the ureters and kidneys.

INCONTINENCE IN THE NEUROLOGIC

PATIENT

SUPRASPINAL DISEASES AND INJURY

Supraspinal diseases usually result in a hyperreflexic bladder, causing urge
incontinence, reduced bladder capacity, and a small PVR, with no
deleterious effects on the upper urinary tract because voiding is
unobstructed.
Cerebrovascular Disease
Large strokes (particularly frontal or pontine) produce an upper motor
neuron bladder (hyperreflexic and small, with urgency and frequency).
Urinary incontinence after a stroke is common and is associated with
overall poor functional outcome.

Parkinson Disease
Voiding dysfunction occurs in 40% to 70% of patients with Parkinson
disease. DH is the most common finding. Pseudodyssynergia occurs as a
consequence of sphincter bradykinesia. Urologic causes, such as benign
prostatic hypertrophy, are frequently associated.

SPINAL CORD DISEASES

Spinal cord diseases account for more than 70% of patients with neurogenic
bladder dysfunction. Following disconnection from the pons, the sphincter
tends to contract when the detrusor is contracting (dyssynergia). Spinal cord
injury produces DH, loss of compliance, and DSD. New reflexes emerge to
drive bladder emptying and cause the DH. During spinal shock, the bladder
is acontractile, but gradually, over weeks, reflex detrusor contractions
develop in response to low filling volumes.

Multiple Sclerosis
About 75% of patients with MS have bladder dysfunction. The types of
bladder complaints can vary, often reflecting a combination of cortical,
brainstem, and spinal disease. Many patients report irritative bladder
symptoms, with DH and DSD occurring in 50% to 90% of MS patients with
bladder complaints.

PERIPHERAL NERVE DISEASES

Because of the bladder’s extensive autonomic innervation, its dysfunction is
most often seen in those generalized polyneuropathies involving small
(autonomic) nerve fibers. Urodynamic studies show impaired detrusor
contractility, decreased bladder sensation, decreased flow rate, and
increased PVR. A classic example is diabetic cystopathy, in which a
progressive loss of bladder sensation and impairment of bladder emptying
eventually result in chronic low-pressure urinary retention. The situation is
similar in other types of neuropathies such as amyloidosis, immune-
mediated polyneuropathies (25% of Guillain–Barré patients have bladder
symptoms), and inherited neuropathies. Injury to pelvic nerves (e.g., by
local radiation or surgery) can produce similar symptoms.

KEY POINTS
● Stroke and spinal cord disease usually produce an upper motor neuron bladder or spastic
bladder, with or without sphincter dyssynergia.
● Small-fiber neuropathies can produce a neurogenic atonic bladder with a high PVR.

TREATMENT
Therapy for a neurogenic bladder includes pharmacologic and
nonpharmacologic approaches. Some behavioral techniques that may help
with the treatment of this condition include toileting assistance, bladder
retraining, and pelvic muscle rehabilitation.
Pharmacologic agents are available to treat bladder dysfunction. The
choice of therapy is based on an understanding of the underlying
mechanism of the dysfunction and therefore the site of the neural injury.
Table 9-2 summarizes treatments for urinary incontinence.

KEY POINTS
● Therapy of urinary incontinence is individualized and often requires adjustments.
● The main management goals are preservation of upper urinary tract function and
improvement of the patient’s urinary symptoms that impair quality of life.

SEXUAL DYSFUNCTION
The sexual response cycle of excitement, plateau, orgasm, and resolution
requires the integrated and coordinated activity of the somatic and
autonomic nervous systems innervating the reproductive system. Sexual
dysfunction affects both men and women and can be caused by a multitude
of psychological and physiologic conditions. Whereas knowledge regarding
female sexual physiology is less advanced than that of male sexual
physiology, approximately 40% of women and 30% of men experience
sexual dysfunction of one cause or another.

ANATOMY AND PHYSIOLOGY

Similar to the bladder, a combination of spinal reflexes consisting of
sympathetic, parasympathetic, and somatic innervation contributes to the
regulation of the sexual phases. Because of the differences in anatomy, the
exact physiology differs between men and women, but the general
principles are the same and there are, in general, more similarities than
differences. The motor and sensory fibers that innervate the penis and
clitoris are carried in the pudendal nerve. The parasympathetic nerves
involved in erection in men and the sexual response in women originate in
the sacral segments S2–S4 and innervate their respective organs via the
pelvic nerves. Activation of the postganglionic parasympathetic neurons
leads to arterial engorgement and thus, expansion of the cavernous spaces
(erection in men and clitoral and vaginal engorgement in women).
Parasympathetic activity also leads to increased prostatic and vaginal
secretions. Local tissue mediators such as nitric oxide and cyclic guanosine
monophosphate (cGMP) are primarily released by parasympathetic activity,
contributing to sustained engorgement. The sympathetic innervation of the
sexual organs arises from cells in the T11 to L2 levels of the spinal cord and
travels through the hypogastric plexus. Sympathetic activity causes
vasoconstriction and loss of erection and is important in ejaculation and
orgasm.

TABLE 9-2. Treatment of Urinary Incontinence

CAUSES OF SEXUAL DYSFUNCTION
The etiology of sexual dysfunction can be multifactorial. Neurogenic causes
include neuropathy, myelopathy, cauda equina lesions, and central nervous
system dysfunction. Other causes include vascular disease, pelvic trauma,
and endocrine disorders such as hypothyroidism, hypogonadism, and
hyperprolactinemia. Chronic illness such as liver and kidney disease,
psychological conditions, and drugs (i.e., antihypertensives,
anticholinergics, antidepressants, sedatives, alcohol, and narcotics) can also
impair sexual function.

DIAGNOSTIC EVALUATION
The evaluation of a patient with sexual dysfunction includes a complete
history and physical examination. Neurologic examination may provide
evidence of cerebral, spinal cord, or peripheral nerve dysfunction.
Laboratory evaluation includes an endocrine panel with levels of sex
hormones, including prolactin, testosterone, and gonadotropins. Sleep
studies can be helpful; erection usually occurs with each episode of rapid
eye movement sleep. EMG and somatosensory-evoked potentials can help
detect and analyze myelopathy or peripheral nerve disease. Vascular studies
evaluate the response of the penis to the injection of vasoactive agents such
as papaverine.

TREATMENT
The management of sexual dysfunction requires recognition of the etiology
and treatment of the underlying disease. Endocrine, metabolic, vascular, and
psychogenic causes must be treated when present. If drugs are responsible,
changes in medication may be beneficial. At present, there are no Food and
Drug Administration–approved therapies for female sexual dysfunction.
Pharmacologic therapy of male erectile dysfunction includes selective
inhibitors of cGMP-specific phosphodiesterases like sildenafil and
vardenafil, intraurethral suppositories, and intracavernosal injections of
alprostadil. A full discussion of available medical and surgical treatments is
beyond the scope of this chapter.

KEY POINTS
● Sexual dysfunction is often multifactorial and can be caused by a variety of neurologic
diseases, including strokes, MS, and diabetes.
● Various medical and surgical therapies are available depending on the underlying cause of
the sexual dysfunction.
 10 Headache and Facial Pain

Headache disorders are among the most prevalent medical problems

worldwide. The World Health Organization estimates that 50% to 75% of
all adults between the ages of 18 and 65 have headaches. This high
prevalence results in significant disability and lost productivity: headache
disorders are the third highest cause of years lost to disability worldwide.
Accordingly, headaches are one of the most common reasons patients
present to physicians in primary care settings, in the emergency department
(ED), or in neurologists’ offices. For clinicians evaluating a patient with
headaches, the first responsibility is to diagnose the type of headache
correctly, and then treat appropriately, because most headache disorders
have excellent treatments available, which can reduce the burden of
disability.
Headache disorders fall into two categories, primary headache
disorders (those caused by the headache disorder itself, not due to other
causes) and secondary headache disorders, those caused by (or
“symptomatic of”) another underlying medical problem. The pain can be
due to the involvement of pain-sensitive structures in the head, including
cranial nerves, cervical nerve roots, blood vessels, meninges, scalp,
temporomandibular joint (TMJ), teeth, pericranial and cervical muscles, and
paranasal sinuses.
Patients may also have multifactorial headaches, so a detailed history and
examination are necessary to identify the contributing factors. Headache
disorders may remain refractory to treatment or have an insufficient
response to treatment if these comorbidities are not identified and
addressed.

DIAGNOSIS
A detailed history and examination are vital in understanding the
headache’s cause. There are no biomarkers currently available for primary
headache disorders.

KEY POINTS FOR THE HISTORY

When obtaining the history the following information must be elicited:
• Onset
• Precipitants and triggers
• Duration
• Location (unilateral or bilateral; frontal, lateral, vertex, or occipital)
• Quality and severity
• Frequency
• Alleviating and exacerbating factors
• Positional influences (better or worse when supine)
• Waking the patient from sleep, or occurring upon awakening
• Associated with menses
• Associated symptoms
Additional aspects of the history important in evaluating a patient with
headache are:
• Analgesic use
• Caffeine use
• Medical history
• Current or recent pregnancy
• Medications (including asking specifically about contraceptive use,
over-the-counter treatments, and supplements)
• Social history, including detailed screening for illicit drugs
• Family history
• Sleep, including a history of insomnia and snoring; symptoms of
obstructive sleep apnea
The semiology of the headache helps to differentiate a primary from a
secondary headache disorder. The history also allows a clinician to identify
red flags that suggest a secondary headache disorder (Box 10-1).

KEY POINTS FOR THE NEUROLOGIC EXAM

Patients with primary headache disorders usually have normal general
medical and neurologic examinations, although an acutely symptomatic
patient with an autonomic cephalalgia may have signs strongly suggesting
that disorder. Some patients with chronic headaches have findings of TMJ
tenderness on palpation, evidence of dental wearing, or pain with palpation
of the cervical muscles or the occipital ridge to suggest comorbid causes of
headache such as cervicalgia.
In the era of the smartphone, patients may bring pictures of themselves to
a clinician for review if they have paroxysmal symptoms and signs (such as
ptosis or lacrimation), which can aid in the diagnosis.
Patients should have a general medical and neurologic exam to assess for
secondary causes of headache. Attention to vital signs is important: Patients
with significant hypertension may be susceptible to developing certain
secondary headaches outlined below; fever may suggest an underlying
infection, including a central nervous system (CNS) infection. A
cardiovascular exam can evaluate for arrhythmia or carotid stenosis, which
can cause secondary headache syndromes. A detailed head and neck exam
includes evaluating for nuchal rigidity, cervical myofascial pain, occipital
Tinel sign (evaluated by eliciting tenderness or tingling when palpating near
the occipital protuberance along the occipital nerve), and palpation of the
TMJ, assessment of dental wearing or chipping to suggest bruxism, and
observing the oropharynx for narrowing that could suggest obstructive sleep
apnea.

BOX 10-1. Red Flags

• Acute onset or progressive worsening from baseline

• New or different headache
• Systemic symptoms:
Fever, weight loss
• Risk factors:
Malignancy
Immunosuppression
IV illicit substance use
Hypercoagulability, including pregnancy
• Smoking
• Age>50, or no prior headache history
• Features of increased ICP:
 Waking patient from sleep
Worsening with Valsalva maneuver
Supine worsening of pain
• Focal features:
Seizures
Mental status abnormality
Cranial nerve deficits
Weakness
Sensory changes (loss of sensation, paresthesias; location and pattern of spread)
• Precipitants:
Trauma
Newly prescribed medications
Infection

A full neurologic exam should also be performed, with emphasis on the

funduscopic exam to assess for papilledema. The cortical sensory exam can
suggest cortical dysfunction that may occur with venous sinus thrombosis.
Focal neurologic deficits, including field cuts, cranial nerve palsies,
weakness, or sensory symptoms, often suggest a secondary headache.

KEY POINTS
● Headaches are divided into primary and secondary headache disorders.
● There are no biomarkers for primary headache disorders.
● Diagnosis is made primarily on a detailed history and examination.
● Always screen for red flags in the history.
● Screen specifically for pregnancy, contraceptive use, immune status, illicit substance use,
and medications.

PRIMARY HEADACHE DISORDERS

Primary headache disorders are those not due to another medical condition.
Diagnosis is established by history and exam. Migraine is by far the most
prevalent primary headache disorder. Table 10-1 outlines common primary
headache disorders based on key features of the history. Figure 10-1 shows
the common locations of pain in the primary headache disorders, compared
to that of headaches caused by sinus disease.
MIGRAINE

Migraine Without Aura

It is estimated that one in seven adults worldwide has migraine. It impacts
women more than men in a 2:1 ratio. Migraine may start in childhood and
manifest occasionally with abdominal symptoms (“abdominal migraine”).
Motion sickness in children is a risk factor for the development of migraine.

TABLE 10-1. Key Features of Primary Headache Disorders

Episodic Episodic Episodic Paroxysmal SUNCT and
Migraine Tension Cluster Hemicrania SUNA
Sex Female > male Female > male Male > female Female > male Male > female
Location Unilateral > Bilateral (band Unilateral Unilateral Unilateral
bilateral around the (behind or (behind or (behind or
head) around the around the around the
eye) eye) eye)
Quality Throbbing, Dull pressure Stabbing, Stabbing, Stabbing,
pulsatile or tightening burning, burning, burning
(vice-like) boring throbbing
Severity Moderate to Moderate Severe Severe Severe
severe
Attack 4–72 h 30 min–7 d 15–180 min 2–30 min 1 s–10 min
duration
Attack Variable Variable From 1 every >5/d to 40/d From 1/d to
frequency other day to 200/d
8/d
Autonomic No No Yes Yes Yes
features
SUNCT, short-lasting unilateral neuraliform headache attacks with conjunctival injection and
tearing; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic
symptoms.

Migraine headaches are most likely to develop in adolescence and early

adulthood. They can be episodic or chronic. The disability and lost
productivity from migraine are substantial, because it impacts people in
their prime working years.
Migraine has numerous identified triggers, including weather changes,
menses, and caffeine (both withdrawal and overuse). Many patients identify
foods and drinks such as alcohol (most commonly red wine), soft cheeses,
and nitrite-heavy foods, such as processed meats, as precipitants, but data
are sparse in this area and many migraine attacks occur without identifiable
triggers.
To diagnose migraine, a patient must have at least five attacks with the
following characteristics:
1. The headache lasts for 4 to 72 hours if untreated.
2. It must include at least two of the following features:
a. Throbbing
b. Unilateral headaches
c. Worsening with activity, such as walking
d. Moderate to severe pain
3. It must be associated with at least one of the following:
a. Nausea, vomiting, or both
b. Photophobia and phonophobia

FIGURE 10-1. Location of pain associated with primary headache disorders. Left to right:
sinus headache, cluster headache, tension headache, migraine headache. (Used with permission of
A.D.A.M.)

Migraine with Aura

Migraine headaches are often preceded by focal neurologic symptoms
known as auras. These are also called classic migraine or complicated
migraine. Auras are defined as fully reversible neurologic symptoms with a
gradual onset, usually followed by a headache. The aura usually lasts for 5
to 60 (often 20) minutes and is typically unilateral. It usually resolves
without lingering neurologic deficits. Patients are diagnosed with this
disorder when they have an aura followed by a headache that meets the
criteria for migraine, as above. Some auras occur without a headache
(“acephalgic migraine”), but these symptoms usually require additional
investigation for a definite diagnosis.
Visual auras are by the far the most common. Some include a
“fortification spectrum” (zigzag lines off the central vision, usually
spreading gradually) or a scintillating (or flickering) scotoma (an area of
decreased visual acuity surrounded by preserved vision).
Migraine auras can also involve sensory symptoms, most commonly
paresthesias (tingling or pins-and-needles sensation). The paresthesias often
“march” or spread gradually over the course of several minutes along a
limb or extend from an arm to the leg or face.
Migraine auras can also include a gradual onset of weakness, a variant
known as hemiplegic migraine when severe. Hemiplegic migraine may be
sporadic but there is also a syndrome of familial hemiplegic migraine,
sometimes associated with well-characterized genes.
Migraine auras are believed to be due to “cortical spreading depression”
in which there is a spread of hyperpolarization of the cortex followed by a
wave of depolarization. Imaging studies have shown decreased regional
cerebral blood flow in the cortex during migraine aura, but not to the level
of worrisome ischemia.

COMPLICATIONS ASSOCIATED WITH MIGRAINE

Status Migrainosus
When migraine lasts for more than 72 hours, the condition is known as
status migrainosus. This is often caused by abortive medication overuse
(often referred to as rebound headache) and frequently requires intravenous
(IV) treatment or a brief course of oral steroids to break the headache cycle.

Stroke Risk Associated with Migraine

Patients with migraine with aura have an increased cardiovascular risk
when compared to healthy controls. The use of estrogen-based
contraceptives is therefore contraindicated in patients with migraine
with aura, as the combination results in a substantially increased stroke
risk.

Migraine and Menses

Women of reproductive age frequently have exacerbations of migraine
during menses, most commonly 1 to 2 days prior to the onset of bleeding,
often persisting for up to 3 days into bleeding. This is thought due to the
withdrawal of estrogen that occurs with menses. Some women have
migraine at the time of menstruation only, a condition known as pure
menstrual migraine. Most, however, have a few episodic headaches at other
times of the month, or menstrually related migraine. It is important to
identify the relationship of menses to migraine because there are specific
treatments that may be helpful for patients with a clear exacerbation around
their menses.

Chronic Migraine
Patients who have a headache more than 15 days/month for more than 3
months are diagnosed with chronic migraine. Some patients with chronic
migraine do not have typical features of migraine with all headaches, but
they must have at least 8 days of headache consistent with migraine to be
diagnosed with chronic migraine. If the headaches are not consistent with
migraine, other diagnoses must be considered.
Patients often describe a history of gradually progressive episodic
migraines that increase in frequency to the point of meeting criteria for
chronic migraine. With frequent headaches, many patients with chronic
migraine have some component of medication overuse headache (MOH).
Importantly, patients with chronic migraine can revert to episodic migraine
after effective treatment.

MIGRAINE TREATMENTS
Migraine treatments are divided into two categories.

Abortive Treatments
Abortive treatments, also called rescue medications, are medications used to
stop a migraine at the onset. All abortive treatments are most effective if the
patient is treated at the onset of the headache. Delay in treatment results in
more prolonged disability, so patients must be counseled on the appropriate
use of abortive treatments.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin
1b/1d agonists) are the mainstays of abortive treatments. Many patients
respond well to NSAIDs alone. For some patients, however, they are
insufficient; some patients have contraindications to using NSAIDS. In
these cases, triptans can be highly effective. There are numerous different
types, with different rates of onset of action and half-lives. There are two
long-acting triptans (naratriptan and frovatriptan) and five fast-acting
triptans (almotriptan, eletriptan, sumatriptan, rizatriptan, and zolmitriptan).
There are also numerous different formulations, including oral pills,
disintegrating tablets, nasal sprays, and injectables.
Historically, ergotamines were prescribed as abortive treatments, but they
carry a higher cardiovascular risk and have been largely replaced by
triptans. Triptans and NSAIDS can be combined when needed and may
have a synergistic effect in treating migraine pain. Caffeine is also often
added to many migraine treatments because it can help abort the pain; many
over-the-counter “migraine preparations” contain caffeine.
Triptans are currently not known to be safe in pregnancy and have a
cardiovascular risk. They also interact with selective serotonin reuptake
inhibitors and serotonin–norepinephrine reuptake inhibitors, with a low risk
of serotonin syndrome. Patients must be counseled on side effects of all
treatments. Identifying the right abortive treatment requires careful
consideration of the patient’s headache features, comorbidities, concurrent
medication use, cost, and family planning goals.
Using abortive treatments on a chronic basis more than twice a week can
result in MOH, so patients should be counseled to not use any of these
treatments chronically more than twice a week to prevent this complication.

Adjuvant Treatments
Because nausea and emesis are frequently associated with migraine, many
patients benefit from antiemetics. Interestingly, prochlorperazine and
metoclopramide are more effective than ondansetron, both in alleviating the
nausea and in reducing the severity of the pain. Antiemetics may also be
useful in preventing patients from vomiting their abortive therapies. They
are frequently used in emergency room (ER) and urgent care settings for
patients with severe or refractory migraine. They are often combined with
ketorolac and diphenhydramine for patients with status migrainosus.

Preventive Treatments
Preventive treatments, also called prophylactic treatments, are used for
patients with chronic migraine or frequent and disabling headaches that do
not respond sufficiently to abortive treatments. Preventive therapy aims to
reduce the frequency and severity of migraine, although patients are
unlikely to become completely headache-free and should be counseled
accordingly. All prophylactic treatments take some time to have an effect;
patients should remain on a treatment for at least a month (barring
significant side effects or other concerns) before assuming that the
treatment is ineffective.
There are three primary categories of preventive oral medications:
antihypertensives, antiseizure medications, and antidepressants. Within each
category, there are specific drugs with the most evidence of efficacy (Table
10-2). In addition to oral therapies, onabotulinum toxin A (often referred to
simply as Botox) was also approved as migraine prophylaxis for chronic
migraine in 2010. In 2018, a new class of preventative therapy for chronic
migraine, Calcitonin Gene-Related Peptide (CGRP) antagonists was
approved by the FDA. Erenumabis is an injectable human monoclonal
antibody that antagonizes CGRP receptor function..
As with abortive treatments, selecting the right prophylactic medication
requires careful consideration of the patient’s comorbidities, concomitant
medications, cost, and family planning goals. Patients must be counseled
about treatment options and side effects, including teratogenicity and
impact on contraceptives. Patients who require preventive therapy also
require abortive treatments. Some abortive treatments interact with
prophylactic medications (such as antidepressants and triptans) which
should be taken into consideration.

TABLE 10-2. Migraine Prophylaxis Oral Medications

Antihypertensives Antiseizure Drugs Antidepressants
Metoprolol Sodium valproate Amitriptyline
Propranolol Topiramate Venlafaxine
Timolol
Medications in bold have level A evidence for efficacy. Medications in italics have level B
 evidence for efficacy.

Lifestyle Modifications
Lifestyle factors are important to identify. A comorbid sleep disorder
(insomnia, obstructive sleep apnea, etc.) makes patients more susceptible to
migraine. Skipping meals, insufficient fluid, excessive caffeine intake, and
lack of exercise make susceptible patients more prone to migraine attacks.
Patients should be counseled on these factors.

KEY POINTS
● Migraines are episodic headaches that commonly cause unilateral, throbbing headaches,
often associated with photophobia, phonophobia, and nausea; they often worsen with
exertion.
● Migraine auras are focal transient neurologic symptoms, most commonly visual, that fully
resolve and are usually followed by the headache.
● Patients with “migraine with aura” should not take estrogen-based contraceptives, as the
combination increases the risk of stroke.
● Migraine treatments are divided into abortive and prophylactic therapies.
● Abortive treatments are most commonly NSAIDs and triptans.
● Prophylactic treatments are mostly antihypertensive, antiseizure, and antidepressant drugs.

TENSION-TYPE HEADACHE
Tension-type headaches (often referred to as tension headaches, stress
headaches, or ordinary headaches) are the next most prevalent primary
headache disorders, occurring in 30% to 70% of adults worldwide. Pain is
usually bilateral and described as pressure or tightness. It is usually mild to
moderate and lasts for under an hour to several days. Unlike migraine, it is
not associated with photophobia, phonophobia, nausea, or vomiting. The
examination is generally normal, but some patients have pericranial
tenderness to palpation of the scalp, neck, or shoulder muscles.
Tension-type headaches can be episodic or chronic (occurring more than
15 days/month). Interestingly, patients with infrequent tension-type
headaches generally do not seek medical attention, because they do not
have significant disability from their symptoms. Patients with frequent or
chronic tension-type headaches benefit from treatment.
TENSION-TYPE HEADACHE TREATMENT
Treatment for tension-type headaches is divided into abortive and
preventive therapies.

Abortive Treatments
Many patients with tension headaches do not require abortive treatments
because the pain is generally mild and does not interfere with the patient’s
functioning. For those with moderate to severe pain, NSAIDs are the
mainstay of treatment. Aspirin and acetaminophen may also be used, but
the latter is often less effective than NSAIDs. Patients should be counseled
about the development of MOH and advised to not use analgesics more
than twice a week for long periods.

Preventive Treatments
Antidepressants are the first-line preventive therapy for chronic tension
headache. The tricyclic amitriptyline is the most studied to date and has
good evidence for efficacy. Other antidepressants, including mirtazapine
and venlafaxine, are second-line therapies. Muscle relaxants such as
tizanidine are helpful sometimes, particularly in patients with a
cervicogenic component.

Adjuvant Treatments
Tension headaches are often reported to be triggered by stress (physical or
emotional); addressing these triggers, if chronic, is important. Biofeedback
(a mind–body technique used to teach patients greater body awareness and
how to control some physical reactions to pain and stress) can be effective.
Poor posture and neck muscle spasm are also frequent contributors to
chronic tension-type headaches, and physical therapy can help.

KEY POINTS
● Tension headaches are bifrontal and are pressure or squeezing pain.
● They are generally not as severe as migraine.
● They are not associated with migraine features such as photophobia, phonophobia, or
nausea.
● Episodic tension-type headaches, when moderate to severe, are treated with NSAIDs.
 ● Chronic tension-type headache is often treated with amitriptyline.

TRIGEMINAL AUTONOMIC CEPHALALGIAS

Trigeminal autonomic cephalalgias (TACs) are the third major category of
primary headache disorders. They are characterized by unilateral pain
associated with cranial autonomic symptoms. The diagnosis is made by
careful evaluation of the pattern of the pain and its associated features. (See
Table 10-1 for a summary of the different headache characteristics.)

CLUSTER HEADACHE
Cluster headaches are severe headaches characterized by unilateral pain
involving the orbit, supraorbitally, at the temple, or combinations of these
(Fig. 10-1). Cluster periods are bouts of recurrent attacks of pain, generally
lasting weeks to months. These periods are followed by remission lasting
anywhere from months to years. The pain is often excruciating. During an
attack, patients are often restless and pacing, unlike in migraine where
activity exacerbates the pain. The pain must be associated with one of the
following cranial autonomic symptoms:
• Conjunctival injection, lacrimation, or both
• Nasal congestion, rhinorrhea, or both
• Eyelid edema
• Forehead and facial sweating or flushing
• Sensation of fullness in the ear
• Miosis, ptosis, or both
Cluster headaches typically last between 15 and 120 minutes. During a
cluster period, headaches can occur several times a day or as infrequently as
every other day.
Cluster headaches are relatively uncommon but are three times more
likely to occur in men. The age of onset is typically in early to mid-
adulthood (20–40 years of age). The cause is unknown, but activation of the
posterior hypothalamic gray matter has been seen in some patients during
attacks. Alcohol, histamines, and nitroglycerin are triggers in susceptible
patients. A Horner syndrome caused by carotid dissection may mimic a
cluster headache (Fig. 10-2) but does not usually have the pain
characteristics of this primary headache disorder.
FIGURE 10-2. Cluster headache. Horner syndrome. Note mild unilateral ptosis (on the
patient’s right side), anisocoria with a smaller pupil on the side of the ptosis, and redness from
associated cluster headache. The common “upside-down” ptosis (i.e., elevation) of the lower lid is
masked by coexisting eyelid laxity and blepharitis, which can be confounding factors in older adults.

Cluster headaches may be episodic or chronic. Chronic cluster headache

is defined as intractable cluster headaches with less than 1 month of
remission before the recurrence of symptoms. Fortunately, less than 15% of
cluster patients have chronic cluster.

CLUSTER HEADACHE TREATMENTS

Abortive Treatments
A first-line abortive treatment for cluster headaches is 100% oxygen,
delivered at 12 to 15 L/min. Patients may receive this treatment in an urgent
care or ED setting and if effective, be prescribed a home oxygen tank. For
patients who do not respond, or who do not have access to home oxygen,
triptans are prescribed. Sumatriptan and zolmitriptan are effective as
abortive therapies. In the past, dihydroergotamine (DHE) was prescribed as
an abortive treatment, but triptans are favored over DHE given their safety
profile. Patients with cluster headache are very susceptible to MOH and
must be counseled appropriately. Occipital nerve blocks can also be
effective to abort a cluster cycle.

Preventive Treatments
Preventive treatments for cluster headache are similar to those used for
migraine and include antihypertensive, antiseizure, and psychiatric
medications. Verapamil is the first-line therapy for cluster headache
prophylaxis. If not tolerated or if there are contraindications,
glucocorticoids (prednisone or dexamethasone) are also effective. Lithium
and topiramate are often used as second-line agents or as add-on therapy
when needed.

SHORT-LASTING UNILATERAL NEURALGIFORM

HEADACHE ATTACKS
Short-lasting unilateral neuralgiform headaches are unilateral, moderate to
severe headaches. Pain is around the orbit or temple but may also occur in
the trigeminal distribution and therefore be mistaken for trigeminal
neuralgia (see section Facial Pain). The headache is a stabbing pain or
recurrent stabbing sensation lasting from 1 second to 10 minutes. Patients
with a lesion in the posterior fossa may present with symptoms suggestive
of short-lasting unilateral neuralgiform headache, so brain imaging with
magnetic resonance imaging (MRI) is important to establish that this is a
primary and not secondary headache disorder.
There are two forms (see below), differentiated by the types of associated
autonomic symptoms (which always occur on the same side as the
headache):
• Short-lasting unilateral neuralgiform headache attacks with conjunctival
injection and tearing (SUNCT): Autonomic symptoms include both
conjunctival injection and lacrimation.
• Short-lasting unilateral neuralgiform headache attacks with cranial
autonomic symptoms (SUNA): Autonomic symptoms include at least
one of the following:
• Forehead or facial sweating or flushing
• Ptosis or pupillary miosis
• Eyelid edema
• Nasal congestion, rhinorrhea, or both
• Ear fullness
• Either conjunctival injection or lacrimation, but not both
Both SUNCT and SUNA can be episodic or chronic. The chronic forms
are diagnosed by persistent symptoms lasting more than a year, or for less
than a year but with less than 1 month of remission.

Abortive Treatment
SUNCT and SUNA are challenging disorders to treat, given the brevity of
symptoms. Intravenous lidocaine has helped abort the cycle in some
patients.

Preventive Treatment
Antiseizure medications including topiramate, gabapentin, and lamotrigine
are used as preventive therapy in patients with frequent or recurrent
symptoms. Occipital nerve blocks can also be helpful, especially when
systemic medications are contraindicated or not tolerated.

HEMICRANIA
The final TAC is hemicrania, a unilateral headache, differentiated from the
other TACs both by the duration of symptoms and by its unique response to
indomethacin. Patients present with a unilateral orbital or temporal
headache associated with one or more autonomic symptoms on the same
side as the headache (the symptoms and signs are the same as for SUNCT
and SUNA).
There are three variants of hemicranias, differentiated by the duration of
symptoms:
• Episodic paroxysmal hemicrania:
• Recurrent attacks separated by at least one pain-free month.
• Attacks last between 2 and 30 minutes but can recur within a day.
• Chronic paroxysmal hemicrania:
• Recurrent attacks without remission, or less than 1 month of
remission before recurrence.
• Attacks last between 2 and 30 minutes but can recur within a day.
• Hemicrania continua:
• Intractable pain and autonomic symptoms consistent with
hemicranias, lasting for more than 3 months.
All three forms respond to indomethacin, and this response to treatment
is required to make the diagnosis. Hemicrania is more common in women
and typically occurs in mid-adulthood (30–40 years of age). As with other
TCAs, MRI to exclude a lesion in the posterior fossa is also advised to
exclude a secondary headache syndrome.

Abortive and Preventive Treatment

Indomethacin is the definitive treatment for hemicranias. An indomethacin
trial is both diagnostic and therapeutic. The dose is titrated gradually over
10 days to a maximum of 225 mg a day, divided into three doses, until the
patient has a therapeutic response. If there is no response, the diagnosis is
not consistent with hemicrania and other etiologies must be considered.

KEY POINTS
● TACs are unilateral headaches with pain around the orbit or temple.
● They are associated with autonomic symptoms on the same side as the headache.
● The differences among TACs are based on the duration of symptoms and associated
features.
● Lesions in the posterior fossa should be excluded before making a diagnosis of a TAC.

OPIOIDS IN HEADACHE MANAGEMENT

Opioids are not more effective than alternate therapies and are generally
strongly discouraged for use in headache medicine. Most headache
conditions are recurrent disorders, so use of opioids in this setting risks
development of a secondary opioid use disorder. Opioids also tend to cause
MOH.

SECONDARY HEADACHE DISORDERS

Secondary headache disorders are headaches caused by a medical
condition or medication. They have a broad differential for causes, ranging
from preeclampsia and pheochromocytoma to fever and medication side
effects. Most secondary headaches are associated with other features in the
history, examination, or laboratory assessment, which aid in the diagnosis.
Treatment is based on addressing the underlying disorder. There are six
major categories of secondary headaches that may present with headache
only and must be considered.

VASCULAR CAUSES
There are numerous vascular causes of headache. All cerebral hemorrhages
can cause headache. This includes subarachnoid hemorrhage (SAH),
intraparenchymal hemorrhage, and subdural and epidural hematomas.
These hemorrhages may be spontaneous (associated with stroke or
hypertension) or traumatic. Patients with intracerebral hemorrhages
typically present with what is referred to as a thunderclap headache; the
onset is abrupt and severe. Emergency imaging, usually with a noncontrast
head computed tomography (CT), is needed to evaluate any abrupt-onset
headache (Fig. 10-3). Cerebral vessel imaging is also warranted if a SAH is
identified, to assess for an aneurysm. Cerebral hemorrhages are discussed
further in Chapter 14.
Ischemic strokes are often associated with headaches. Their semiology is
nonspecific, but typically abrupt in onset. Patients may have focal
neurologic deficits which aid in the diagnosis. Cerebral thrombosis, either
arterial or venous, can also cause headache. Patients with venous sinus
thrombosis often have headaches with features of increased intracranial
pressure (ICP). Thrombosis should be considered particularly in patients
with hypercoagulability states, including pregnancy. The diagnosis is made
on imaging, including that of cerebral vessels (Fig. 10-4).
FIGURE 10-3. Examples of intracerebral hemorrhages on CT scans. (A) Epidural
hemorrhage. (B) Subdural hemorrhage. (C) Intraparenchymal hemorrhage. (D) Subarachnoid
hemorrhage. Arrows point to the subdural hematoma.
FIGURE 10-4. Deep venous sinus thrombosis in a pregnant woman. Sagittal image from a
magnetic resonance venogram (MRV) demonstrating occlusion of the deep venous system,
including the straight sinus (red arrow). The superior sagittal sinus (green arrow) and right
transverse sinus (blue arrow) and sigmoid sinus (orange arrow) are patent.

Cerebral vasculitis frequently causes a nonspecific headache. When part

of a systemic vasculitis, it is considered a secondary angiitis. If the
vasculitis occurs in the cerebral vessels alone, it is referred to as primary
CNS angiitis. In addition to headache, patients often have paroxysmal focal
neurologic deficits. Cerebral arterial vessel imaging and lumbar puncture
(LP) are often required to make this diagnosis; peripheral vessel biopsies
may be necessary.
Giant cell arteritis (GCA), also called temporal arteritis, is a peripheral
cranial arterial vasculitis that often presents with a unilateral headache.
Patients are generally above the age of 50 and report additional symptoms
including vision changes (amaurosis fugax), jaw claudication, fever, and
scalp tenderness. Involvement of the branches of the external carotid artery,
including the ophthalmic artery, can result in blindness if not readily
identified and treated promptly. Patients usually have elevated
inflammatory markers (erythrocyte sedimentation rate and C-reactive
protein). Empiric steroids should be started in any patient with a high
clinical concern. Temporal artery biopsy is the gold standard, but GCA can
cause “skip lesions” and may require serial biopsies to identify the
pathology.

INFECTIOUS OR INFLAMMATORY CAUSES

Intracranial infections, such as encephalitis and meningitis, usually present
with headache and often with fever. They may also have nuchal rigidity and
altered mental status. As the infection progresses, seizures and focal
neurologic deficits may occur. Infections can be bacterial, viral, fungal, or
parasitic; the headache semiology does not help to differentiate the
underlying cause. LP is the crucial diagnostic test and necessary in any
patient for whom there is concern for a CNS infection. There are often other
signs of infection, and the headache has a temporal correlation to the
infection (see also Chapter 21 on CNS infections). CNS inflammatory and
autoimmune conditions such as sarcoidosis and lupus frequently present
with headache.

NEOPLASTIC CAUSES
Intracranial neoplasms may present with headaches, especially when there
is significant mass effect. The headache semiology may be nonspecific but
may have features of intracranial hypertension, including wakening the
patient from sleep, being worse when supine, and worse with Valsalva
maneuver. The headache may occur early or late with neoplasms and with
any type of primary cancer (see also Chapter 19 on CNS neoplasms).
TRAUMATIC CAUSES
Head and neck injuries often result in headache. To be attributed to trauma,
the headache must develop with a temporal association to the injury. The
severity of the injury does not necessarily correlate with the severity of the
headache; even minor head injuries or whiplash may cause headaches.
There is no specific headache semiology that helps with the diagnosis. In
patients with a history of significant head or neck injury, it is important to
assess for an intracranial hemorrhage or dissection of cervical vessels—
which may require additional treatment.

INTRACEREBRAL PRESSURE DISORDERS

Intracranial hypertension and hypotension can cause headaches, but with
markedly different semiologies.
Intracerebral hypertension may be “idiopathic” (most common in
obese young women) or due to medications or systemic disorders. The
headache is often described as worse when supine or sleeping (awakening
the patient from sleep), or with Valsalva maneuver. It improves with
standing. Patients often have other associated features, including
papilledema, pulsatile tinnitus, or visual symptoms. Patients should have
imaging to exclude a mass lesion or venous sinus thrombosis. If the
imaging is unrevealing, the diagnosis is made with an LP when the patient
is in the lateral decubitus position with legs extended. Intracerebral pressure
(ICP) is elevated if above 200 mm cerebrospinal fluid (CSF).
Acetazolamide is the first-line treatment for idiopathic intracranial
hypertension (IIH). Patients require monitoring of their visual fields, and
treatment for obesity is warranted when present.
Intracerebral hypotension may be spontaneous or traumatic. This
headache improves when the patient is supine but worsens with standing.
The pain is often most severe at the vertex and can be associated with neck
pain or tinnitus. It is frequently traumatic—occurring after an attempted
epidural puncture or LP. Generally, the dural leak causing the headache
heals gradually, without intervention, but when symptoms persist or when
the headache etiology is unclear, brain MRI may be helpful; it may show
evidence of sagging (Fig. 10-5). The definitive diagnosis is made with an
LP showing an opening pressure below 60 mm CSF. If a patient remains
symptomatic from intracranial hypotension, a blood patch may be
attempted to cover the dural leak (if it can be found).

FIGURE 10-5. Intracranial hypotension. Gadolinium-enhanced MRI scan of a patient with

intracranial hypotension. There is widespread, symmetric meningeal enhancement (arrows).

MEDICATION CAUSES
Medications associated with headaches are numerous. They range from
hormonal therapies, including contraceptives, to nitric oxide. Withdrawal of
a medication or other treatment may also cause a headache; the most
common example is a caffeine withdrawal headache. Headache semiology
is nonspecific, but the temporal association to medication change helps
establish the diagnosis.
Medication overuse headache (MOH), also referred to as rebound
headache or drug-induced headache, is a chronic headache occurring in
patients with a primary headache disorder. The baseline headache disorder
is typically markedly exacerbated (i.e., more frequent, severe, or both)
when the medication is overused. MOH is diagnosed when patients use an
abortive therapy 10 or more times per month for more than 3 months with
an increase in headaches.
 KEY POINTS
● The history and associated signs and symptoms aid in the diagnosis of secondary
headaches.
● Emergency cerebral imaging (usually a CT scan) should be obtained in patients with a
thunderclap headache.
● In patients with suspected meningitis or encephalitis, an LP is needed to make the
diagnosis.

FACIAL PAIN
In addition to the causes of primary and secondary headache disorders
outlined above, there are structural causes of headache and facial pain, as
well as neuropathic causes.

HEAD AND NECK DISORDERS

There are many different structural disorders that can cause headache.
Treatments are based on the specific causes identified, and these disorders
may occur simultaneously with other primary or secondary headache
disorders.
Sinusitis is commonly associated with a headache. It may be bifrontal or
unilateral. Acute sinusitis is often associated with other symptoms of a
respiratory tract infection. Temporomandibular joint disorder (TMD) is
another common cause of headache and may be unilateral or bilateral. On
exam, there may be evidence of dental wearing (chipped and flattened
teeth) and discomfort on palpation of the joint. Cervicogenic headaches
are also common and may be identified by palpation of myofascial trigger
points in the neck. Cervical range of motion is often reduced.

TRIGEMINAL NEURALGIA
The pain of trigeminal neuralgia is shock-like, occurring in one or all
branches of the trigeminal nerve. The pain is usually paroxysmal and
recurrent. It may be triggered by common activities such as brushing hair or
teeth. It may be idiopathic or due to structural causes such as a mass or
vascular lesion, or a demyelinating lesion of multiple sclerosis.
Carbamazepine is a common first-line treatment.

SUMMARY
Migraines, tension headaches, and TACs are the three most common types
of primary headache disorders. The International Headache Society
maintains an evidence-based categorization of primary and secondary
headache disorders. If a headache history and pattern is not consistent with
a primary headache disorder, the clinician should consider a secondary
headache disorder, review the rare types of primary headache disorders, or
consider that the headache may be a combination of more than one
headache disorder.

CLINICAL VIGNETTES

VIGNETTE 1
A 28-year-old woman is seen in the ER for the recent onset of daily
headaches. She describes the headaches as holocranial, aggravated by
straining to defecate and worst first thing in the morning when she
wakes up. She has also noticed tinnitus in her right ear. The headaches
are not preceded by an aura, but she has had a few brief episodes of
transient blurring of vision in the right eye. Examination shows height
of 5′2″, weight of 120 lb, and blood pressure 112/70 mm Hg. There is
no neck stiffness. There is binocular double vision on rightward gaze
with slight limitation of abduction of the right eye. Visual fields are
normal on bedside confrontation testing, and the optic discs have a
normal appearance. Neurologic examination is otherwise normal.
1. Which of the following is the most likely diagnosis?
a. Migraine
b. Tension-type headache
c. Low-pressure headache
d. Idiopathic intracranial hypotension
e. Chronic daily headache
 2. You suspect a diagnosis of IIH, but recognize that there is an
important differential diagnosis of secondary headache syndromes
to exclude. Which of the following evaluations or investigations is
least appropriate?
a. Formal ophthalmologic evaluation
b. Brain MRI
c. Imaging of the cerebral venous sinuses
d. LP
e. Transcranial Doppler (TCD) ultrasound
f. Pregnancy test
3. Formal visual fields are normal. MRI of the brain is normal, and
there is no evidence for venous sinus thrombosis. Opening pressure
at the time of LP was 29 cm H2O, but CSF contents are normal.
You confirm the diagnosis of IIH. Which of the following
therapeutic options is not routine for patients with IIH?
a. Carbonic anhydrase inhibitors (e.g., acetazolamide, topiramate)
b. Endovascular venous sinus stenting
c. Optic nerve sheath fenestration
d. Repeated LP
e. Lumboperitoneal shunting

ANSWERS

VIGNETTE 1 QUESTION 1
Answer D:
There are two characteristics to this patient’s headaches that suggest
raised intracranial pressure: They are most severe first thing in the
morning, and there is an exacerbation with Valsalva maneuver.
Moreover, the double vision on lateral gaze with limited abduction of
the right eye suggests a partial VIth nerve palsy that may be a sign of
raised intracranial pressure. Her visual symptoms are likely to be
transient visual obscurations, reflecting intermittent hypoperfusion of
the optic nerve head. IIH is high on the differential diagnosis, despite a
normal body mass index. In patients with this history, it is also
important to screen for exposure to medications that can cause or
worsen increased intracranial pressure, such as tetracycline derivatives.

VIGNETTE 1 QUESTION 2
Answer E:
Formal ophthalmologic evaluation should be performed to obtain more
detailed information about the visual fields and to look carefully for
signs of early papilledema. MRI of the brain is appropriate to exclude
structural or mass lesions, and some form of imaging of the venous
sinuses is appropriate because venous sinus thrombosis is an important
mimic of IIH. The diagnosis of IIH requires that the CSF is normal in
content (e.g., without white blood cells), hence the importance of a LP.
TCD ultrasound does not have a role in the evaluation of patients with
suspected IIH. All premenopausal women presenting to the ED with
headache should undergo a pregnancy test to inform decisions regarding
work-up and treatment.

VIGNETTE 1 QUESTION 3
Answer B:
Carbonic anhydrase inhibitors such as acetazolamide and topiramate are
the primary medical treatments for patients with IIH based on their
mechanism of action—reduced production of CSF. Repeated LPs to
promote CSF drainage may also be effective. Optic nerve sheath
fenestration (ONSF) may be appropriate for patients with papilledema
who have visual loss but no or minimal headache and have been
refractory to other treatments. For those with papilledema, visual loss,
and headache, a lumboperitoneal shunt may be appropriate. Aggressive
management with ONSF or shunting is typically used to prevent or treat
catastrophic or rapidly progressive visual loss. Endovascular venous
sinus stenting has been proposed (based on the observations that it may
reduce cerebral venous pressure, reduce intracranial pressure, and
improve symptoms), but the risk of serious complications is high, so
this procedure is not considered routine for the management of IIH. It
should be noted that in patients with comorbid obesity, weight loss is
also essential for treatment.
 PART
NEUROLOGIC DISORDERS
III
11 Aphasia and Other Disorders of
Higher Cortical Function

The behavioral neurology syndromes, including the aphasias, are some of

the most interesting clinical syndromes to both physicians and laypersons.
Popular writings of Oliver Sacks that describe these disorders of higher
cortical function are commonly cited as reasons to enter the field of
neurology on residency applications. The intellectual appeal of such
syndromes is not difficult to understand: The higher cognitive functions are
what allow us to carry out essential social activities. From a historical
perspective, disorders of language and other cortical functions were among
the first to be described as being caused by dysfunction of discrete areas of
the brain, giving rise to the concept of cerebral localization in the 19th
century.

APHASIA
Aphasia is an acquired disorder of language due to brain dysfunction. It is
distinguished from dysarthria, which is a disorder of the mechanical
production of speech. Disorders of attention may also masquerade as
language disorders, but mental status assessment of the inattentive patient
will show dysfunction that extends beyond language. Patients with hearing
difficulties may also be misdiagnosed as having aphasia, especially older
patients who may not have their hearing aids during hospitalization.

DIAGNOSIS
For the purposes of this chapter, the left hemisphere will be considered the
dominant hemisphere for language; this is true in greater than 90% of right-
handed people and in 50% of left-handed people. There are several forms of
aphasia (Table 11-1) that are classically caused by lesions in specific areas
of the brain (Fig. 11-1) and can be distinguished from each other by focused
examination of the elements of language such as fluency, comprehension,
repetition, and the presence and types of paraphasic errors (Table 11-2).
Anomia (an inability to name an object) is seen to some degree in almost
all aphasias, so testing confrontation naming is one of the most sensitive
screening tests for aphasias—but it is not specific for determining which
type of aphasia the patient has. Common items such as a watch or coat are
high-frequency objects that are relatively easy for patients to name.
Components of these items such as a watch dial or lapel of a coat, however,
are lower frequency words and, thus, more sensitive for mild anomia. It is
important to note, however, that impaired naming of low-frequency items
might also reflect a general knowledge deficit related to the patient’s
educational background rather than to an acquired language disorder.

KEY POINTS
● Aphasia is an acquired disorder of language due to brain dysfunction.
● Other causes of impaired communication—including problems with hearing, attention,
initiative, or articulation—are not truly aphasias.
● Anomia is seen in almost all types of aphasia.

BROCA APHASIA
Broca aphasia is primarily a disorder of fluent language production. Patients
cannot produce phrases of more than a few words, and speech is often
described as telegraphic: “me go store.” Content-rich words such as nouns
and verbs predominate, whereas connector words such as conjunctions and
prepositions are notably absent. Overly used phrases such as “how are you”
tend to be preserved in patients with a Broca aphasia. Paraphasic errors
(word substitutions) occur often and are usually of the phonemic type, in
which sound substitutions are made (e.g., “spool” rather than “spoon”).
Patients are aware of and frustrated by their inability to communicate.
Comprehension is relatively preserved compared to fluency, but patients
have difficulty understanding sentences with complex syntax, such as when
the passive voice is used. For example, patients with a Broca aphasia will
not be able to understand a sentence such as “on top of the pen, place the
paper” but may do better with a sentence such as “put the paper on top of
the pen.” Repetition is poor: It may be preserved at the level of individual
words, but longer phrases and those with any grammatical complexity
prove challenging to repeat.

TABLE 11-1. Aphasias

Type Fluency Comprehension Repetition Commonly Lesion
Associated Location
Signs
Broca Impaired Relatively Impaired Right Broca’s area
preserved hemiparesis (inferior
(especially frontal)
face)
Wernicke Preserved, but Impaired Impaired Right upper Wernicke’s
often quadrantanopia area (superior
nonsensical or temporal)
“jargon
aphasia”
Conduction Preserved Preserved Impaired Many Arcuate
paraphasic fasciculus,
errors insula,
temporal
isthmus
Transcortical Impaired Preserved Preserved. In Right Subcortical,
motor some cases hemiparesis adjacent to
repetition is Broca area
the only
verbal output
Transcortical Preserved Impaired Preserved – Subcortical,
sensory adjacent to
Wernicke area
Global Impaired Impaired Impaired Severe right Large left
hemiparesis, hemisphere
gaze deviation lesion
to left
Subcortical Variable Variable Variable, Hypophonia, Left basal
often often in ganglia,
preserved patients with thalamus
basal ganglia
lesions
FIGURE 11-1. Higher cortical (language) centers in the left hemisphere.

Anatomically, a Broca aphasia is associated with lesions in the left

posterior–inferior frontal region, also known as Broca’s area. The most
common cause of a Broca aphasia is infarction in the superior division of
the left middle cerebral artery, but other causes including hemorrhage,
tumor, and encephalitis can also produce a Broca aphasia. Because this area
of the cerebral cortex is adjacent to the motor cortex, patients with a Broca
aphasia often have right-sided weakness that is worse in the face and arm
than it is in the leg.

TABLE 11-2. Examination of Language Function

Function Testing
Fluency Listen to patient’s spontaneous speech to see if words are strung
together into phrases of at least seven words. Overused phrases (e.g.,
“how do you do?”) do not count.
Repetition Least challenging: Ask patient to repeat single words
Most challenging: Ask patient to repeat syntactically complex
sentences, such as “no ifs, ands, or buts about it”
Comprehension Least challenging: Ask patient to follow simple midline commands,
such as “close your eyes” or “open your mouth”
Most challenging: Ask patient to follow multistep appendicular
commands that cross the midline, such as “point to the ceiling, then
touch your left ear with your right hand”
Paraphasic errors Listen to patient’s spontaneous speech and observe for word
substitutions. Phonemic paraphasic errors are substitutions of sounds
(e.g., “stadler” instead of “stapler”). Semantic paraphasic errors are
 substitutions of words in related categories (e.g., “lamp” instead of
“flashlight”).
Naming Least challenging: Ask patient to name high-frequency objects, like
watch or tie
Most challenging: Ask patient to name low-frequency objects or
parts of objects, like dial of watch or lapel
Reading Ask patient to read written material aloud and to follow written
instructions
Writing Ask patients to write a sentence of their choosing or a sentence
dictated by the examiner Simply having patients write their names
does not count (it is an overlearned task)

KEY POINTS
● Broca aphasia is primarily a disorder of language production.
● Verbal output in Broca aphasia is nonfluent and telegraphic, with phonemic paraphasic
errors. Comprehension is impaired but is relatively preserved for simple phrases.
Repetition is poor.
● Anatomically, Broca aphasia is caused by lesions in the left posterior–inferior frontal lobe
(Broca’s area).

WERNICKE APHASIA
Wernicke aphasia is often described as a “receptive aphasia” in which the
primary deficit is in understanding spoken language. Patients have difficulty
following basic commands, even at the single word level. Although patients
with Wernicke aphasia are fluent, they also have difficulties with verbal
expression: Their speech is often nonsensical and is described as taking on
the character of a “word salad” or “jargon aphasia.” They make many
paraphasic errors, mostly of the semantic type (word substitutions based on
word meanings such as “chair” for “table”). Some of these paraphasic
errors are completely new words, termed neologisms. Repetition is poor,
even at the single word level. Patients with a Wernicke aphasia often have
little insight into their deficits and comport themselves as if they do not
have a communication problem.
The classical anatomic locus in a Wernicke aphasia is in the posterior part
of the superior temporal gyrus in the left hemisphere, known as Wernicke’s
area. Stroke in the inferior division of the middle cerebral artery is the most
common cause, but other causes including hemorrhage, tumor, and
inflammation can also produce a Wernicke aphasia. Often, patients with a
Wernicke aphasia have no other clinical deficits, but a contralateral
homonymous superior quadrantanopia may be present, and there may be
mild contralateral weakness or sensory loss.

KEY POINTS
● Wernicke aphasia is primarily a disorder of language comprehension.
● Speech is fluent and often excessive, but difficult to understand because patients have
excessive paraphasic errors, including neologisms.
● The lesions that typically cause a Wernicke aphasia are in the posterior part of the superior
temporal gyrus (Wernicke’s area).

OTHER APHASIAS
Conduction aphasia is characterized by poor repetition and frequent
paraphasic errors. Patients have difficulty correcting errors during
spontaneous speech and they make successive approximations while
searching for a target word. Fluency and comprehension are both preserved.
The classical localization of conduction aphasia is the arcuate fasciculus,
which is a white matter tract that connects Wernicke’s area to Broca‘s area.
In practice, however, conduction aphasia is due to lesions in various
locations within the temporal lobe, parietal lobe, or insula.
Transcortical motor aphasia, like Broca aphasia, is a disorder in which
language is nonfluent with relatively preserved comprehension. Repetition
is spared and, in some cases, is the only verbal output that a patient has. The
lesions that cause a Broca aphasia are usually in the frontal white matter
adjacent to Broca’s area. Anterior cerebral artery strokes may cause
transcortical motor aphasia, which distinguishes them from most vascular
aphasic disorders, which are due to strokes in the territory of the middle
cerebral artery.
Transcortical sensory aphasia is similar to Wernicke aphasia in that
fluency is preserved but comprehension is poor. Unlike in a Wernicke
aphasia, however, repetition is relatively spared. Lesions that produce
transcortical sensory aphasia are usually in the subcortical white matter
underlying Wernicke’s area. Acute-onset transcortical sensory aphasia is
rare compared to other aphasia syndromes. The aphasia that develops more
chronically as part of Alzheimer disease often resembles a transcortical
sensory aphasia.
Global aphasia is characterized by nonfluent verbal output with poor
comprehension and repetition. It may range from complete mutism to minor
deficits in each of the aspects of language. The most common cause of
global aphasia is a large left hemisphere infarction due to ipsilateral internal
carotid artery occlusion. Other deficits including contralateral hemiplegia
and ipsilateral eye deviation often accompany a global aphasia.
In a mixed transcortical aphasia, repetition is spared but fluency and
comprehension are impaired. This aphasia is also known as isolation of the
speech area and is due to large left hemisphere lesions that spare the
extrasylvian cortex. This is another rare aphasia, which is most often seen
in patients who have sustained global hypoxic injuries or carbon monoxide
poisoning.
Subcortical aphasias are due to lesions in the deep left hemisphere
including the basal ganglia and thalamus. They are often difficult to classify
using typical methods, although more anterior lesions tend to produce more
problems with fluency and posterior lesions tend to produce more problems
with comprehension.

KEY POINTS
● Aphasias that involve the perisylvian cortex such as a Broca aphasia, a Wernicke aphasia,
conduction aphasia, and global aphasia produce impaired repetition. Aphasias that spare
the perisylvian cortex, such as the transcortical aphasias, spare repetition.
● In conduction aphasia, the primary problem with spontaneous speech is the multitude of
paraphasic errors, whereas on formal language assessment, repetition is the main deficit
identified.

DISORDERS OF WRITTEN COMMUNICATION

Aphasic disorders affect all aspects and applications of language, not just
spoken language. Reading and writing deficits tend to parallel spoken
language deficits, although deficits are often amplified when patients
attempt to read or write. Aphemia is a disorder in which the opposite is
true: Some patients with restricted left frontal lobe infarctions lose fluency,
often to the point of mutism, but their ability to write is preserved. Patients
with such strokes often recover quickly, unlike patients with a Broca
aphasia.
Alexia without agraphia is a syndrome in which patients cannot read
but are able to write. In fact, they are usually not able to read something
they have just written. This syndrome is usually caused by a left posterior
cerebral artery infarction involving the left occipital lobe and adjacent
splenium of the corpus callosum. The left occipital lesion produces a right
homonymous hemianopia, and the callosal lesion disconnects the visual
cortex in the right occipital lobe from the language centers in the left
temporal and parietal lobes. Thus, the patient is not able to transmit any
visual signals intact to the language centers. The parietal lobe itself, where
much of the writing function resides, is preserved so patients are still able to
write.

APRAXIA
Apraxia is the inability to carry out a learned motor task in response to the
stimulus that normally produces it, in the absence of a disorder of one of the
component cognitive or motor functions such as language, attention, or
strength. Patients with apraxia have difficulty interacting with the
environment and more specifically, with using tools. They may use the right
tool for a task with the wrong action or be completely unable to use it. The
traditional terminology for the apraxias, devised by Liepmann, divides them
into ideomotor, ideational, and limb-kinetic forms. This nosology, however,
can be confusing, and it is probably more useful to simply describe what a
patient can and cannot do.
Examination for apraxia should assess both conceptual and actual use of
tools. First, ask the patient to pretend to perform an action without
physically holding the tool that would be used for that action, for example,
“pretend to hold a toothbrush and brush your teeth.” Next, pantomime the
use of the toothbrush and ask the patient to do the same. Finally, give the
patient a toothbrush and see how he or she uses it. With each step, look for
problems with orientation or action of the imaginary or real tool with
respect to its target. Test several actions including saluting, hammering with
a nail, and cutting with a knife. Both hands need to be examined in isolation
and in conjunction. Also, it is helpful to determine whether a patient can
identify if an action is being performed properly—by having the examiner
perform the task correctly and then incorrectly, and asking which one was
correct. Some patients have oral rather than limb apraxia that may be
identified by asking the patient to whistle or blow out a match.
Apraxia is usually due to left hemisphere lesions. Isolated lesions of the
left parietal lobe produce difficulty with both performing and recognizing
appropriate actions. Left frontal lesions, mostly in the supplementary motor
area, produce difficulty with performing actions, but patients can typically
recognize when the examiner is performing the action correctly or
incorrectly. Lesions in the body of the corpus callosum or right frontal lobe
may produce isolated left-hand apraxia by disconnecting the praxis centers
in the left hemisphere from the motor control areas of the left hand in the
right hemisphere.

KEY POINTS
● Apraxia is the inability to carry out a learned motor task in response to the stimulus that
normally produces it, in the absence of a disorder of one of the component cognitive or
motor functions such as language, attention, or strength.
● Bedside testing of apraxia should include asking a patient to pantomime use of a tool,
imitate the examiner using a tool, and use the tool physically.
● Lesions that produce apraxia involve the frontal or parietal lobes of the left hemisphere,
the callosal region, or the frontal lobe of the right hemisphere.

AGNOSIA
Agnosia is the inability to recognize an object despite preservation of the
primary sensory modality. The agnosias are a rare group of disorders that
are most commonly described in relation to vision. Apperceptive agnosia
is an inability to recognize a visual form. For example, a patient will not
recognize what a fork is or that it is a utensil used for eating. The patient
will not be able to copy a picture of a fork. Associative agnosia is an
inability to recognize an object, although the patient is able to describe it
and copy a picture of it. Although there is some variability, apperceptive
agnosia most often occurs with left occipitoparietal lesions, whereas
associative agnosia most often occurs with left occipitotemporal lesions.
Prosopagnosia is an inability to recognize faces and is usually caused by
either right-sided or bilateral occipitotemporal lesions of the fusiform gyrus.

KEY POINTS
● Agnosia is a very rare disorder in which a patient cannot recognize an object despite
preservation of the primary sensory modality.
● Examples of agnosia include apperceptive agnosia, associative agnosia, and
prosopagnosia.

GERSTMANN SYNDROME
Gerstmann syndrome is the tetrad of agraphia (inability to write); acalculia
(inability to perform arithmetical calculations); right–left confusion; and
finger agnosia (inability to recognize one’s own fingers or the fingers of the
examiner). It is a rare syndrome caused by lesions in the left parietal lobe,
specifically the angular and supramarginal gyri. The term Gerstmann
syndrome should be used when the clinical tetrad is complete and not
accompanied by other deficits: disorders of attention may produce difficulty
with all of the components of the syndrome as well as other cognitive
abnormalities.

KEY POINTS
● Gerstmann syndrome is characterized by the combination of agraphia, acalculia, right–
left confusion, and finger agnosia.
● Lesions in the angular and supramarginal gyri of the left hemisphere may produce a pure
Gerstmann syndrome.

NEGLECT AND RIGHT HEMISPHERIC

SYNDROMES
Neglect is a disorder of directed attention that is usually due to right
hemisphere lesions. Patients lack awareness of what is happening in the left
half of space, even in their own left limbs. Neglect may affect visual,
auditory, and tactile modalities, and in some patients all of these modalities
are affected simultaneously. In its most severe form, a patient with neglect
denies that the left side exists, and when presented with his own hand says
that it is the examiner’s hand. In milder forms, neglect may be detected on
targeted mental status examination only (Fig. 11-2). For example, asking a
patient to bisect a line may result in the line being bisected well to the right
of the midline, ignoring much of the left half of the line. A target
cancellation test in which a patient is asked to cross out target letters (“cross
out all the As”) will also show evidence for neglect: The patient will not
cross out letters on the left side of the page. Finally, extinction to double
simultaneous stimulation, in which a patient detects only a right-sided
stimulus such as a brief touch on the right hand when both hands are
touched simultaneously, is another subtle manifestation of neglect.
Neglect is often accompanied by other behavioral abnormalities due to
right hemisphere dysfunction. Anosognosia is a patient’s inability to
recognize that there is anything wrong, for example, not knowing that the
left side is paralyzed and stating that there are no problems.
Anosodiaphoria is a lack of concern about a deficit; the patient recognizes
that the deficit is present but does not seem disturbed by it. Aprosodia is a
loss of the rhythmic and dynamic components of language, resulting in a
monotone voice with very little fluctuation in tone and volume.
The most common source of neglect is a large right hemispheric lesion
involving both the frontal and parietal lobes, particularly an infarction in the
distribution of the right middle cerebral artery. Patients with frontal lesions
may exhibit more prominent signs of motor neglect, in which they do not
use the left hand as much as the right hand. When severe, neglect is usually
associated with a left hemiparesis or hemiplegia and gaze deviation to the
right side.

KEY POINTS
● Neglect is a disorder in which there is inattention paid to one hemispace, usually the left.
● Patients with severe neglect may not be able to describe things presented to them from the
left side, including their own limbs.
 ● Milder neglect may be manifested by poor line bisection, difficulty with target
cancellation, and extinction to double simultaneous stimulation.
● Neglect is usually caused by lesions in the right parietal and frontal lobes.

FIGURE 11-2. Drawing illustrating neglect of the left side.

CLINICAL VIGNETTES

VIGNETTE 1
You are called to the emergency room to evaluate a 78-year-old man
brought in by his family. They report that he was fine the night before
but awoke in the morning with a paucity of verbal communication.
When you evaluate him, he seems awake and alert, looking around at
his environment, but he offers little spontaneous speech. When you ask
him questions, he responds with two or three word phrases only. He is
able to repeat complex phrases. Comprehension is largely intact.
1. Which of the following terms best describes this type of language
disorder?
a. Broca aphasia
b. Transcortical motor aphasia
c. Wernicke aphasia
d. Conduction aphasia
e. Transcortical sensory aphasia
 2. Which is the most likely location for the acute lesion responsible
for this aphasia?
a. Arcuate fasciculus
b. Superior temporal lobe
c. Perisylvian cortex
d. Insula
e. Frontal lobe
3. Which of the following is almost invariably a manifestation of all
aphasias?
a. Anomia
b. Anosognosia
c. Apraxia
d. Prosopagnosia
e. Acalculia

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The reduced verbal fluency with relatively preserved comprehension
suggests a more anteriorly located aphasia. Repetition would be
impaired in a Broca aphasia, but normal, as in this case, with a
transcortical motor aphasia. Wernicke and transcortical sensory aphasia
are incorrect as both are characterized by impaired comprehension.
Conduction aphasia is characterized primarily by impaired repetition.

VIGNETTE 1 QUESTION 2
2. Answer E:
Broca aphasia localizes to the inferior frontal lobe, Wernicke to the
superior temporal lobe, and conduction aphasia to a variety of locations
including the arcuate fasciculus, temporal isthmus, and insula.
Transcortical aphasias spare the perisylvian arcuate fasciculus.
Transcortical motor aphasia localizes to the frontal lobe adjacent to
Broca area and transcortical sensory aphasia to the inferior temporal
lobe.
VIGNETTE 1 QUESTION 3
3. Answer A:
Anomia is an inability to name, the sine qua non of aphasias. When
testing language, it is always wise to test the patient’s ability to name
both high- and low-frequency objects. Anosognosia, prosopagnosia,
apraxia, and acalculia are nonlinguistic disorders of higher cortical
function. Anosognosia signifies a patient’s lack of awareness of his or
her neurologic deficit; it typically reflects a nondominant hemisphere
dysfunction. Apraxia is the inability to carry out a learned motor task
despite preservation of the primary motor, sensory, and coordination
functions needed for the task. Prosopagnosia is a specific form of
agnosia (inability to recognize objects), in which there is an inability to
recognize faces. Acalculia is an inability to calculate.
 12 Dementia

Dementia is the term to describe intellectual and cognitive deterioration of

sufficient severity to interfere with normal functioning. Dementia is not a
specific disease and can variably affect multiple aspects of cognitive
function including memory, orientation, visuospatial perception, language,
and higher executive functions, for example, planning, organizing, and
sequencing. This differs from delirium, which implies an often acute and
reversible, global disturbance of mental function (discussed further in
Chapter 3).

EPIDEMIOLOGY
Dementia is most common in the elderly but can occur at a younger age,
particularly in those with a hereditary predisposition. Approximately 5% of
people between the ages of 65 and 70 years have dementia; this increases to
more than 45% above age 85 years. Alzheimer disease (AD) accounts for
50% to 70% of cases of dementia. Cerebrovascular disease may account for
an additional 15% to 20%, and the other causes presented in Box 12-1
account for most of the rest. The societal financial burden of dementia is
substantial, with recent studies estimating more than $150 billion spent in
the United States annually on dementia-related care, a cost on par with
those of cancer and heart disease.

CLINICAL MANIFESTATIONS
There is some degree of cognitive slowing that accompanies normal aging.
In general, however, most patients with actual dementia have more
significant and progressive difficulties, often affecting short-term memory,
followed by an indolent deterioration of cognitive function that may involve
language, praxis, and personality. Many dementing illnesses manifest
characteristic symptoms and clinical findings that are helpful in establishing
an etiologic diagnosis.

DIAGNOSTIC EVALUATION
The initial recognition of dementia is difficult. Normal aging can mimic
some of its features. Rarely is the patient aware of cognitive deterioration;
in most cases, the family brings the patient to the doctor months or years
after problems have started. Recent research has demonstrated, however,
that subjective cognitive decline reported by older adults can be an early
indicator of dementia, even in the absence of objective cognitive
dysfunction. Thus, the most important information in the diagnosis of
dementia is the clinical history (including reports by relatives) and the
physical examination, especially a very detailed mental status examination.
Diagnosis of the cause of dementia consists of matching the major clinical
features of the individual patient with the characteristics of known
dementing illnesses. Of note, it is important to rule out an underlying
depression as the cause for cognitive symptoms, as the associated cognitive
abnormalities of depression can mimic dementia (“pseudodementia”). In
addition, depending on the clinical history and examination, laboratory
studies may be helpful in finding reversible causes of dementia. Box 12-2
summarizes some tests to consider in the workup of cognitive dysfunction.

KEY POINTS
● Symptoms and signs of dementia include memory loss, abnormalities of speech,
difficulties with problem solving and abstract thinking, impaired judgment, personality
changes, and emotional lability.
● The diagnosis of the cause of dementia requires a detailed history and neurologic and
physical examination.

BOX 12-1. Causes of Dementia

Degenerative
 Alzheimer disease
Lewy body dementia
Frontotemporal dementia
Progressive supranuclear palsy
Parkinson disease
Huntington disease
Spinocerebellar degeneration
Amyotrophic lateral sclerosis with frontotemporal dementia
Olivopontocerebellar atrophy
Metabolic
Hypothyroidism
Vitamin B12 deficiency
Wilson disease (copper deficiency)
Hypercalcemia
Addison disease
Lipid storage diseases and leukodystrophies
Toxic
Drug intoxication
Alcohol
Arsenic, mercury, and lead intoxication
Infectious
HIV
Syphilis
Subacute sclerosis panencephalitis (postmeasles)
Vascular
Vascular dementia
Vasculitis
Structural, traumatic, autoimmune, and inflammatory
Chronic traumatic encephalopathy
Chronic subdural hematoma
Hydrocephalus
Neoplastic and paraneoplastic
Other
Undetermined
Mixed (Alzheimer plus vascular)

CAUSES OF DEMENTIA
ALZHEIMER DISEASE
In 1907, Alois Alzheimer, a German clinician and neuropathologist,
published the landmark case of a 51-year-old woman with deterioration of
her mental state. Her autopsy showed the classic pathology of Alzheimer
disease (AD): neurofibrillary tangles (NFTs) and senile plaques in the
cerebral neocortex and hippocampus.

BOX 12-2. Tests to Consider in a Patient with Dementia

Hematologic screening, including erythrocyte sedimentation rate
Vitamin B12 and folate
Blood calcium
Liver function tests, including ammonia
Electrolytes
Serum urea nitrogen and creatinine levels
Infection workup, including syphilis, HIV, tuberculosis, etc.
Thyroid function tests
EEG should not be ordered routinely in a dementia assessment. Its use is justified when the
patient has evidence of fluctuations in cognitive status that could be seizures. The EEG
may be useful at the initial presentation in patients with suspected CJD
Computed tomography or MRI of the brain: It rules out structural abnormalities such as
tumor, subdural hematoma, and hydrocephalus and evaluates cortical atrophy
Neuropsychological assessment: It is useful in early stages to establish the diagnosis of
dementia and to use as a comparison tool in the progression of the disease
Brain biopsy: It is only indicated in specific cases such as CJD, HIV, CNS vasculitis, and so
on, to confirm the diagnosis and find or exclude possible treatable causes.

CJD, Creutzfeldt–Jakob disease; CNS, central nervous system; EEG, electroencephalography;

HIV, human immunodeficiency virus; MRI; magnetic resonance imaging.

Clinical Manifestations
“Doctor, my mother is 75 years old, and over the last 3 years I have noted
that she is having more difficulty with her memory. She remembers her
marriage 50 years ago, but she does not remember that we were here
yesterday. She asks the same questions repeatedly and forgets my answers.
She is unable to balance her checkbook, and yesterday she could not find
the way home from the drugstore.” This history illustrates the characteristic
features of AD. At the beginning of the illness, the examination shows no
difficulty with language, reasoning, or performance of normal social and
personal behaviors. Only those close to the patient notice small slip-ups,
suggesting that something is wrong (becoming lost while driving,
misplacing objects, the kitchen stove left unattended, missed appointments,
loss of social and interpersonal interactions). Later, the patient has more
difficulty with activities of daily life.
 As the disease progresses, other aspects of cognitive function are lost,
including the ability to speak, understand, and make decisions.
Characteristically, in contrast to patients with vascular dementia, elementary
neurologic functions (motor, visual, somatosensory, and gait) remain
normal until very late in the disease. Psychiatric manifestations are common
at this time: personality changes (apathetic or impulsive), aggressive
behavior (physical or verbal), paranoid thoughts and delusions (persecution,
things being stolen), sleep disturbances (the word “sundowning” is used to
describe worsening psychiatric manifestations during the evening and
night), hallucinations (uncommon, and often a side effect of medications),
and depression.
The disease course is relentlessly progressive. The average length of time
from onset of symptoms until diagnosis is 2 to 3 years, with subsequent
nursing home placement after 3 to 6 years. AD patients typically spend 3
years in nursing homes before death. Thus, the total duration of AD is
typically 9 to 12 years.

Epidemiology
Recent estimates suggest that more than 2 million people have AD in the
United States alone, with nearly 4% of people older than 65 years
incapacitated by severe AD. Because of increased life expectancy, the
population at risk for AD is the fastest-growing segment of society.
Annually, approximately 100,000 people die of AD and more than $25
billion is spent on the institutional care of patients with AD.

Etiology and Risk Factors

Many factors are associated with an increased frequency of AD, including
age, female sex, cerebrovascular disease, diabetes, and severe head trauma.
There are also many putative genetic risk factors. The gene for ApoE4
(on chromosome 19) is associated with both early- and late-onset AD of
both sporadic and familial varieties. Early-onset AD has been associated
with many different mutations in presenilin genes PSEN1 and PSEN2 on
chromosomes 14 and 1, respectively. Adults with Down syndrome have a
high risk of AD, in part because of the triplication of the gene for amyloid
precursor protein (APP) located on chromosome 21. Another mutation in a
gene on chromosome 12 that encodes α2-macroglobulin has been
associated with AD. The ApoE alleles and the α2-macroglobulin mutation
predispose individuals to early onset of sporadic AD, and even more to late-
onset AD. Other mutations in APP, PS1, and PS2 are associated with early
onset of AD in the third through sixth decades.

Diagnostic Evaluation
With the exception of those patients with identified mutations in known
causative genes (APP, PSEN1, and PSEN2), the diagnosis of AD is a
clinical one and can only be confirmed with brain biopsy. The diagnosis is
suggested by the clinical features and by the insidiously progressive course.
Investigations are designed to exclude other causes of dementia (Box 12-2).
Elevated tau protein and low amyloid-beta (Aβ)-42 levels in the
cerebrospinal fluid (CSF) have been suggested as early diagnostic markers
for AD. Magnetic resonance imaging (MRI)-based volumetric
measurements may show reduction of up to 40% in the size of the
hippocampus, amygdala, and thalamus. Functional neuroimaging, such as
positron emission tomography (PET) and single-photon emission computed
tomography (SPECT) used to quantify cerebral metabolism and blood flow,
may help to differentiate AD from other dementias. In AD, PET and
SPECT scans show bilateral temporoparietal hypometabolism, but this is
not specific enough to be diagnostic.

Pathology
The major pathologic features of AD are brain atrophy, senile plaques, and
NFTs, associated with a substantial gliosis and loss of neurons in the
cerebral cortex. NFTs represent intracellular accumulation of
phosphorylated tau protein. Senile plaques are extracellular deposits of
amyloid surrounded by dystrophic axons. How exactly each of the known
gene mutations associated with AD causes these changes is not established.
In the case of APP, mutations are known to cause increased Aβ production
and change the normal structure of the protein, altering its recognition by
metabolizing enzymes, therefore leading to a progressive accumulation of
the peptide. Other pathophysiologic mechanisms have been proposed,
including inflammatory, oxidative, metabolic, nutritional, and immune
processes.
Treatment
At present, there is no satisfactory treatment for patients with AD. Therapy
consists of the following:
• Preventing associated symptoms: This includes treatment of
depression, agitation, sleep disorders, hallucinations, and delusions.
• Preventing or delaying progression: This includes therapy with
acetylcholinesterase inhibitors such as donepezil or rivastigmine, as well
as memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist.
• Prophylaxis: Until now, there have been no successful single-drug
clinical trials demonstrating decreased dementia incidence. This may be
due, in part, to the heterogeneity of the underlying cause of AD,
prolonged time course of the illness, and the likely presence of a
protracted, preclinical disease state. In addition to clinical trials focusing
on lifestyle-related interventions (i.e., physical activity, diet), trials
investigating preventative and disease-modifying drugs may one day
provide therapeutic options for the aging population. Table 12-1
provides information regarding therapy for AD.

TABLE 12-1. Alzheimer Disease Therapy

Medication Mechanism of Action Comments
Donepezil (Aricept) Cholinesterase inhibitor Rare: hepatic toxicity.
Common: diarrhea and
abdominal cramps.
Rivastigmine (Exelon) Cholinesterase inhibitor GI disturbances during dose
adjustment. Rare: hepatic
toxicity.
Memantine (Namenda) NMDA receptor antagonist Dizziness, headache, confusion
Galantamine (Razadyne) Cholinesterase inhibitor GI side effects, weight loss
GI, gastrointestinal; NMDA, N-methyl-D-aspartate.

KEY POINTS
● AD is the most common neurodegenerative disease of the brain and accounts for 50% to
70% of all instances of dementia.
● Risk factors for developing AD include older age, cerebrovascular disease, head trauma,
female sex, and family history.
● Potentially treatable causes of dementia should be excluded through laboratory testing and
brain imaging.
 ● The average duration of AD is typically 9 to 12 years from symptom onset. Patients
typically succumb from a combination of neurologic and medical problems.

VASCULAR DEMENTIA
This dementia (previously referred to as multi-infarct dementia) may
develop in patients with cerebrovascular disease. There are two recognized
types: macrovascular, related to large infarcts, and microvascular, in which
the pathophysiologic mechanism of brain injury is subcortical ischemia
associated with cerebral small vessel disease (lacunes or deep white matter
changes on MRI). Dementia related to extensive microvascular changes of
the white matter is called Binswanger disease. Vascular dementia has the
same risk factors as cerebrovascular disease, including hypertension,
diabetes, age, embolic sources, and extensive large artery atherosclerosis. It
is common for vascular dementia and other diseases (AD, Lewy body
disease) to coexist in the same patient. For this reason, it is unclear exactly
how commonly dementia can arise from a purely vascular etiology.

Clinical Manifestations and Diagnostic Evaluation

The criteria for diagnosis of vascular dementia include presence of
dementia and two or more of the following: focal neurologic signs on
examination; onset that is abrupt, stepwise, or stroke-related; or brain
imaging showing multiple strokes, lacunes, or extensive deep white matter
changes. Most patients with vascular dementia are hypertensive, diabetic, or
both. The diagnosis requires investigation of the cause of stroke. Cardiac
and hypercoagulable workups should be considered in selected cases.

Treatment
The prevention and treatment of vascular dementia are essentially the same
as prevention and treatment of stroke (see Chapter 14).

KEY POINTS
● Vascular dementia may be a common cause of dementia, but it often coexists with other
causes.
● Vascular dementia is associated with microvascular disease (Binswanger), lacunar infarcts,
and large strokes.
DEMENTIAS ASSOCIATED WITH
EXTRAPYRAMIDAL FEATURES
This group of dementias includes a wide array of neurodegenerative
syndromes, including but not limited to Lewy body dementia (LBD),
frontotemporal dementias (FTDs), progressive supranuclear palsy (PSP),
corticobasal degeneration, striatonigral degeneration, Huntington disease
(HD), and Wilson disease. Some important examples of these diseases are
discussed here.

DEMENTIA WITH LEWY BODIES

Friedrich Lewy first described the cytoplasmic inclusions found in the
substantia nigra in Parkinson disease (PD) in 1912, but it was not until 1961
that these later-named “Lewy bodies” were noted in the cortex of patients
with dementia. LBD is now thought to be the second leading cause of
dementia (rather than vascular dementia). The clinical picture of LBD is
that of a parkinsonian dementia syndrome; it is considered to be on a
spectrum with PD dementia.

Clinical Manifestations
LBD patients typically present with early progressive cognitive decline,
frequently beginning after age 55. Visual hallucinations, often manifesting
as small children or animals, tend to be a prominent feature. Unlike in AD,
cognitive domains such as attention and visuospatial skills are typically
affected earlier than memory difficulties. The extrapyramidal symptoms can
also be slightly different in that rest tremor is less common, and signs are
often symmetric. Bradykinesia and gait impairment are more common than
rest tremor. Marked fluctuations of alertness, delusions, and an
extraordinary sensitivity to neuroleptics (i.e., marked worsening with drugs
like haloperidol) are also key features of LBD.

Diagnostic Evaluation
The pathologic hallmark of this disease is the Lewy body, an eosinophilic
intracellular inclusion of the protein alpha synuclein. In LBD and PD,
widespread limbic and cortical Lewy bodies are found, to the point that it
can be difficult, based on autopsy, to distinguish pathologically from which
clinical syndrome a patient suffered. Other pathologic abnormalities can
also be present, including varying degrees of AD-type abnormalities such as
NFTs and amyloid plaques.

Treatment
Management of LBD can be complex, because treatment of the
parkinsonian syndrome may worsen neuropsychiatric dysfunction and
treatment of the neuropsychiatric disorder may exacerbate the parkinsonian
syndrome. Low doses of atypical neuroleptics such as risperidone and
quetiapine have been used to treat behavioral symptoms.

KEY POINTS
● LBD may be the second most common type of dementia.
● Fluctuations of alertness, visual hallucinations, and an extraordinary sensitivity to
neuroleptics are the three key distinguishing features of dementia with Lewy bodies.
● Death typically ensues after 10 to 15 years.

FRONTOTEMPORAL LOBAR DEGENERATION

Frontotemporal lobar degeneration (FTLD) is the underlying pathology
associated with a heterogeneous group of degenerative disorders that
collectively account for up to 20% of dementias. Together, these disorders
are a leading cause of dementia in patients presenting before 65 years of
age. First described at the turn of the previous century in reports by Arnold
Pick and Alois Alzheimer, FTLDs are pathologically notable for marked,
preferential degeneration of the anterior temporal and frontal lobes, with
prominent tau accumulation.

Clinical Manifestations
Unlike AD, FTLD often presents with behavior changes and nonmemory
cognitive deficits of the early, prominent involvement of the frontal or
temporal cortices. The range of clinical symptoms caused by FTLD can
vary such that there are at least three distinct clinical syndromes. These are
behavioral variant frontotemporal dementia (FTD), semantic variant
primary progressive aphasia (PPA), and nonfluent/agrammatic variant PPA.
In addition, there are forms of FTD associated with parkinsonism and with
motor neuron disease.

Diagnostic Evaluation
As noted earlier with LBD, the clinicopathologic correlations of FTDs vary
significantly, likely because of the heterogeneity of the underlying cause of
the FTLD. There are multiple known genetic mutations associated with
FTLD, and nearly 40% of patients with FTD have a first-degree relative
with dementia. The inheritance of FTD has been linked to numerous genetic
mutations, including mutations in chromosome 9 open reading frame 72
(C9ORF72), microtubule-associated protein tau, fused in sarcoma (FUS),
TAR DNA-binding protein-43 (TDP-43), and granulin. Interestingly,
mutations in C9ORF72, FUS, and TDP-43 are also associated with
inherited motor neuron disease amyotrophic lateral sclerosis (ALS) and
FTD-ALS overlap syndromes, a point that again illustrates the complexity
with which these genetic mutations lead to neurologic disease.

KEY POINTS
● FTLD includes multiple clinical disorders affecting the frontal and temporal lobes
prominently.
● FTD is a common cause of early-onset dementia (before age 65 years).
● Personality changes early in the disease are common in FTD, in contrast to the findings in
AD.
● Nearly 40% of patients with FTLD have a first-degree family member with a history of
dementia.

PROGRESSIVE SUPRANUCLEAR PALSY

PSP is a rare, progressive syndrome first described in 1964. Initially, it was
felt to be a type of Parkinson’s disease, but several features led to its
classification as a distinct disorder. Today, it is estimated that PSP may
account for 2% to 3% of dementias. No clear predisposing or genetic
factors have been identified.

Clinical Manifestations
PSP typically presents in mid- to late adulthood. Its main features are
supranuclear gaze palsy, that is, an impairment of vertical eye movement;
prominent postural instability; and falls. Additional features of PSP include
dysarthria, dysphagia, extrapyramidal rigidity, gait ataxia, and dementia. As
such, there are many subtypes of PSP based on the prominent clinical
abnormalities. Dementia may occur early or develop later, and frontal lobe
abnormalities predominate. Patients become apathetic. In early stages, PSP
may be mistaken for AD.

Diagnostic Evaluation
PSP remains a clinical diagnosis. Similar to AD, PSP is a tauopathy, but
unlike the cortical accumulation of tau in AD, there is a predominantly
subcortical disease burden in PSP, with atrophy of the dorsal midbrain,
globus pallidus, and subthalamic nucleus. The course is progressive, with a
median survival of 6 to 10 years.

KEY POINTS
● PSP is a form of subcortical dementia with prominent extrapyramidal features.
● The characteristic clinical findings are limitation of vertical gaze, abnormal gait, and
frequent or early falls.
● Median survival is 6 to 10 years.

HUNTINGTON DISEASE
Huntington disease (HD) is an autosomal dominant neurodegenerative
disease with typical clinical onset between the ages of 35 and 45 years. Key
clinical manifestations include chorea, behavioral changes, personality
changes (frequently obsessive-compulsive disorder), and dementia.
Diagnosis is by family history, clinical signs, early caudate atrophy (often
very prominent) on brain imaging, and demonstration of more than 40 CAG
repeats in the HD gene on chromosome 4. Management is usually with
dopaminergic antagonists, including neuroleptic drugs, for the chorea.
Despite these therapies, the clinical decline is relentless. Genetic counseling
for the family is fundamental. See Chapter 16, Movement Disorders, for
further discussion of HD.

KEY POINTS
● HD is characterized by chorea, dementia, and personality and behavioral changes.
● The clinical course is relentless, and death occurs 10 to 20 years after onset. Suicide is not
rare in at-risk and early-onset HD patients.

PARKINSON DISEASE
PD may produce subcortical dementia. Cognitive impairment develops in
about 30% of patients with idiopathic PD. The distinction from other types
of dementia is based on the natural history and the presence of associated
symptoms. The clinical manifestations include those of subcortical
dementia, with marked psychomotor involvement. For more information
regarding PD, see Chapter 16, Movement Disorders.

DEMENTIAS CAUSED BY INFECTIOUS

AGENTS
PRION-RELATED DISEASES
Prion-related diseases include Creutzfeldt–Jakob disease, or CJD (familial
and sporadic); Gerstmann–Sträussler–Scheinker syndrome; and fatal
familial insomnia. These so-called transmissible spongiform
encephalopathies are a group of disorders characterized by spongy
degeneration, neuronal loss, gliosis, and astrocytic proliferation resulting
from the accumulation in the brain of a mutated protease-resistant prion
protein.
CJD is the most common of these disorders. It is characterized by a
rapidly progressive dementia with pyramidal signs, myoclonus, cerebellar
or extrapyramidal signs, and periodic sharp waves in the
electroencephalogram (EEG). MRI with diffusion-weighted images may
show evolving cortical and basal ganglionic abnormalities during the course
of the disease. CSF is typically normal, but the presence of protein 14-3-3 is
relatively sensitive and specific for CJD. There is no therapy. This
syndrome evolves over weeks to months, and death usually occurs within a
year.

KEY POINTS
● CJD is rare.
● CJD presents as a rapidly progressive dementia, often with focal neurologic signs and
myoclonus.
● EEG and MRI are not diagnostic, but they become more specific in the setting of the
appropriate clinical history.

HUMAN IMMUNODEFICIENCY VIRUS–ASSOCIATED

DEMENTIA COMPLEX
Most patients with human immunodeficiency virus (HIV) disease have
central nervous system (CNS) involvement. This virus can produce an
encephalitis and also makes the individual susceptible to CNS infections
such as toxoplasmosis, tuberculosis, and syphilis, which can also cause
dementia. HIV-associated dementia complex is a clinical entity recognized
in HIV patients (usually with low CD4 cell counts) and is characterized by
progressive deterioration of cognitive function.

Clinical Manifestations
Patients report memory problems, difficulty with concentration, and poor
attention. The pathophysiologic bases for this cognitive impairment have
not been clarified.

Diagnostic Evaluation
MRI usually shows cortical and subcortical atrophy. White matter changes
may also be prominent.

Treatment
Highly active antiretroviral therapy (HAART) should be used and has
reduced the incidence of HIV-associated dementia in recent years.

KEY POINTS
● HIV-associated dementia is common in HIV patients with low CD4 cell counts.
● Therapy includes HAART.

METABOLIC CAUSES OF DEMENTIA

Vitamin B12 deficiency may present as a progressive dementing illness.
Usually, however, there are many other neurologic features and signs on
physical examination, including dysfunction of the spinal cord (subacute
combined degeneration) and peripheral nervous system, such that the
diagnosis becomes evident even prior to the development of dementia. The
most common neurologic symptoms are those of neuropathy (paresthesias
in hands and feet, sensory ataxia, visual loss, orthostatic hypotension) and
memory loss. Other systemic manifestations include anemia and a sore
tongue. Appropriate replacement of vitamin B12 should suffice in the
treatment. Other metabolic causes of dementia are reviewed in Box 12-1.

CLINICAL VIGNETTES

VIGNETTE 1
A 71-year-old woman is brought into the neurologist’s office by her
husband because he has noticed that she has been forgetting things over
the past 2 years. She herself does not notice any particular memory
problems, but he notes that she has forgotten to pay the bills on several
occasions, needs to use the global positioning system device in the car
to navigate, even to fairly familiar locations, and often struggles to
remember recent news events and conversations, despite watching TV
news every night. She still recalls remote biographical information such
as details of their wedding and her childhood but cannot remember
much about a recent trip they took together.
1. Which of the following diagnostic assessments is not appropriate
initially as part of an outpatient evaluation for the patient’s
symptoms?
a. Screening for depression
b. EEG
c. Neuropsychological testing
d. Serum B12 testing
e. Neuroimaging
2. Neurologic examination shows that the patient has intact attention,
but can learn only 2 items from a list of 10 despite multiple
repeated attempts. Some hesitancy with word-finding and a few
semantic paraphasic errors are noted in the patient’s language, and
she demonstrates some difficulties with copying a complex figure.
There are no focal abnormalities on the remainder of her neurologic
examination. A screening questionnaire does not suggest
depression; brain MRI shows mild cerebral atrophy; and serum B12
and thyroid-stimulating hormone are within the normal range.
Which of the following would be an appropriate treatment to
consider for this patient?
a. Warfarin
b. Vitamin D
c. Donepezil
d. Carbidopa/levodopa
e. Clonazepam

VIGNETTE 2
A 59-year-old man presents with a year-long history of decline in
function. He has not been able to keep his job because of problems with
concentration and his supervisor’s concern about his lack of reliability
and professionalism. He has had odd visual hallucinations and episodes
in which he has been very sleepy and confused during the day. In the
past couple of months, his gait has become slower and stiffer.
Neurologic examination demonstrates mild limb rigidity, bradykinesia,
and decreased arm swing. Upon presenting to an emergency room
during a prolonged episode of confusion, he was given haloperidol,
which led to a severe encephalopathy with stupor and extreme rigidity.
1. Which of the following is the most likely diagnosis?
a. CJD
b. PD
c. Normal pressure hydrocephalus
d. Dementia with Lewy bodies
e. AD
2. Further history from the patient’s wife indicates that he has had
episodes in which he has been thrashing around in bed violently, for
which he has no memory in the morning. Occasionally, he reports
vivid dreams after these events in which he is being chased by
others down a long corridor. Which of the following would be an
appropriate pharmacologic treatment to consider for these nighttime
episodes?
a. Phenytoin
b. Methylphenidate
c. Clonazepam
d. Carbidopa/levodopa
e. Modafinil

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The patient is presenting with symptoms consistent with dementia.
Initial steps in evaluation include ruling out mimics of dementia (such
as depression with “pseudodementia”), establishing the severity and
nature of cognitive deficits using detailed mental status or formal
neuropsychological testing, and ruling out reversible or structural causes
of cognitive decline (such as B12 deficiency, hypothyroidism, or
subdural hematomas or mass lesions). In this case, the patient’s lack of
awareness of her own symptoms, in the setting of concern by her
spouse, is more suggestive of true dementia rather than depression, but
screening for depression should still be performed. Neuropsychological
evaluation to quantify cognitive deficits is appropriate. B12 deficiency
and subdural hematomas should be ruled out because they might require
specific interventions. EEG would generally only be recommended in
the setting of suspected seizures; periodic discharges on an EEG can be
seen in CJD, but this diagnosis is not otherwise suggested by the
patient’s history and time course of illness.

VIGNETTE 1 QUESTION 2
2. Answer C:
The most likely diagnosis is AD, with memory problems, visuospatial
problems, and a milder language problem that is similar to a
transcortical sensory aphasia. Treatments for AD include
acetylcholinesterase inhibitors (such as donepezil) and memantine (an
NMDA receptor antagonist). The other pharmacologic agents listed do
not have a specific role in AD.

VIGNETTE 2 QUESTION 1
1. Answer D:
The constellation of cognitive impairment, parkinsonian signs,
fluctuations in alertness, and visual hallucinations is highly
characteristic of dementia with Lewy bodies. This is a degenerative
disorder that is diagnosed pathologically by the widespread presence of
Lewy bodies within cortical neurons and is differentiated from
idiopathic PD by the timing of cognitive versus motor symptoms and
the early psychotic features. Dementia with Lewy bodies differs from
AD in that a more subcortical pattern of dementia is often present, with
less effect on memory and more on comportment and executive
function. An exquisite sensitivity to the adverse effects of neuroleptics
is a notable feature of dementia with Lewy bodies; these agents must be
used with extreme caution if this diagnosis is suspected.

VIGNETTE 2 QUESTION 2
2. Answer C:
The most likely diagnosis for these episodes is rapid eye movement
(REM) sleep behavior disorder, a condition most common in elderly
men, characterized by the “acting out” of dreams during REM sleep.
The usual atonia of REM sleep is defective in this condition. REM sleep
behavior disorder can occur in association with dementia with Lewy
bodies and PD and can even be the presenting symptom of these
conditions. Confirmation of the diagnosis is usually obtained through
polysomnography. Current treatment options for REM behavior
disorder include melatonin and clonazepam.
 13 Sleep Disorders

PHYSIOLOGY OF SLEEP
Sleep is a process necessary for life and is considered essential for
restoration of energy, consolidation of memory and learning, and
maintenance of the immune system. From a physiologic perspective, sleep
can be divided into four stages: rapid eye movement (REM) sleep and three
stages of nonrapid eye movement (nREM) sleep. REM sleep is
distinguished not only by rapid eye movements, as its name indicates, but
also by atonia of all skeletal muscles other than the extraocular muscles and
diaphragm. The three stages of nREM sleep are distinguished from each
other by electroencephalogram (EEG) features. Stage N1 is a transitional
state between wakefulness and sleep and is characterized
electrophysiologically by attenuation of the posterior dominant background
rhythm on EEG. Stage N2 is intermediate sleep and features sleep spindles
and K complexes. Stage N3 is also known as deep or slow wave sleep and
is characterized by an EEG background that consists of more than 20% of
the record in the delta frequency (0.5–2 Hz) range.
A typical night of sleep contains four to six cycles lasting approximately
90 minutes each, with an orderly progression between stages as shown in
Figure 13-1. Note that stage N1 sleep is absent after the first sleep cycle and
that both N3 and REM sleep follow stage N2. Infants spend approximately
50% of sleep in REM, with this percentage decreasing to the typical young
adult value of 20% to 25% between ages 2 and 5 years. Healthy older adults
have a decrease in REM sleep to 15% to 20% of the night. As illustrated in
Figure 13-1, REM sleep accounts for a greater percentage of sleep as the
night progresses.
Certain drugs and toxins may alter the proportion of the night spent in the
various stages of sleep. For example, benzodiazepines suppress stage N3,
whereas antidepressants and alcohol suppress REM sleep.

KEY POINTS
● Sleep is divided into four stages: REM sleep and three stages of nREM sleep.
● Sleep spindles and K complexes characterize stage N2 sleep.
● Adults spend between 20% and 25% of their sleep in REM.

POLYSOMNOGRAPHY
Apart from the history and physical examination, polysomnography (PSG)
is the most important step in the evaluation of a patient with a suspected
sleep disorder. The PSG consists of a limited EEG montage, which records
brain activity and helps with the staging of sleep, electro-oculography to
monitor eye movements, surface electromyography electrodes attached to
the chin and legs to monitor skeletal muscle activity, transducers to measure
airflow and chest movements, pulse oximetry to measure oxygen saturation,
and electrocardiogram to monitor cardiac activity. Standard PSG may be
augmented by video monitoring to investigate for parasomnias such as
REM sleep behavior disorder and somnambulism.

FIGURE 13-1. Stages of sleep. Rapid eye movement (REM) sleep and the three stages of non-
REM sleep alternate throughout the night in cycles that last approximately 90 minutes. There are
typically four to six cycles each night in a healthy young adult.
CIRCADIAN RHYTHMS AND SLEEP-PHASE
DISORDERS
The body is governed by roughly 24-hour cycles of sleep and activity
known as circadian rhythms. These rhythms are coordinated by the
suprachiasmatic nucleus of the hypothalamus, with important inputs from
melatonin produced by the pineal gland. Pathologic circadian rhythms
include advanced sleep-phase disorder in which patients sleep or awaken
earlier than they desire and delayed sleep-phase disorder in which sleep
onset is delayed until early morning, with consequent awakening later than
desired. Diagnosis of a circadian rhythm disorder is made by keeping a
sleep log. Bright light therapy and melatonin can treat sleep-phase disorders
by resetting circadian rhythms.

RESTLESS LEGS SYNDROME/PERIODIC

LIMB MOVEMENTS OF SLEEP
Restless legs syndrome (RLS) is a common sleep disorder characterized by
an urge to move the legs, usually during periods of rest or inactivity.
Patients describe uncomfortable crawling sensations in the legs, with
worsening discomfort if the legs remain still, and relief when they are
moved. Typically, restless legs symptoms occur in the evening or at night.
They are often accompanied by periodic limb movements of sleep, which
are repetitive involuntary movements of the toe, ankle, knee, and hip that
last 2 to 3 seconds and are followed by slow recovery of the normal leg
position. These movements can awaken the patient, but generally are more
bothersome to the bed partner. RLS is more common in women, and in
some families an autosomal dominant inheritance pattern is probable.
Diagnosis of RLS is made by clinical history. PSG may help to confirm
the diagnosis but is often not necessary. Laboratory evaluation of RLS
should include measurement of ferritin levels, as many patients with RLS
have iron deficiency.
The dopamine agonists ropinirole and pramipexole are often the
preferred initial treatments for RLS. Typically, they are administered 2 to 3
hours prior to symptom onset in the evening. Many patients require an
afternoon dose. Side effects of dopamine agonists include nausea,
lightheadedness, and sometimes sleep attacks (falling asleep suddenly in the
daytime). The most important side effect of dopamine agonists for RLS
patients, however, is augmentation in which symptoms develop
progressively earlier in the day. If augmentation becomes a severe problem
or RLS symptoms worsen despite treatment with dopaminergic agents,
other options include gabapentin, pregabalin (which may be less likely to
produce augmentation than dopaminergic agents), levodopa, opioids, and
benzodiazepines. Rotigotine is a transdermal dopamine agonist, which may
produce less augmentation. Correction of iron deficiency can help to relieve
symptoms, although dopaminergic agents are often required even after this
is accomplished.

NARCOLEPSY/CATAPLEXY
The four components of the narcolepsy/cataplexy syndrome are excessive
daytime sleepiness with narcolepsy, cataplexy, sleep paralysis, and
hypnagogic hallucinations. Narcolepsy is the irresistible urge to sleep, often
taking the form of sleep attacks, that is, falling asleep suddenly in the
daytime. Cataplexy is characterized by the sudden loss of muscle tone,
often in the setting of laughter or other strong emotions, and is the most
specific feature of the syndrome. Hypnagogic hallucinations are those that
occur immediately upon falling asleep.
Onset of narcolepsy/cataplexy syndrome usually occurs in the late teens
or twenties. The pathophysiology of narcolepsy/cataplexy is related to loss
of hypocretin-secreting neurons in the hypothalamus. A cerebrospinal fluid
hypocretin level <110 pg/mL is diagnostic for the syndrome in the
appropriate clinical setting. More typically, however, the diagnosis is
established by performing a special type of PSG known as the multiple
sleep latency test (MSLT). An MSLT involves several short naps and
monitoring of the latency to sleep onset and latency to REM onset. Sleep
latency of less than 8 minutes, with more than two episodes of REM at
sleep onset, is diagnostic for narcolepsy/cataplexy.
Modafinil, an alerting agent with an unclear mechanism of action, is
typically the first agent employed for patients with narcolepsy.
Amphetamines such as methylphenidate and dextroamphetamine are also
employed, but less frequently due to safety concerns and potential for
abuse. Cataplexy is most often treated with the gamma-aminobutyric acid
metabolite sodium oxybate. Tricyclic antidepressants such as clomipramine
and selective serotonin reuptake inhibitors including fluoxetine and
venlafaxine are also options for treating cataplexy.

KEY POINTS
● The clinical tetrad of narcolepsy/cataplexy is excessive daytime sleepiness with
narcolepsy, cataplexy, sleep paralysis, and hypnagogic hallucinations.
● Shortened sleep onset latency and REM at sleep onset are features identified on MSLT in
patients with narcolepsy/cataplexy.
● Modafinil has become the agent of choice for the treatment of narcolepsy.
● Sodium oxybate, tricyclic antidepressants, and selective serotonin reuptake inhibitors are
used to treat cataplexy.

PARASOMNIAS AND DYSSOMNIAS

Parasomnias are abnormal behaviors that occur during sleep or sleep–wake
transition. There is a wide variety of these disorders, and only a few of the
more common ones will be discussed here.

AROUSAL DISORDERS
These parasomnias are characterized, as their name suggests, by abnormal
arousals from sleep. In confusional arousals, patients awaken with
disorientation, slow speech, and incoordination. Sleep terrors involve rapid
awakening from sleep with fearful behavior, often beginning with a scream,
and are associated with autonomic hyperactivity such as facial flushing,
diaphoresis, and tachycardia. Patients with sleep terrors may be difficult to
console upon awakening. A lack of memory for the event helps to
distinguish sleep terrors from nightmares. Somnambulism is characterized
by interruption of sleep by a variety of complex motor activities, including
not only walking, but also dressing, driving, or eating.

REM SLEEP–RELATED PARASOMNIAS

A variety of parasomnias may arise from REM sleep. Nightmares are
frightening, vivid dreams that usually occur during the second half of the
night and are remembered well by patients, unlike sleep terrors. Sleep
paralysis is the perception of being unable to move, usually on awakening.
REM behavior disorder is characterized by the loss of the normal skeletal
muscle atonia during REM sleep, with the patient acting out the dreams. A
wide range of behaviors including punching, kicking, jumping, and yelling
may occur. In some cases, these result in injury to the patient or the bed
partner. Patients with this disorder are at increased risk of developing a
synucleinopathy such as Parkinson disease, Lewy body dementia, or
multiple system atrophy. Clonazepam administered at bedtime is the
preferred treatment for REM behavior disorder.

SLEEP–WAKE TRANSITION DISORDERS

Nocturnal cramps are experienced as a painful tightness, most often in leg
muscles. Treatment options include gentle exercise before bedtime,
potassium and magnesium supplementation, antihistamines,
anticonvulsants, and quinine. Somniloquy is unintelligible mumbling during
sleep, which can be provoked by talking to the patient.

OTHER PARASOMNIAS
Sleep starts or hypnic jerks are commonly experienced myoclonic jerks that
occur with sleep onset. Enuresis is abnormal nocturnal bedwetting, defined
as more than three episodes per week. Boys are more likely to have enuresis
than girls. Most cases of enuresis resolve spontaneously, although
conditioning the child or using imipramine may hasten this resolution.
Bruxism is teeth grinding during sleep; treatment of underlying dental
abnormalities or use of a biteplate is often helpful. Sleep-related
dissociative disorders occur in the transition between sleep and
wakefulness, usually in patients with psychiatric disorders. Patients enact
complex, bizarre, and nonstereotyped behaviors, some of which are
prolonged.

SLEEP APNEA
Sleep apnea is the cessation of airflow during sleep. It may be divided into
obstructive sleep apnea (OSA), in which a mechanical obstruction of the
upper airway prevents airflow, and central apnea, in which airflow is
reduced because of diminished central nervous system–derived ventilatory
effort. Many patients have both obstructive and central dysfunction.
Symptoms of OSA include excessive daytime sleepiness, snoring, cessation
of breathing in the middle of the night, and morning headaches. Untreated
OSA may lead to cognitive complaints including word-finding difficulties,
lack of motivation, and memory loss. In addition, OSA increases the risk
for stroke, hypertension, and cardiopulmonary disease. Risk factors for the
development of OSA include obesity (body mass index >30 kg/m2 or neck
circumference greater than 17 inches in men or 16 inches in women), a
crowded airway (enlarged tongue, tonsils, and palate), and advanced age.
PSG confirms OSA: A combination of more than five apneas,
hypopneas, or respiratory event–related arousals per hour is required to
establish the diagnosis. Apneas are defined as respiratory pauses with 90%
or greater airflow reduction lasting 10 seconds or more. Hypopneas are
defined as reduction of 30% to 90% or more airflow for more than 10
seconds with at least 4% reduction in baseline oxygen saturation.
Respiratory event–related arousals occur when criteria for apneas and
hypopneas are not met, but there is a decrease in airflow accompanied by an
arousal identified by EEG.
Continuous positive airway pressure (CPAP) is the standard treatment for
OSA. This apparatus delivers air at a predetermined pressure through a tube
connected to a facemask. Patients with a diagnosis of OSA may have a
“split-night” PSG in which the first part of the night is spent in diagnosing
and quantifying the severity of the disorder, whereas the second part of the
night is spent titrating the CPAP to best prevent episodes of interrupted
breathing. In addition to CPAP, patients with OSA benefit from weight loss,
alcohol cessation, and sleeping on their sides rather than on their backs.
Surgical intervention may be indicated should CPAP and behavioral
modification prove ineffective or poorly tolerated: Options include
uvulopalatopharyngoplasty to relieve upper airway obstruction and
hypoglossal nerve stimulation.
 KEY POINTS
● CPAP is the treatment of choice for OSA.

INSOMNIA
Insomnia is defined as difficulty initiating or maintaining sleep.
Consequences of insomnia include excessive daytime sleepiness, poor
concentration, and irritability. Insomnia has a variety of causes including
psychological disorders, medical conditions, toxins and medications,
circadian rhythm disorders (see above), and poor sleep hygiene. In most
cases, therefore, a careful medical and sleep history is essential in
establishing its diagnosis. PSG may be needed to make the diagnosis in
some cases, particularly sleep state misperception in which a patient thinks
that he or she is sleeping less than is actually the case. The first step in
treating insomnia is to identify and treat any medical or psychiatric
disorders that may be contributing. Behavioral therapy, including improving
sleep hygiene and facilitation of relaxation before bedtime, is also important
in improving insomnia. Agents including melatonin, antihistamines,
benzodiazepines, nonbenzodiazepine medications (e.g., zolpidem, zaleplon,
and eszopiclone), or the selective melatonin receptor agonist ramelteon may
be required for some patients. Many of these agents have addictive
properties, however, and should be used cautiously and for short periods of
time.

KEY POINTS
● Insomnia is the most common sleep disorder and is often due to a medical or psychiatric
disorder.
● Behavioral modification is the mainstay of treatment, with sedatives reserved for patients
with refractory insomnia.

CLINICAL VIGNETTES
VIGNETTE 1
A 22-year-old woman presents for evaluation of excessive daytime
sleepiness. For the last 2 years, she has felt tired throughout the day and
needs to take several short naps. She cannot fight the need to nap—
which seems to develop rather suddenly. She goes to bed at 11 PM each
night and wakes up at 7 AM. She has no difficulty initiating sleep and
does not snore. She does not drink caffeine. She has fallen asleep while
driving three times, on one occasion having a serious accident.
1. Based on this information, what is the most likely diagnosis?
a. Sleep-related dissociative disorder
b. Delayed sleep-phase disorder
c. Insomnia
d. Narcolepsy
e. OSA
2. What is the next step in the evaluation of this patient?
a. Brain magnetic resonance imaging (MRI)
b. 24-hour video EEG with sphenoidal electrodes
c. MSLT
d. Polysomnogram
e. Sleep log
3. Which of the following would be the most appropriate treatment for
this patient?
a. Behavioral modification
b. Caffeine
c. Carbamazepine
d. Modafinil
e. Zolpidem

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
Narcolepsy presents with the clinical tetrad of excessive daytime
sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis.
By history, this patient has excessive daytime sleepiness with
narcolepsy (including sleep attacks). In sleep-related dissociative
disorder, patients enact complex, bizarre, and non-stereotyped
behaviors. Delayed sleep-phase disorder is characterized by a delay of
sleep onset to the early morning with awakening not taking place until
the later morning or early afternoon. Excessive daytime sleepiness may
be a feature of delayed sleep-phase disorder, but sleep attacks are not.
Insomnia is a difficulty initiating or maintaining sleep, but sleep attacks
are not a feature of idiopathic insomnia. OSA is uncommon at this
patient’s age, and her history is not consistent with this diagnosis.

VIGNETTE 1 QUESTION 2
2. Answer C:
MSLT showing a rapid onset of REM sleep is diagnostic for
narcolepsy/cataplexy. Brain MRI and EEG do not have a role in the
evaluation of this patient. Standard PSG is useful for many sleep
disorders, but the MSLT is most appropriate for this patient. Sleep logs
are the diagnostic test of choice for circadian rhythm disorders.

VIGNETTE 1 QUESTION 3
3. Answer D:
Modafinil and amphetamines are the most appropriate treatments for
patients with narcolepsy/cataplexy. Behavioral modification is
successful for many patients with insomnia. Caffeine may help with
excessive daytime sleepiness, but is less effective than modafinil or
amphetamines for patients with narcolepsy/cataplexy. Carbamazepine is
prescribed most commonly for patients with epilepsy rather than for
those with sleep disorders. Zolpidem is useful for insomnia, but is not
appropriate for this patient.
 14 Vascular Disease

A stroke is a neurologic injury caused by an abnormality of the blood

vessels supplying the central nervous system. Although strokes may occur
in the spinal cord, they are uncommon and this chapter will focus on strokes
that involve the brain. In the United States each year, about 800,000
individuals have a stroke and 130,000 die from a stroke, that is, a stroke
every 40 seconds and death from stroke every 4 minutes. Stroke is the fifth
leading cause of death in the United States and a very important cause of
prolonged disability. Although strides have been made in the prevention and
treatment of stroke in the last 25 years, the economic, social, and
psychological costs of stroke remain huge.
Many medical conditions and behaviors predispose to stroke. These
include hypertension, diabetes, obesity, hyperlipidemia, sedentary life style,
smoking, cardiac disease, and heavy alcohol use. Prevention of stroke is
very important and can be accomplished by physicians attending to these
stroke risk factors, advising patients about their lifestyles and habits, and
prescribing appropriate medications. Primary prevention is prevention of a
first stroke, whereas secondary prevention is prevention of stroke
recurrence. Second and third strokes are most often due to the same stroke
subtype as the initial stroke. Identification of stroke etiology, therefore, is
the most important step in avoiding recurrence.

VASCULAR ANATOMY
The nature of neurologic symptoms and signs helps to localize dysfunction
to a particular area of the brain and a particular vascular supply. Intimate
knowledge of the vascular anatomy of the brain, therefore, is necessary. The
cerebral vasculature is divided into the anterior and posterior circulations,
with the anterior (carotid) circulation supplying the cerebral hemispheres
except for the medial temporal lobes and a portion of the occipital lobes,
and the posterior (vertebrobasilar) circulation supplying the brainstem,
thalami, cerebellum, and the posterior portions of the cerebral hemispheres
(Fig. 14-1).

ANTERIOR CIRCULATION
The right common carotid artery (CCA) branches from the innominate
artery. The left CCA arises directly from the aorta. The CCA divides in the
neck into the internal carotid artery (ICA) and the external carotid artery.
The ICA travels behind the pharynx, entering the skull where it forms an S-
shaped curve—the carotid siphon. This portion of the ICA gives rise to the
ophthalmic artery. The ICA then penetrates the dura and gives off the
anterior choroidal and posterior communicating arteries before bifurcating
into the anterior cerebral (ACA) and middle cerebral arteries (MCA).
The ACA supplies the anterior medial cerebral hemispheres, the caudate
nuclei, and the basal frontal lobes. The anterior communicating artery
connects the two ACAs. The MCA courses laterally, giving off
lenticulostriate artery branches to the basal ganglia and internal capsule.
The MCA trifurcates into small anterior temporal branches and large
superior and inferior divisions. The superior division supplies the lateral
cerebral hemispheres superior to the sylvian fissure, whereas the inferior
division supplies the temporal and inferior parietal lobes.
The anterior choroidal artery arises from the ICA after the ophthalmic
and posterior communicating arteries. It courses along the optic tract giving
off branches to the globus pallidus and posterior limb of the internal capsule
and then supplies the medial temporal lobe and the lateral geniculate body.
FIGURE 14-1. Schematic diagram of the vascular territories of the brain. [coronal section.
ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral arteries.]

POSTERIOR CIRCULATION
The first branch of each subclavian artery is the vertebral artery (VA). The
VA enters the spinal column via the transverse foramina of C5 or C6 and
runs within the intravertebral foramina, exiting to course behind the atlas
before piercing the dura mater to enter the foramen magnum. The
intracranial VAs join to form the basilar artery at the ponto-medullary
junction.
The intracranial VA gives off posterior and anterior spinal artery
branches, penetrating arteries to the medulla, and the posterior inferior
cerebellar artery (PICA). The basilar artery then runs in the midline along
the clivus giving off bilateral anterior inferior cerebellar artery and superior
cerebellar artery (SCA) branches before dividing at the pontomesencephalic
junction into the posterior cerebral arteries (PCA). Small penetrating
arteries arise at the basilar artery bifurcation to supply the medial portions
of the midbrain and thalami.
 The vascular supply of the brainstem includes large paramedian arteries
and smaller, short circumferential arteries that penetrate the basal portions
of the brainstem into the tegmentum. Long circumferential arteries course
around the brainstem and give off branches to the lateral tegmentum. The
PCA gives off penetrating arteries to the midbrain and thalamus, courses
around the cerebral peduncles, and then supplies the occipital lobe and
inferior surface of the temporal lobe.
The circle of Willis connects the anterior circulations of each side
through the anterior communicating artery, and the posterior and anterior
circulations of each side through the posterior communicating artery (Fig.
14-2).

KEY POINTS
● Each carotid artery supplies two-fifths of the brain; the vertebrobasilar circulation, one-
fifth.
● The anterior circulation supplies mainly the cerebrum, whereas the posterior circulation
supplies the brainstem, cerebellum, thalami, and the visual cerebral cortex.

BRAIN ISCHEMIA
About 80% of strokes are ischemic whereas 10% each are due to
subarachnoid and intracerebral hemorrhages. Ischemic strokes are divided
into thrombotic, embolic, and systemic hypoperfusion mechanisms.

THROMBOSIS
Thrombosis refers to obstructed blood flow due to a localized occlusive
process within one or more vessels. The most common vascular pathology
is atherosclerosis, in which fibrous tissue and lipid materials form plaques
that encroach on the lumen. Atherosclerosis affects mostly the large cervical
and intracranial arteries. Less commonly, a clot forms within the lumen due
to a primary hematologic problem, for example, polycythemia,
thrombocytosis, or hypercoagulability. Vessel wall pathologies leading to
thrombosis include vasoconstriction, fibromuscular dysplasia, and arterial
dissection. Thrombosis of penetrating intracranial arteries is most often the
consequence of hypertension, with hypertrophy of the media and deposition
of fibrinoid material. Microatheromas can obstruct the penetrating artery
origins.

FIGURE 14-2. Arteries of the circle of Willis. [ACA, anterior cerebral artery; AICA, anterior
inferior cerebellar artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior
cerebral arteries; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery.]

EMBOLISM
An embolus occurs when clot material formed elsewhere within the
vascular system lodges in a vessel and blocks blood flow. The material
arises proximally, mostly from the heart; from major arteries such as the
aorta, ICAs, and VAs; and from systemic veins. Cardiac sources of
embolism include the heart valves, endocardium, and clots or tumors within
the atrial or ventricular cavities. Artery-to-artery emboli are composed of
clot, platelet clumps, or fragments of plaques. They may begin in large
arteries and occur in the context of arterial dissection. Thrombi originating
in systemic veins travel to the brain through cardiac defects such as an atrial
septal defect or a patent foramen ovale, a process termed paradoxical
embolism. Occasionally, air, fat, cholesterol crystals, bacteria, and foreign
bodies enter the vascular system and embolize to brain vessels.

SYSTEMIC HYPOPERFUSION
Decreased blood flow to brain tissue may be caused by low systemic
perfusion pressure. The most common causes are cardiac pump failure
(most often due to myocardial infarction or arrhythmia) and systemic
hypotension (due to blood loss or hypovolemia). The lack of perfusion is
more generalized than in localized thrombosis or embolism and affects the
brain diffusely and bilaterally. Poor perfusion is most critical in border zone
or so-called watershed regions at the periphery of the major vascular supply
territories, for example, between the ACA and MCA or between the MCA
and PCA.

KEY POINTS
● Ischemia can be due to a localized process within an artery (thrombosis), blockage of an
artery by emboli arising proximally, or a general decrease in blood flow (systemic
hypoperfusion).
● Emboli most often come from the heart, aorta, and proximal portions of the neck or
intracranial arteries.
● Atherosclerosis most often affects the large cervical and intracranial arteries.

COMMON ISCHEMIC STROKE

SYNDROMES
Clinical localization often involves matching patterns of clinical deficits
with corresponding vascular localizations.

ANTERIOR CIRCULATION
1. Left cerebral hemisphere strokes lead to
a. Right hemiparesis: often arm, hand, and face > leg
b. Right hemisensory loss
c. Aphasia
d. In large lesions, conjugate deviation of the eyes to the left; right
hemianopia or hemi-inattention
e. When caused by ICA occlusive disease, transient left monocular
visual loss may also occur.
2. Right cerebral hemisphere strokes cause
a. Left hemiparesis: often arm, hand, and face > leg
b. Left hemisensory loss
c. Poor drawing and copying
d. Neglect of the left visual field
e. In large lesions, conjugate deviation of the eyes to the right, left
hemianopia
f. When the signs are due to ICA occlusive disease, transient right
monocular visual loss may accompany the brain signs.
These cerebral hemispheric lesions are most often caused by carotid
artery occlusion, embolism to the MCA or its branches, or basal ganglionic
intracerebral hemorrhages.

POSTERIOR CIRCULATION
1. Lateral medullary stroke (Wallenberg syndrome, usually due to
intracranial VA occlusion) causes
a. Ipsilateral facial pain, or reduced pain and temperature sensation on
the ipsilateral face, or both
b. Loss of pain and temperature in the contralateral limbs and body
c. Ipsilateral Horner syndrome
d. Nystagmus
e. Incoordination of the ipsilateral arm
f. Leaning and veering while sitting or walking, with gait ataxia
g. In deep lesions, dysphagia and hoarseness
2. Bilateral pontine base and often medial tegmentum stroke (usually due
to basilar artery occlusion, or pontine hemorrhage) causes
a. Quadriparesis
 b. Unilateral or bilateral conjugate gaze paresis; sometimes internuclear
ophthalmoplegia or sixth nerve palsy
c. When the medial tegmentum is involved bilaterally, coma
3. Cerebellar infarction (usually due to embolism to the PICA or SCA, or
cerebellar hemorrhage) causes
a. Gait ataxia; often inability to walk
b. Dysarthria
c. Ipsilateral arm dysmetria
4. Left PCA territory stroke causes
a. Right homonymous hemianopia
b. At times, amnesia
c. Alexia without agraphia when the splenium of the corpus callosum is
involved
5. Right PCA territory stroke causes
a. Left homonymous hemianopia
b. At times, left-sided visual neglect
PCA territory infarcts are most often caused by embolism arising from
the heart, aorta, or VAs.

LACUNAR SYNDROMES
Lacunar strokes are most often due to occlusion of a penetrating artery.
Similar to large-vessel strokes, they produce a fairly limited range of
presentations. Lacunar strokes may occur in either the anterior or the
posterior circulations. Classic lacunar stroke syndromes include the
following:
Pure motor lacune: weakness of the contralateral arm, face, and leg
without sensory, visual, or cognitive or behavioral signs. Common
locations of lacunes producing pure motor stroke include the corona
radiata, posterior limb of the internal capsule, and pons.
Pure sensory lacune: paresthesiae of the contralateral body, limbs, and
face without motor, visual, or cognitive abnormalities. The most
common location of a lacune producing pure sensory symptoms is the
ventral posterior thalamus.
Sensorimotor lacune: combination of motor and sensory lacunes. This
syndrome is due to infarction in the ventral posterior thalamus and
adjacent posterior limb of the internal capsule.
Dysarthria—clumsy hand syndrome: slurred speech and clumsiness of
the contralateral hand. The most common location of a lacune
producing this syndrome is in the base of the pons.
Ataxic hemiparesis: weakness and ataxia of the contralateral limbs, often
greater in the leg and foot than in the arm and hand. The most common
locations for lacunes producing ataxic hemiparesis are the base of the
pons, the posterior limb of the internal capsule, and the corona radiata.

ARTERIAL DISSECTION
Dissection of the carotid or vertebral arteries may lead to ischemic stroke.
Carotid dissection typically presents with severe retro-orbital headache
ipsilateral to the lesion. Strokes involve the anterior circulation and occur
either by thrombosis of the ICA or more commonly by an embolus arising
from the dissection. On physical examination, patients with carotid artery
dissection may have an ipsilateral Horner’s syndrome due to the
involvement of the ascending oculosympathetic tract. Perspiration is
preserved because those fibers ascend with the external carotid artery. VA
dissection may be produced by neck manipulation or trauma and is
commonly associated with ipsilateral neck pain and stroke in the posterior
circulation.

DIAGNOSTIC EVALUATION
After taking a thorough history, performing a general examination
emphasizing the heart and blood vessels, and performing a neurologic
examination, the next step in evaluation of a patient with a suspected stroke
is usually a brain image. Computed tomography (CT) and magnetic
resonance imaging (MRI) scans are used to separate brain infarction from
hemorrhage. Figure 14-3 shows a deep brain hemorrhage. Figure 14-4
shows a brain infarction on CT scan. MRI with diffusion-weighted imaging
is more sensitive to acute brain infarction than is CT (Fig. 14-5).
FIGURE 14-3. Intracerebral hemorrhage. A computed tomographic scan showing a right basal
ganglionic hemorrhage due to hypertension. The hemorrhage has extended into the right frontal horn
of the lateral ventricle.
FIGURE 14-4. Computed tomographic scan of the head demonstrates a wedge-shaped
hypodensity in the distribution of a branch of the left middle cerebral artery.

The symptoms and signs, when combined with brain imaging, should
allow localization to the left or right anterior circulation, the posterior
circulation, or to a lacunar syndrome. In patients with cerebral infarction,
the heart, aorta, and neck and intracranial arteries and their branches should
be imaged. This can be performed using echocardiography, extracranial and
transcranial ultrasound, CT angiography (CTA), or MR angiography
(MRA). In patients in whom the signs localize to the anterior circulation,
vascular imaging of the ICAs should be emphasized, whereas in posterior
circulation cases, the VAs and their intracranial branches should be
emphasized. In cases of suspected arterial dissection, CTA, or MRA with
fat-suppressed imaging (“fat sats”), to evaluate the cervical carotid and
vertebral arteries should be obtained. The blood should be checked for
abnormalities of erythrocytes, leukocytes, and coagulation by ordering a
complete blood count, platelet count, and prothrombin time reported as an
international normalized ratio. Intensive investigation for coagulopathy may
be required for some patients.

FIGURE 14-5. Bright signal is seen on an MRI with diffusion-weighted imaging (DWI),
indicating a recent infarction.

KEY POINTS
● The course of symptom development and results of brain imaging should allow separation
of ischemia from hemorrhage, and in case of ischemia, identification of the most likely
stroke mechanism: thrombosis, embolism, or systemic hypoperfusion.
● Cardiac, brain, and vascular imaging should help to identify stroke etiology.

TREATMENT
In patients seen soon after the onset of neurologic symptoms, an attempt
should be made to reperfuse the ischemic brain if a large artery is occluded
and if a large portion of the brain area supplied by that artery is not already
infarcted. Cerebral and vascular imaging (usually CTA) can show the
location and extent of brain infarction and vascular occlusion. Reperfusion
can be attempted using intravenous thrombolysis, intra-arterial
thrombolysis, or mechanical means. The intravenous thrombolytic agent
tissue plasminogen activator (tPA) improves stroke outcome if given to
patients with disabling stroke within 4.5 hours of stroke onset. Intravenous
thrombolysis can be associated with cerebral hemorrhage, and patients must
undergo careful evaluation for factors that would increase this risk even
further, such as thrombocytopenia, bleeding diatheses, and recent surgery.
Hyper- and hypoglycemia must also be excluded before initiating tPA
because abnormally high or low blood glucose levels may mimic the
symptoms and signs of acute stroke. Intra-arterial tPA is used for patients
who have had symptoms for longer than the 4.5-hour window for IV tPA
and a well-defined occlusion visualized by CTA or conventional
angiography. Mechanical thrombectomy using clot-retrieving stent devices
is helpful for patients with internal carotid or proximal MCA occlusions
who are not tPA candidates.
Prevention of further brain ischemia starts with maximizing cerebral
blood flow: Lowering the blood pressure should be avoided unless there is
other evidence of end-organ damage (e.g., cardiac ischemia or pulmonary
edema). Almost all patients will require an antithrombotic agent as
secondary prophylaxis. For most patients, antiplatelet drugs such as aspirin,
clopidogrel, or a combination of aspirin and modified-release dipyridamole
are the agents of choice. In patients with stroke due to intracranial
atherosclerosis, dual antiplatelet therapy with aspirin and clopidogrel is
favored. Anticoagulation with warfarin is useful in specific instances,
mostly in patients with atrial fibrillation, cerebral venous sinus thrombosis,
and inherited hypercoagulable states. The newer oral anticoagulants
apixaban, dabigatran, and rivaroxaban may be more effective and have
better safety profiles than warfarin, and are used as secondary prophylaxis
for patients with atrial fibrillation and sometimes for other indications that
would require anticoagulation. Control of stroke risk factors (hypertension,
diabetes, obesity, hyperlipidemia, and smoking) is accomplished by
attention to lifestyle, behavior, nutrition, and exercise, and by prescribing
appropriate medications.

KEY POINTS
● Acute and preventive treatments should be tailored to the individual patient.
● Maximizing cerebral blood flow to ischemic regions can be facilitated by opening blocked
arteries chemically or mechanically and by increasing blood flow in collateral vessels.

TRANSIENT ISCHEMIC ATTACK

A transient ischemic attack (TIA) is defined as a focal neurologic syndrome
produced by brain ischemia that lasts for 24 hours or less. The mechanisms
of TIA are identical to those of ischemic stroke. Patients who have had a
TIA have a 10% risk of stroke in the 90 days following the event, and the
greatest risk of stroke is within the first 24 hours following a TIA.
Therefore, the evaluation should be identical to that for a completed stroke
and should be conducted just as quickly. This evaluation includes brain
MRI with diffusion-weighted imaging (which is abnormal in 50% of
patients with TIA), lipid profile, echocardiography, cardiac telemetry, and
carotid artery imaging as appropriate. Preventive treatment strategies are
identical to those described above for ischemic stroke.

INTRACRANIAL HEMORRHAGE
Bleeding inside the skull can be divided into subarachnoid, intracerebral,
epidural, and subdural hemorrhages. The latter two types of hemorrhages
are almost always traumatic and are discussed in Chapter 17. Intracerebral
hemorrhage (ICH) and subarachnoid hemorrhage (SAH) have different
causes, clinical findings, and management.

SUBARACHNOID HEMORRHAGE
SAH is often due to traumatic injury. More serious, though, is SAH caused
by bleeding from an aneurysm located along the circle of Willis. The most
common sites of cerebral aneurysms are shown in Figure 14-6. When blood
under arterial pressure is suddenly released into the space around the brain,
patients develop sudden-onset, severe headache. Often, they vomit and
cease what they are doing at the time of the hemorrhage. When intracranial
pressure increases rapidly or the insulae are affected, coma or death may
ensue. An example of SAH is shown in Figure 14-7.

FIGURE 14-6. Common sites of aneurysm in the circle of Willis. (From Ginsberg L. Lecture
Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:87. Copyright © 2005 L Ginsberg.
Reprinted by permission of John Wiley & Sons, Inc.)

Treatment is aimed at preventing the rebleeding and vasoconstriction that

often follow SAH. Aneurysms can be clipped surgically or “coiled” by
interventional techniques. The calcium-channel blocker nimodipine is used
to minimize vasoconstriction and delayed brain ischemia.
FIGURE 14-7. Subarachnoid hemorrhage. A computed tomographic scan showing extensive
subarachnoid blood within the sulci of the brain. The largest area of bleeding is seen in the left
frontal region.

INTRACEREBRAL HEMORRHAGE
ICH is bleeding directly into brain parenchyma. The earliest symptoms are
headache and neurologic signs referable to the region in which the bleeding
occurs. Hypertension is the most common cause of ICH. The most common
locations for hypertensive ICH are the basal ganglia-internal capsule,
caudate nucleus, thalamus, pons, and cerebellum. Cerebral amyloid
angiopathy is a cause of ICH that is more frequent in the elderly and
preferentially affects the parietal and occipital lobes. Trauma, vascular
malformations, and bleeding diatheses (especially with patients who are
taking anticoagulants) are other common causes. ICH is often a devastating
condition, and large hemorrhages are associated with high mortality rates.
Treatment involves correcting any coagulopathy. In certain situations
(particularly cerebellar hemorrhages), surgical decompression is necessary.
Management of risk factors for hemorrhage, specifically hypertension, is
necessary to prevent recurrence.
VASCULAR MALFORMATIONS
There is a variety of congenital and acquired vascular anomalies that have
the potential to bleed, either within the brain (ICH) or around it.
Arteriovenous malformations (AVMs) contain arteries that empty into
arterialized veins. These lesions contain no recognizable normal capillary
bed, but abnormal gliotic parenchyma can be found between the component
vessels. In addition to causing ICH, AVMs may result in seizures. AVMs
may be treated with embolization or surgical resection. Cavernous
angiomas consist of a relatively compact mass of sinusoidal vessels close
together, without intervening brain parenchyma. The lesions are well
encapsulated. Cavernous angiomas bleed or lead to seizures occasionally
but are not as threatening as AVMs are. In general, cavernous angiomas
may be followed with serial neuroimaging studies. Surgery is required
rarely. They may require antiseizure drug treatment if recurrent seizures
develop. Developmental venous anomalies (DVAs) are composed of
anomalous veins usually separated by morphologically normal brain
parenchyma and are the most common vascular malformations of the brain.
They seldom hemorrhage and are generally not treated surgically or
followed with serial neuroimaging studies. Telangiectasias are dilated
capillaries with intervening brain parenchyma. They are incidental findings
and do not require treatment.

KEY POINTS
● AVMs, DVAs, cavernous angiomas, and telangiectasis are different types of
malformations, each with differing clinical findings and management.
● Medical therapy, surgery, interventional obliteration, and radiotherapy are all used in
treating brain vascular malformations.

CLINICAL VIGNETTES

VIGNETTE 1
A 78-year-old man with a history of hypertension and
hypercholesterolemia lost the ability to speak and move the right side of
his body an hour ago. On examination, he has a blood pressure of
168/92 mm Hg and a heart rate of 88 beats/minute. He is globally
aphasic and has a moderate right hemiparesis. Visual fields are full and
his sensation is preserved. He has never had a similar event and
otherwise has no recent medical or surgical history.
1. The most likely localization of this patient’s deficits is:
a. Left cerebellar hemisphere
b. Left frontal lobe
c. Left internal capsule
d. Left parietal lobe
e. Left thalamus
2. The most appropriate imaging study for this patient at this time is:
a. MRI of the brain with diffusion-weighted imaging
b. Noncontrast head CT
c. MRA of the brain
d. Carotid ultrasound
e. MRI of the brain with susceptibility weighting
3. The patient’s initial head CT was normal. What is the most
appropriate step at this point?
a. Administer tPA
b. MRI of the brain with diffusion-weighted imaging
c. Administer labetalol to lower his blood pressure
d. Check complete blood count, glucose level, and coagulation
profile
e. Anticoagulate with heparin

VIGNETTE 2
A 29-year-old woman presents with vertigo, neck pain, right-sided
facial pain, and clumsiness that developed 1 day ago, after a session of
neck manipulation.
1. Which of the following might be expected on examination?
a. Left limb ataxia
b. Left hemibody sensory loss
c. Left-sided Horner syndrome
d. Left hemiparesis
 e. Rightward deviation of the tongue
2. The patient underwent an MRI of the brain that showed infarction
of the right lateral medulla. What other imaging modality would be
most appropriate?
a. Carotid ultrasound
b. Echocardiogram
c. Hypercoagulable profile
d. Magnetic resonance angiogram of the cervical arteries
e. Susceptibility-weighted MRI of the brain
3. What would be the best treatment option for this patient?
a. Aspirin
b. Carotid endarterectomy
c. Intravenous tPA
d. Intra-arterial tPA
e. VA stenting

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
This patient presents with signs and symptoms that are most consistent
with a left cerebral hemisphere infarction, specifically in the left frontal
lobe, causing global aphasia and contralateral hemiparesis. A left
cerebellar hemisphere infarction would produce ipsilateral limb ataxia,
but not hemiparesis or aphasia. Left internal capsule infarction could
produce contralateral hemiparesis, but should not result in any language
disturbance. Left parietal lobe infarction would produce more sensory
deficits and possibly a visual field cut. Left thalamic infarction would
lead to a hemisensory deficit, among other problems, but would not
cause hemiparesis.

VIGNETTE 1 QUESTION 2
2. Answer B:
In a patient with suspected acute stroke, CT scan without contrast is the
most appropriate study. Although it may be less sensitive to acute
ischemic stroke than MRI of the brain with diffusion-weighted imaging,
it is sufficient to exclude an intracerebral hemorrhage and allow
consideration of thrombolysis. MRA of the brain produces images of
the cerebral vasculature but is not necessary in the acute setting. Carotid
ultrasound is useful for diagnosing carotid artery stenosis and planning
carotid endarterectomy but would not be useful when making initial
treatment decisions. Susceptibility-weighted MRI is used to detect
intracranial hemorrhage and has sensitivity for blood that is equal to or
greater than CT scan. CT scan, however, is more quickly obtained and,
for that reason, it is the preferred imaging study in this setting.

VIGNETTE 1 QUESTION 3
3. Answer D:
This patient is a candidate for intravenous thrombolysis and should
undergo laboratory testing to make sure that he is not at an increased
risk for hemorrhage and that he does not have an abnormal glucose
level that could mimic an ischemic stroke. This testing should include a
complete blood count, glucose level, and coagulation profile. These
must be checked before administering tPA. MRI of the brain with
diffusion-weighted imaging may establish the diagnosis of ischemic
stroke with greater certainty but will delay his care. Unless there are
signs of end-organ damage, high blood pressure should not be treated
aggressively in patients with acute ischemic stroke. Heparin may be
appropriate for patients with stroke due to arterial dissection, venous
sinus thrombosis, or a hypercoagulable state, but none of these
diagnoses has been established for this patient.

VIGNETTE 2 QUESTION 1
1. Answer B:
This patient has a history most consistent with right lateral medullary
infarction. She would be expected to have left hemibody sensory loss.
Her limb ataxia and Horner syndrome would be ipsilateral to the lesion
on the right side. Lateral medullary syndrome is not associated with
hemiparesis. The hypoglossal nucleus is in the midline of the medulla
and would not be affected in a lateral medullary syndrome.

VIGNETTE 2 QUESTION 2
2. Answer D:
The most likely mechanism of injury is right VA dissection. This
diagnosis is best established with MRA or CTA of the neck. Carotid
ultrasound would be inappropriate for a patient with a posterior
circulation stroke. Echocardiogram could be used to define a
cardiogenic source of stroke. Although hypercoagulability is a common
cause of stroke in younger people, the history is more suggestive of VA
dissection. Susceptibility-weighted MRI of the brain would be useful to
diagnosis intracranial hemorrhage.

VIGNETTE 2 QUESTION 3
3. Answer A:
Antiplatelet agents are the best treatment for most patients with stroke
and are equivalent in effectiveness to anticoagulation for patients with
cervical arterial dissections. Carotid endarterectomy would not address
the affected vessel. Thrombolysis with tPA is not appropriate for this
patient, as she presents well outside of the “tPA window” of 4.5 hours.
VA stenting is a treatment option for patients with refractory
vertebrobasilar stenosis but should not be employed for dissection.
 15 Seizures

Seizures are among the most common problems in neurology. Up to 10% of

the population will have a seizure at some point in their lives. In addition,
seizures can be among the most dramatic forms of nervous system
dysfunction. Although seizures have many different causes and
manifestations, by definition a seizure is an abnormal hypersynchronous
electrical discharge of neurons in the brain, producing a clinical
dysfunction. Epilepsy is defined as a condition in which there is a tendency
to have recurrent unprovoked seizures. Practically, the diagnosis of epilepsy
is often applied after a patient has had two unprovoked seizures.

CLASSIFICATION
Seizures can arise from one specific focus within the brain (focal) or
involve both cerebral hemispheres at the onset (generalized). The diagnosis
and categorization of the seizure is based primarily on the semiology (i.e.,
signs or symptoms) characterizing the event. Those that arise from one
portion of the brain can evolve and spread to involve the whole brain
(secondarily generalized). Among focal seizures, those in which
awareness is impaired are termed “with impaired awareness” (previously
“complex”), whereas those in which awareness is preserved are termed
“aware” (previously “simple”) (Table 15-1).

FOCAL SEIZURES
By definition, focal seizures (previously termed “partial”) begin in a focal
area of the brain and do not impair awareness, at least at the onset (Fig. 15-
1A). In general, such seizures lead to positive rather than negative
neurologic symptoms (e.g., tingling rather than numbness; hallucinations
rather than blindness). The manifestations of focal seizures depend on their
site of origin in the brain. These are designated as motor or nonmotor.
Focal motor seizures, in which one part of the body may stiffen or jerk
rhythmically, involve the motor cortex in the frontal lobe. The classic
Jacksonian march occurs when the electrical discharge spreads along the
motor strip, leading to rhythmic jerking that spreads along body parts
following the organization of the motor homunculus. Focal nonmotor
seizures from other regions of the brain can cause sensory phenomena
(sometimes parietal), visual phenomena (usually occipital), or gustatory,
olfactory, and psychic phenomena (frequently temporal). The latter may
include déjà vu, jamais vu, or sensations of depersonalization (“out of
body”) or derealization.

TABLE 15-1. Types of Seizures

Focal-onset:
Motor Myoclonic (jerking)
Epilepsia partialis continua (sustained rhythmic jerking)
Clonic (rhythmic movements)
Tonic (stiffening)
Hypermotor (e.g., running)
Focal-onset with secondary generalization (generalized convulsion)
Non-motor Focal-onset with impaired awareness (old “complex partial’)
Sensory, e.g., olfactory, somatosensory, or hemianopic
Focal-onset with altered cognition, e.g., aphasic, amnestic, ‘psychic’ /
‘emotional’
(e.g., altered mood, rage)
Autonomic
Generalized–onset:
Motor Generalized, tonic (then) clonic, convulsion (‘grand mal’)
Myoclonic
Tonic
Atonic (lack of tone, with falls)
Non-motor: Absence
Other primary absence-like seizures, eyelid myoclonia
Myoclonic–absence
Generalized nonconvulsive seizures in comatose or ICU patients
Autonomic
FIGURE 15-1. Characteristics of seizure types. (A) Focal-onset seizures. (B) Generalized
seizures. (Reprinted with permission from Ford SM. Roach’s Introductory Clinical Pharmacology.
11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2017. Figure 29.1.)

FOCAL SEIZURE WITH IMPAIRED AWARENESS

Focal seizures with impaired awareness (previously termed complex
partial seizures) have a focal onset and involve an impairment of awareness.
Many arise in the temporal lobe, but a frontal lobe focus is also common.
Focal seizures with impaired awareness may include automatisms
(stereotyped motor actions without clear purpose) such as lip-smacking,
chewing movements, or picking at clothing. The patient may have speech
arrest or may speak in a nonsensical manner. By definition, the patient does
not respond normally to the environment or to questions or commands.
Occasionally, patients may continue the activities they were participating in
at the onset of the seizure, sometimes to remarkable lengths: Patients may
continue folding laundry during a seizure or even finish driving home.
Focal seizures with impaired awareness of frontal lobe origin may
involve strange bilateral movements, such as bicycling or kicking, or
behavior such as running in circles. If the patient’s awareness is not known,
the seizure is termed a focal seizure with unknown awareness.
The last classification of focal seizure is termed focal to bilateral tonic–
clonic. This term refers to the pattern of seizure propagation from one type
of focal seizure to bilateral symptoms. Focal to bilateral tonic–clonic was
previously termed partial onset with secondary generalization.

GENERALIZED SEIZURES
Generalized seizures include two categories: motor seizures and absence
seizures (Fig. 15-1B).

GENERALIZED MOTOR SEIZURES

Generalized motor seizures were previously referred to as generalized
tonic–clonic (GTC) seizures or grand mal seizures. This is the seizure type
with which the lay public is most familiar. They typically begin with a tonic
phase, lasting several seconds, in which the entire body becomes stiff
(including the chest and pharyngeal muscles, sometimes leading to a
vocalization known as the epileptic cry). This is followed by the clonic
phase, in which the limbs jerk rhythmically, more or less symmetrically,
typically for less than 1 to 2 minutes. Toward the end of the clonic phase,
the frequency of the jerking may decrease and stop as the body becomes
flaccid. The patient may bite the tongue and become incontinent of urine
during a generalized motor seizure. There is typically a postictal state after
the seizure, lasting minutes to hours, during which the patient may be tired
or confused, before returning to normal activity slowly.
FIGURE 15-2. Characteristic EEG findings in absence seizures. (A) Normal EEG recording in
an awake adult. The top four channels are derived from electrodes over the left side of the head, from
front to back; the bottom four are derived from the right side of the head. A normal sinusoidal alpha
rhythm is seen most prominently over the posterior head regions bilaterally (fourth and eighth
channels). (B) Midway through the recording, rhythmic 3-Hz generalized spike-and-slow-wave
discharges appear. This is the typical EEG pattern of an absence seizure. During these discharges, the
patient may stare and be unresponsive. (From Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford:
Blackwell Publishing; 2005:75. Copyright © 2005 L Ginsberg. Reprinted by permission of John
Wiley & Sons, Inc.)

ABSENCE SEIZURES
An absence seizure is a generalized seizure that most commonly occurs in
children or adolescents and is characterized primarily by an unresponsive
period, often with staring, that lasts for several seconds, with immediate
recovery thereafter. Absence seizures can occur tens or even hundreds of
times a day and may be noticed first by schoolteachers and assumed to be
daydreaming or difficulty concentrating. A classic 3-per-second generalized
spike-and-wave electroencephalogram (EEG) pattern accompanies
absence seizures (Fig. 15-2). Hyperventilation is a common trigger.

OTHER GENERALIZED SEIZURE TYPES

Less common seizure types include myoclonic–atonic, clonic–tonic–clonic,
myoclonic absence, and absence with eyelid myoclonia, all of which are
generalized in onset (Table 15-1). Seizures that are myoclonic (without
other features) may be generalized or focal.

UNKNOWN ONSET
Unknown onset is the last seizure classification and is used when the
semiology and onset of the seizure are unknown. This term should be used
when the onset of the seizure was not witnessed or the description is
unclear. Any information about the seizure semiology that is known should
be added to the diagnosis, such as motor or nonmotor as well as the
description of awareness during the seizure.

UNCLASSIFIED
If no information is known about the seizure semiology, the seizure is
labeled as unclassified. This is a term that should be reserved for patients
for whom no additional information is available. This term should be
revised when additional clinical information about the seizure semiology
becomes available.

KEY POINTS
● A seizure is an abnormal hypersynchronous electrical discharge involving neurons in the
brain, with a clinical correlate.
 ● Epilepsy is a tendency to have recurrent unprovoked seizures.
● Focal seizures may manifest with motor, sensory, or psychic phenomena and are usually
characterized by positive rather than negative neurologic symptoms.
● Focal seizures originate in a focal area of the brain but may become bilateral tonic–clonic
seizures; awareness is preserved during the focal seizures but becomes impaired during
secondary generalization.
● Generalized seizures originate in the entire brain at once; tonic–clonic and absence
seizures are examples.

EPIDEMIOLOGY AND ETIOLOGIES

Seizures have a U-shaped distribution in age of onset—they are more
common in the very young and the very old. Etiologies vary depending on
the age of onset. In infants, a variety of neonatal infections, hypoxic-
ischemic insults, genetic syndromes, and congenital brain malformations
are common causes of seizures.
Febrile seizures are a special case. They are the most common cause of
seizures in children, affecting up to 3% to 9% of this age group. They occur
between 6 months and 5 years of age in the setting of a febrile illness
without evidence of intracranial infection and are usually generalized in
onset. Most children with febrile seizures do not have neurologic deficits.
For the event to be considered a febrile seizure, the fever may be present
before the seizure or must develop in the immediate postictal period. The
risk of subsequent epilepsy is relatively small unless the seizures are
prolonged or focal in onset or if other neurologic abnormalities or a family
history of epilepsy is present.
Older children may also develop seizures related to head injury,
meningitis, encephalitis, or vascular diseases, and genetic syndromes
continue to be a significant etiology in this age group. Among young adults,
head injury, substance use, and excessive alcohol use are common causes of
new-onset seizures, but brain tumors and strokes become more common
etiologies by middle age. In the elderly, strokes become the most common
etiology, but substance abuse and alcohol are not uncommon causes.
Metabolic disturbances from systemic problems such as severe hypo- or
hyperglycemia, hepatic failure, or renal failure are also frequent causes.
 KEY POINTS
● The incidence of new-onset seizures has a U-shaped distribution, highest among the very
young and the very old.
● Common etiologies of new-onset seizures differ depending on the age of onset.
● Febrile seizures in children are common and generally carry a benign prognosis.
● Seizures may occur as part of specific epilepsy syndromes characterized by distinctive
seizure types, EEG patterns, or associated neurologic abnormalities.

Frequently, seizures occur in children (and sometimes adults) as part of a

syndrome that may include specific seizure types, EEG patterns, and
associated neurologic abnormalities. Many of these are called “idiopathic
generalized epilepsies”—usually considered to be genetic conditions in
almost all cases. The diagnosis of a specific syndrome may have
implications both for genetic testing and for the proper choice of
pharmacologic treatments. Examples of epilepsy syndromes are outlined in
Table 15-2.

TABLE 15-2. Epilepsy Syndromes: Features and Treatment

Selected Epilepsy Syndromes
Age of Seizure Associated EEG Commonly
Onset Types Findings Findings Used
Treatments
Lennox– Childhood Tonic, atonic, Major cognitive Slow (1- to 2- Valproic acid,
Gastaut myoclonic, impairment and per-second) lamotrigine,
syndrome generalized disability spike-and- felbamate,
tonic–clonic, wave rufinamide,
absence discharges clobazam
Focal motor Childhood Simple partial Nocturnal Centrotemporal Carbamazepine;
seizure, e.g., seizure preponderance spikes sometimes no
benign involving the of seizures treatment
rolandic mouth and necessary
epilepsy face,
infrequent
generalized
tonic–clonic
Absence Childhood Absence; Hyperventilation 3-per-second Ethosuximide,
epilepsy and sometimes, as trigger generalized valproic acid,
adolescence generalized spike-and- lamotrigine
tonic–clonic wave
seizures
Juvenile Adolescence Myoclonic, Early morning 4- to 6-per- Valproic acid,
 myoclonic and young absence, preponderance second lamotrigine,
epilepsy adulthood generalized of seizures polyspike-and- levetiracetam
tonic–clonic wave
EEG, electroencephalogram.

CLINICAL MANIFESTATIONS

HISTORY
The diagnosis of seizures is a clinical one. Most commonly the patient is
seen after an event has occurred, and the diagnosis must be made on the
history alone. In these cases, the patient (and more importantly, witnesses, if
the seizure was generalized in onset) must be questioned for an exact
description of the event itself (and especially the onset), any premonitory
symptoms, and the character of the recovery period in order for the clinician
to decide whether the event was a seizure, and, if so, what type of seizure it
was. The clinical details should allow for the differentiation of seizures
from other paroxysmal neurologic events (Table 15-3).

PHYSICAL EXAMINATION
The neurologic examination is most helpful diagnostically in the (relatively
uncommon) instances in which the patient is observed during the event or
shortly thereafter. In the latter case, a postictal hemiparesis, or Todd’s
paralysis, may be detected after a bilateral tonic, then clonic seizure; this
suggests that the seizure was of focal onset, even if not apparent to
observers at the time. Other abnormalities on neurologic exam may also
suggest the presence of a focal brain lesion. Of course, the general physical
exam may yield findings suggestive of infection or other systemic disease
that might explain a new-onset seizure. In particular, signs of meningitis
should be sought in any patient who has had a seizure.

TABLE 15-3. Characteristics of Focal Seizures and Other Paroxysmal

Neurologic Events
Focal Seizures Transient Ischemic Migraine
Attacks
Onset Progression of symptoms Sudden onset of symptoms Progression of
over seconds symptoms over 15–20
 min
Neurologic Positive motor or sensory Negative motor, sensory, or Positive sensory and,
symptoms symptoms; “psychic” visual symptoms (loss of especially, visual
symptoms such as déjà vu function) symptoms such as
scintillating scotomata
Duration Usually less than a few Usually less than 30 min, Symptoms for 15–20
minutes always less than 24 h min, typically followed
by headache for hours
Consciousness Preserved or impaired Preserved Preserved
Headache Occasionally postictal Infrequent Throbbing pain, often
unilateral, following
the progression of
initial symptoms
Recovery Postictal confusion, Rapid Fatigue common
sleepiness
Risk factors Structural brain lesion, Hypertension, Family history of
family history of seizures hyperlipidemia, smoking, migraines
diabetes, atrial fibrillation,
stenotic intracranial or
extracranial vessels,
hypercoagulability

DIAGNOSTIC EVALUATION

LABORATORY STUDIES
Laboratory testing may show an underlying metabolic abnormality, such as
hyponatremia or hypocalcemia, that explains a new-onset seizure. After a
generalized seizure, there is commonly a lactic acidosis, resulting in
decreased serum bicarbonate. A toxicology screen for common substances
of abuse, as well as an alcohol level, should be done in all patients. Female
patients of reproductive age should also have a pregnancy test. In cases
where infection is suspected, a lumbar puncture should be performed.

BRAIN IMAGING
An uncomplicated seizure in a patient with known epilepsy does not
generally warrant brain imaging. With rare exceptions, however,
neuroimaging should be performed in patients with new-onset seizures. For
seizures of probable focal onset, a magnetic resonance imaging (MRI) is a
necessary part of the diagnostic workup, to look for a structural abnormality
that is a focus for that seizure. A head computed tomography may suffice in
the urgent setting.

KEY POINTS
● Most neurologists begin drug therapy after two unprovoked seizures.
● Each drug has its own set of indications and adverse effects.
● Monotherapy is a desired goal of antiseizure therapy; most patients’ seizures are well
controlled on one medication.

ELECTROENCEPHALOGRAPHY
An EEG may be useful for several reasons: It may identify a potential focus
of seizure onset; it may show abnormalities characteristic of a specific
epilepsy syndrome (e.g., with rapid, narrow, generalized spike and
polyspike discharges in a patient with a “primary generalized epilepsy”);
and it may establish whether a patient who has had a seizure and is not
regaining alertness promptly is postictal or is having ongoing continuous
nonconvulsive seizures. The diagnosis of whether a particular paroxysmal
event was a seizure or not, however, rests primarily on clinical grounds; in
patients with known epilepsy, up to 50% of routine EEGs are normal.

TREATMENT
DRUGS
The mainstay of epilepsy treatment is pharmacologic. The number of
available antiseizure drugs (ASDs) has more than doubled in recent years,
and there is now a large selection of agents from which to choose, each with
its own set of indications and possible adverse effects (Table 15-4).

TABLE 15-4. Selected Antiseizure Drugs

Site of Action Seizure Types Characteristic Side
Treateda Effects
Phenytoin (Dilantin) Na+ channel Focala Gingival hyperplasia,
coarsening of facial
 features, ataxia
Carbamazepine + Focal Hyponatremia, diplopia
Na channel
(Tegretol)
Valproic acid Na+ channel, GABA Focal, generalized GI symptoms, tremor,
(Depakote) receptor weight gain, hair loss,
hepatotoxicity,
thrombocytopenia,
teratogenicity
Phenobarbital GABA receptor Focal, generalized Sedation
Ethosuximide 2+ Absence GI symptoms
T-type Ca channel
(Zarontin)
Gabapentin Unknown, possibly Focal Sedation, weight gain
(Neurontin) voltage-gated Ca2+ (occasional)
channel
Lamotrigine (Lamictal) Na+ channel, glutamate Focal, generalized Diplopia, rash (rare
receptor Stevens–Johnson
syndrome; more with
rapid introduction)
Topiramate (Topamax) Na+ channel, GABA Focal, generalized Word-finding
activity difficulty, renal stones,
weight loss
Tiagabine (Gabitril) GABA reuptake Focal Sedation
Levetiracetam Poorly understood Focal, generalized Insomnia, anxiety,
(Keppra) (synaptic vesicle irritability
modulation of
neurotransmitter
effects)
Oxcarbazepine Na+ channel Focal Sedation, diplopia,
(Trileptal) hyponatremia
Zonisamide (Zonegran) Unknown; probably Focal, generalized Sedation, renal stones,
multiple mechanisms weight loss
Lacosamide (Vimpat) Na+ channel Focal Sedation, headache,
syncope
Pregabalin (Lyrica) Voltage-gated Ca2+ Focal Sedation, peripheral
channel edema, weight gain
Clobazam (Onfi) Benzodiazepine Generalized Sedation, mood
receptor symptoms, fever
a
Drugs effective for focal seizures are also used for secondarily generalized seizures.
GABA, gamma-aminobutyric acid; GI, gastrointestinal.

An ASD is typically not started after a single seizure unless there is

reason to believe that a second seizure is likely. This applies especially to
symptomatic seizures, i.e., those due to a treatable or reversible condition,
such as meningitis, alcohol withdrawal, or hyponatremia. Most neurologists
would also not start an ASD after a single seizure for which no underlying
cause is found.
ASD treatment is usually begun after two seizures that are not provoked.
The primary goals of ASD treatment are to eliminate seizures and avoid
side effects, ideally with monotherapy—i.e., using a single drug. Most
neurologists increase the dose of a single drug until either seizure control is
achieved or adverse effects become intolerable. If the latter occurs, the dose
is lowered and a second drug may be added. If seizure control is achieved,
an attempt is often made to taper the first drug, leaving the second as
monotherapy. For about 70% of epilepsy patients, seizures will be well
controlled on ASDs, often with one of the first drugs tried. For the
remainder, two or more ASDs may be required, or the seizures may remain
refractory to medical therapy.

KETOGENIC DIET
The ketogenic diet is a high-fat, high-protein, low-carbohydrate diet often
considered for treatment of patients with epilepsy. It produces urine and
plasma ketones, which are used for monitoring therapy. It can be effective
in reducing the seizure frequency in both adult and pediatric patients. There
are several epilepsy syndromes, mostly pediatric, for which there is good
evidence of efficacy of the ketogenic diet. It can be difficult for patients to
tolerate and is not known to be safe for other medical comorbidities,
including lipid disorders.

VAGUS NERVE STIMULATION

The vagus nerve stimulator is a device shown to be effective in the
treatment of partial and generalized seizures. It is implanted subcutaneously
below the clavicle and stimulates the left vagus nerve through programmed
electrical impulses delivered through leads placed in the neck. Various
devices for direct brain stimulation including transcutaneous magnetic
stimulation and deep brain stimulation also have promise for epilepsy
treatment in the future, but they are still under development.

SURGERY
Patients refractory to medical management may be candidates for epilepsy
surgery. Exactly what constitutes being medically refractory will depend on
an individual patient’s circumstances; contributing factors typically include
seizure type and frequency, tolerance of ASD therapy, number of ASDs
tried, and the effect on the patient’s quality of life. The most common
surgical procedure is resection of the epileptogenic area, typically following
a presurgical evaluation in which continuous video-EEG monitoring
combined with neuroimaging and other tests is used to identify the focus of
seizure onset. For seizures of medial temporal lobe origin (the most
common target of epilepsy surgery), the rate of complete seizure freedom
following resective surgery can be over 60%. Other less commonly used
surgical procedures include corpus callosotomy, hemispherectomy, or
multiple subpial transection.

STATUS EPILEPTICUS
Status epilepticus (SE) is an abnormal state in which either seizure activity
is continuous for a prolonged period or seizures are so frequent that there is
no recovery of consciousness between them. There are several types of SE,
including the generalized convulsive form (ongoing clonic movements of
the limbs) and more subtle forms in which the patient may be unresponsive
and might have subtle motor signs such as eyelid twitching or nystagmus.
Potential causes of SE include acute metabolic disturbances, toxic or
infectious insults, hypoxic-ischemic damage to the brain, and underlying
epilepsy. Morbidity from SE can be high; outcome depends largely on
etiology and duration. SE is a medical emergency, the management of
which centers on stopping the seizure activity and preventing the
occurrence of systemic complications (Table 15-5). It is particularly
important to consider the possibility of ongoing nonconvulsive seizures in
patients whose convulsions have ceased but whose mental status has not
improved, or in whom the mental status is disproportionately impaired
compared to what is expected from other comorbidities. It is also important
to note that a cluster of frequent seizures may warrant similarly aggressive
management, particularly because this condition may evolve to SE quickly.
There are evidence-based guidelines on how to approach adults and
children in SE. These guidelines are updated on a regular basis as new
ASDs and procedures become available.
SPECIAL TOPICS
FIRST AID FOR SEIZURES
All physicians should be familiar with first aid measures for patients having
a seizure. In general, the goal is to prevent the patient from becoming
injured (and to prevent well-meaning bystanders from intervening
unwisely). The patient with complex partial seizures may wander or make
semipurposeful movements; if necessary, he or she should be gently guided
out of harm’s way. More aggressive attempts at restraint may provoke a
violent reaction. The patient with GTCs should be laid on his or her side, if
possible, so that vomiting does not lead to aspiration. Tight clothing should
be loosened. Nothing should be placed in the mouth. Most GTCs stop
within 1 to 2 minutes; immediate medical attention should be sought if a
seizure becomes more prolonged.

TABLE 15-5. Management of Status Epilepticus

Phases Timing Steps Monitoring
Stabilization 0–5 min • Airway • ECG
• Breathing • IV access
• Circulation • Labs studies: CBC, chemistry,
• Oxygen toxicology screen, antiseizure
Blood glucose (finger stick) drug level, if known to be on
• Thiamine and D5W if treatment
glucose <60 mg/dL
If seizures continue:
Initial 5–20 min Administer benzodiazepines.
treatment One of the following:
• IM midazolam
• IV lorazepam
• IV diazepam
If seizures continue:
Second 20–40 min Administer antiseizure drug.
treatment One of the following:
• IV fosphenytoin
• IV valproic acid
• IV levetiracetam
• IV lacosamide
• IV phenobarbital
If seizures continue:
Third 40–60 min Repeat treatments in second • Initiate continuous EEG
treatment phase or sufficient continuous IV monitoring
 infusion of seizure-suppressing • Admit to ICU
(“anesthetic”) medications: • If continuous IV infusion of
midazolam, propofol, or sedating drugs is
pentobarbital (or thiopental) administered, patient requires
intubation
These steps to stabilize a patient in status epilepticus are a suggested guideline; clinicians may
and should adapt these steps appropriately to the individual patient’s presentation.
CBC, complete blood count; ECG, electrocardiogram; EEG, electroencephalogram; ICU,
intensive care unit; IM, intramuscular; IV, intravenous.

SUDDEN UNEXPECTED DEATH IN EPILEPSY

Sudden unexpected death in epilepsy (SUDEP) is a rare and devastating
outcome from epilepsy. It is defined as a “sudden, unexpected death of a
person with epilepsy who is otherwise healthy” (AAN Guideline). SUDEP
in children is rare, occurring in 1 of every 4,500 children with epilepsy. In
adults, SUDEP is more common, resulting in the death of 1 in 1,000 adults
with epilepsy per year. The causes and mechanisms of SUDEP are
unknown. Risk factors include the following:
• GTCs, especially with a high frequency of GTCs. (Effectively treating
and reducing the frequency of seizures results in a decreased risk of
SUDEP.)
• Longer duration of the diagnosis of epilepsy
• Age: 18 to 40 years
• Alcohol use
• Missing ASD doses
Although this can be anxiety provoking to discuss, patients and families
should be counseled about the risk of SUDEP and that adherence to
effective ASD treatment probably decreases the risk.

SEIZURES AND DRIVING

Each state has its own licensing requirements for people with epilepsy.
Physicians who care for seizure patients should be aware of them. Most
states require a specific seizure-free interval before a patient may drive;
exceptions can sometimes be made for purely nocturnal seizures or those
with a prolonged focal onset that provides the patient with a warning
without impaired awareness. A few states require physicians to report
patients with seizures to the department of motor vehicles. All patients
should be counseled about driving restrictions.

ANTISEIZURE DRUGS AND PREGNANCY

Women taking ASDs have a somewhat higher risk of fetal malformations
than does the general population, but the absolute risk is still low. Valproic
acid has been specifically associated with a higher rate of neural tube
defects. All women with epilepsy who are considering becoming pregnant
should take folic acid (at least 1 mg per day). It is reasonable to consider
modifying the ASD regimen prior to conception, depending on the severity
of a woman’s epilepsy, but the risk of ASD-related teratogenicity must be
balanced with the risk of seizures during pregnancy.

PSYCHOGENIC NONEPILEPTIC SEIZURES

A reported 10% to 30% of patients evaluated at tertiary referral centers for
medically refractory epilepsy actually have events resembling seizures that
have no EEG correlate and are psychogenic in nature. These are referred to
as psychogenic nonepileptic seizures. Some of these patients may have
“true” epileptic seizures at other times. Many patients with psychogenic
events have comorbid psychiatric illnesses or a history of abuse.
Continuous video-EEG monitoring to record the typical events is usually
the most reliable method of differentiating psychogenic events from
epileptic seizures.

CLINICAL VIGNETTES

VIGNETTE 1
A 23-year-old man has recurrent episodes in which he stares blankly,
makes smacking movements with his lips, and rubs his hands together.
He has no memory of the events afterward, but typically he realizes
there has been a lapse in time. His EEG is normal.
1. Which of the following is a potential cause of his symptoms?
a. Subdural hematoma
b. Mesial temporal sclerosis
 c. Prior head injury
d. Benign brain tumor
e. All of the above
2. The patient sees a neurologist, who diagnoses him with epilepsy
and prescribes oxcarbazepine. MRI of the brain shows left mesial
temporal lobe sclerosis. Unfortunately, the seizures continue despite
the use of oxcarbazepine and further trials of three other antiseizure
medications. Which of the following would be an appropriate
treatment to consider for this patient at this point?
a. Electroconvulsive therapy
b. Resective brain surgery
c. Ethosuximide
d. Neuromuscular blocking agents
e. Trigeminal nerve stimulation

VIGNETTE 2
Outside the hospital, you witness a young woman lying on the street
unconscious, with symmetric convulsive movements of all limbs.
1. Which of the following is an appropriate immediate measure to take
in the field?
a. Restrain the patient’s arms to prevent self-injury
b. Restrain the patient’s legs to prevent self-injury
c. Insert a tongue depressor into patient’s mouth to prevent tongue
biting
d. Turn patient onto her side to prevent aspiration
e. Elevate the head to lower cerebral blood flow
2. The convulsions stop, and the patient is brought directly into the
hospital’s emergency department. Five minutes later, she remains
unarousable but has no focal abnormalities on neurologic
examination. She has evidence of a tongue laceration and urinary
incontinence. Before further evaluation can be performed and
before she awakens, two more generalized convulsive seizures
occur in rapid succession. Which of the following would be the first
pharmacologic agent used in this situation?
a. Lorazepam
b. Carbamazepine
 c. Phenytoin
d. Phenobarbital
e. Propofol

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer E:
The patient’s symptoms and behavior are consistent with focal-onset
epileptic seizures with impaired awareness (previously termed complex
partial seizures). A normal EEG does not rule out the clinical diagnosis
of seizures. The lip-smacking and hand-rubbing movements are
consistent with automatisms, which are nonpurposeful, stereotyped
movements frequently seen in association with focal seizures, often in
those of temporal lobe origin. Many different acute and remote brain
insults can lead to focal-onset seizures, including subdural hematoma,
sclerosis of the mesial temporal lobe, prior traumatic brain injury, CNS
infections, and benign tumors such as meningiomas and pilocytic
astrocytomas. Although epilepsy can arise at any stage of life, the most
common underlying causes differ according to the age of onset.

VIGNETTE 1 QUESTION 2
2. Answer B:
Most patients with epilepsy attain good seizure control with antiseizure
medications alone, usually with just a single drug, and often with the
first drug tried. This patient’s seizures are refractory to multiple
medications, so it is appropriate to consider nonpharmacologic options
at this point. Of the choices listed, resective brain surgery is the only
standard therapy for those with focal-onset seizures and is particularly
likely to be effective in patients with mesial temporal sclerosis.
Electroconvulsive therapy is not a standard treatment for epilepsy.
Ethosuximide is used for absence seizures only, not for those with focal
onset. Neuromuscular blocking agents stop the motor signs of seizures
but not the actual brain electrical activity itself. Vagus nerve
stimulation, not trigeminal nerve stimulation, is an approved therapy for
seizures.
VIGNETTE 2 QUESTION 1
1. Answer D:
Appropriate measures to take for a patient having a presumed GTCS
include loosening of tight clothing and repositioning the patient into a
lateral decubitus position to prevent aspiration in the event of vomiting.
Attempts at restraint will generally be ineffective and could increase the
risk of injury. Nothing should be inserted in the mouth, as this increases
the chance of dental injury or foreign object ingestion. Lowering
cerebral blood flow is not an appropriate intervention for acute seizures.

VIGNETTE 2 QUESTION 2
2. Answer A:
At this point, the patient appears to be in generalized convulsive SE,
defined as ≥5 minutes of either continuous seizure activity or the
recurrence of one seizure after another, without return to a normal
condition between seizures. (In this case, she is having repeated
convulsive seizures without intervening recovery.) SE is a medical
emergency, and pharmacologic treatment usually begins with
administration of an intravenous benzodiazepine, such as lorazepam.
Phenytoin, phenobarbital, and propofol can be used in later steps of SE
treatment, if needed. Carbamazepine is not available in parenteral form
and is not generally used for SE. Airway, Breathing and Circulation (
ABCs) are always addressed concomitantly in patients with SE.
 16 Movement Disorders

PARKINSON DISEASE
Idiopathic Parkinson disease (PD) is the most common neurodegenerative
movement disorder and is the most important form of parkinsonism, the
clinical syndrome characterized principally by bradykinesia and rigidity.
Features of other parkinsonian syndromes are reviewed in Table 16-1.

EPIDEMIOLOGY
PD is most common in middle-aged and older patients, affecting
approximately 1% of people over 60 years. It is typically a sporadic
disorder, but hereditary forms of PD due to mutations in genes such as
PRKN, PINK1, LRRK2, and GBA may affect younger patients.

PATHOLOGY
The precise source of PD is not known, but the essential motor
manifestations of the disease are due to degeneration of dopaminergic
neurons in the substantia nigra pars compacta. The key histopathologic
finding of PD is the Lewy body, which is an alpha-synuclein containing
eosinophilic cytoplasmic inclusion that accumulates in neurons of the
brainstem, cerebral cortex, and sympathetic autonomic ganglia.

CLINICAL MANIFESTATIONS
The four cardinal motor manifestations of PD are tremor, rigidity,
bradykinesia, and postural instability. Approximately 80% of patients with
PD have a resting tremor, which is characteristically asymmetric, involves
the hands, recurs about 4 times per second (4 Hz), and is worse with
distraction. A “pill-rolling” tremor involving the thumb and forefinger is
classic. Bradykinesia or slowness of movement is often the most disabling
feature of PD and involves both axial and appendicular muscles. Speech
and swallowing difficulties in PD are manifestations of bradykinesia.
Rigidity is an increase in muscle tone, which is equal in both flexion and
extension of a body part. In patients with PD, rigidity tends to be greater in
the limbs than in the trunk. Postural instability is the final cardinal motor
manifestation of PD: Patients with advanced PD have difficulty with
postural control and tend to fall backward when pulled from behind.

TABLE 16-1. Parkinsonian Syndromes

Parkinsonian Syndrome Distinguishing Clinical Features
Progressive supranuclear palsy Supranuclear ophthalmoplegia, with greatest limitation of
downward gaze; axial rigidity; early falls due to rigidity,
impaired postural reflexes, neck hyperextension, and
inability to look down
Corticobasal ganglionic degeneration Limb apraxia; cortical sensory impairment; alien-limb
phenomenon; asymmetric rigidity; dementia
Diffuse Lewy body disease Early dementia; prominent visual hallucinations; cognitive
fluctuations; extreme sensitivity to extrapyramidal side
effects of antidopaminergic neuroleptic drugs
Vascular parkinsonism “Lower-half” parkinsonism in which rigidity in the legs is
greater than in the arms, resulting in slow, shuffling gait
Multiple system atrophy Early and prominent features of autonomic dysfunction
(MSA-A); cerebellar dysfunction (MSA-C); parkinsonism
refractory to levodopa (MSA-P); high-pitched, quivering
dysarthria

PD also has important “nonmotor” features. Rapid eye movement

(REM) sleep behavior disorder is characterized by violent enacting of
dreams: The patient’s bed partner will describe them as fighting, kicking, or
running while asleep. This phenomenon is due to the failure to induce
muscle atonia in REM sleep and often predates overt PD by many years.
Autonomic dysfunction, especially orthostatic hypotension, is common in
patients with PD. Constipation due to gastrointestinal hypomotility is
another nonmotor feature of PD. Dementia, often accompanied by
psychotic features, occurs in 25% to 30% of PD patients and is more
common with advanced disease.

TREATMENT
The most effective medical treatment for PD is replacement of deficient
endogenous dopamine with levodopa. (Indeed, if this does not help, one
should consider the possibility of illnesses other than idiopathic PD.)
Levodopa is combined with carbidopa, an inhibitor of peripheral dopamine
decarboxylase, which allows the levodopa to cross the blood–brain barrier
and reach its target, while also reducing peripheral dopaminergic side
effects including nausea, vomiting, and hypotension. Initially, levodopa is
quite effective for most patients with PD, but over time it loses its
effectiveness, and disabling dyskinesias develop. The long-term treatment
of PD is complicated (Table 16-2).
The monoamine oxidase B inhibitors rasagiline and selegiline may
provide slight benefit to patients with PD and are often used in early stages
of the disease as monotherapy or as a supplement to levodopa.
The dopamine agonists pramipexole and ropinirole are also options for
the treatment of mild or early PD. These medications may improve
symptoms and reduce levodopa requirement, thereby minimizing the long-
term probability of dopamine-related dyskinesias. Rotigotine is a dopamine
agonist available in patch form and is designed to prevent excessive
fluctuation in drug levels.
Other medications are used for specific applications in PD.
Anticholinergics including benztropine and trihexyphenidyl are used to treat
tremor but generally have little effect on other PD symptoms. Amantadine
is helpful in the management of dyskinesias and dystonia associated with
PD. The catechol-O-methyl transferase inhibitor entacapone inhibits
levodopa metabolism, thereby extending the duration of levodopa action in
patients who experience “wearing off.” Drug treatments are summarized in
Table 16-3.

TABLE 16-2. Therapeutic Strategies in Parkinson Disease

Scenario/Problem Therapeutic Approach
Initial treatment Levodopa, dopamine agonist, or MAO inhibitor
Poor or no response to initial Increase levodopa dose and consider alternative diagnoses
treatment
Tremor-predominant disease Anticholinergic or amantadine
Overnight or early morning Consider overnight controlled-release preparation of
bradykinesia levodopa
Levodopa-induced hallucinations Discontinue concurrent therapy with anticholinergics,
amantadine, selegiline, or dopamine agonists
 Decrease dose of levodopa
Low-dose atypical antipsychotic (with quetiapine,
clozapine, or pimavanserin)
“Wearing off” More frequent dosing
Extended release formulation of levodopa
Add COMT inhibitor
Dyskinesia Reduce dose of levodopa
Add or increase dose of dopamine agonist
Change dopamine agonist
Add amantadine
Consider deep brain stimulation
COMT, catechol O-methyl transferase; MAO, monoamine oxidase.

Deep brain stimulation of the subthalamic nucleus (STN) and globus

pallidus internus may be helpful for patients with advanced disease.

KEY POINTS
● Idiopathic PD is the most common form of parkinsonism and results from loss of
dopaminergic neurons in the substantia nigra.
● Tremor, rigidity, bradykinesia, and postural instability are the four cardinal motor features
of PD.
● There are many nonmotor features of PD, including REM behavior disorder and
autonomic dysfunction.
● A wide variety of medical and surgical treatment options are available for PD.

DRUG-INDUCED MOVEMENT DISORDERS

Medications which block dopamine receptors including antipsychotic
medications (both traditional dopamine blockers and newer, atypical agents)
and the promotility agent metoclopramide may produce a variety of
movement disorders:
Acute dystonic reactions occur when patients are introduced to
dopamine-blocking medications or given high doses of dopamine blockers
to which they are not accustomed. Intermittent or sustained contraction in
any of the muscles in the face, limbs, or trunk may occur. Forced
contraction of the extraocular muscles and tonic deviation of the eyes may
occur. Acute dystonic reactions are best treated with anticholinergic agents
and benzodiazepines. The reaction is short-lived and does not produce any
long-term consequences.
Parkinsonism may occur as the result of long-term use of any
neuroleptic agent. The symptoms are similar to those seen in PD, but tremor
is less common and patients tend to be less responsive to levodopa.

TABLE 16-3. Pharmacologic Treatment of Parkinson Disease

Drug Mechanism of Dosing Side Effects
Action
Levodopa/carbidopa Dopamine Start with a half of a Anorexia, nausea,
precursor/dopa 25/100 tablet bid; psychosis,
decarboxylase inhibitor increase dose as hallucinations,
needed; typically dosed orthostatic
3–5 times a day hypotension,
dyskinesia
Trihexyphenidyl Anticholinergic Start with 1 mg bid– Dry mouth,
tid; increase to 4 mg tid constipation, urinary
as needed retention, confusion,
hallucinations, narrow-
angle glaucoma
Benztropine Anticholinergic Start with 0.5–1 mg at As above
bedtime; increase to 2
mg qid as needed
Amantadine NMDA antagonist 100 mg bid Hallucinations, leg
edema, livedo
reticularis
Pramipexole Dopamine agonist Start with 0.125 mg Lightheadedness, sleep
tid; titrate gradually to attacks, pathologic
1.5 mg tid as needed gambling, and other
impulse control
disorders
Ropinirole Dopamine agonist Start with 0. 25 mg tid; As above
titrate gradually to 1
mg tid as needed
Rotigotine patch Dopamine agonist 2 mg qd; titrate to 6 mg As above, patch site
qd reactions
Entacapone COMT inhibitor 200 mg with each L- Nausea, diaphoresis,
dopa dose lightheadedness
Rasagiline MAO-B inhibitor 1 mg qd Dizziness, flulike
syndrome
Selegiline MAO-B inhibitor 5 mg bid Confusion, orthostatic
hypotension, nausea
COMT, catechol O-methyl transferase; MAO-B, monoamine oxidase B; NMDA, N-methyl d-
aspartate.
 Neuroleptic malignant syndrome occurs when patients are exposed to
high doses of dopamine-blocking medications or when levodopa or
dopamine agonists are withdrawn abruptly. The syndrome includes fever,
autonomic instability, encephalopathy, and muscular rigidity. The offending
agent must be stopped, but a combination of bromocriptine, dantrolene, and
benzodiazepines is usually required to control the muscle rigidity.
Tardive dyskinesia (TD) is a disorder that occurs after chronic exposure
to dopamine-blocking agents. Commonly observed movements include
chewing, grimacing, lip smacking, and tongue thrusting. The limbs, trunk,
and even diaphragm may be affected. Treatment of TD is challenging:
Withdrawal of the offending agent often makes the movements worse. The
dopamine-depleting agent tetrabenazine may be helpful.

KEY POINTS
● Dopamine-blocking agents are the most common cause of drug-induced movement
disorders.
● Treatment of TD is challenging, and it may be refractory to any treatment strategy.

TREMOR
Tremor is an involuntary oscillatory movement of a body part (arm, leg,
head, jaw, lips, palate). It can be divided into resting (occurring when the
body part is at rest), postural (occurring when maintaining a fixed posture),
or action (occurring with movement). Postural and action tremors usually
accompany each other. The term intention tremor is applied when an action
tremor worsens as the body part approaches its target. Common types and
causes of tremors are summarized in Box 16-1.
Essential tremor (ET) is the most common tremor and overall, the most
common movement disorder. It can begin at any age and tends to get worse
over time. Because there is often a family history, the term “familial
tremor” is sometimes applied. The tremor is a postural and action tremor,
which involves the hands, head, and voice. It often improves with small
quantities of alcohol, though this is not recommended as a treatment
strategy. The most effective treatment options are propranolol and
primidone. Deep brain stimulation of the ventral intermediate nucleus of the
thalamus may help patients with disabling ET refractory to medications.

KEY POINTS
● Tremor is an involuntary rhythmic oscillation of a body part.
● PD causes a resting tremor.
● ET is the most common cause of postural and action tremors.
● Intention tremor suggests disease of the cerebellum or its connections.

HUNTINGTON DISEASE AND OTHER

CAUSES OF CHOREA
Chorea is an irregular, twisting or jerky movement of a group of muscles. In
most cases, chorea flows from one muscle group to an adjacent group in a
random-appearing pattern. Chorea is usually accompanied by athetosis, a
writhing movement of the limbs. Motor impersistence often occurs with
chorea; two examples are the darting tongue and milkmaid handgrip, which
are seen in patients with Huntington disease (HD). Chorea has many causes,
as highlighted in Box 16-2.

CLINICAL MANIFESTATIONS
HD, an autosomal dominant neurodegenerative disorder is the most
important and serious cause of chorea. HD is characterized by chorea,
cognitive impairment, dystonia, and psychiatric illness. Symptoms usually
appear between the ages of 35 and 45 years and include the triad of chorea,
behavioral changes or personality disorder (frequently obsessive-
compulsive disorder), and dementia. The three may occur together at onset,
or one may precede the others by years.

BOX 16-1. Tremor

Resting
Idiopathic Parkinson disease
Other parkinsonian syndromes
 Postural/Action
Essential tremor
Physiologic tremor
Drugs (e.g., theophylline, β-agonists)
Alcohol
Orthostatic tremor
Intention
Cerebellum and cerebellar outflow tract dysfunction (e.g., infarction, multiple sclerosis,
tumor, Wilson disease, drugs)

BOX 16-2. Chorea

Hereditary
Huntington disease (HD)
HD-like syndromes
Neuroacanthocytosis
Dentatorubral pallidoluysian atrophy
Wilson disease
Drugs
Neuroleptics
Antiparkinsonian medications
Toxins
Alcohol
Anoxia
Carbon monoxide
Metabolic
Hyperthyroidism
Nonketotic hyperglycemia
Hepatocerebral degeneration
Pregnancy
Chorea gravidarum
Immunologic
Systemic lupus erythematosus
Antiphospholipid antibody syndrome
Poststreptococcal (Sydenham chorea)
Vascular
Caudate infarction or hemorrhage

DIAGNOSTIC EVALUATION
Diagnosis is by personal and family history, clinical signs, imaging, and
genetic testing.
 Caudate atrophy, sometimes severe, is the characteristic finding on
magnetic resonance imaging (MRI). Definitive diagnosis is made by
finding an expansion of more than 40 cytosine–adenine–guanine
trinucleotide repeats in the HTT gene on chromosome 4.

PATHOLOGY
Pathologic examination shows severe destruction of the caudate and
putamen (striatal and nigral GABA-ergic neurons) and loss of neurons in
the cerebral cortex (layer 3). The molecular mechanisms of HD are unclear
but involve accumulation of abnormal intracellular proteins which triggers
cell death.

TREATMENT
Pharmacologic management of dementia and chorea often involves
dopaminergic antagonists, including neuroleptic drugs, but it is far from
adequate. Neuroleptics can ameliorate the chorea, but the other
neuropsychiatric symptoms ultimately prove disabling. Unfortunately, HD
is a progressive and ultimately fatal disorder; death occurs 10 to 20 years
after onset. Suicide is not rare in at-risk and early-onset HD patients.
Genetic counseling is crucial.

KEY POINTS
● Chorea is characterized by involuntary, abrupt, and irregular movements that flow
randomly between muscle groups. It is usually accompanied by athetosis, a twisting or
writhing movement.
● Important causes of chorea include HD, neuroacanthocytosis, poststreptococcal infection,
systemic lupus erythematosus, thyrotoxicosis, and pregnancy.
● HD is characterized by chorea, dementia, and personality and behavioral changes.

BALLISM
Ballism is a brief flinging movement of a limb, most often unilateral
(hemiballismus). The classic lesion responsible for hemiballismus is an
ischemic stroke in the contralateral STN, though lesions in other
components of the basal ganglia may be causative. In many cases, ballism
resolves on its own, but dopamine-blocking agents may be helpful if this
spontaneous improvement does not occur.

DYSTONIA
Dystonia is a sustained contraction of agonist and antagonist muscles
producing twisting movements or abnormal postures. Dystonia may be
focal (affecting one body part), segmental (affecting one region), or
generalized (affecting multiple body parts). The abnormal movements are
worsened by movement and relieved by sensory tricks such as touching or
stroking the affected body part.
Focal dystonia is more common in adults, and various body parts have
characteristic dystonias. Torticollis is excessive contraction of the neck
muscles resulting in a fixed head position; it is often quite painful.
Blepharospasm involves sustained contraction of the orbicularis oculi and
forced closure of the eyelids. Spasmodic dysphonia involves the laryngeal
muscles and may result in choppy or strangled speech (adductor spasmodic
dysphonia) or a breathy voice quality (abductor spasmodic dysphonia).
Writer’s cramp is a focal dystonia of the hand and arm muscles that
prevents a patient from using a writing implement properly. In general,
botulinum toxin injections are the best treatment option for the focal
dystonias.
Generalized dystonias are more common in children than in adults. The
most common of these is DYT-TOR1A dystonia, an autosomal dominant
disorder caused by a mutation in the gene that encodes the protein torsinA.
DYT-TOR1A dystonia starts in childhood or adolescence and often begins
in the foot and leg muscles. Treatment options include anticholinergic
agents such as trihexyphenidyl, or baclofen, benzodiazepines, and deep
brain stimulation of the globus pallidus interna. The dopa-responsive
dystonias are an important group of childhood-onset dystonias and are
caused most often by a mutation in the gene encoding the enzyme GTP
cyclohydrase 1. Parkinsonism may accompany the dystonia. As the name
suggests, this group of conditions is responsive to dopamine; for this
reason, a trial of levodopa is warranted in all children who develop
dystonia.
 Dystonia may also occur as a manifestation of other central nervous
system disorders including Wilson disease (WD), PD, HD, anoxic brain
injury, stroke, multiple sclerosis, and medication-induced movement
disorders.

KEY POINTS
● Dystonia is a sustained muscle contraction leading to twisting movements or abnormal
postures.
● Dystonia may be focal, segmental, or generalized.
● Dopa-responsive dystonia is an important cause of childhood-onset dystonia.

MYOCLONUS
Myoclonus is a sudden jerking movement of a muscle that is sufficient to
move a joint. Asterixis is a negative form of myoclonus in which a patient
is suddenly, but briefly, unable to hold the arms and hands up against
gravity, resulting in an erratic and repetitive downward jerking movement.
Both are signs of central nervous system dysfunction.
The etiologic categories of myoclonus are physiologic, essential,
epileptic, and symptomatic (Box 16-3). Physiologic myoclonus includes
common movements such as jerks that occur just at sleep onset (“sleep
starts” or “hypnic jerks”) and hiccups. Essential myoclonus occurs in
isolation without other neurologic symptoms or signs. It may occur in
familial and sporadic forms and may be responsive to alcohol; some
patients may note a striking improvement with small quantities of alcohol.
Epileptic myoclonus occurs as a manifestation of juvenile myoclonic
epilepsy and other “benign” epilepsy syndromes, and with some of the
more malignant progressive myoclonic epilepsies. Symptomatic
myoclonus accompanies a wide variety of metabolic disturbances and
neurodegenerative diseases.
Clonazepam and valproate are often effective in controlling myoclonus,
but an underlying source should be identified and treated if possible.
 KEY POINTS
● Myoclonus is a sudden, brief jerking movement of a muscle or group of muscles.
● Myoclonus has a wide variety of causes and may respond to medications such as
clonazepam or valproate.

TICS
Tics are abnormal, brief muscle contractions that may involve the face,
extremities, or speech. They tend to vary in intensity and are irregular in
frequency, sometimes occurring in runs of multiple tics and often
suppressible for short periods of time. Patients with tics describe an internal
sensation of an urge to move or perform the tic, with a sense of relief after
the tic has occurred. Stress tends to exacerbate tics.
Tics can be divided into motor and vocal tics. These, in turn can be
divided into simple and complex tics. Simple motor tics include eye blinks,
facial grimaces, and shoulder shrugs. Complex motor tics include spitting
and finger cracking. Examples of simple vocal tics include grunting, throat
clearing, and coughing. Complex vocal tics are more extensive vocal
utterances of several words blurted out, including foul language
(coprolalia). Tics are most often idiopathic, but head trauma, encephalitis,
and cerebrovascular disease may produce tics.

BOX 16-3. Myoclonus

Physiologic
Hypnic jerks (sleep starts)
Anxiety and exercise induced
Hiccups
Essential
Epileptic
Primary generalized epilepsies (e.g., juvenile myoclonic epilepsy)
Myoclonic epilepsies (often associated with progressive encephalopathy, e.g., Lafora body
disease, Unverricht–Lundborg disease, sialidosis)
Symptomatic
Metabolic encephalopathy (uremia, liver failure, hypercapnia)
Wilson disease
Creutzfeldt–Jakob disease and other advanced dementias
 Hypoxia (post-anoxic brain injury or Lance-Adams syndrome)

Gilles de la Tourette syndrome is a pediatric-onset disorder in which

patients develop motor and vocal tics. It has a presumed genetic origin, but
a single responsible gene mutation has not been identified. Boys tend to be
affected more often than girls. Multiple motor and vocal tics are present;
they may change over time and even go into periods of remission. There is
a tendency for the tics to improve in adulthood. Obsessive-compulsive
disorder, attention-deficit hyperactivity disorder, and depression often
accompany Tourette syndrome.
Pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infections (PANDAS) are a combination of tics, obsessive-
compulsive disorder, and anxiety following group A β-hemolytic
streptococcal infection. The etiology of PANDAS is controversial, but
presumably the streptococcal infection triggers an autoimmune reaction
against the basal ganglia. The symptoms are temporary and respond to
treatment with antibiotics and immunomodulatory therapy.
Tic treatment options include dopamine antagonists (haloperidol,
risperidone, and pimozide are used most commonly), guanfacine,
clonazepam, and clonidine. In many cases, tics improve during youth and
disappear by the teenage years or early adulthood.

KEY POINTS
● Tics are abnormal, repetitive, stereotypical movements or vocalizations.
● Gilles de la Tourette syndrome is a pediatric-onset disorder, which produces both motor
and vocal tics.
● Dopamine antagonists, guanfacine, clonidine, and clonazepam are treatment options for tic
disorders.

WILSON DISEASE
WD is an autosomal recessive disorder that produces neuropsychiatric and
hepatic dysfunction. It is caused by a mutation in the hepatic protein
ATP7B, which normally incorporates copper into apoceruloplasmin to form
ceruloplasmin. This results in the accumulation of copper in the liver,
cornea, and central nervous system.
There are multiple neurologic manifestations of WD including tremor,
dysarthria, parkinsonism, ataxia, dystonia, and cognitive decline. The
classic but not universally present tremor is described as a coarse tremor
that can resemble a bird flapping its wings (“wing-beating tremor”).
Dystonia of the facial muscles may produce a grimace known as risus
sardonicus. Kayser–Fleischer rings are golden brown or greenish rings
within the Descemet membrane of the cornea. They are usually present in
patients with neurologic manifestations of WD, but slit lamp examination
may be required to detect them.
Laboratory findings in WD include increased serum copper, decreased
serum ceruloplasmin, and increased 24-hour urinary copper excretion. Liver
biopsy may be required to confirm the diagnosis.
Treatment options for WD include the copper-chelating agents trientine
and penicillamine, zinc supplementation, and restriction of copper-
containing foods such as liver, shellfish, and mushrooms. Earlier treatment
results in better long-term neuropsychiatric and hepatic outcome. Liver
transplantation may be necessary for patients with fulminant symptoms
including hepatic failure.

KEY POINTS
● WD is an autosomal recessive disorder of copper metabolism, which produces a variety of
hyperkinetic and hypokinetic movement disorders as well as cognitive and hepatic
dysfunction.
● Kayser–Fleischer rings represent copper deposition in the cornea and are highly suggestive
of the diagnosis of WD.
● Elevated serum copper levels, low ceruloplasmin levels, and elevated 24-hour urinary
copper are useful screening tests for WD. Liver biopsy is the definitive diagnostic test.
● Copper chelation therapy with trientine or penicillamine is the mainstay of WD treatment.

STIFF-PERSON SYNDROME
Stiff-person syndrome is an autoimmune or paraneoplastic condition
characterized by disabling muscle rigidity and spasms. Symptoms typically
start with axial and trunk muscles and spread throughout the body over
time. In addition to progressive muscle stiffness, patients have episodic
worsening of their muscle stiffness often provoked by physical or
psychological stress.
Other autoimmune diseases including diabetes and thyroiditis are often
present. Finding antibodies to glutamic acid decarboxylase-65 (GAD-65)
supports the diagnosis. Antispasmodic medications including
benzodiazepines and baclofen are the standard treatments for stiff-person
syndrome. For patients with refractory disease, immunosuppressive therapy
including corticosteroids and intravenous immunoglobulin may be helpful.

KEY POINTS
● Stiff-person syndrome is characterized by chronic muscle rigidity with a predilection for
axial muscles.
● Stiff-person syndrome is an autoimmune or paraneoplastic condition that may be
associated with anti-GAD-65 antibodies.

PAROXYSMAL DYSKINESIAS
Paroxysmal dyskinesias are rare, episodic movement disorders, which
typically take the form of chorea, athetosis, or dystonia. Consciousness is
preserved during episodes, and there are no other neurologic symptoms. In
paroxysmal kinesigenic dyskinesia, the dyskinetic movements are
triggered by sudden movements and are brief, lasting for seconds or
minutes. Paroxysmal nonkinesigenic dyskinesias occur independent of
movement and tend to last for minutes to hours. They are often triggered by
alcohol, fatigue, and stress. Carbamazepine is often a helpful treatment for
paroxysmal dyskinesias.

CLINICAL VIGNETTES

VIGNETTE 1
A 48-year-old man presents to the emergency room (ER) with a 2-day
history of involuntary “jerking” movements of the right arm. Symptoms
were mild initially but became more severe over the 48 hours prior to
presentation. He is also aware of similar, but milder symptoms in the
right leg. His wife reports some improvement in symptoms when her
husband is asleep. Apart from mild hypertension and
hypercholesterolemia, he is otherwise healthy. On neurologic
examination, he is awake, alert, and oriented. Speech is fluent, and
language function is normal. Intermittent and irregular “flinging”
movements of large amplitude are noted in the right arm. Muscle bulk,
strength, and reflexes are all normal.
1. Which of the following terms most accurately describes the
observed movement disorder?
a. Chorea
b. Athetosis
c. Ballismus
d. Tremor
e. Dystonia
2. Which of the following diagnostic tests would be most likely to
help to determine the origin of hemiballismus?
a. Electroencephalogram (EEG)
b. Electromyography (EMG)
c. MRI of the brain
d. MRI of the cervical spine
e. Serum glucose measurement

VIGNETTE 2
A 27-year-old woman presents to the ER with a 2-day history of
diarrhea, nausea, and vomiting. She is diagnosed with gastroenteritis
and receives prochlorperazine for nausea along with intravenous fluids
for rehydration. Within an hour, she is observed to have some abnormal
movements, and the attending ER physician requests a neurology
consultation. When you examine her, you find that she is awake but
having difficulty communicating due to persistent facial grimacing and
forced movements of the jaw. Her eyes and neck turn periodically to
one side. The movements seem erratic and unpredictable rather than
stereotypic.
1. Which of the following is the most likely diagnosis?
a. Cerebral sinus thrombosis due to dehydration
b. Seizures induced by the prochlorperazine
c. Hysteria
d. Acute dystonic reaction caused by the prochlorperazine
e. Viral meningoencephalitis caused by the same organism
responsible for her gastroenteritis
2. You diagnose this young woman as having an acute dystonic
reaction due to D2 antagonism caused by the administration of
prochlorperazine. The most appropriate course of action is:
a. Reassurance that the effects of the drug are transient and should
wear off quickly
b. Administration of the anticholinergic agent diphenhydramine
c. Administration of a D2 agonist such as pergolide, pramipexole,
or ropinirole to reverse the D2 antagonism caused by the
prochlorperazine
d. Intubation because dystonia of the airway may compromise
respiratory function
e. Order physical restraints to prevent self-injury

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer C:
Ballism is the term used to describe large-amplitude, poorly patterned
flinging or flailing movements of a limb. Movements are often
unilateral, in which case the term hemiballismus is used. Chorea, by
contrast, describes abrupt, irregular movements that flow as if randomly
from one body part to another. Patients are often unaware of chorea,
even when severe. Athetosis refers to a slow, writhing, involuntary
movement of muscle groups. Tremor is an involuntary rhythmic
oscillation of a body part. Dystonia is a sustained muscle contraction,
often leading to repetitive twisting movements or abnormal postures.
VIGNETTE 1 QUESTION 2
2. Answer C:
Hemiballismus is most often due to a structural lesion (e.g., infarction)
in the contralateral caudate, putamen, or STN. Metabolic disturbances,
notably nonketotic hyperosmolar hyperglycemia, are far less common
causes of such movements. EEG can be helpful in the diagnosis of
seizures and encephalopathy, but these are not consistent with the
patient’s presentation. EMG would be used to evaluate lesions of the
peripheral nervous system. MRI of the cervical spine would be helpful
in identifying a compressive lesion of the cervical spinal cord or nerve
roots, but these would not be useful for the evaluation of hemiballismus.

VIGNETTE 2 QUESTION 1
1. Answer D:
The most likely diagnosis is a drug-induced acute dystonic reaction.
Prochlorperazine (Compazine) is a member of the phenothiazine class
of drugs. Its mechanism of action includes blockade of dopamine (D2)
receptors. It is well known to cause an acute dystonic reaction. Whereas
dehydration is a risk factor for cerebral sinus thrombosis, this typically
manifests with headache, seizures, and visual disturbances. Seizures
should be more stereotyped. A meningoencephalitis should cause a
fever, headache, altered level of arousal, and stiff neck and should not
cause dystonic movements of this sort.

VIGNETTE 2 QUESTION 2
2. Answer B:
The most appropriate course of action is administration of an
anticholinergic medication such as diphenhydramine or benztropine.
The symptoms should resolve quickly following administration of one
of these drugs. Of course, the offending drug should not be administered
again. Although an acute dystonic reaction may potentially compromise
bulbar and respiratory function, preemptive intubation is seldom
necessary.
 17 Head Trauma

EPIDEMIOLOGY
Estimates of the annual number of head injuries in the United States range
from 500,000 to 1.5 million, with the large majority being mild in severity.
In young adults, motor vehicle accidents are the most common cause of
head trauma, whereas in the elderly, falls are the most common. Men are
more often the victims of head trauma than are women, by a ratio of at least
2:1.

TYPES OF HEAD TRAUMA

EPIDURAL HEMATOMA
An epidural hematoma is an accumulation of blood between the skull and
dura mater. It is usually the result of a severe head injury with a temporal
bone fracture and resulting laceration of the middle meningeal artery. Less
frequently, laceration of the middle meningeal vein or a dural venous sinus
may produce an epidural hematoma. The classic presentation of epidural
hematoma is a “lucid interval” in which the patient has preserved
consciousness immediately after the precipitating event, followed by a
decline in the level of consciousness, often with rapid progression to coma
as the hematoma enlarges. Brain herniation, especially uncal herniation (see
later discussion), may develop as a result of the hematoma expansion. The
characteristic computed tomography (CT) scan appearance of an epidural
hematoma is a lens-shaped hyperdense lesion between the skull and dura
(Fig. 17-1). Surgical evacuation is required and, if performed in a timely
fashion, can be life-saving.
FIGURE 17-1. Computed tomographic scan of the head demonstrating the typical hyperdense
lens-shaped appearance of an epidural hematoma (arrows). Note the compression of the ipsilateral
ventricles and modest midline shift. (Reproduced with permission from Daffner RH. Clinical
Radiology: The Essentials. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.)

SUBDURAL HEMATOMA
A subdural hematoma is an accumulation of blood between the dura mater
and the brain. It results from tearing of bridging veins that connect the
surface of the brain and the dural sinuses. Subdural hematoma may have an
acute or chronic presentation. Acute subdural hematoma develops shortly
after head trauma and can be life-threatening. Headache is the most
common symptom, but the hematoma may also lead to contralateral
hemiparesis, seizures, and a wide variety of cortical dysfunction. If
sufficiently large, a subdural hematoma can increase intracranial pressure
(ICP), with a resulting diminution in the level of consciousness. The CT
scan in Figure 17-2 shows a subdural hematoma as a crescent-shaped
hyperdensity overlying the brain surface and underlying the skull. Subdural
hematoma can be distinguished radiologically from an epidural hematoma
by its ability to cross suture lines. Acute subdural hematoma may require
treatment with surgical drainage depending on its size, severity, and clinical
progression.

FIGURE 17-2. Computed tomographic scans of the head showing subdural hematomas
overlying the right cerebral hemisphere: a smaller hematoma with classic crescent shape in A and
major mass effect with compression of the right lateral ventricle and marked shift of the midline in B.
(Modified with permission from Haines DE. Neuroanatomy in Clinical Context. 9th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2014. Figure 4-5.)

Chronic subdural hematoma typically develops after mild head trauma

and is more common in the elderly, particularly those who are
anticoagulated. Like the acute variety, chronic subdural hematoma may
produce one of several neurologic symptoms, including headache,
hemiparesis, seizures, and behavioral changes. A chronic subdural
hematoma may resolve on its own; indications for operation include rapidly
expanding lesions and progressive clinical deficits. Anticoagulation should
be discontinued to allow the best chance for recovery.

CONCUSSION
A concussion is an alteration of brain function produced by head trauma.
The symptoms of a concussion are the result of a functional rather than
structural change, and brain imaging studies are typically normal. Patients
may have loss of consciousness (though this is not required for the
diagnosis of concussion), short periods of amnesia for events that occurred
before the injury (retrograde amnesia), and difficulty learning new material
after the incident (anterograde amnesia). The severity of a concussion is
correlated with the duration of loss of consciousness and consequent
amnesia. Other consequences of concussion include headache,
disorientation, dizziness and vertigo, nausea, and cortical blindness.
Concussions are frequent in sporting events, particularly in children.
Athletes who are suspected of having had a concussion should be removed
from play. There is no clear consensus for when return to play should be
allowed, but gradual reintroduction of activity is recommended until an
athlete is asymptomatic, because a history of concussions increases the risk
for future concussions.

POSTCONCUSSION SYNDROME
Postconcussion syndrome is usually the consequence of mild traumatic
brain injury. The cause of the syndrome is unclear, but structural,
biochemical, and psychological components have been implicated. Features
of the syndrome include headache, dizziness, sleep disturbance, cognitive
impairment, and behavioral abnormalities such as irritability. Neuroimaging
studies are almost always normal. Pending litigation or workers’
compensation issues and depression are associated with prolonged
postconcussion syndrome. Management should focus on the individual
components of the syndrome, with treatment of headache, sleep
disturbance, and psychological problems, including mood problems.
FIGURE 17-3. Diffuse axonal injury shown on magnetic resonance imaging with fluid-
attenuated inversion recovery sequences.

DIFFUSE AXONAL INJURY

Diffuse axonal injury is associated with severe head trauma and may be
seen on CT as multiple areas of punctate hemorrhage in the deep white
matter and corpus callosum (Fig. 17-3). In many cases, though, it is not well
visualized with standard neuroimaging studies. The presence of diffuse
axonal injury is usually associated with poor prognosis.

KEY POINTS
● Epidural hematoma is usually caused by laceration of the middle meningeal artery; it is
often clinically associated with a “lucid interval.”
● Subdural hematoma is usually caused by tearing of bridging veins and can produce a
variety of neurologic deficits including headache, hemiparesis, and seizures.
● Concussion is a loss or alteration of consciousness produced by head injury and is usually
accompanied by normal neuroimaging.
 Components of the postconcussion syndrome include headache, dizziness, cognitive
●
impairment, sleep disturbance, and behavioral abnormalities.

POSTTRAUMATIC SEIZURES AND EPILEPSY

Seizures after head trauma can be divided into early (within 1 week of head
trauma) and late (beginning at least 1 week later). Approximately 25% of
patients with acute severe head injury (characterized by intracranial
hematoma or depressed skull fracture, without regard to the duration of loss
of consciousness or posttraumatic amnesia) have early posttraumatic
seizures, most often generalized tonic–clonic convulsions. Of these, 25% go
on to develop epilepsy (recurrent unprovoked seizures). Antiseizure drugs
(ASDs) reduce the incidence of early seizures but do not change the overall
risk for the later development of epilepsy.
Overall, posttraumatic epilepsy occurs in about 2% of patients with head
trauma, with a higher frequency in patients with severe head injuries. About
50% of patients who develop posttraumatic epilepsy do so within 1 year of
the trauma. Patients who have a single late seizure usually require treatment
with ASDs, as they are at high risk for posttraumatic epilepsy, that is,
recurrent seizures.

KEY POINTS
● Treatment of early posttraumatic seizures does not alter the long-term likelihood of
developing epilepsy.
● Late posttraumatic seizures (those occurring more than a week after head injury) increase
the risk of epilepsy and usually necessitate prophylactic ASD treatment.

HERNIATION SYNDROMES
Brain herniation is a life-threatening condition that occurs when increased
ICP causes a shift of brain contents, resulting in compression of brain
parenchyma, obstruction of the ventricles, and occlusion of cerebral blood
vessels.
CENTRAL (TRANSTENTORIAL) HERNIATION
Diffuse cerebral edema or a large supratentorial mass may cause downward
herniation of the diencephalon through the tentorial notch. The central
herniation syndrome is heralded by a decrease in the level of alertness,
shortly followed by small, reactive pupils due to disruption of sympathetic
pathways from the hypothalamus. As central herniation proceeds, the
patient may assume a decorticate posture upon stimulation. Progressive
herniation leads to midbrain compression, with fixed, midposition pupils
and decerebrate posturing. In the final stages, the patient becomes
motionless and unresponsive to stimulation, and eventually progresses to
death.

UNCAL HERNIATION
Uncal herniation is most often produced by the expansion of a mass located
laterally within the brain, resulting in a medial shift of the uncus of the
temporal lobe. Uncal herniation may be preceded by neurologic deficits,
particularly hemiparesis related to the mass itself. As the brain begins to
shift away from the mass, the first clinical deficit is often an ipsilateral third
nerve palsy, accompanied or shortly followed by an impairment of
consciousness. Continued uncal herniation produces compression of the
contralateral cerebral peduncle against the free edge of the tentorium with a
resulting hemiplegia ipsilateral to the herniating uncus, the “Kernohan
notch” phenomenon. Compression of the posterior cerebral artery may
produce medial temporal lobe or occipital lobe ischemia or infarction. As
signs of uncal herniation appear, neurologic deterioration may be rapid and
often irreversible.

SUBFALCINE HERNIATION
Expanding frontal lobe masses may produce herniation of the cingulate
gyrus beneath the falx cerebri. Most often, the patient has been
symptomatic from the frontal lobe mass, and subfalcine herniation may not
alter the clinical picture appreciably, although compression of the anterior
cerebral arteries may lead to a stroke and leg weakness.
 KEY POINTS
● The herniation syndromes are life-threatening conditions that must be addressed
immediately.
● A dilated pupil ipsilateral to the side of a mass lesion is an early sign of uncal herniation.
● Uncal herniation is also associated with ipsilateral hemiplegia due to compression of the
contralateral cerebral peduncle against the free edge of the tentorium.

INITIAL ASSESSMENT OF HEAD TRAUMA

Head trauma may be life-threatening, and careful attention to the patient’s
airway, breathing, and circulation is essential to its initial management.
Once life support is assured, the neurologic aspects of head trauma can be
addressed by clinical examination and CT scan. One tool for grading the
severity of traumatic brain injury is the Glasgow Coma Scale (GCS) (Table
17-1). Scores of 13 to 15 are classified as mild head injury, 8 to 12
moderate, and 3 to 7 severe. Limitations of the GCS include inaccurate
assessment of patients who are already intubated and sedated and a lack of
utility in tracking serial changes. Although the GCS assesses the severity of
coma, it does not assist with the diagnosis of its cause.

TABLE 17-1. Glasgow Coma Scale

Points Best Eye Opening Best Verbal Best Motor
6 — — Obeys commands
5 — Oriented Localizes pain
4 Spontaneous Confused Withdraws to pain
3 To speech Inappropriate Decorticate posturing
2 To pain Incomprehensible Decerebrate posturing
1 None None None

MANAGEMENT OF INCREASED
INTRACRANIAL PRESSURE
In adults, normal ICP is <15 mm Hg. Because the skull is a rigid container,
the total volume of its three components (brain, blood vessels, and
cerebrospinal fluid [CSF]) is fixed and there is no room for expansion.
Change in the volume of one of these compartments can compromise the
status of the other two. In patients with head trauma, intracranial masses, or
other causes of cerebral edema, ICP monitoring may be necessary to
determine whether cerebral perfusion pressure (CPP) is adequate. CPP is
defined as the difference between the mean arterial pressure and ICP. A
goal CPP is between 60 and 75 mm Hg; excessively high CPP can cause
hypertensive encephalopathy and cerebral edema, whereas lower pressures
may result in diffuse cerebral ischemia. ICP monitoring, usually in the form
of an intraventricular pressure monitor, should be considered in any head
injury patient with a Glasgow Coma Score of <9 and an abnormal head CT
scan.
Correction of the proximate cause of increased ICP, whether by resection
of a tumor or drainage of a hematoma, is the most effective therapy. There
are situations, however, in which this is not possible, and other treatments
for increased ICP must be employed. The first and easiest step to reduce
ICP is to elevate the head of the bed, usually to 30 degrees, in order to
improve venous drainage. Hyperventilation to a PCO2 between 25 and 30
mm Hg can be useful in the short term. Low PCO2 results in
vasoconstriction, reducing cerebral blood volume and ICP, but prolonged
hyperventilation may lead to excessive vasoconstriction and increase the
risk for cerebral infarction. Mannitol, an osmotic diuretic, or hypertonic
saline may help to lower ICP. Intravenous barbiturates, especially
pentobarbital, can reduce cerebral metabolism but should not be used for
extended periods because they are associated with several complications.
CSF drainage with a ventricular drain may be employed to reduce ICP. As
stated earlier, correction of the cause of increased ICP is the definitive
therapy, and in some cases, this may require hemicraniectomy to allow the
intracranial contents to expand.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old woman hit the left side of her head while skiing. Initially,
she was responsive, but within half an hour, she developed slurred
speech and appeared confused. Half an hour later, she lost
consciousness and was brought to the hospital. A CT of her head
without contrast was performed.
1. Which of the following is the most likely finding?
a. Blood in the subarachnoid space
b. Crescent-shaped hyperdensity overlying the brain
c. Large ischemic infarct of the left frontal lobe
d. Lens-shaped hyperdensity between the dura and the skull
e. Normal image; magnetic resonance imaging (MRI) would be
more sensitive to pathology at this stage
2. When you examine the patient, you find that she is comatose with
an unreactive left pupil. She is intubated immediately. Her blood
pressure is 124/62 and her pulse is 72. What is the next appropriate
step in her management?
a. Epinephrine infusion to increase her mean arterial pressure and
maintain CPP
b. Induce coma with pentobarbital
c. Ophthalmologic consultation to evaluate anisocoria
d. Surgical clipping of a left posterior communicating artery
aneurysm
e. Surgical decompression of epidural hematoma
3. After urgent surgical drainage of the epidural hematoma, the patient
was transferred to the intensive care unit. On her third hospital day,
she had a generalized convulsion. Which of the following is true
concerning seizures and epilepsy in this patient?
a. Anti-seizure drugs (ASDs) will prevent the development of
posttraumatic epilepsy
b. Intracranial hematoma and depressed skull fracture increase the
risk of early posttraumatic seizures
c. Complex partial seizures are the most common type of
posttraumatic seizures
d. Electroencephalogram (EEG) will show a 3-Hz spike-and-wave
pattern
 e. This seizure would be defined as a late posttraumatic seizure
because it happened more than 24 hours after head trauma

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
The history is most consistent with an epidural hematoma: She had a
lucid interval after head trauma, followed by confusion and then coma.
Epidural hematoma is characterized radiologically by a lens-shaped
hyperdensity overlying the dura. Subarachnoid hemorrhage presents
with a sudden-onset, severe headache, but not with a lucid interval. A
crescent-shaped hyperdensity overlying the brain would be
characteristic of a subdural hematoma. An ischemic infarct of the left
frontal lobe would be less likely in a patient who had just sustained a
head injury. Although head MRI is more useful than CT in many
contexts, CT is preferred acutely for most patients with head trauma. A
normal head CT with an abnormal MRI occurs in a number of scenarios
(e.g., acute ischemic stroke), but not in epidural hematoma.

VIGNETTE 1 QUESTION 2
2. Answer E:
The patient is comatose with an unreactive pupil, suggesting uncal
herniation. Surgical decompression of the responsible epidural
hematoma is the most appropriate treatment and should be performed
urgently. Epinephrine infusion is not indicated for this patient. Coma
induction with pentobarbital may reduce the cerebral metabolic rate but
should not take precedence over addressing the cause of her coma. The
best explanation for her anisocoria is uncal herniation; ophthalmologic
consultation is not needed and will delay definitive treatment. Although
a left posterior communicating artery aneurysm can cause an unreactive
left pupil, her history is not consistent with aneurysmal rupture.

VIGNETTE 1 QUESTION 3
3. Answer B:
Risk factors for early posttraumatic seizures include intracranial
hematoma and depressed skull fracture. ASDs may be used to reduce
the incidence of early posttraumatic seizures, but they do not decrease
the chance of developing epilepsy, that is, later unprovoked seizures.
Generalized convulsions, not complex partial seizures, are the most
common type of posttraumatic seizures. The 3-Hz spike-and-wave EEG
pattern is seen in absence seizures, not posttraumatic seizures.
Posttraumatic seizures are divided into early (<1 week after head
trauma) and late (>1 week after head trauma). This patient’s seizure
occurred on hospital day 3 and would thus be classified as an early
posttraumatic seizure.
 18 Systemic Conditions with
Neurologic Manifestations

Central and peripheral neurologic dysfunction can arise in the setting of

conditions with primary endocrine, electrolyte, hematologic, or metabolic
causes. Nutritional and toxic factors also contribute to a host of neurologic
conditions. Paraneoplastic processes link malignancy and neurologic
syndromes through an immune-mediated process. Similarly, rheumatologic
diseases with inflammatory (or auto-inflammatory) underpinnings can have
neurologic complications. In some cases, the neurologic syndrome is the
presenting feature of a systemic condition—and can even predate the
“primary” diagnosis by years. It is therefore helpful to understand
neurologic disorders in the context of personal and family histories, a
comprehensive review of systems, and results of basic investigatory tests.
This chapter highlights systemic conditions with neurologic manifestations.
Because the nervous system can reflect injury in a limited number of
ways, very different disease processes can cause similar symptoms and
signs. The related neurologic dysfunction can be life-threatening—or minor
enough that related signs are incidentally noted on a meticulous neurologic
exam. Perhaps one of the most important take-home points of this chapter,
then, is that non-neurologic causes of neurologic symptoms are important to
consider when evaluating patients in any clinical setting.

ENDOCRINE DYSFUNCTION
Diabetes mellitus can have several neurologic manifestations, including the
neuropathies detailed in Box 18-1. One of the most easily recognized
complications of diabetes is a diabetic polyneuropathy, a distal, symmetric
neuropathy affecting sensory and motor nerves. Autonomic fibers can be
involved, as well. Diabetes is also a risk factor for stroke. Diabetic
lumbosacral radiculoplexus neuropathy (a.k.a. diabetic amyotrophy) and
compression neuropathies (e.g., carpal tunnel syndrome) are more common
in patients with diabetes. Rarely, muscle infarction can occur in the setting
of diabetes. Pain, often in the thigh or calf, associated with warmth, redness,
and swelling, in the absence of trauma should raise this possibility—
especially when conditions such as infection and deep vein thrombosis have
been excluded. Thus, diabetes is associated with deficits at all levels of the
neuraxis.

BOX 18-1. Diabetic Neuropathies

Hyperglycemic neuropathy
Generalized neuropathies
Distal symmetric predominantly sensory polyneuropathy
Autonomic neuropathy
Chronic inflammatory demyelinating polyradiculoneuropathy
Focal neuropathies
Cranial neuropathies (especially III, IV, and VI)
Thoracolumbar radiculopathy
Focal compression and entrapment neuropathies
Diabetic lumbosacral radiculoplexus neuropathy (diabetic amyotrophy)

In general, the treatment is to optimize control of blood sugar. Of note,

lowering glycosylated hemoglobin (HbA1c) too quickly (e.g., a decrease of
> 4% HbA1c over 3 months), however, can cause a painful polyneuropathy
referred to as treatment-induced diabetic neuropathy or “insulin neuritis.”
This is a reminder that both chronic and acute shifts in blood sugar to a
range that is too high or too low can have neurologic complications.
Similarly, excess or deficient levels of endocrine hormones can be
associated with conditions such as myopathy or seizures (Box 18-2). Box
18-2 also gives examples of the neurologic symptoms and signs of
hematologic diseases and electrolyte disturbances.

BOX 18-2. Examples of Systemic Conditions with Neurologic

Manifestations

Category of Syndromes of Excess Syndromes of Deficiency

Systemic
Dysfunction
Hematologic
Anemia Stroke, seizure
Polycythemia Stroke, vasculitic neuropathy
vera
Amyloidosis Polyneuropathy (small fiber,
autonomic), compression
neuropathies
Endocrine
Glucose Stroke, radiculoplexus neuropathy, Tremor, dysarthria, confusion,
polyneuropathy, muscle infarction seizure, coma/extensor posturing
(glc < 30)
Thyroid Seizures, myopathy, tremor, brisk Cognitive slowing, myopathy,
reflexes “hung up” reflexes
Cortisol Lethargy, tremor, seizure, aphasia,
ataxia, long tract signs
Hepatic Confusion, asterixis
failure
Renal failure Uremic encephalopathy: decreased
arousal, confusion, asterixis,
myoclonus, seizure
Electrolyte/mineral
Calcium Confusion, weakness Confusion, papilledema
Magnesium Tetany, tremor, fasciculations
Potassium Flaccid paralysis Weakness, muscle twitching
Sodium Confusion Confusion, seizure
Copper Myelopathy
Vitamin
Vitamin A Pseudotumor cerebri Optic atrophy
Vitamin B1 Wernicke–Korsakoff,
encephalopathy, sensorimotor
polyneuropathy (Beri beri)
Vitamin B3 Dementia, encephalopathy, seizure,
ataxia, polyneuropathy
Vitamin B6 Polyneuropathy Seizure
Vitamin B12 Polyneuropathy, subacute combined
degeneration
Vitamin E Polyneuropathy, nystagmus,
myelopathy, ophthalmoplegia,
ataxia
 Although hyperthyroidism and hyperparathyroidism may have
neurologic manifestations, it is particularly important for neurologists to be
aware of how hypothyroidism can manifest (Box 18-3). From a central
nervous system (CNS) perspective, cognitive slowing can occur.
Neuromuscular complications such as carpal tunnel syndrome and a distal
symmetric polyneuropathy may also result. Myopathy, characterized by
stiffness, myalgias, and elevated creatine kinase (CK) levels, can develop in
the context of hypothyroidism—and can improve with return to a euthyroid
state.

BOX 18-3. Neurologic Manifestations of Hypothyroidism

Mental state: poor concentration and memory; dementia, psychosis, coma
Sleep: obstructive and central apnea
Seizures
Headaches: intracranial hypertension
Cerebellum: truncal and gait ataxia more than limb ataxia; dysarthria; nystagmus
Cranial nerves: papilledema, ptosis, tonic pupil, trigeminal neuralgia, facial palsy, tinnitus,
hearing loss
Nerves: entrapment neuropathy (e.g., carpal tunnel); axonal polyneuropathy; delayed
relaxation of deep tendon reflexes
Neuromuscular junction: worsening of myasthenia gravis.
Muscles: cramps, pain and stiffness; proximal more than distal; creatine kinase level may be
markedly increased

KEY POINTS
● Diabetes is associated with increased risk of stroke, lumbosacral radiculoplexus
neuropathy, polyneuropathy, individual entrapment neuropathies such as carpal tunnel
syndrome, and even muscle infarction.
● A decrease in glycosylated hemoglobin at an accelerated rate can lead to the development
of a painful treatment-induced diabetic polyneuropathy.
● Hypothyroidism can be associated with cognitive dysfunction, carpal tunnel syndrome,
polyneuropathy, and myopathy—all of which can improve with thyroid hormone
replacement.
ELECTROLYTE, MINERAL, AND
NUTRITIONAL FACTORS
Shifts in electrolyte levels can alter mental status, strength, or movement.
Disturbances in sodium and calcium balance can cause confusion and
seizures, whereas potassium abnormalities can cause weakness (Box 18-2).
Abnormal movements, including twitching and tremor, can occur with
disturbances of calcium and other electrolytes. Neuro-ophthalmologic
dysfunction (including nystagmus, ophthalmoplegia, or optic atrophy),
polyneuropathy, or both can be caused by vitamin deficiency or excess,
stemming from dietary choices, supplements, medications, renal or hepatic
dysfunction, or hematologic conditions (Box 18-2).
Subacute combined degeneration (SCD). Interestingly, anemia need not
be present for B12 deficiency to cause neurologic sequelae, including SCD.
As outlined in Chapter 22, vitamin B12 deficiency can cause spasticity and
paraparesis because of the involvement of dorsolateral white matter tracts in
the spinal cord. Patients can also develop concurrent polyneuropathies.
Thus, patients may present with a combination of paresthesias, ataxia, and
weakness. Correction of the vitamin B12 deficiency can be therapeutic.
When hyponatremia has been present for at least 2 days, it is important
that its correction be carried out gradually (e.g., less than 6–8 mEq/L over
24 hours, with serum sodium checks every 2–3 hours at the outset). If
hyponatremia is corrected too quickly, central pontine myelinolysis (CPM),
also known as osmotic demyelination syndrome, can result. Affected
patients may have abnormal speech and swallowing, limb weakness,
movement abnormalities (including tremor, myoclonus, dystonia, and
choreoathetosis), seizures, and mental status changes. In addition to
adventitious movements, pathologically brisk and primitive reflexes may
become evident on exam. The time course is important: Symptoms tend to
develop 2 to 6 days following sodium correction, and magnetic resonance
imaging (MRI) may appear normal for as long as a month before showing
the demyelination. Prevention is key, because some of the resultant deficits
can be permanent.
 KEY POINTS
● Electrolyte abnormalities can cause alterations in mental status, strength, and movement.
● B12 deficiency can cause spasticity, weakness, paresthesias, and ataxia through central and
peripheral nervous system damage in SCD.
● While correcting electrolyte imbalances is generally therapeutic, it is important to correct
subacute-chronic hyponatremia carefully to avoid CPM.

METABOLIC DISORDERS
In addition to acquired forms of kidney and liver disease, the term
“metabolic disorders” can include inherited illnesses such as “inborn errors
of metabolism” (IEM) in which a genetic abnormality causes important
changes in the levels or function of enzymes or their cofactors. Although
IEMs have broad systemic effects, neurologic deficits are common.
Symptoms and signs may include developmental delay, ataxia, abnormal
tone, dystonia, lethargy, seizure, polyneuropathy, and weakness.
Such multifaceted neurologic deficits are also evident in mitochondrial
disorders, a subset of metabolic diseases. Stroke-like episodes of
mitochondrial encephalomyopathy with lactic acidosis and stroke-like
episodes (MELAS) can result in cortical blindness, hemiparesis, and other
neurologic deficits. Findings on MRI are atypical for classic ischemic
infarcts because they do not correspond to vascular territories. The clinical
characteristics and family history can provide important hints that MELAS
is on the differential. It is maternally inherited and can be diagnosed by
genetic testing.

KEY POINTS
● IEMs are genetic abnormalities that change the levels or function of enzymes or their
cofactors.
● IEMs commonly affect the nervous system and present with a variety of developmental,
mental status, movement, coordination, and neuromuscular features.
● MELAS is a maternally inherited mitochondrial disorder in which MRI findings often do
not correspond to typical vascular territories.
TOXINS
Exposure to heavy metals, environmental toxins, recreational drugs, and
even prescribed medications, including chemotherapy, can cause neurologic
injury. Combined use of tobacco and alcohol can cause a toxic optic
neuropathy called tobacco–alcohol amblyopia in which painless,
progressive, bilateral vision loss is characteristic.

TABLE 18-1. Effects of Alcohol on the Nervous System

Condition Manifestations
Peripheral neuropathy Distal sensorimotor axonal neuropathy; recovery
with abstinence is slow and incomplete
Cerebellar degeneration Gait ataxia greater than limb ataxia, dysarthria,
typically no nystagmus
Tobacco-alcohol amblyopia Insidious and painless loss of vision; centrocecal
scotoma
Marchiafava–Bignami syndrome Frontal-type dementia, seizures, and pyramidal
signs; focal demyelination and necrosis of
corpus callosum
Acute intoxication Impaired cognition, ataxia, dysarthria,
nystagmus, diplopia
Acute withdrawal Agitation, insomnia, tremulousness,
hallucinations, seizures
Wernicke encephalopathy Confusion, ataxia, ophthalmoplegia
Korsakoff syndrome Isolated memory disturbance with confabulation

Excessive alcohol use can have wide-ranging effects on the nervous

system (Table 18-1) and can predispose to Wernicke encephalopathy and
Korsakoff syndrome, due to thiamine deficiency. Frequently, confusion is
the first symptom of Wernicke encephalopathy. Inattention, apathy, and
disorientation may be particularly apparent during cognitive assessments.
An ataxic gait characterized by a wide base and shortened stride length,
along with ocular abnormalities (e.g., bilateral gaze-evoked nystagmus or
lateral rectus palsies) may also develop as part of the traditional triad.
Mammillary body atrophy can be detected on MRI in about 80% of cases.
MRI may also show T2 and fluid-attenuated inversion recovery
hyperintensities around the aqueduct and third and fourth ventricles. If
Wernicke encephalopathy is suspected, it is important to provide parenteral
thiamine before glucose is administered; glucose can precipitate or worsen
the condition. Although recovery is often incomplete, eye movement
abnormalities can start to resolve within hours to days. Mental status may
improve within days to weeks, and ambulation thereafter. Typically
occurring after an acute episode of Wernicke encephalopathy, Korsakoff
syndrome includes retrograde and anterograde amnesia. Although
confabulation may also develop and there is typically a lack of insight into
the patient’s own illness, there is relative sparing of other cognitive
function. Excessive alcohol use and nutritional deficiency can also be
linked with subcortical white matter lesions and necrosis of the corpus
callosum in Marchiafava–Bignami disease.

KEY POINTS
● Excessive alcohol use and thiamine deficiency are associated with Wernicke
encephalopathy and Korsakoff syndrome; treatment requires the administration of
thiamine before glucose to prevent symptom exacerbation.
● In addition to changes in mental status, Wernicke encephalopathy can be associated with
oculomotor and gait abnormalities on exam and mammillary body atrophy on imaging.
● The hallmark of Korsakoff syndrome is antero- and retrograde amnesia with preservation
of other cognitive functions.

PARANEOPLASTIC PHENOMENA
As reviewed in Chapter 19, tumors can cause neurologic dysfunction from
compression or invasion of neurologic tissue. Less commonly, a remote
tumor can cause a neurologic syndrome, even years before the cancer is
found, through an immune-mediated process. This is thought to occur
because a common antigen is expressed by both the tumor and elements of
the nervous system. Whereas antibodies to synaptic and neuronal surface
proteins (e.g., N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-
menthl-4-isoxazolepropionic acid (AMPA) may be identified independent
of a malignancy, antibodies to the intracellular neuronal proteins shown in
Table 18-2 are usually linked to an underlying tumor. Antibodies can be
detected in serum and cerebrospinal fluid (CSF). When the paraneoplastic
syndrome is well described, discovery of the specific antibodies can inform
the next steps in investigation. Treatment may include immunosuppression
as well as directed therapy for any identified tumor.

KEY POINTS
● Through an immune-mediated process, occult and identified malignancies can be
associated with dysfunction involving any element of the central or peripheral nervous
system.
● Antibodies can be detected in serum and CSF.
● Cancer-specific treatment and immunosuppression are the mainstays of therapy.

TABLE 18-2. Examples of Paraneoplastic Antibodies, with Associated

Cancers and Neurologic Syndromes
Antibody Associated Cancers Clinical Syndromes
Anti-Hu (ANNA-1) Small cell lung (SCLC) Encephalomyelitis, cerebellar
degeneration, sensory
ganglionopathy
Anti-Yo (PCA-1) Gynecologic, breast Cerebellar degeneration
Anti-Ri (ANNA-2) Breast, gynecologic, SCLC Cerebellar degeneration,
brainstem encephalitis,
opsoclonus-myoclonus
Anti-Ma proteins (Ma1, Ma2) Testicular germ cell tumors, Limbic, hypothalamic,
lung cancer, other solid tumors brainstem encephalomyelitis
Anti-CV2/CRMP5 SCLC, thymoma, other Encephalomyelitis, cerebellar
degeneration, chorea, peripheral
neuropathy
Caspr2 Thymoma, variable solid Morvan syndrome, limbic
tumors encephalitis, neuropathic pain,
peripheral neuropathy,
autonomic dysfunction,
cerebellar ataxia, isolated
neuromyotonia
Anti-amphiphysin Breast, lung cancer Stiff-person syndrome,
encephalomyelitis
NMDA Ovarian teratoma; rarely, other Multistage syndrome with
tumors in older patients or men psychosis, insomnia, memory
and behavioral disturbances,
seizures, dyskinesias, and
autonomic dysfunction
LGI1 Thymoma Limbic encephalitis, seizures,
facio-brachial dystonic seizures
NMDA, N-methyl-D-aspartate.
RHEUMATOLOGIC DISEASES
Neurology and rheumatology often overlap; subspecialists in both
disciplines evaluate patients with diseases such as systemic lupus
erythematosus (SLE), a chronic inflammatory disorder with variable
involvement of the skin, musculoskeletal, hematologic, and nervous
systems. SLE patients may have polyneuropathy, seizures, cognitive
dysfunction, and strokes; strokes are more likely to occur when the patient
has antiphospholipid antibodies.
Although the antiphospholipid antibody syndrome (APS) can occur in
isolation or with other rheumatologic conditions, it is more common in the
setting of SLE. APS is diagnosed when an individual has a stroke,
peripheral thrombosis, or a pregnancy complication (often a spontaneous
abortion) and has at least one of three antibodies (anti-cardiolipin, anti-
beta2-glycoprotein1, or lupus anticoagulant). Given the propensity for
thrombotic events, it makes sense that strokes are more common in patients
with APS. APS should be considered particularly when young people
without clear risk factors present with stroke. Vasculopathy-related white
matter changes may also be evident on brain MRIs in this population, in
whom migraine, epilepsy, and movement disorders (e.g., hemiballism and
chorea) can be seen.
Just as APS is more frequent in SLE, so is reversible posterior
leukoencephalopathy syndrome (RPLS), also referred to as posterior
reversible encephalopathy syndrome (PRES). Immunosuppressive
medications, hypertension, and renal failure are risk factors for RPLS. Most
commonly, patients present with a generalized tonic–clonic or other form of
seizure. Other potential manifestations are visual symptoms, such as auras
or hallucinations, or visual signs, including hemianopia or neglect. In
addition to changes in mental status, including agitation or sleepiness,
patients may report a headache unresponsive to treatment. An MRI may
show symmetric white matter abnormalities posteriorly in the cerebral
hemispheres—as suggested by the name of the syndrome.
Similar to SLE in that it affects multiple organ systems, sarcoidosis is a
granulomatous disease typically associated with bilateral hilar adenopathy.
Extra-pulmonary involvement is not uncommon, and up to 10% of patients
develop neurologic comorbidities. Although any element of the nervous
system may ultimately become involved, CNS sequelae usually precede
peripheral manifestations. Granulomatous disease may cause myopathy,
mono- (including cranial) and polyneuropathies, radiculopathies,
myelopathy, and neuroendocrine dysfunction. Skin changes, including
painful red nodules (i.e. erythema nodosum), may be a manifestation of
sarcoidosis. There is no single definitive diagnostic test for sarcoidosis.
Rather, diagnosis depends on characteristic symptoms and signs, the
exclusion of other diagnostic explanations, and finding noncaseating
granulomas on a biopsied lesion.

KEY POINTS
● SLE can be associated with polyneuropathy, seizures, cognitive dysfunction, and stroke.
● APS is diagnosed when a vascular event, such as ischemic stroke, occurs in the setting of
at least one of three associated antibodies.
● Neurologic sarcoidosis can involve any aspect of the CNS or peripheral nervous system.

TOXIC METABOLIC ENCEPHALOPATHY

Perturbations in the balance of immune, neurotransmitter, fluid, electrolyte,
and hormonal factors, alone or in combination, can lead to a common
clinical syndrome of toxic metabolic encephalopathy (TME). This umbrella
term refers to global cerebral dysfunction in the absence of a structural
cause. Because the underlying systemic illness disrupts circuits on which
complex cognitive function and arousal depend, patients with TME often
have impaired alertness or attention or both, disorientation, and sleep–wake
dysregulation. Fluctuating levels of arousal or alertness are characteristic.
Seizures are not uncommon. Generalized tonic–clonic seizures are
identified easily, but nonconvulsive seizures may be identified on
electroencephalogram (EEG) even when unaccompanied by motor
manifestations. Other abnormal movements such as asterixis, myoclonus,
and tremor can develop. Primitive or pathologically increased reflexes and
extensor plantar responses may be noted on exam. Signs of dysautonomia,
including tachycardia and hypertension, may accompany TME. The three
primary categories of conditions causing TME are the metabolic
disturbances discussed above, drugs, and infections (including systemic
infections, not necessarily direct CNS infections).
TME is a common neurologic diagnosis for intensive care unit patients
but also appropriate to consider with less dramatic changes in mental status,
mood, or behavior. Structural causes must be ruled out by imaging of the
brain and cerebral vessels. In the absence of a structural explanation, blood
work (e.g., a complete blood count, coagulation studies, a chemistry panel,
liver and thyroid function assays, ammonia level, osmolality, cortisol and
vitamin levels, and alcohol and toxicology screens) can help identify
specific causes. Urinalysis, blood cultures, and a chest X-ray can identify
contributing infections. A lumbar puncture is important if there is concern
for a CNS infection. EEG plays a key role in the assessment of TME,
confirming the presence of global dysfunction (with a slow background
rhythm, and sometimes with “triphasic waves”) or in some cases, seizures.
Importantly, these EEG abnormalities support a diagnosis of TME, but they
do not specify the exact cause in an individual case.

KEY POINTS
● TME is a global cerebral dysfunction in the absence of a structural cause.
● Clinical signs of TME include decreased arousal, impaired attention, seizures, abnormal
movements, increased reflexes, and dysautonomia.
● TME is most often caused by a metabolic derangement, drug, or infection.
● EEG often shows a slow background rhythm and, sometimes, triphasic waves, findings
which support the diagnosis of TME but do not identify the underlying etiology. It may
occasionally show evidence of seizures.
● Blood work, and in some cases lumbar puncture results, can provide a more definitive
diagnosis.

CLINICAL VIGNETTES

VIGNETTE 1
A 47-year-old man with hypertension and high cholesterol is seen in the
Neurology clinic for new onset pain, atrophy, and weakness of the right
leg. He reports that symptoms began several weeks earlier, with the
onset of sharp pain in the right hip and thigh. He has since developed a
foot drop on the same side, along with weakness of the right quadriceps.
He has lost about 15 lb in weight despite a healthy appetite. He denies
back pain. Examination shows atrophy of the right quadriceps muscle,
with weakness of hip flexion, knee extension, and ankle dorsiflexion on
the right. The patellar reflex on the right is absent, but the ankle reflex is
present. Motor examination in the left leg, and in both arms, is normal.
There is very mild distal stocking-pattern sensory loss in the toes of
both feet.
1. Which of the following is the most likely diagnosis?
a. Femoral neuropathy
b. Sciatic neuropathy
c. Lumbosacral radiculoplexus neuropathy
d. Polyneuropathy
e. Lumbosacral polyradiculopathy
2. You correctly make a diagnosis of lumbosacral radiculoplexus
neuropathy. What is the most likely cause?
a. Hypertension
b. Hypercholesterolemia
c. Undiagnosed type 2 diabetes mellitus
d. Undiagnosed hypothyroidism
e. Undiagnosed neurosarcoidosis

VIGNETTE 2
A 54-year-old woman presents to the emergency room with a 2-day
history of left facial droop. She also reports a mild headache and rash on
both shins. Examination shows weakness of both the upper and lower
parts of the face on the left, but no other neurologic deficits. You also
notice erythematous nodules over the shins that are tender to palpation.
1. The most likely neurologic diagnosis is:
a. Bell’s palsy
b. Sarcoidosis
c. Stroke
d. Trigeminal neuralgia
e. Lyme disease
 2. You suspect that she may have sarcoidosis, but need to confirm the
diagnosis. Which of the following tests is likely to be least helpful?
a. Serum angiotensin-converting enzyme (ACE)
b. Chest CT scan
c. Deep punch biopsy of one of the skin lesions
d. MRI of the head
e. EEG
3. Chest CT shows enlarged lymph nodes, and you arrange for a CT-
guided biopsy. Which of the following most accurately describes
the expected pathologic findings?
a. Caseating granulomata
b. Noncaseating granulomata
c. Vasculitis
d. Granulomatous inflammation
e. Histiocytosis

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer: C
The history of asymmetric pain followed by weakness and atrophy in
one leg is very characteristic of lumbosacral radiculoplexus neuropathy.
The distribution of weakness (that includes foot dorsiflexion) is not
compatible with a femoral neuropathy (which could cause weakness of
hip flexion and knee extension). Similarly, the pattern of weakness is
not consistent with a sciatic neuropathy (which would spare both hip
flexion and knee extension, but could cause foot drop). Polyneuropathy
is typically length dependent and symmetric. Although the bilateral
distal sensory loss may reflect an underlying polyneuropathy, this is not
the cause of the asymmetric pain, weakness, and atrophy. Lumbosacral
polyradiculopathy is possible, but the absence of back pain or pain that
radiates from the back into the buttock and leg makes this less likely.

VIGNETTE 1 QUESTION 2
2. Answer: C
Undiagnosed type 2 diabetes is the most common cause of lumbosacral
radiculoplexus neuropathy (also known as diabetic amyotrophy),
although it also occurs in type 1 diabetes. There is also a nondiabetic
form of lumbosacral radiculoplexus neuropathy, but there is no
association with hypertension or high serum cholesterol.
Hypothyroidism may certainly affect the peripheral nervous system but
typically causes entrapment neuropathies (e.g., carpal tunnel syndrome)
or an axonal polyneuropathy. Sarcoidosis may also affect the nervous
system but more often causes cranial neuropathies, a
meningoencephalitis, or hypothalamic dysfunction.

VIGNETTE 2 QUESTION 1
1. Answer: B
The distribution of weakness, involving both the upper and lower face,
indicates that dysfunction of the lower motor neuron (rather than the
corticobulbar upper motor neuron) is responsible for the facial
weakness. As such, her presentation is not due to a stroke. Instead, she
has a lower motor neuron seventh cranial (facial) neuropathy. Both
Lyme disease and sarcoidosis are important causes of a facial
neuropathy. The term Bell’s palsy is used to describe a facial neuropathy
when the cause is unknown. The associated rash in this patient is a clue
to the underlying cause. Both Lyme disease and sarcoid may produce a
rash. The rash of sarcoid is known as erythema nodosum and typically
manifests as painful red nodules over both shins, as in this patient.
Lyme disease typically produces a “bull’s-eye” rash, usually over the
trunk. This is not a case of trigeminal neuralgia, which presents with
facial pain rather than facial weakness.

VIGNETTE 2 QUESTION 2
2. Answer: E
An elevated serum ACE level may be a clue to the diagnosis. It is worth
checking but lacks sensitivity. Definitive diagnosis of sarcoid requires
histology consistent with a noncaseating granuloma from affected
tissue. Hilar and paratracheal lymph nodes are often enlarged in
sarcoidosis, reflecting pulmonary involvement by the disease. They are
evident on chest CT and often amenable to biopsy. The skin lesions may
also be biopsied and typically show panniculitis with inflammation in
the fat and around blood vessels. An MRI of the head could help ensure
that there is no contributory structural lesion, such as a tumor in the left
cerebellopontine angle. EEG is not helpful in establishing the diagnosis
of sarcoidosis.

VIGNETTE 2 QUESTION 3
3. Answer: B
The typical pathology of sarcoidosis is the nonnecrotizing or
noncaseating granuloma. A granuloma is an organized collection of
macrophages. The pathology of tuberculosis, by contrast, is that of the
necrotizing or caseating granuloma. Sarcoidosis may be associated with
a systemic vasculitis, but this is not the hallmark pathology.
Granulomatous inflammation is a nonspecific term that may be used to
describe the pathology of not only sarcoid but also several other
disorders. Histiocytosis is a general term that describes a group of
conditions characterized by an increase in the number of immune cells
called histiocytes; biopsy may show the presence of Langerhans cells.
 19 Central Nervous System Tumors

The most common tumors in the central nervous system (CNS) are
metastases from distant neoplasms, with lung cancer accounting for nearly
half of such tumors. Primary brain tumors (PBTs) are a heterogeneous
group of neoplasms originating from CNS tissue and meninges. These
tumors range from benign to aggressive. Although primary CNS tumors
have historically been named according to their cellular origin and
histologic appearance, advances in molecular genetics have led to further
characterization and classification based on phenotypic and genotypic
parameters. The official classification of brain tumors by the World Health
Organization includes key genetic information in the grading of tumors,
leading to “integrated diagnoses” and allowing for improved tumor grading.
As for location, PBT can occur anywhere in the intracranial or spinal space.
In adults, 70% of PBTs are supratentorial, and of those, 80% to 90% are
gliomas and meningiomas. The remaining 30% of PBTs in adults are
infratentorial, including schwannoma, hemangioblastoma, and meningioma
in adults. In children, approximately 70% of PBTs are infratentorial, most
commonly medulloblastoma, cerebellar astrocytoma, brainstem glioma, and
ependymoma.

EPIDEMIOLOGY
Approximately 79,000 new cases of CNS tumors are diagnosed in the
United States each year. These include primary malignant and
nonmalignant tumors. At present, there are more than 100 histologically
distinct types of primary CNS tumors. Approximately one-third of these
tumors are malignant. Overall survival after diagnosis with a PBT varies
significantly by age, histology, and molecular markers. The median age at
diagnosis of all PBTs is 59, with PBTs being the 10th leading cause of death
in adults in the United States. PBTs are also the most common cancers of
childhood and have surpassed leukemia as the leading cause of cancer-
related death in children under age 14. In general, CNS tumors are more
common in men (male to female ratio of 1.5:1) with the exception of
meningiomas, which are more common in women (1:1.8).

TABLE 19-1. Hereditary Syndromes Associated with Primary Brain

Tumors
Syndrome Chromosome Tumors
Neurofibromatosis 1 17 Glioma (optic nerve) and
ependymoma
Neurofibromatosis 2 22q12 Meningioma and glioma
von Hippel–Lindau 3p25 Hemangioblastoma
Li–Fraumeni cancer family 17p13.1 (inherited p53 Glioma and medulloblastoma
syndrome mutation)

CAUSES AND GENETICS

PBTs generally originate from genetic disruptions in cells, causing them to
bypass normal growth regulatory mechanisms, with simultaneous evasion
of the immune system. Some brain tumors have a strong hereditary
component (Table 19-1). Ionizing radiation used in therapeutic dosages has
been associated with an increased risk of meningiomas, astrocytomas, and
sarcomas. The use of mobile phones, low-frequency electromagnetic fields,
specific infections (various viruses, Toxoplasma gondii, etc.), diet (nitrates,
aspartame), tobacco, alcohol, and history of head trauma have not been
validated in epidemiologic studies as risk factors for CNS tumors.

CLINICAL FEATURES
There are no specific clinical symptoms or signs of brain tumors. The
clinical presentation depends on the location of the tumor, the rate of
growth, and the degree of invasion of surrounding structures. Tumors can
mimic many other CNS disorders and should be considered part of the
differential diagnosis of almost any neurologic dysfunction. In general,
tumor symptoms tend to present as progressive, nonremitting neurologic
symptoms. Nonetheless, a tumor can present as an acute, subacute, or
chronic neurologic problem. The most common symptoms include
headaches as the result of traction of pain-sensitive structures (arteries,
veins, and meninges) or from increased intracranial pressure; focal or
generalized seizures, particularly when tumors infiltrate the cortex; and
altered mental status such as memory loss, lack of concentration, changes
in personality, and apathy. In children, the predilection of tumors for the
posterior fossa may lead to presentation with a decreased appetite and
weight loss, reduced school performance, dizziness, ataxia (especially of
gait), neck pain, bulbar weakness, eye movement abnormalities, or
opisthotonos. The clinical findings depend on the location of the tumor and
can include cognitive, motor, sensory, visual, and coordination
abnormalities.

DIAGNOSTIC EVALUATION
Imaging studies (magnetic resonance imaging [MRI] and computed
tomography [CT]) play a central role in the diagnosis of brain tumors.
Blood work, electroencephalogram, and plain X-rays are of limited use.
MRI with contrast may show a ring-enhancing mass because of the
disruption of the blood–brain barrier by the infiltrating neoplasm, but a
ring-enhancing lesion can also be seen with an abscess, subacute infarction,
resolving hematoma, multiple sclerosis plaques, thrombosed aneurysms,
arteriovenous malformations, and radiation necrosis. Depending on the size
and location of the tumor, MRI features can include hydrocephalus, midline
shift, hemorrhages, large areas of edema surrounding the lesion, meningeal
enhancement, and so on. MR spectroscopy can detect changes in brain
tissue that are associated with the type and grade of the tumor (including a
decreased peak of N-acetyl aspartate associated with neuronal loss). The
definitive diagnosis of brain tumors requires histologic examination of
samples obtained either by brain biopsy or open surgery.

KEY POINTS
 ● The two most important prognostic factors for brain tumors are histologic type and patient
age.
● Brain tumors tend to present as progressive nonremitting neurologic symptoms.
● The most common type of brain tumor is metastatic tumor from a systemic malignancy.
The most common PBTs are gliomas and meningiomas.
● Headache and seizures are among the most common presenting symptoms of intracranial
tumors.

PRIMARY BRAIN TUMORS

GLIOMAS
Gliomas are a group of tumors that originate from glial cells, the supportive
nonneuronal cells of the CNS. Glioma is a generic histologic term used for
four different CNS tumors: astrocytoma, oligodendroglioma, ependymoma,
and choroid plexus papilloma.

GLIOBLASTOMA MULTIFORME
• Origin: Arises from astrocytes.
• Epidemiology: 15% of all intracranial tumors, and the most common
PBT (50%–60%) in adults. Peak onset age 40 to 60 years; more common
in men.
• Pathology: Highly malignant tumors with anaplasia, high cellularity,
round and pleomorphic cells, nuclear atypia, vascular proliferation, and
necrosis. Necrosis and neovascular proliferation help to differentiate
between anaplastic astrocytoma (grade III) and glioblastoma (grade IV).
Occasionally, glioblastomas are multifocal or infiltrate the brain widely
(“gliomatosis cerebri”). Mitotic activity is very high. Certain genetic
mutations, namely isocitrate dehydrogenase 1 (IDH1) and O-6-methyl-
guanine-DNA methyltransferase (O6-MGMT) have clear associations
with prognosis.
• Presentation: Headaches 30% to 50%, seizures 30% to 60%, focal
neurologic deficits 40% to 60%, mental status changes 20% to 40%, at
the time of diagnosis. Symptoms may start when the tumor has grown
substantially.
• Imaging: CT or MRI demonstrates a solitary brain lesion (commonly in
the deep white matter, basal ganglia, or thalamus; rarely infratentorial)
with contrast enhancement and surrounding edema. About 4% to 10% of
glioblastoma multiforme (GBM) do not enhance. Commonly, the tumor
infiltrates white matter tracts involving the corpus callosum, producing
the typical “butterfly” pattern (Fig. 19-1).
• Treatment: Current standard treatment options include maximal-safe
surgical resection followed by radiation with concurrent temozolomide
(TMZ; a cytotoxic alkylating agent), followed by adjuvant TMZ for 6
months. Treatment with TMZ is maximally beneficial for patients with a
methylated form of O6-MGMT. Stereotactic radiosurgery and
antiangiogenesis therapies such as the humanized monoclonal antibody
bevacizumab (which sequesters vascular endothelial growth factor that is
highly expressed in gliomas) can be used for local recurrences. More
antiangiogenic agents are being evaluated. GBMs contain nests of
“cancer stem cells” that are resistant to chemotherapy and radiation and
can repopulate the entire tumor. These stem cells represent a new target
for future therapies.
• Prognosis: Poor outcome, with median life expectancy of 15 to 17
months; fewer than 16% survive more than 3 years.
FIGURE 19-1. Contrast-enhanced computed tomographic scan of the brain showing
glioblastoma multiforme (arrow). Note the irregular enhancement pattern with a central area of
necrosis. The tumor has also crossed the corpus callosum. (Reproduced with permission from Patel P.
Lecture Notes: Radiology. Oxford, UK: Blackwell Publishing; 2005:268.)

LOW-GRADE GLIOMAS (GRADE I AND II)

• Origin: Astrocytes (glial cells) or ependymal cells.
• Epidemiology: Up to 10% of PBTs; can occur throughout the brain; in
children, more common in the cerebellar hemispheres.
• More common in the fourth decade of life.
• Pathology: Genotype–phenotype correlation defines the tumor grade.
Examples of grade I tumors include pilocytic astrocytoma and
subependymal giant cell astrocytoma. Examples of grade II include
diffuse astrocytoma with IDH-mutant and pleomorphic
xanthoastrocytoma.
• Presentation: Seizure is a typical presentation of slow-growing tumors.
• Imaging: MRI with contrast is the study of choice. Most lesions are
bright on T2 and fluid-attenuated inversion recovery, usually without
enhancement (Fig. 19-2).
• Treatment: Close observation with serial neuroimaging may be the first
approach, depending on prognostic factors. Surgical removal can be
curative for grade I astrocytomas; it can be considered for grade II
tumors if a “gross total” resection is possible, but it is often not curative.
Radiation or chemotherapy can be used depending on other prognostic
factors.
• Prognosis: Median survival around 7 years.
FIGURE 19-2. T2-weighted magnetic resonance imaging scan of the brain showing a large
glioma characterized by high-intensity signal in the right hemisphere. The tumor is displacing and
compressing the ventricular system. (Reproduced with permission from Armstrong P, Wastie M,
Rockall A. Diagnostic Imaging. 5th ed. Oxford, UK: Blackwell Publishing; 2004:401.)

OLIGODENDROGLIOMA
• Origin: Arises from oligodendrocytes. High frequency of co-deletion of
chromosomal arms 1p and 19q is considered a “genetic signature” of
oligodendroglioma.
• Epidemiology: 10% of all gliomas; 2% to 4% of PBTs; peak incidence at
age 35 to 45. Common in the frontal lobes, but can appear in the basal
ganglia and thalamus. Typically very slow growth.
• Pathology: Calcifications are common. Most distinctive microscopic
feature is the “fried egg” appearance (perinuclear halos with swollen
cytoplasm).
• Presentation: Seizures in up to 70%.
• Imaging: MRI shows low intensity on T1, high intensity on T2;
vasogenic edema uncommon. Contrast enhancement is a negative
prognostic factor, usually seen with anaplastic oligodendroglioma. CT
scan better to visualize intratumoral calcifications.
• Treatment: Total resection if possible, local radiation and PCV
(procarbazine, lomustine, and vincristine) chemotherapy. TMZ is used
increasingly and is less marrow-toxic. Patients with 1p/19q co-deletion
seem to have a better response to therapy.
• Prognosis: Better survival with surgery plus radiation; can be decades.
Tends to recur locally and progress into a malignant form.

EPENDYMOMA
• Origin: Arises from ependymal lining of the ventricles.
• Epidemiology: 6% to 9% of PBTs; 30% of PBTs in children under age 3.
In children, 90% are intracranial (often in the fourth ventricle) with a
tendency toward subarachnoid spread. In adults, 75% arise within the
spinal canal as intramedullary tumors.
• Pathology: Perivascular pseudorosettes (a halo of cells surrounding a
central vascular lumen) are the histologic hallmark.
• Presentation: Intraventricular location can produce obstructive
hydrocephalus with raised intracranial pressure (papilledema, cranial
nerve palsies, cerebellar dysfunction, etc.). Myxopapillary
ependymomas of the conus and cauda equina can produce conus
medullaris or cauda equina syndromes.
• Imaging: MRI enhancement is variable.
• Treatment: Surgery to decrease tumor burden, followed by radiation and
chemotherapy. Recurrence rates are high; close MRI follow-up is
necessary.
• Prognosis: Overall 10-year survival 45% to 55%, depending on tumor
grade.

MENINGIOMA
• Origin: Arises from meningothelial (mesodermal) cells of the dura
mater. Almost always benign. Can occur intracranially (with predilection
for cerebral convexities, falx cerebri, and the sphenoid wing) or within
the spinal canal.
• Epidemiology: Second most common PBT after GBM; 15% to 20% of
all PBTs. More common in women between the ages of 40 and 60.
Incidence increases with age. Some genetic conditions are associated
with an increased susceptibility to develop meningiomas, as with NF-2
(Table 19-1), associated with abnormalities on chromosome 22.
• Pathology: Histology shows sheets of plump, uniform meningothelial
cells with the tendency to form whorls. Progesterone receptors are found
frequently.
• Presentation: Slow growth; symptoms produced by local impingement
on brain (seizures) and nerves (weakness) or compression of nearby
structures (weakness, headache, apathy).
• Imaging: MRI usually shows a rounded extra-axial mass adjacent to
dura. In general, isointense on T1 and T2, with intense contrast
enhancement and associated “dural tail” of enhancement (Fig. 19-3).
• Calcification is seen on CT. Angiography can show rich vascularization.
Also noted on CT or plain X-rays is “hyperostosis” (osteoblastic
reaction) that may represent tumor invasion of the bone.
• Treatment: Surgical removal, often preceded by endovascular
embolization of the feeding vessels, but many lesions <4 cm are treated
with radiosurgery, with good control rates. Stereotactic radiosurgery
such as gamma knife radiosurgery is an option when resection or other
radiation is difficult or dangerous. Recurrent meningiomas are difficult
to treat.
• Prognosis: 5-year survival is 70% to 95%; malignant transformation is
very rare.
FIGURE 19-3. Axial (A) and sagittal (B) magnetic resonance imaging scans of the brain
showing a brightly enhancing meningioma (arrows). On the sagittal view, the arrow tip points to the
dural tail at the margin of the tumor. (Reproduced with permission from Patel P. Lecture Notes:
Radiology. Oxford, UK: Blackwell Publishing; 2005:269.)

MEDULLOBLASTOMA
• Origin: Primarily at the medullary velum of the fourth ventricle (Fig. 19-
4); up to 30% from the cerebellar hemispheres. It is among the primitive
neuroectodermal tumors.
• Epidemiology: Rare in adults, accounting for less than 2% of PBTs, but
common in children, making up 18% of all pediatric brain tumors. More
than 70% are diagnosed in children under age 10.
• Pathology: Small round cells with a high mitotic index.
• Presentation: Rapidly growing tumor that infiltrates surrounding tissue
and extends toward the fourth ventricle, producing hydrocephalus (with
morning headache, unsteadiness, nausea, and vomiting); may spread via
the cerebrospinal fluid (CSF) intracranially, and to the spinal cord (“drop
metastases”). Can also spread extracranially to bone and bone marrow.
• Imaging: MRI of the brain usually shows a heterogenous contrast
enhancing midline tumor compressing the fourth ventricle. MRI of the
brain and spinal cord helps to evaluate subarachnoid metastasis. CSF
studies are often done to look for malignancy (if no contraindication).
Bone scan and bone marrow aspiration are indicated due to the possible
extracranial extension of the tumor.
FIGURE 19-4. Medulloblastoma (arrow) in a child, as shown by sagittal magnetic resonance
imaging scan with contrast enhancement. Note that the fourth ventricle and middle portion of the
cerebral aqueduct are obliterated, resulting in hydrocephalus, including dilatation of the third and
lateral ventricles. (Reproduced with permission from Patel P. Lecture Notes: Radiology. Oxford, UK:
Blackwell Publishing; 2005:271.)

• Treatment: Surgery plus radiation and chemotherapy. Corticosteroids for

vasogenic edema. Children <3 years are more susceptible to adverse
effect of radiation on brain development. In those cases, chemotherapy
may allow the delay of radiation treatment. High recurrence rate.
• Prognosis: 20% to 30% relapse after initial treatment. Poor prognosis in
children with metastatic disease or subtotal resection. Good prognostic
factors include radical resection and radiation dose above 50 Gy to the
entire neuroaxis. Under these conditions, recurrence-free survival is
>50% at 5 years.

SCHWANNOMA
• Origin: Arises from Schwann cells.
• Epidemiology: ~7% of all intracranial tumors and the most common
tumor of peripheral nerves. More common in middle-aged women. More
common in the vestibular (VIII) cranial nerve (acoustic neuromas)
where they can occupy the cerebellopontine angle, involving trigeminal
and facial nerves. Bilateral acoustic schwannomas can be associated
with NF-2 (neurofibromatosis).
• Pathology: Tumor is made up of sheets of uniform spindle cells, forming
palisades called “Verocay bodies.”
• Presentation: Can be asymptomatic, or present with loss of function of
the affected nerve (hearing loss, vestibular symptoms, facial
paresthesias, or pain, etc.).
• Imaging: MRI with contrast tends to show circumscribed lesions which
displace but do not invade adjacent structures. Larger tumors show
cystic degeneration.
• Treatment: If symptomatic, stereotactic radiosurgery (i.e., gamma knife)
is the first choice, particularly when the lesion does not compress the
brainstem and is smaller than 3 cm. Surgery (microsurgical approach) is
an alternative but can be complicated by focal nerve deficits.
• Prognosis: Good.

LESS COMMON PRIMARY BRAIN TUMORS

GANGLIOGLIOMA
These infrequent PBTs are commonly seen in children and young adults and
include a mixture of neurons and glial cells. They are usually located in the
cerebral hemisphere and characterized by slow growth, with long duration
of symptoms (e.g., seizures). MRI shows increased T2 signal with
characteristic swollen gyri. Surgical removal usually produces an excellent
outcome. Radiation is reserved for those with frankly malignant features, or
inoperable or recurrent tumors.

HEMANGIOBLASTOMA
These uncommon cystic lesions account for nearly 2% of intracranial
tumors, with a predilection for the posterior fossa. Approximately 10% of
patients with hemangioblastoma are affected with von Hippel–Lindau
disease (hereditary retinal angiomas, pancreatic cysts, and kidney tumors).
Hemangioblastomas can occur at any age but are most common in patients
in the fourth decade.

PRIMARY CNS LYMPHOMA

Lymphoma involving the CNS can be primary or metastatic from systemic
non-Hodgkin lymphoma. Primary CNS lymphoma (PCNSL) accounts for
less than 2% of PBTs, affecting men more than women (2:1) and with a
higher incidence in acquired immunodeficiency syndrome patients.
PCNSLs are almost exclusively intermediate to high-grade non-Hodgkin
lymphomas of B cell origin. The clinical presentation is usually insidious,
with progressive neurologic dysfunction (change in mental status, seizures,
focal deficits, etc.). Ocular lymphoma may occur in up to 20% of patients
prior to CNS manifestations. A systemic work up is appropriate to rule out
disseminated disease, as CSF analysis shows tumor dissemination in up to
40% of cases. MRI appearance varies significantly, with single or multiple
lesions, a butterfly appearance, enhancing or non-enhancing lesions, etc.
The role of surgery in CNS lymphoma is limited to biopsy. Prognosis is
poor, with survival approximately 1.5 months if untreated, 10 to 18 months
after radiation therapy, and 44 months after chemotherapy plus radiation.
High-dose systemic methotrexate-based chemotherapies (along with
cytarabine, TMZ, rituximab) with or without radiation are the treatment of
choice. PCNSL are radiosensitive, but radiation is used as palliation. A
dementia incidence of up to 50%, however, can be observed in patients who
survive more than 18 months on these regimens (often ascribed to the
radiation therapy). PCNSL can show a dramatic response to steroids, but
the tumor invariably recurs within months. Even with best treatment,
recurrence is very common (median time to recurrence: 4 to 5 years).

SELLAR AND SUPRASELLAR TUMORS

Pituitary tumors originate in the pituitary gland in the sellar region (Fig. 19-
5). They can be classified as microadenomas (<1 mm) and macroadenomas
(>1 mm). Their histologic cell of origin is responsible for the initial
symptoms, usually related to the production of pituitary hormone. When
tumors become large enough, they can compress neighboring structures
(optic chiasm, cavernous sinus, etc.), producing focal symptoms. In general,
diagnosis is by imaging studies and laboratory evaluation of hormonal
status. Surgical removal may be through a trans-sphenoidal approach.

FIGURE 19-5. Sagittal (A) and coronal (B) post-contrast magnetic resonance imaging scans of
the brain demonstrating a pituitary adenoma (arrows). Note that the tumor is anterior to the brainstem
and extends upward, compressing the optic chiasm. (Reproduced with permission from Armstrong P,
Wastie M, Rockall A. Diagnostic Imaging. 5th ed. Oxford, UK: Blackwell Publishing; 2004:406.)
 Suprasellar craniopharyngioma is a slow-growing tumor characterized by
the benign nature of its cells but malignant behavior of its growth. It
accounts for 1% to 3% of intracranial tumors and 13% of suprasellar tumors
in adults and 50% in children. It tends to invade neighboring structures,
complicating treatment. Tumors present with headache, visual disturbance,
and endocrine dysfunction. The radiologic hallmark is the appearance of a
suprasellar calcified cyst. Treatment can entail full surgical resection, or
minimal resection with radiation or radiosurgery.

SECONDARY (METASTATIC) BRAIN

TUMORS
Metastases are the most common brain tumors and originate from
malignant neoplasms outside the CNS. Metastatic lesions occur in 100,000
to 200,000 cases per year in the U.S. and account for 20% of cancer deaths
annually. The most frequent metastatic brain tumors originate in the lung,
skin (melanoma), kidney (renal cell carcinoma), breast, and colon.
Malignant cells reach the brain via the bloodstream (crossing the blood–
brain barrier) or through Batson’s plexus (pelvic and gastrointestinal
tumors). In general, metastatic lesions are located at the junction of white
and gray matter and tend to be solitary, but multiple metastases are not
unusual. MRI with contrast is the preferred diagnostic study (Fig. 19-6).
Treatment depends on the number of metastases, the immediate mass effect
of the lesion(s), and the general status of the patient. Single lesions can be
resected, followed by whole brain radiation or radiosurgery. Radiosurgery is
used more often for three or fewer lesions, especially if the systemic disease
is under good control—to prevent the long-term side effects of whole brain
radiation, chemotherapy, or both. The prognosis is poor because metastases
usually represent a more advanced stage and extension of the primary
cancer.
FIGURE 19-6. Contrast-enhanced computed tomographic scan of the brain showing several
metastatic lesions characterized by rounded areas of hyperdensity. (Reproduced with permission from
Armstrong P, Wastie M, Rockall A. Diagnostic Imaging. 5th ed. Oxford, UK: Blackwell Publishing;
2004:402.)

KEY POINTS
● General medical treatment of brain tumors includes glucocorticoids (to reduce vasogenic
edema due to the tumor and following radiation) and anticonvulsant medication.
Anticoagulation is not contraindicated in patients with brain tumor.
● “Drop metastases” are intradural extramedullary spinal metastases that arise from
intracranial lesions. They are most frequently seen with ependymomas or
medulloblastomas but can also occur with other PBT.
● Medulloblastoma and other posterior fossa tumors: Avoid lumbar puncture unless CT
shows no obstructive lesion—to prevent cerebellar tonsillar herniation due to increased
intracranial pressure.
● NF2 (neurofibromatosis)-associated tumors: bilateral vestibular schwannomas,
meningiomas, and intramedullary ependymomas.
● In PCNSL, remember to evaluate the patient’s immune status and look for ocular
involvement by careful ophthalmologic exam.
● Brain metastases that bleed easily include melanoma, renal cell carcinoma, and
choriocarcinoma.
CLINICAL VIGNETTES

VIGNETTE 1
A 46-year-old woman with no significant medical history presents with
the new onset of a witnessed 2-minute generalized tonic–clonic seizure.
She has no history of recent infection, other illness, or head trauma. She
denies pain anywhere. On examination, she has normal vital signs and is
afebrile, and her neck is supple. Her mental status, cranial nerves,
strength, coordination, and sensation are all normal. Blood work and
toxicology screen are also normal.
1. Which of the following is the most likely explanation for her
seizure?
a. Large stroke
b. Tumor
c. Meningitis or encephalitis
d. Intracranial hemorrhage
e. Nonepileptic seizure (“pseudoseizure”)
2. The most common cause of tumors at this age is:
a. Meningioma
b. GBM
c. Metastatic disease
d. Oligodendroglioma
e. PCNSL
3. The initial head CT with contrast shows a solitary left frontal lesion
with evidence of a smaller, intralesional hemorrhage. If this is a
metastatic lesion, the most likely primary tumor is:
a. Colon carcinoma
b. Prostate cancer
c. Melanoma
d. Breast cancer
e. Lung cancer

VIGNETTE 2
A 62-year-old woman is brought to the neurologist for evaluation of a
few months of progressive short-term memory problems, difficulty
“finding words,” and headache. She has a history of depression and
hypertension. Her mental status examination shows some paraphasic
errors and an inability to recall three objects after 5 minutes; she has a
mild right pronator drift. She is not depressed.
1. Which of the following is the best next step to assess the cause of
her symptoms and signs?
a. Lumbar puncture
b. Magnetic resonance angiogram (MRA) of the brain
c. Head CT without contrast
d. MRI of the brain without contrast
e. MRI of the brain with and without contrast
2. The MRI shows a large intracranial mass with contrast
enhancement and an area of surrounding edema. Based on the
clinical findings, where would you expect the lesion is located?
a. Right parietal lobe
b. Right temporal lobe
c. Left occipital lobe
d. Left temporal lobe
e. Right occipital lobe
3. The patient undergoes a tumor biopsy. The pathology report
concludes that the tumor is a glioblastoma multiforme. The best
available treatment is:
a. Surgery without radiation
b. Surgery followed by radiation
c. Surgery followed by radiation and concurrent TMZ
d. Surgery followed by TMZ without radiation
e. No treatment is available for this kind of tumor

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
This patient presents with a new-onset generalized convulsion, is only
46 years old, and has no cardiovascular risk factors to suggest stroke—
and she has a normal neurologic examination. She has no history to
suggest infection, is afebrile, and has a supple neck, making meningitis
or encephalitis unlikely. The normal exam and lack of severe headache
make an acute intracranial hemorrhage or large stroke unlikely. With
this presentation and examination, tumor is most likely.

VIGNETTE 1 QUESTION 2
2. Answer C:
The most common tumors in the CNS are metastases from a primary
neoplasm elsewhere. Each of these tumors can present with seizures as
the first clinical manifestation.

VIGNETTE 1 QUESTION 3
3. Answer C:
The most common primary neoplasms to cause brain metastases with
hemorrhagic components are melanoma, renal cell carcinoma, and
choriocarcinoma. The other primary cancers mentioned above can
produce metastases to the brain, but they far less often undergo
hemorrhagic transformation.

VIGNETTE 2 QUESTION 1
1. Answer E:
This patient presents with progressive neurologic dysfunction
characterized by headaches, memory problems, and dysphasia, and with
no earlier headaches. The dysfunction is progressive, not acute. The
onset of a new and progressive headache at this age raises concern for
an intracranial tumor. MRI of the brain, with and without contrast, is the
best imaging technique to look for a tumor (or other mass lesion) and is
far superior to head CT. Lumbar puncture should be preceded by brain
imaging when there is a question of increased intracranial pressure.
MRA provides an assessment of intracranial vasculature; it is often used
in patients with strokes.

VIGNETTE 2 QUESTION 2
2. Answer D:
A left temporal lobe mass would explain memory and language
problems and might often be associated with a right pronator drift
(likely because of the vasogenic edema or direct infiltration of the tumor
affecting some descending motor fibers). The other locations do not
match the clinical presentation. Left frontal lobe lesions could also
present with a similar constellation of symptoms.

VIGNETTE 2 QUESTION 3
3. Answer C:
Current accepted best treatment for GBM requires maximal-safe
surgical resection followed by radiation with concurrent TMZ (a
cytotoxic alkylating agent), followed by adjuvant TMZ for 6 months.
All the other combinations are inferior to option c.
 20 Demyelinating Diseases of the
Central Nervous System

MULTIPLE SCLEROSIS
Demyelinating diseases of the central nervous system (CNS) are
characterized pathologically by an acquired loss of myelin with a relative
preservation of axons. The most common and best known of the CNS
demyelinating diseases is multiple sclerosis (MS). For many reasons, MS is
also one of the most feared diagnoses in Neurology: it strikes young,
healthy people in the prime of their lives; its course is marked by
unpredictable relapses; almost any aspect of neurologic function may be
affected; and some patients develop lifelong motor disability requiring a
wheelchair.
MS has a wide range of presentations and an equally wide range of
prognoses. Effective treatments aimed both at the underlying disease
process and at some specific complications are available. For the student,
the study of demyelinating diseases provides an excellent opportunity to
learn about the dysfunction of different parts of the CNS and to master the
wide variety of neurologic exam abnormalities that accompany these
disorders.

EPIDEMIOLOGY
MS is a chronic neurologic disease that begins most commonly in young
adulthood. The peak incidence of MS is between 20 and 30 years of age.
Women are affected twice as often as men. MS prevalence in the United
States is about 90 cases per 100,000 people. There are epidemiologic
findings to suggest both genetic and environmental influences, as discussed
below.
 Geographically, MS is more common in northern latitudes. The incidence
in Scandinavian countries is higher than that in southern Europe, and the
incidence in the northern United States is higher than that in the South.
There are racial differences as well, with a higher prevalence in white
populations. Interestingly, those who move from a low-risk to a high-risk
geographic region or vice versa before the age of 15 adopt the risk of MS
associated with their new home, whereas those who migrate after age 15
retain the risk associated with their childhood home. The implications of
this finding are unclear, but one theory is that a latent viral infection
acquired in childhood may play a role in the pathogenesis of the disease.
There is strong evidence supporting a genetic predisposition to MS as
well. For example, there is a greater incidence of MS in monozygotic, when
compared with dizygotic, twins of patients with MS, as well as an increased
incidence in association with particular human leukocyte antigen alleles.

KEY POINTS
● The peak incidence of MS occurs in young adulthood, between 20 and 30 years of age.
● MS is more common in women and more common in whites.
● The epidemiology of MS supports both environmental and genetic influences.

CLINICAL MANIFESTATIONS
Classically, MS is diagnosed by finding multiple white matter lesions
separated in space and time. This means that multiple distinct areas of the
CNS must be involved (rather than one area recurrently, for example), and
that the disease must not be simply a monophasic illness (with multiple
areas affected simultaneously but not recurring).
The clinical features are defined, as might be expected, by the location of
the lesions. Thus, a right occipital lesion could result in a left homonymous
hemianopia, whereas a right cervical spinal cord lesion may lead to an
ipsilateral hemiparesis and loss of joint position sense, with contralateral
loss of pain and temperature sensation. Almost any neurologic symptom, in
fact, can be produced by an MS lesion.
Common clinical features (Table 20-1) include corticospinal tract signs
such as weakness and spasticity, cerebellar problems such as intention
tremor and ataxia, sensory abnormalities such as paresthesias and loss of
vibration and proprioception sensation, and bladder dysfunction. Fatigue is
a common complaint. In later stages, cognitive and behavioral
abnormalities may occur. A few syndromes characteristic of MS warrant
further description:

TABLE 20-1. Common Clinical Features of Multiple Sclerosis

Neurologic System Clinical Sign or Symptom
Cranial nerves Optic nerve dysfunction
Visual acuity loss
Red desaturation
Papilledema or optic disc pallor
RAPD
Eye movement disorders
Internuclear ophthalmoplegia
Nystagmus
Motor system Weakness
Spasticity
Reflex abnormalities
Increased muscle stretch reflexes
Babinski signs
Clonus
Sensory system Paresthesias
Vibratory loss
Joint position sense loss
Lhermitte’s sign
Cerebellar function Ataxia
Intention tremor
Dysarthria
Autonomic system Bladder dysfunction
Other Fatigue
Depression
Uhthoff’s phenomenon
RAPD, relative afferent pupillary defect.

Optic neuritis (ON) is a common initial presenting symptom of MS.

(This fact reminds us that the optic nerve is actually an extension of the
CNS rather than a peripheral nerve.) ON is characterized by a mildly
painful loss of visual acuity in one eye. The visual loss may range from
mild blurriness with a loss of color discrimination to a severe episode with
complete blindness. Pulling or tugging pain is most prominent when the eye
moves. On examination, there is loss of acuity and color vision. Most
patients have retrobulbar ON and the optic disc appears normal in the acute
stage. In severe cases, however, the optic disc may be swollen, with
indistinct margins (papilledema). A past history of ON is suggested by the
presence of red desaturation (subtle loss of color appreciation), optic disc
pallor or atrophy, and a relative afferent pupillary defect (RAPD, see
Chapter 4).
Transverse myelitis is inflammatory demyelination in the spinal cord.
Most commonly, this affects particular tracts at the level of the lesion in a
patchy way, rather than producing complete involvement of the spinal cord.
There may be unilateral or bilateral weakness or sensory loss below the
lesion. Bowel and bladder function may be disrupted. Reflexes may be
exaggerated below the lesion, and Babinski signs may be present. Patients
may report a band of tingling or pain around the torso at the level of the
lesion.
Internuclear ophthalmoplegia (INO) is a characteristic finding in MS.
INO results from dysfunction of the medial longitudinal fasciculus and
leads to an inability to adduct one eye when looking toward the opposite
side, with associated nystagmus of the abducting eye. The adduction of both
eyes when observing a near target (convergence) is preserved. The presence
of INO in a young person suggests few other diagnostic possibilities. See
Fig 4-2 for a more complete discussion of the pathophysiology of an INO.
The other clinical features characteristic of MS include Lhermitte’s sign,
a tingling, electric sensation down the spine when the patient flexes the
neck, and Uhthoff’s phenomenon, a worsening of symptoms and signs in
the heat.

KEY POINTS
● MS is characterized by multiple lesions separated in space and time.
● Almost any neurologic symptom can occur, depending on the location and burden of
lesions.
● The features characteristic of MS include ON, transverse myelitis, INO, Lhermitte’s sign,
and a worsening of symptoms in the heat.

CLINICAL COURSE AND PROGNOSIS

Most MS patients begin with a relapsing-remitting course (Fig. 20-1), in
which there are discrete episodes of neurologic dysfunction (relapses or
“flares”) that resolve after several weeks or months. Unfortunately, such a
course usually evolves into one in which recovery from each relapse is
incomplete and baseline function deteriorates (secondary progressive).
Rarely, patients may have a relentlessly progressive course from the onset,
either with superimposed relapses (progressive-relapsing) or without
(primary progressive).
FIGURE 20-1. Clinical course of multiple sclerosis: (A) relapsing-remitting, (B) secondary
progressive, (C) primary progressive, (D) progressive-relapsing. (From Ginsberg L. Lecture Notes:
Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:131. Copyright © 2005 L Ginsberg.
Reprinted by permission of John Wiley & Sons, Inc.)

To put the prognosis in broad terms, about 60% of MS patients lead lives
of minimal disability and continue to work, about 20% require a walking
aid but will remain ambulatory, and about 20% have severe disability,
typically becoming wheelchair-bound. There has been and will likely
continue to be a trend toward better prognoses in the future because of a
greater use of effective disease-modifying agents. Features predicting a
good prognosis include young age at onset, female sex, rapid remission of
initial symptoms, mild relapses that leave little or no residual deficits, and a
presentation with sensory symptoms or ON rather than motor symptoms.

KEY POINTS
● Most MS patients have a relapsing-remitting course, which frequently evolves into a
secondary progressive course.
● Prognosis is quite variable and ranges from minimal to severe disability.

DIAGNOSTIC EVALUATION
The diagnosis of MS begins with a thorough history and examination.
Patients often present with what appears to be a single episode of
neurologic dysfunction, but upon further questioning recall earlier episodes
of seemingly unrelated neurologic symptoms that may in fact represent
prior lesions. It is important to inquire specifically about past neurologic
symptoms that suggest ON, transverse myelitis, and other typical MS
features. On examination, evidence of old optic nerve or other neurologic
lesions should be sought.
The two most useful laboratory studies are magnetic resonance imaging
(MRI) and cerebrospinal fluid (CSF) analysis. On MRI, new MS lesions
appear as discrete T2-hyperintense areas in the white matter of the brain or
spinal cord (Figs. 20-2 and 20-3). Fluid-attenuated inversion recovery
sequences also show these lesions particularly well. Acute lesions may not
be evident on T1-weighted images but may enhance with gadolinium. Old,
chronic MS lesions may become T1-hypointense, with a “black hole”
appearance. MS lesions are most often ovoid in shape and have a
predilection for particular areas, including the periventricular white matter,
juxtacortical regions, corpus callosum, and cerebellar peduncles. Sagittal
images may demonstrate foci of demyelination spreading perpendicularly
from the corpus callosum, termed Dawson’s fingers.

FIGURE 20-2. T2-weighted MRI demonstrating multiple periventricular hyperdensities in both

A and B (arrows), consistent with a diagnosis of MS. [MRI, magnetic resonance imaging; MS,
multiple sclerosis.] (Reproduced with permission from Daffner RH. Clinical Radiology: The
Essentials. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.)
FIGURE 20-3. T2-weighted MRI demonstrating a demyelinating plaque at the C3 level in the
cervical spinal cord in a patient with MS. [MRI, magnetic resonance imaging; MS, multiple
sclerosis.] (Reproduced with permission from Eisenberg RL. An Atlas of Differential Diagnosis. 4th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)

The characteristic CSF finding in MS is an elevation in the concentration

of oligoclonal bands (OCBs), found in more than 90% of MS patients at
some point during the illness. OCBs reflect intrathecal production of IgG
antibodies by plasma cell clones. Although highly suggestive of MS, they
can also be found in other neurologic disorders. CSF studies during an acute
relapse may show a moderate pleocytosis and elevated protein. Calculation
of the IgG index, on the basis of relative levels of IgG and albumin in the
CSF and serum, can also suggest intrathecal antibody production.
Finally, visual evoked potentials can be used in suspected MS to
document evidence of old ON. There is often an increased latency of the
P100 wave on the affected side.
 KEY POINTS
● The diagnosis of MS begins with a thorough history and examination, particularly directed
toward identifying the past episodes of neurologic dysfunction.
● MRI is the best imaging modality to detect both new and old MS lesions.
● The characteristic CSF abnormality is the presence of OCBs.
● Visual evoked potentials may provide evidence of old ON.

PATHOLOGY
The histologic appearance of an acute MS lesion is a sharply defined area of
myelin loss with relative preservation of axons and associated signs of
perivascular inflammation, including the presence of macrophages,
lymphocytes, and plasma cells. Reactive astrocytes may be present. Chronic
MS lesions show axon loss and extensive glial proliferation.

TREATMENT
Treatment for MS falls into three categories: acute therapies for relapses,
chronic therapies that treat the underlying disease process, and symptomatic
therapies that address the various complications of the disease.
Acute relapses of MS are most commonly treated with corticosteroids. A
course of intravenous methylprednisolone for 3 to 5 days, with or without
an oral prednisone taper, is a common protocol. Although the effect of
steroids on the long-term outcome is unclear, steroids do shorten the
duration of acute relapses. The Optic Neuritis Treatment Trial demonstrated
that intravenous steroids for patients with ON delayed but did not prevent
the subsequent development of MS.
Disease-modifying agents (Table 20-2) are important treatments for
preventing relapses and potentially for improving long-term outcomes.
These include beta-1a interferon and beta-1b interferon, which are
injectable medications that have been shown to decrease the rate of
relapses, the burden of lesions seen on MRI, and the rate of accumulated
disability. Both are currently used in patients with relapsing-remitting MS
and in some patients with secondary progressive disease. Side effects can
include flu-like symptoms, depression, and injection-site reactions. It is
important to check a complete blood count and liver function test routinely;
interferons may cause leukopenia and reversible transaminitis. Patients who
are doing poorly with interferons may have developed neutralizing
antibodies that reduce drug effectiveness.
Glatiramer acetate is a polypeptide formulation injected subcutaneously,
which is also used in relapsing-remitting patients.

TABLE 20-2. Immune-Modulating Agents Used in the Treatment of

Multiple Sclerosis
Drug Administration Side Effects
Interferon beta-1a (Avonex) 30 µg IM every week Flu-like symptoms, anemia,
depression, development of
neutralizing antibodies
Interferon beta-1b (Betaseron) 250 µg SC every other day Injection-site reactions, flu-like
symptoms, depression,
hematologic/liver
abnormalities, development of
neutralizing antibodies
Interferon beta-1b (Rebif) 44 µg SC three times a week Flu-like symptoms, anemia,
depression, development of
neutralizing antibodies
Glatiramer acetate (Copaxone) 20 mg SC daily Injection-site reactions,
injection-related chest pain and
shortness of breath
Natalizumab (Tysabri) 300 mg IV every 4 wk Progressive multifocal
leukoencephalopathy,
hepatotoxicity, hypersensitivity
reaction
Fingolimod (Gilenya) 0.5 mg PO every day Bradycardia, leukopenia,
macular edema
Dimethyl fumarate (Tecfidera) 240 mg PO bid Flushing, lymphopenia,
gastrointestinal intolerance
Teriflunomide (Aubagio) 7–14 mg qD Hair loss, transaminitis, and
gastrointestinal symptoms,
teratogenicity
Alemtuzumab (Lemtrada) First course: 60 mg IV over 5 d. Infusion reactions, autoimmune
Second course, 12 mo later: 36 disease, increased cancer risk
mg IV over 3 d
Ocrelizumab (Ocrevus) 600 mg IV every 6 mo Infusion reactions, upper
respiratory tract infection,
cannot be administered to
patients with active hepatitis B
infection
IM, intramuscular; IV, intravenous; PO, by mouth; SC, subcutaneous.
 In patients who no longer respond to interferons or glatiramer acetate or
who have progressive disease from onset, other immunosuppressive agents
may be used. Natalizumab is a monoclonal antibody against alpha-4-
integrin that prevents lymphocytes and monocytes from crossing the blood–
brain barrier. It is administered as a series of monthly infusions. Although it
is likely more effective than interferons in preventing relapses and disease
progression, natalizumab is associated with a small but significant risk of
developing progressive multifocal leukoencephalopathy (PML), an
untreatable and often fatal disorder. Patients without antibodies to John
Cunningham (JC) virus (the virus that produces PML) are at a lower risk for
PML, and these antibodies should be measured prior to starting treatment
with natalizumab. In addition, natalizumab should not be used in
combination with other immunomodulatory agents used to treat MS.
Fingolimod is a mixed agonist/antagonist of the sphingosine-1P1-
receptor. It was the first oral medication approved for use in MS. Its main
activity in MS is thought to be sequestration of autoreactive T cells in
lymph nodes. The most serious potential side effects of fingolimod are
bradycardia and macular edema. Thus, patients must be monitored with an
electrocardiogram during the first administration and undergo ocular
coherence tomography to screen for macular edema.
Dimethyl fumarate is another oral medication used to treat MS. Its exact
mechanism is uncertain. Potential side effects include flushing,
lymphopenia, and gastrointestinal intolerance.
Teriflunomide is an oral antimetabolite that is effective in reducing
relapse rate in MS. The side effects to monitor for include hair loss,
transaminitis, and gastrointestinal symptoms. It is highly teratogenic and
should be used cautiously in women of childbearing age.
Alemtuzumab is a CD52 monoclonal antibody indicated for patients with
relapsing forms of MS who have failed two other MS medications.
Potential side effects include infusion reactions, a precipitation of
autoimmune disease, and an increased risk for malignancy.
Ocrelizumab is a CD20 monoclonal antibody that is indicated for
relapsing-remitting and primary progressive forms of MS. It is administered
intravenously at a dose of 600 mg every 6 months. Side effects include
infusion reactions and upper respiratory tract infections. It is
contraindicated in patients with active hepatitis B infection.
 Several of the symptomatic complications that accompany MS have
specific treatments. Fatigue is often the most disabling and persistent
symptom of MS. Good sleep hygiene and a gentle exercise program may be
helpful. Medication treatment options include amantadine, aspirin,
modafinil, and amphetamines. Spasticity can be managed with baclofen,
diazepam, tizanidine, or botulinum toxin injections. Bladder dysfunction
can be managed with anticholinergic agents (for urinary urgency) and with
intermittent self-catheterization. It is particularly important to address
urinary problems in order to prevent recurrent infections, which can trigger
MS relapses or lead to chronic renal disease. Tremor and ataxia are
disabling MS symptoms that are often difficult to treat.

KEY POINTS
● Acute MS relapses are treated with intravenous corticosteroids.
● Disease-modifying agents are used to prevent disease flares and are possibly effective in
preventing the accumulation of disability.
● Symptomatic therapies include those for spasticity and bladder dysfunction.

ACUTE DISSEMINATED
ENCEPHALOMYELITIS
Acute disseminated encephalomyelitis (ADEM) is a monophasic illness
leading to areas of demyelination within the CNS, commonly following an
antecedent viral infection or vaccination. ADEM may be difficult to
distinguish from the initial presentation of MS.

CLINICAL AND RADIOLOGIC MANIFESTATIONS

As in MS, almost any neurologic symptom or sign can occur, depending on
the location of the demyelinating lesions. In ADEM, the lesions are
multiple and are frequently more patchy, bilateral, and confluent than in
MS, where the lesions may be more discrete. ADEM lesions have a
predilection for the posterior cerebral hemispheric white matter. Clinically,
behavioral and cognitive abnormalities and seizures are often seen in
ADEM, whereas they are uncommon until the late stages of MS.
Radiologically, all areas of demyelination in ADEM appear acute and may
enhance with gadolinium.

DIAGNOSTIC EVALUATION
The diagnosis of ADEM may be suspected on the basis of clinical
presentation and radiologic findings. CSF typically will show a
lymphocytic pleocytosis (usually with more white blood cells than seen in
MS) and an elevated protein. OCBs are rarely present. When the illness is
indistinguishable clinically or radiologically from the initial episode of MS,
a definitive diagnosis of MS may not be possible until a second episode of
neurologic dysfunction occurs.

PROGNOSIS AND TREATMENT

By definition, ADEM is a monophasic illness with a generally favorable
outcome. A course of intravenous corticosteroids is typically administered
to shorten the duration of the episode and lessen the severity of the
symptoms.

KEY POINTS
● ADEM is a monophasic disorder characterized by demyelination of the CNS.
● It is often difficult to distinguish ADEM from MS at presentation, and time is required to
establish the diagnosis.

NEUROMYELITIS OPTICA (DEVIC

DISEASE)
Neuromyelitis optica (NMO) is characterized by the development of
transverse myelitis and ON. The two components of the disorder may
develop simultaneously or there may be delay of one or even two years
between them. Demyelination of the brain should be absent or relatively
minor. Pain is a more common and severe component of the transverse
myelitis and ON of NMO than is seen in MS, and the deficits tend to be
more severe in NMO than in MS. MRI of the spine in NMO is more likely
to show lesions that extend over several segments of the cord and to involve
an individual level of the cord in a complete rather than a patchy fashion.
CSF pleocytosis, sometimes with a neutrophilic pleocytosis, is also seen
with greater frequency in NMO than in MS. The diagnosis of NMO is
confirmed with greatest certainty by finding antibodies to the aquaporin-4
channel (NMO Ab). For patients who are NMO Ab-negative, myelin
oligodendrocyte glycoprotein antibodies (MOG Ab) may be present. It is
important to investigate thoroughly for NMO, because treatments that are
used for MS are often harmful to patients with NMO. Acute treatment of
NMO includes steroids and sometimes plasmapheresis for patients who do
not improve quickly. Chemotherapeutic agents such as azathioprine,
mycophenolate mofetil, and rituximab are used to prevent recurrence. The
prognosis is often poor, with patients developing paralysis and blindness in
the long term.

LEUKOENCEPHALOPATHIES
Progressive multifocal leukoencephalopathy is characterized by
dementia, focal cortical dysfunction, and cerebellar abnormalities. It is seen
almost exclusively in patients with AIDS, leukemia, lymphoma, and other
immunocompromised states (particularly in patients treated for MS with
natalizumab). The JC virus is the causative agent and leads to
demyelination by infecting oligodendrocytes. MRI characteristically shows
multiple foci of white matter abnormalities, particularly in the posterior
regions of the brain. CSF analysis is usually normal. So far, treatments for
PML have not been particularly effective.
Posterior reversible encephalopathy syndrome (PRES) is a
leukoencephalopathy that develops in the context of rapidly developing
hypertension, eclampsia, or due to calcineurin-inhibiting
immunosuppressants used to prevent organ transplant rejection (tacrolimus
and cyclosporine). Most commonly, this condition is characterized by an
acute confusional state and cortical visual loss (blindness with preserved
pupillary reactivity). MRI shows posterior white matter hyperintensities on
T2-weighted images. PRES can be treated by addressing the underlying
cause: correcting hypertension, treating eclampsia, or lowering the dose of
the offending immunosuppressant. Calcium channel blockers may be
effective. Despite its name, PRES is not always a reversible syndrome and
can result in coma or death.

CLINICAL VIGNETTES

VIGNETTE 1
A 24-year-old woman presents with 3 days of retrobulbar pain and a
progressive loss of visual acuity in the right eye. On examination, she
has an acuity of 20/70 in the right eye and 20/20 in the left eye. She has
a RAPD and red desaturation on the right. The remainder of her
neurologic examination is normal.
1. What is the most appropriate diagnostic test at this point?
a. Computed tomography (CT) scan of the brain with and without
contrast
b. Lumbar puncture with measurement of OCBs
c. Measurement of aquaporin-4 antibodies
d. MRI of the brain with and without contrast
e. Visual evoked potentials
2. The patient’s MRI shows contrast enhancement of the right optic
nerve and three periventricular white matter lesions, one of which
enhances with contrast. What is the most appropriate initial
management?
a. Glatiramer acetate
b. Interferon B-1b
c. Intravenous methylprednisolone
d. High-dose oral prednisone followed by a taper
e. Plasma exchange
3. The patient is treated with intravenous methylprednisolone. On the
basis of her clinical presentation and imaging studies, you make a
diagnosis of MS and choose to start a disease-modifying agent.
Which of the following is true about disease-modifying therapy?
a. Fingolimod is associated with tachycardia.
 b. Glatiramer acetate increases the risk of progressive multifocal
leukoencephalopathy.
c. Interferon B-1b decreases the rate of relapses in MS.
d. Dimethyl fumarate is the only oral therapy available for MS.
e. Natalizumab and interferon B-1b combination therapy is used
most often for primary progressive MS.

VIGNETTE 2
A 31-year-old woman develops severe, acute mid-back pain followed
by weakness of both legs over the course of several days. On
examination, she has dense weakness and numbness in both legs, a
sensory level for both pinprick and vibratory perception at T6, and
bladder incontinence. MRI of the thoracic spine is performed and shows
a confluent T2 white matter hyperintensity extending from T1 to T5.
1. Which of the following features in this case is atypical for MS?
a. Age of onset
b. Bladder incontinence
c. Extensive spinal cord lesion
d. Female gender
e. Loss of vibratory perception
2. The history of which of the following would be most likely to help
establish the diagnosis:
a. A 3-day episode of cerebellar ataxia 3 years ago
b. A diagnosis of Lyme disease
c. An episode of severe bilateral visual loss a year ago
d. An earlier episode of incontinence of bowel and bladder
e. A family history of MS
3. On further questioning, the patient reports an episode of severe
bilateral visual loss that occurred a year ago and was treated with
intravenous steroids with partial improvement. Which of the
following tests would be most helpful in establishing the diagnosis?
a. Lumbar puncture to evaluate for neutrophilic pleocytosis
b. Measurement of aquaporin-4 antibodies
c. MRI of the brain, with and without contrast
d. MRI of the cervical spine, with and without contrast
e. Visual evoked potentials
ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer D:
This patient presents with ON. The most appropriate diagnostic test is
MRI of the brain with and without contrast to look for other lesions that
would suggest MS. MRI also serves a second purpose: to confirm the
diagnosis of ON. CT scan is less useful than MRI in diagnosing MS or
ON. Although OCBs in the CSF would support the diagnosis of MS,
they are not as useful as MRI in the initial evaluation. Aquaporin-4
antibodies are present in NMO, but the patient’s history is not
suggestive of that diagnosis. Although visual evoked potentials could
confirm the presence of ON, the clinical history and examination are
sufficient in this case. The main clinical utility of visual evoked
potentials in MS is to investigate for prior optic nerve lesions.

VIGNETTE 1 QUESTION 2
2. Answer C:
The Optic Neuritis Treatment Trial demonstrated that intravenous (but
not oral) steroids hastened recovery from an episode of ON and delayed
the development of MS in the short term. Glatiramer acetate and
interferon B-1b are disease-modifying agents that are mostly used for
relapsing-remitting MS. They can be started at this stage of the disorder,
but intravenous steroids are the appropriate initial treatment. Plasma
exchange is sometimes used to treat aggressive MS but not for ON.

VIGNETTE 1 QUESTION 3
3. Answer C:
Interferon B-1b decreases the rate of relapses in relapsing-remitting MS
and is often initiated at disease diagnosis. Dimethyl fumarate,
fingolimod, and teriflunomide are oral medications available for the
treatment of MS. Fingolimod may lead to bradycardia, not tachycardia.
Natalizumab, rather than glatiramer acetate, increases the risk of
progressive multifocal leukoencephalopathy. Natalizumab should not be
combined with interferon B-1b or other immunosuppressants.
VIGNETTE 2 QUESTION 1
1. Answer C:
Longitudinally extensive spinal cord lesions are more consistent with
idiopathic transverse myelitis or NMO than they are with MS. The other
features listed are all typical of MS.

VIGNETTE 2 QUESTION 2
2. Answer C:
The patient presents with an episode of severe, painful transverse
myelitis. Although this may occur in isolation, the diagnosis of NMO
needs to be considered. A prior episode of severe (especially bilateral)
visual loss would support this diagnosis. A prior episode of cerebellar
ataxia or family history of MS would be more consistent with a
diagnosis of MS. Lyme disease, in rare cases, may present with
demyelination of the CNS, but this is uncommon. Incontinence of
bowel and bladder might occur in any severe myelopathy and would not
change the clinical impression of NMO in this case.

VIGNETTE 2 QUESTION 3
3. Answer B:
Finding aquaporin-4 antibodies would support the diagnosis of NMO.
Lumbar puncture may show neutrophilic pleocytosis in NMO, but this
is less sensitive than finding aquaporin-4 antibodies. MRI of the brain,
with and without contrast, is typically normal in NMO, although
patients with NMO-spectrum disorders may have an abnormal brain
MRI. MRI of the cervical spine may show other demyelinating lesions
but would not change the diagnosis. Visual evoked potentials may
confirm the clinical history of ON but would not establish the diagnosis
of NMO as clearly as aquaporin-4 antibodies would.
 21 Infections of the Nervous System

It is important for physicians to be familiar with the common types and

manifestations of nervous system infections for several reasons. First, this
category of neurologic illness can be quite acute in presentation. Additionally,
some nervous system infections can have severe and potentially life-
threatening consequences. Finally, for many infections, specific therapies are
available, and tailored to the identified etiologic organism.

BACTERIAL INFECTIONS
Three common and important forms of bacterial nervous system infection are
acute bacterial meningitis, brain abscess, and spinal epidural abscess.

ACUTE BACTERIAL MENINGITIS

Clinical Findings
Acute bacterial meningitis is a medical emergency. It is critical for all
physicians to know its presentation, its initial diagnostic evaluation, and the
urgency with which a potential case of bacterial meningitis needs to be
addressed. The cardinal findings include headache, fever, and neck stiffness.
Patients can also be confused or have a depressed level of consciousness,
develop seizures, or have other focal neurologic symptoms or signs, depending
on the extent to which the meningeal infection or inflammatory process also
affects the brain parenchyma (thus causing meningoencephalitis). In
immunosuppressed patients, as well as in the very elderly, there may be no
fever, so it is vital to have a high degree of clinical suspicion in these
populations. On exam, patients often have nuchal rigidity, that is, rigidity with
flexing the neck forward. Two classically described physical signs associated
with meningitis (Fig. 21-1), although not specific to the bacterial form, are:
FIGURE 21-1. Kernig sign is elicited by flexion of the hip at 90 degrees. If the patient experiences
pain by extending the knee, the Kernig sign is positive. Brudzinski sign is elicited by flexing the patient’s
neck. The sign is positive if the patient flexes the hips and knees in response. (Reused with permission
from Lippincott’s Clinical Simulations. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.)

• Kernig sign: The patient lies supine, and the knee is extended passively
while the hip is flexed. If the patient is unable to extend the knee because of
pain, the sign is positive.
• Brudzinski sign: An involuntary flexion at the hips when the neck is
flexed.

Etiology
The most common organisms causing bacterial meningitis vary depending on
the patient’s age at presentation (Table 21-1). The introduction of vaccines
against Streptococcus pneumoniae (“pneumococcus”), Neisseria meningitides
(“meningococcus”), and Haemophilus influenzae has substantially reduced the
incidence of acute bacterial meningitis among children in the United States. In
most cases, bacteria reach the subarachnoid space by hematogenous spread
from the respiratory tract, although bacterial meningitis may also be a direct
sequela of traumatic or mechanical invasion of the subarachnoid space, such
as after neurosurgical procedures or open head injury. It is also possible to
have direct infiltration of the subarachnoid space from parameningeal foci,
such as the sinuses.

TABLE 21-1. Common Causes of Meningitis by Age, and Empiric

Antibiotic Treatment
Age Bacterial Empiric Treatments
0–3 mo —Group B Streptococcus Ampicillin + cefotaxime
—Streptococcus pneumonia OR ampicillin + an aminoglycoside
 —Listeria monocytogenes
—Escherichia coli
3–24 mo —S. pneumonia Vancomycin + a third-generation
—Neisseria meningitides cephalosporin
—Haemophilus influenza type B
—Group B Streptococcus
2–18 y —N. meningitides Vancomycin + a third-generation
—S. pneumonia cephalosporin
Older adults —S. pneumonia Vancomycin + ampicillin + a third-
—N. meningitides generation cephalosporin
—H influenza, type B
—Group B Streptococcus
—L. monocytogenes

Diagnostic Workup
The critical test in the diagnosis of acute bacterial meningitis is cerebrospinal
fluid (CSF) analysis from a lumbar puncture (LP). Because of the concern that
LP may precipitate brain herniation in the presence of a focal intracranial mass
with increased intracranial pressure, head imaging (usually with computed
tomography [CT], because it is available more readily) should be performed
before LP when papilledema is present on fundoscopic examination or if there
is any focal sign on neurologic examination suggesting the possibility of an
intracranial lesion. Many neurologists advocate head imaging prior to LP
under any circumstances with an acute presentation.
The characteristic CSF profile in acute bacterial meningitis includes an
elevated white blood cell (WBC) count, with a predominance of
polymorphonuclear leukocytes (generally never acceptable in a CSF sample),
elevated protein, and low glucose (<40 mg/dL or less than two-thirds of a
simultaneously measured serum glucose level) (Table 21-2). The differential
on the CSF WBC must be interpreted with caution early in the course of
meningitis because patients with bacterial meningitis may present initially
with a lymphocytic predominance. Patients with viral meningitis may also
have a neutrophil predominance early in the course. Severely
immunosuppressed patients with pancytopenia may also not have classic CSF
patterns. CSF Gram stain can demonstrate the bacteria and narrow the
differential diagnosis of causative organisms. CSF cultures in acute bacterial
meningitis can often identify the specific organism, which can then be tested
for antibiotic sensitivity.

TABLE 21-2. Common Cerebrospinal Fluid Patterns in Different Forms of

 Meningitis
Bacterial Viral Fungal TB
Opening Elevated Normal May be normal or May be normal or
pressure elevated elevated
WBC ≥100 cells/µL <100 cells/µL <500 cells/µL <500 cells/µL
Cell type Polymorphonucleocytes Lymphocytes Lymphocytes Lymphocytes
Glucose Low May be normal Low Low
Protein Elevated Elevated Elevated Elevated
TB, tuberculosis; WBC, white blood cells.

Because of the potentially life-threatening nature of acute bacterial

meningitis, a prolonged delay in obtaining CSF may necessitate the institution
of empiric antibiotic coverage prior to LP—using antibiotics that are effective
against the most likely organisms, at doses that ensure adequate penetration
into the subarachnoid space, or “meningitis doses.” In this case, CSF cultures
may not grow organisms if they were not obtained until well after antibiotic
therapy was begun, and it may be necessary to complete an entire course of
empiric therapy.

Treatment
Appropriate antibiotic therapy needs to be administered promptly upon the
diagnosis of acute bacterial meningitis, with specific drugs initially chosen on
the basis of the most likely organisms, and subsequently modified on the basis
of Gram stain or culture results (Table 21-1). In addition to the antibacterial
therapy, some adjunctive therapies may also be helpful in certain situations.
Corticosteroids are often used in children in an attempt to prevent some long-
term complications of acute bacterial meningitis, such as deafness.

KEY POINTS
● Acute bacterial meningitis is a medical emergency.
● The typical clinical presentation consists of headache, fever, neck pain, or stiffness, and often,
altered consciousness.
● Immunocompromised patients may lack some of the cardinal features of meningitis such as
fever.
● The classic CSF profile of bacterial meningitis demonstrates a high WBC count (mostly
polymorphonuclear leukocytes), high protein, and low glucose.
● Antibiotic treatment should be initiated early and is tailored on the basis of the identification
of responsible organisms and penetration into the subarachnoid space.
BRAIN ABSCESS

Clinical Findings
Brain abscesses typically present much like any other focal intracranial
lesions, with headache, focal neurologic signs (that depend on the location of
the abscess), seizures, and potentially, signs of increased intracranial pressure.
Fever may be present, but this is not invariable.

Etiology
Solitary brain abscesses often arise from invasion of the intracranial space
from neighboring sites of infection, such as the sinuses, or from direct open
trauma or mechanical instrumentation. The first stage of brain abscess
development is often cerebritis in which there is an active infection in the
brain but not yet walled off. CSF studies are abnormal, and imaging studies or
electroencephalogram (EEG) or both may also be abnormal. In the second
stage, the infection becomes organized and walled off to form a classic
abscess. Multiple brain abscesses are typically the result of hematogenous
dissemination, such as from infective bacterial endocarditis, or with
immunocompromised states. Responsible organisms depend on the etiology:
respiratory pathogens may invade from the sinuses; abscesses from trauma or
instrumentation are often skin flora; multiple abscesses are often caused by
organisms that cause infective bacterial endocarditis. Most abscesses contain
multiple organisms, often a mixture of aerobic and anaerobic pathogens (Table
21-3).

TABLE 21-3. Causes of Brain Abscesses

Source of Infection Bacterial Causes
Traumatic brain injury Staphylococcus aureus
Staphylococcus epidermidis
Pseudomonas aeruginosa
Enterobacter species
Neurosurgery Staphylococcus aureus
Staphylococcus epidermidis
Pseudomonas aeruginosa
Propionibacterium acnes
Streptococcus species
Hematogenous spread Staphylococcus aureus
Streptococcus viridans
Klebsiella pneumoniae
Ear Proteus mirabilis
 Streptococcus milleri group organisms
Streptococcus pneumonia
Dental Streptococcus species
Bacteroides fragilisus

Diagnostic Workup
The diagnosis of brain abscess is usually made by neuroimaging. CT or
magnetic resonance imaging (MRI) with intravenous contrast agents will
usually demonstrate a mass lesion, often surrounded by “ring enhancement”
and signs of central necrosis within the brain parenchyma (Fig. 21-2). There
may be surrounding edema. At the top of the radiologic differential diagnosis
are malignant neoplastic lesions, which often have a similar ring-enhancing
mass appearance. Sometimes, single photon emission computed tomography
(SPECT) scanning can help differentiate a neoplastic process from an abscess.
Depending on the source of the infection, blood cultures may identify the
responsible organisms, but neurosurgical drainage is often necessary for
definitive pathogen identification.

FIGURE 21-2. Presentation of brain abscess on CT and MRI. On noncontrast CT (A), the abscess
appears hypodense (asterisk). On MRI (B), the edema (arrow) surrounding the abscess appears
hyperintense, and contrast enhancement (C) visualizes the capsule (arrow). On diffusion-weighted
imaging (D), the abscess cavity appears hyperintense (arrow). [CT, computed tomography; MRI,
magnetic resonance imaging.] (Reprinted with permission from Scheld WM, Whitley RJ, Marra CM.
Infections of the Central Nervous System. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2014. Figure 31.15.)

Treatment
Prolonged courses of intravenous antibiotics, either chosen empirically for
broad-spectrum coverage of aerobic and anaerobic organisms or tailored
specifically on the basis of culture results, are the mainstay of treatment for
brain abscesses. If the lesion does not respond to antibiotics, surgical drainage
may be required. If the lesion causes mass effect and the patient is at risk of
herniation, surgical drainage may also be necessary.

CENTRAL NERVOUS SYSTEM EMPYEMA

Collections of pus, known as empyemas can occur in the central nervous
system (CNS) as in other tissues. CNS empyemas most commonly occur in the
subdural or epidural spaces. One must have a high degree of clinical suspicion
because the empyema may be difficult to differentiate from a subdural
hematoma on a scan. Consequently, these lesions are missed frequently.
Patients may present with fever and headache. The infection typically arises
from direct spread from an adjacent tissue (sinus, bone, or skin) or
hematogenous spread (Fig. 21-3).

FIGURE 21-3. Frontal sinusitis with intracranial empyema. T1-weighted, contrast-enhanced image
confirming likely subcortical infarction. Blue arrow: empyema. Violet arrow: subcortical infarct.
(Reprinted with permission from Mancuso AA. Head and Neck Radiology. 1st ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2010. Figure 13.16.)

SPINAL EPIDURAL ABSCESS

Clinical Findings
Spinal epidural abscesses typically present with the combination of neck or
back pain and focal neurologic signs consistent with spinal cord compression
or cauda equina involvement, depending on the spinal level of the abscess. For
thoracic or lumbar abscesses, clinical signs may include leg weakness, sensory
loss with a discernible sensory level on examination, and urinary and sexual
dysfunction. Cervical abscesses may present with the same symptoms as those
at lower levels, but the arms may be involved as well, resulting in arm
weakness or sensory symptoms there, or both. Fever is not necessarily present.
Symptoms may come on acutely or more insidiously; an acute, rapid
presentation raises concern for a spinal cord infarction.

Etiology
Spinal epidural abscesses can be sequelae of spinal instrumentation, including
epidural or spinal anesthesia or spine surgery. In these cases, the responsible
organisms are often skin pathogens such as staphylococcal species. Abscesses
can also be the result of spread from more anterior infections, including
vertebral body osteomyelitis or diskitis.

Diagnostic Workup
If there is a clinical suspicion on the basis of history and exam, spine imaging
should be obtained urgently because an intraspinal lesion such as an epidural
abscess can cause cord compression with resulting paralysis. In general, the
administration of contrast (with either CT or MRI) can help demonstrate the
enhancing nature of spinal epidural abscesses (Fig. 21-4). LP is
contraindicated in most situations before the anatomic extent of the lesion is
defined clearly by imaging, because there is a theoretical possibility of seeding
the subarachnoid space with bacteria using the spinal needle. As with
intracranial abscesses, blood cultures can sometimes demonstrate the
responsible organisms, but in many cases, radiologically guided biopsy or
surgical drainage for microbiologic studies is necessary.

KEY POINTS
● Abscesses affecting the CNS are mass lesions that are often ring-enhancing on imaging
studies with contrast.
● They present with focal neurologic signs that are dependent on their intracranial or spinal
location.
● Prolonged courses of intravenous antibiotics are the mainstay of treatment, but surgical
drainage is necessary sometimes.
● MRI or CT imaging should be obtained urgently in patients for whom there is a high clinical
concern for epidural abscess, because there is a risk of cord compression from these lesions.
● Patients with evidence of cord compression or a cauda equina syndrome often require surgical
decompression in addition to antibiotic treatment for the abscess.
FIGURE 21-4. Sagittal T2-weighted MRI of the lumbosacral spine demonstrating a large spinal
epidural abscess (orange arrow). [MRI, magnetic resonance imaging.] (Reprinted with permission from
Rathmell JP. Atlas of Image-Guided Intervention in Regional Anesthesia and Pain Medicine. 2nd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2011. Figure 5.27B.)

Treatment
Prolonged courses of intravenous antibiotics are the mainstay of treatment for
spinal epidural abscesses, although in some cases neurosurgical drainage is
necessary. When a clinical syndrome of acute cord compression or cauda
equina involvement is present, surgical decompression may be required
urgently.

TUBERCULOSIS
One-third of the global population is infected with tuberculosis. In the United
States, it is less common (3.0 cases per 100,000 people). Mycobacterium
tuberculosis affects the nervous system in several ways: tuberculous
meningitis, intracranial tuberculomas, and Pott’s disease (tuberculoma of the
spine).

Tuberculous Meningitis
Tuberculous meningitis arises from hematogenous dissemination of
mycobacteria from a pulmonary source. A number of features distinguish
tuberculous meningitis from acute pyogenic bacterial meningitis (described
previously). First, meningitis caused by M. tuberculosis has a predilection for
affecting the basal meninges (those at the base of the brain) and can thus
present with cranial nerve palsies in addition to the usual features of acute
bacterial meningitis. A basal meningitis can also lead to hydrocephalus or
brain infarctions from inflammation affecting cerebral vessels. Second,
tuberculous meningitis tends to have a more subacute or chronic, insidious
presentation than acute bacterial meningitis, so a prolonged prodrome of
malaise and fairly nonspecific constitutional symptoms may precede the
appearance of frank neck pain or stiffness. Finally, the CSF profile in
tuberculous meningitis typically demonstrates a leukocytosis with lymphocytic
predominance, rather than polymorphonuclear predominance (except initially),
and the CSF glucose is often very low (Table 21-2). Acid-fast bacilli staining
of the CSF can identify mycobacterial infection, but culture of this organism
takes weeks to grow, and some never become positive. Fortunately,
polymerase chain reaction (PCR) testing of mycobacterial antigens is
available. The treatment of tuberculous meningitis requires a regimen of
multiple antituberculous drugs that penetrate the intrathecal space effectively,
usually with isoniazid, rifampin, pyrazinamide, and streptomycin.

Intracranial Tuberculoma
Tuberculomas are mass lesions caused by M. tuberculosis infection. Although
uncommon in the United States, tuberculomas are one of the most common
focal brain lesions in the developing world. Typically, they present with
features that would be expected for any inflammatory mass lesion within the
brain, including headache, focal neurologic symptoms and signs, and seizures.
They can calcify, be variably enhancing on radiologic studies with contrast,
and sometimes be associated with hydrocephalus. The radiologic differential
diagnosis typically includes brain tumor, bacterial abscess, or cysticercosis
(see below). Appropriate treatment includes prolonged courses of
antituberculous therapy and neurosurgical intervention if needed.

KEY POINTS
● Tuberculosis affects the nervous system in several different ways, including meningitis, focal
brain lesions, or focal spine lesions.
● Tuberculous meningitis has a predilection for the basal meninges, is typically insidious, can
present with cranial nerve palsies, and has a different CSF profile from bacterial meningitis.
 Pott’s disease, or tuberculosis of the spine, affects the nervous system when there is direct
●
invasion into the epidural space.
● Diagnosis is based on history, radiographic findings, and cultures.

Pott’s Disease
Pott’s disease, or tuberculosis of the spine, typically presents with neurologic
symptoms and signs when a vertebral body infection extends into the epidural
space, leading to subacute spinal cord or cauda equina compression,
depending on the level of involvement. Fever and back pain are common.
Spread through disk spaces to adjacent vertebral bodies often suggests Pott’s
disease (Fig. 21-5), usually differentiating it from metastatic cancer. Treatment
includes antituberculous drugs and spine stabilization procedures if necessary.

LYME DISEASE
Lyme disease, caused by the spirochete Borrelia burgdorferi and transmitted
by the deer tick, is a common infection in the northern United States and in
Europe. Lyme disease affects the nervous system in several ways, including
Lyme-associated meningitis, cranial nerve palsies, and a syndrome of
polyradiculopathy.
FIGURE 21-5. Tuberculous spondylitis (Pott’s disease). A vertebral body is almost completely
replaced by tuberculous tissue. Note the preservation of the intervertebral disks. (Reprinted with
permission from Rubin R, Strayer DS, Rubin E. Rubin’s Pathology. 6th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2011. Figure 26.22.)

Clinical Findings
Although the typical rash of erythema chronicum migrans (Fig. 21-6) can
occur within the first week after a bite from an infected tick, neurologic
manifestations typically do not appear until the more disseminated stage of
Lyme disease, several weeks after the bite. Headache, neck stiffness, and
myalgias may develop into more frank signs of meningismus, along with
cranial nerve palsies. Patients commonly present with a unilateral or bilateral
facial nerve (CN VII) weakness (Fig. 21-7). In the persistent stage of systemic
disease, several months after the initial bite, there may be a polyradiculopathy
(often with significant pain), polyneuropathy, encephalopathy (with signs of
white matter signal change on MRI), or combinations of these.
FIGURE 21-6. Erythema migrans, the characteristic rash of Lyme disease. This photograph depicts
the “bull’s-eye” pattern rash at the site of a tick bite on the upper arm of a woman who subsequently
contracted Lyme disease. (Reprinted with permission from Engleberg NC, Dermody T, DiRita V.
Schaechter’s Mechanisms of Microbial Disease. 5th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2012. Figure 25.2.)
FIGURE 21-7. Facial weakness due to a seventh nerve lesion, as can be seen in Lyme disease.
Patients exhibit a lower motor neuron pattern of facial weakness with the features noted above.
(Reprinted with permission from Bhatnagar SC. Neuroscience for the Study of Communicative
Disorders. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Figure 1.17.)

Diagnostic Workup
Serologic tests of the blood or CSF can be diagnostic, but sometimes not until
late in the course of the disease. The Centers for Disease Control and
Prevention (CDC) has clear guidelines on the diagnostic approach to Lyme
serology (Fig. 21-8). The routine CSF profile typically demonstrates a
lymphocytic pleocytosis with elevated protein and normal glucose. A PCR
assay of the CSF is available for spirochetal antigen. This is very sensitive but
can give a false positive in patients with neurosyphilis. Serology may also
remain positive for years after treatment, which poses a challenge for patients
in establishing a new diagnosis. In cases of encephalopathy, MRI of the brain
can sometimes show patchy foci of signal change in the white matter. These
can resemble findings in patients with multiple sclerosis or migraine and may
be nonspecific. In cases of peripheral nervous system involvement,
electromyographic (EMG) and nerve conduction studies (NCS) may be useful
to identify the pattern of the polyradiculopathy or polyneuropathy.

Treatment
Patients with isolated facial weakness and negative CSF studies can often be
treated with oral antibiotics, whereas signs of more disseminated neurologic
infection suggest the need for intravenous antibiotics at dosages that can
penetrate the subarachnoid space. IV ceftriaxone, cefotaxime, and penicillin
are effective treatments for both peripheral and central Lyme disease.

FIGURE 21-8. Serologic testing for Lyme disease. [EIA enzyme immunoassay; IFA,
immunofluorescence assay; IgG, immunoglobulin G; IgM, immunoglobulin M.] (Based on Centers for
Disease Control and Prevention. Health Care Providers. CDC guidelines, 2017.
https://www.cdc.gov/lyme/healthcare/index.html.)

KEY POINTS
● Lyme disease, caused by the spirochete B. burgdorferi, is a common infection in the northern
United States and in Europe.
● The CDC has clear diagnostic criteria on diagnosis.
● Early neurologic manifestations of Lyme disease include an aseptic meningitis, facial nerve
weakness, or both, within weeks after infection.
● Later neurologic manifestations include leukoencephalopathy, cranial neuropathies, and
painful polyradiculopathy or polyneuropathy or both, sometimes months after the initial
infection.

VIRAL INFECTIONS
Most viral infections of the nervous system present as one of several clinically
recognized syndromes. The evolving field of neuroinfectious diseases
continues to identify new viruses that can present with CNS manifestations. It
is, therefore, important for clinicians to be aware of the endemic pathogens
and screen patients for travel or other exposures that would put them at risk for
exposure to pathogens from other regions. Viral meningitis and encephalitis
are discussed in the following sections.

VIRAL MENINGITIS
Viral meningitis is commonly caused by enteroviruses, such as
Coxsackievirus, or arboviruses, such as West Nile virus. Clinically, the
presentation may be very similar to that of acute bacterial meningitis, and it is
mainly the latter that needs to be considered and ruled out immediately, even if
viral meningitis is suspected to be more likely. The CSF profile differs from
that of acute bacterial meningitis, in that viral meningitis usually features a
lymphocytic predominance of WBCs (except initially, when
polymorphonuclear leukocytes can be present) and an elevated protein without
a concomitant significant lowering of CSF glucose (Table 21-2). Gram stain
and bacterial culture of CSF are, of course, unrevealing. Testing the blood and
CSF for virus-specific serologies and PCR assays can help identify the
responsible virus. Treatment generally involves just supportive care, unless
herpes simplex virus (HSV) 1 is suspected.

ENCEPHALITIS
Viral encephalitis, which affects the brain parenchyma itself, usually presents
with headache, fever, altered consciousness or behavior, and often seizures,
focal neurologic abnormalities, or both. Although most viruses causing
encephalitis have no specific anti-infective therapy available, encephalitis
caused by HSV1 leads to some distinct clinical features and warrants specific,
emergency therapy. HSV1 encephalitis has a predilection for the base of the
brain, specifically including the medial temporal lobes and orbitofrontal
regions of the cortex (Fig. 21-9). Limbic dysfunctions, including complex
partial seizures of mesial temporal lobe origin, olfactory hallucinations, and
memory disturbances (including sometimes profound anterograde amnesia and
some degree of retrograde amnesia), are common parts of the clinical
presentation. The CSF in HSV1 encephalitis often demonstrates an elevated
red blood cell count in addition to leukocytosis (and thus needs to be
distinguished from traumatic LP results). A CSF PCR test is available for
HSV1. EEG recording may demonstrate periodic epileptiform discharges over
one or both temporal regions, particularly after several days of infection.
HSV1 encephalitis is treated with a prolonged course of intravenous acyclovir.
This drug can be started empirically if there is initial clinical or laboratory-
based suspicion for HSV1 encephalitis, while awaiting results of the more
definitive CSF PCR test to return, which can take several days. Other cases of
viral encephalitis are managed with supportive care, including analgesics for
headache and anticonvulsants for seizures, as appropriate.

FIGURE 21-9. MRI findings in HSV encephalitis. T2-weighted coronal MRI demonstrating
predominantly right mesial temporal hyperintensity and swelling in presumed HSV1 encephalitis. [HSV,
herpes simplex virus; MRI, magnetic resonance imaging.] (Reprinted with permission from Wyllie E.
Wyllie’s Treatment of Epilepsys. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure
32-3a.)

ZIKA VIRUS
Zika virus has become recognized recently as another serious cause of viral
encephalitis, transverse myelitis, and Guillain–Barré syndrome (GBS).
Clinically significant neurologic manifestations of Zika occur in about one-
quarter to one-fifth of infected patients. The virus can also be transmitted both
during pregnancy and at birth. Congenital Zika infections often cause serious
birth defects, including microcephaly, dysmorphic faces, hypertonia,
sensorineural hearing loss, eye abnormalities, and arthrogryposis; seizures are
common. Zika infections can be diagnosed by virus serology or by a real-time
reverse-transcription PCR for Zika virus RNA. Treatments include supportive
care and treatment of seizures; immune globulin has been used to treat patients
with GBS due to Zika infection.

KEY POINTS
● Viral meningitis may resemble acute bacterial meningitis but has a different CSF profile, and
specific anti-infective therapy is generally not available.
● Viral encephalitis can be caused by a number of different agents, but HSV1 encephalitis is
associated with some distinct clinical features and is treated with intravenous acyclovir.

FUNGAL INFECTIONS
There are numerous mycoses that cause nervous system infection. The most
common are Cryptococcus neoformans, Aspergillus, and various Candida
species. Others include Coccidioides immitis, blastomycosis, zygomycosis,
dematiacious (Cladophialophora), and Histoplasma capsulatum. Mycotic
infections are most common in immunosuppressed patients. The causes of
immune suppression are broad, including chronic steroid use, chemotherapy,
organ transplantation, HIV/AIDS, malignancies, and other chronic diseases.
Many fungal infection occur worldwide, but there are several with
geographically endemic regions:
• Coccidioides: Southwest US; Mexico
• Blastomyces: Mississippi valley; Northern-Central and Mid-Atlantic US
• Histoplasma: Central Mississippi and Ohio Valley; Latin America

TABLE 21-4. CNS Signs of Fungal Infections

Aspergillosis Cryptococcosis Histoplasmosis Coccidioidomycosis Candidiasis
Meningitis
Focal
mass
Stroke
syndrome
Spinal
syndrome
 It is, therefore, important to screen patients for exposures including travel.
Fungal infections present with varied neurologic syndromes. Meningitis and
intracranial mass lesions (abscesses or granulomas) are the most common
findings. The presentation of a mycotic infection is influenced by the type of
fungus and method of spread in the CNS (hematogenous vs. local). Table 21-4
outlines different neurologic syndromes associated with mycotic infections.
The CSF profiles of fungal infections are listed in Table 21-2. Diagnosis is
made by LP and serologies. Treatment with antifungal therapy is vital because
patients with fungal infections have a high mortality. The initiation of therapy
can result in immune reconstitution inflammatory syndrome, so patients
require very close monitoring. Cryptococcus is one of the most common form
of fungal meningitis and is discussed here.

CRYPTOCOCCAL MENINGITIS
Cryptococcal meningitis typically affects immunocompromised subjects but
occasionally immunocompetent people, as well. It is acquired by inhalation of
the fungus (which is present in soil and pigeon droppings) and is then
disseminated hematogenously. Cryptococcal meningitis often presents
insidiously with headache, neck pain, and confusion; fever is variably present.
The CSF profile demonstrates a lymphocytic predominance of WBCs (except
initially), elevated protein, and low glucose, which is a pattern seen across
most fungal infections. Although India Ink staining of CSF was historically a
time-honored way of detecting the presence of Cryptococcus organisms, a
rapid latex agglutination assay for cryptococcal antigen is the standard
diagnostic test now. Treatment includes the use of antifungal agents such as
amphotericin.

KEY POINTS
● Mycotic infections occur most commonly in immunocompromised individuals.
● Different fungi are endemic in different geographic regions.
● Meningitis and mass lesions are the most common clinical syndromes and often have an
insidious presentation.
● The CSF profile of fungal infections is distinct from that of most bacterial and viral infections.
PARASITIC INFECTIONS OF THE NERVOUS
SYSTEM
CNS parasitic infections remain prevalent in certain regions of the world and
have a high morbidity and mortality. Neurocysticercosis is the most common
parasitic infection, followed by toxoplasmosis. They are discussed in the
following sections. There are numerous less common parasitic infections,
including the following: American trypanosomiasis (Chagas disease),
schistosomiasis, Human African Trypanosomiasis, malaria, echinococcosis,
onchocerciasis, paragonimiasis, toxocariasis, and angiostrongyliasis.
Clinically, patients often present with seizures and sometimes with focal
neurologic deficits. Some parasitic infections also cause meningitis. LPs in
patients with parasitic infections often show eosinophilia.

TOXOPLASMOSIS
Toxoplasma gondii is an intracellular parasite that most commonly affects
humans either as a congenital infection (it is one of the TORCH infections, the
others being “other,” rubella, cytomegalovirus, and herpes simplex) or as an
intracranial infection in patients with AIDS or severe immune incompetence.
Humans are exposed through cat feces or ingestion of undercooked meat.
Clinically, toxoplasmosis in the AIDS patient presents as expected for any
intracranial mass lesion, with headache, mental status changes, seizures, and
focal neurologic signs and symptoms that depend on the lesion location. Fever
may be present. Imaging studies typically show multiple ring-enhancing
lesions in the basal ganglia or at the gray matter–white matter junction.
Serologies, CSF PCR assays, and CSF Wright or Giemsa stains can help
confirm the diagnosis. Primary CNS lymphoma is often in the radiologic
differential diagnosis in AIDS patients with such intracranial lesions (Fig. 21-
10). In some cases, brain biopsy may be necessary to make a definitive
diagnosis, particularly if empiric antitoxoplasmosis therapy has not led to any
improvement.
FIGURE 21-10. CNS toxoplasmosis. Contrast-enhanced MR shows ring-enhancing lesions, one of
which demonstrates eccentric target-like enhancement (arrowhead), a relatively specific sign for
toxoplasmosis. Note the second ring-enhancing lesion in the left thalamus (arrow). [CNS, central
nervous system; MR, magnetic resonance.] (Reprinted with permission from Scheld WM, Whitley RJ,
Marra CM. Infections of the Central Nervous System. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2014. Figure 3.16.)

NEUROCYSTICERCOSIS
Neurocysticercosis, an infection caused by the pork tapeworm Taenia solium,
is the most common parasitic infection of the CNS and one of the most
common causes of new-onset focal seizures in much of the developing world.
It is endemic in, among other places, Central and South America and is thus
commonly seen in immigrant populations in the United States. Clinically,
nervous system infection presents with seizures, headache, and signs of
increased intracranial pressure. Imaging studies demonstrate multiple cystic
lesions, which can be ring-enhancing or calcified, and often have surrounding
edema (Fig. 21-11). Anti-infective treatment includes albendazole, and
steroids are often used to control the inflammation and edema that accompany
the initial treatment because this inflammation can lead to increased
symptoms. Anticonvulsant medications are used to control seizures.
 KEY POINTS
● Toxoplasmosis, acquired from cat feces or undercooked meat, is a common cause of
intracranial mass lesions in severely immunosuppressed patients, including AIDS patients.
● Congenital toxoplasmosis is one of the TORCH infections.
● Cysticercosis, caused by a pork tapeworm, is the most common parasitic infection of the CNS
and one of the most common causes of new-onset focal seizures in the world.

NERVOUS SYSTEM COMPLICATIONS OF HIV

INFECTION
The retrovirus human immunodeficiency virus (HIV) is associated with a
variety of nervous system syndromes in about half of all infected patients.
Some of these appear to be late complications of direct HIV infection and
prolonged immunosuppression (HIV-associated dementia, vacuolar
myelopathy), some of which are due to opportunistic infections
(toxoplasmosis, cryptococcal meningitis, progressive multifocal
leukoencephalopathy), some of which reflect peripheral nervous system
involvement (discussed in Chapter 23), and some of which are neurologic
complications of antiretroviral therapy (ART).

HIV-ASSOCIATED DEMENTIA
HIV-associated dementia is a late complication of HIV infection, generally
occurring after prolonged periods of immunosuppression. Its incidence has
declined in recent years with the widespread use of combination ART.
Clinically, this syndrome presents as a subcortical dementia, with cognitive
impairment and psychomotor slowing. MRI can show patchy T2
hyperintensity in the white matter, as well as cerebral atrophy. There is no
specific treatment other than aggressive ART and supportive therapies. Prior to
ART, the development of HIV-associated dementia was often seen as one of
the final stages of terminal illness due to HIV.
 FIGURE 21-11. Neurocysticercosis: contrast-enhanced CT (A) showing a single, small, ring-
enhancing lesion with a well-defined eccentric scolex, and perilesional edema (arrow). T2-weighted
MRI (B) showing a single cysticercosis lesion with a scolex and bright perilesional edema (arrow).
[CT, computed tomography; MRI, magnetic resonance imaging.] (Reprinted with permission from
Shaffner DH, Nichols DG. Rogers’ Textbook of Pediatric Intensive Care. 5th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2015. Figure 91.11a.)

VACUOLAR MYELOPATHY
Vacuolar myelopathy is also a late complication of HIV infection that occurs
with severe immunosuppression. Clinically, this disorder resembles the
subacute combined degeneration syndrome associated with vitamin B12
deficiency, in that patients develop posterior column signs and symptoms (loss
of vibration and joint position sense, with sensory ataxia) and signs of
corticospinal tract dysfunction (spasticity and hyperreflexia) bilaterally.
Urinary and sexual dysfunction may also occur. Treatment involves ART and
supportive therapy.
PROGRESSIVE MULTIFOCAL
LEUKOENCEPHALOPATHY
Progressive multifocal leukoencephalopathy (PML) is a demyelinating
disease of the CNS caused by infection of oligodendrocytes by the John
Cunningham (JC) virus. JC virus is a ubiquitous polyomavirus for which most
humans are seropositive because they were exposed early in life. The virus
becomes activated and causes PML in the context of immune suppression such
as from HIV or with immunomodulatory treatment for illnesses such as
multiple sclerosis and Crohn disease. The presentation may be insidious, and
patients may present with cognitive dysfunction, encephalopathy, ataxia,
visual symptoms or weakness, depending on the cerebral territories involved.
MRI of the brain shows patchy nonenhancing foci of T2 hyperintensity within
the subcortical white matter (Fig. 21-12). Treatment in HIV patients involves
ART and supportive therapy when appropriate.
Primary CNS lymphoma, which is thought to be mediated by Epstein–
Barr virus, is discussed in Chapter 19.
FIGURE 21-12. Progressive multifocal leukoencephalopathy: (A) axial CT; (B) postcontrast T1-
weighted MRI; (C) T2-weighted MRI. Images show a subcortical focus of abnormality within the high
left frontal lobe (arrows), corresponding to the motor association region. The characteristic features of
this demyelinating process include minimal to no mass effect, even when very large, and essentially no
contrast enhancement or hemorrhage. A very low T-cell count reflecting an immunocompromised status
is also key to the diagnosis. In an immunocompetent patient, differential diagnostic considerations for
this type of lesion include posterior reversible encephalopathy syndrome, which can have a similar
appearance. [CT, computed tomography; MRI, magnetic resonance imaging.](Reprinted with permission
from Brant WE, Helms C. Fundamentals of Diagnostic Radiology. 4th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2012. Figure 7.14.)

CLINICAL VIGNETTES
VIGNETTE 1
A 67-year-old woman who recently underwent a lumbar epidural steroid
injection for low back pain now presents with low-grade fever, worsened
back pain, and difficulty walking. She has not urinated in 2 days.
Examination shows mild weakness in both legs, absent knee and ankle
reflexes, and sensory loss involving the perineum, posterior thighs, and
posterolateral legs bilaterally.
1. Which of the following is the appropriate initial step in evaluation and
management?
a. Brain imaging
b. Spine imaging
c. Lumbar puncture
d. Electromyography and NCS
e. Physical therapy
2. MRI of the lumbar spine, with and without contrast, is performed. An
epidural mass with contrast enhancement is identified at the level of
the L2 vertebral body. A radiologically guided biopsy is performed,
and microbiologic studies sent. Which of the following organisms is
most likely to be responsible for this infectious lesion?
a. Staphylococcus aureus
b. HSV type 2
c. HIV
d. Streptococcus group A
e. Cytomegalovirus

VIGNETTE 2
A 45-year-old man is brought to the neurologist’s office by his girlfriend
because of recent problems with memory and behavior over the past few
days. He has appeared confused and cannot remember recent
conversations or events. He has been complaining of odd, overpowering
smells that are not noticed by others. Surprisingly, he is relatively
unconcerned by these symptoms despite their rapid onset and progression.
The neurologist sends the patient to the emergency room for evaluation.
He is afebrile and appears systemically well. An MRI of the brain shows
bilateral medial temporal and orbitofrontal lesions that are bright on T2-
weighted images and enhance after gadolinium administration. An EEG
shows periodic epileptiform discharges over both temporal lobes.
1. Which of the following might be expected on CSF analysis?
a. Hypoglycorrhachia (low CSF glucose)
b. Gram-positive cocci in clusters
c. Cytoalbuminologic dissociation
d. Infectious organisms revealed by India Ink staining
e. Elevated red blood cell count
2. The patient is admitted to the inpatient Neurology service, and CSF is
sent for HSV1 PCR on the basis of a clinical suspicion for HSV1
encephalitis. Which of the following pharmacologic agents would be
appropriate to begin immediately?
a. Prednisone
b. Methylprednisolone
c. Acyclovir
d. Valacyclovir
e. Warfarin

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The patient is presenting with symptoms concerning for a cauda equina
syndrome, with bladder dysfunction, motor and reflex abnormalities in the
legs, and saddle anesthesia. This requires urgent attention to prevent
permanent neurologic deficits. Although an LP may be necessary as part of
the evaluation for cauda equina syndrome, in this case, urgent spine
imaging should be performed first to rule out a structural lesion. In
particular, an LP carries the theoretical risk of seeding the subarachnoid
space in the presence of a spinal epidural abscess, a distinct possibility
here. Spinal epidural hematoma is another structural concern, especially in
patients on anticoagulation. Parasagittal brain lesions can cause bilateral
leg motor and sensory problems, but this is rare, and the constellation of
symptoms and signs, particularly the saddle anesthesia, render this very
unlikely. EMG/NCS and physical therapy are not part of an urgent
approach to a cauda equina syndrome.
VIGNETTE 1 QUESTION 2
2. Answer A:
The MRI finding is consistent with a spinal epidural abscess. In this case,
the instrumentation that occurred with the recent epidural steroid injection
is likely to have been related and suggests that skin bacteria, such as
staphylococci, are the most likely pathogens responsible for this abscess.
HSV type II, HIV, and CMV are all potential viral causes of a lumbosacral
polyradiculopathy but would be unlikely to cause an epidural mass lesion.

VIGNETTE 2 QUESTION 1
1. Answer E:
This clinical presentation is most consistent with HSV1 encephalitis. This
infection has a predilection for the base of the brain, including the medial
temporal lobes and orbitofrontal regions, as seen on his MRI. Common
clinical features include memory disturbances, olfactory hallucinations,
and complex partial seizures. Periodic temporal lobe discharges on EEG
are a characteristic feature, particularly after several days of infection. The
CSF profile in HSV1 encephalitis, although sharing features in common
with other viral encephalitides (including leukocytosis, high protein, and
normal glucose), is distinctive in that elevated red blood cells can be seen.
Bacterial infection is unlikely here without fever and with the lack of signs
of systemic illness. Cytoalbuminologic dissociation is seen in GBS. India
Ink staining shows Cryptococcus neoformans organisms.

VIGNETTE 2 QUESTION 2
2. Answer C:
Although most viral encephalitides do not have specific treatments, HSV1
encephalitis is an exception and can be treated with a prolonged
intravenous course of acyclovir. In the appropriate clinical setting,
acyclovir should be started while awaiting PCR results because those
results can take several days to return and HSV1 encephalitis can be fatal
if left untreated. Supportive care would also be appropriate, including
hydration, analgesics for headaches, and anticonvulsants for clinical
seizures, as appropriate. Corticosteroids are not generally used, nor is
valacyclovir (which is available only in oral form). Warfarin is not
appropriate.
 22 Disorders of the Spinal Cord

The central nervous system (CNS) comprises the brain and the spinal cord.
The spinal cord plays a particularly important role in relaying sensorimotor
signals between the brain and the body. An understanding of the anatomic
arrangement of cord structures can help an examiner to localize related
lesions.

ANATOMY
The spinal cord extends from the medulla, through the foramen magnum,
and down the spinal canal. The filum terminale, a connective tissue band,
anchors the cord to the end of the canal. Anterior to the cord are 7 cervical,
12 thoracic, 5 lumbar, and 5 sacral vertebral bodies. These vertebral bodies
are related to the motor and sensory nerve roots that emerge from the
ventral and dorsal aspects of the cord along its length. Both the vertebral
bodies and nerve roots are numbered, but those sets of numbers do not
match consistently. Most cervical nerve roots (i.e., C1 to C7) emerge above
the corresponding cervical vertebral bodies (e.g., the C6 nerve root
traverses between the C5 and C6 vertebral bodies), but the C8 nerve roots
exit between the seventh cervical and first thoracic vertebral bodies (i.e., at
the C7-T1 level), because there is no C8 vertebral body. Distal to the T1
level, nerve roots are located below the corresponding vertebral body so the
L3 nerve root is located between the L3 and L4 vertebral bodies, or at the
L3-4 level (Fig. 22-1). The spinal cord extends to approximately the level
of the L1 vertebral body. Accordingly, safe lumbar punctures can be
performed below this level because there is no spinal cord in the canal
there.
In cross section, the spinal cord contains the “central gray” matter and
neuron cell bodies, distributed in the shape of an H (Fig. 22-2). Each side of
this central gray has an anterior and posterior (dorsal) horn. The anterior
horns contain primarily the alpha motor neurons and motor nerve fibers
innervating skeletal muscles. The dorsal horns represent the gateway for
sensory information. The right and left aspects of the central gray matter are
connected by the transverse commissure.
Surrounding the gray matter are white matter tracts traveling to and from
the brain. The most important descending motor tract is the corticospinal
tract (CST) (Fig. 22-3). After descending from the cortex, the CST crosses
at the medulla before descending in the lateral aspect of the cord.
Accordingly, fibers from the left motor cortex cross at the medullary
pyramids before descending on the right side of the spinal cord to serve the
right limbs, and vice versa. Thus, spinal cord injuries that involve the right
CST cause right body (ipsilateral) motor deficits.
The lateral aspect of the cord also contains autonomic fibers from the
hypothalamus and brainstem. Sympathetic fibers course from T1 to L2
where they exit the spinal cord. Injuries to autonomic fibers proximal to S2
can result in a “neurogenic bladder.” This term describes automatic,
involuntary bladder emptying when a certain level of distention occurs.
Parasympathetic nerve fibers leave the spinal cord in the S2 to S4 cord
segments. Injuries to peripheral nerve fibers at these distal levels can result
in overflow incontinence from a flaccid bladder.
There are two important ascending sensory tracts: the dorsal column and
the spinothalamic tracts (Fig. 22-2). The dorsal columns refer to the heavily
myelinated tracts in the posterior aspect of the spinal cord that mediate joint
position, discriminative touch, and, to some degree, vibration sense. These
tracts are arranged with fibers ascending from the cervical spinal cord
(fasciculus cuneatus) lateral to the fibers ascending from the lumbosacral
segments (fasciculus gracilis) medially. These ascending fibers remain
ipsilateral to their site of origin until they cross at the level of the medulla,
en route to the ventroposterolateral nucleus of the thalamus. Thus, spinal
cord injuries affecting the right dorsal columns may impair proprioception
in the right limbs. The lateral spinothalamic tracts are unmyelinated and
carry pain and temperature sensory information. After these fibers enter the
spinal cord and ascend about two levels, they cross in the ventral white
commissure. Thus, a spinal cord lesion involving the right lateral
spinothalamic tracts may impair pain and temperature sensation starting a
few levels below the level of the lesion on the left (because these ascending
fibers have already crossed).

FIGURE 22-1. Posterior view of vertebral bodies in the cervical (A) and lumbar (B) regions
showing the relationship that can exist between a herniated nucleus pulposus (pink) and the spinal
nerve roots. (Note that there are eight cervical nerves and only seven cervical vertebrae.) In the
lumbar region, the emerging L4 nerve roots emerge laterally, close to the pedicles of the fourth
lumbar vertebra, and are not closely related to the intervertebral disk between the fourth and fifth
lumbar vertebrae. Pressure on the L5 motor nerve root can prvoduce weakness of dorsiflexion at the
ankle. (From Snell RS. Clinical Neuroanatomy. 7th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2009.)
FIGURE 22-2. Transverse section of the spinal cord showing the sensory pathways. The
posterior columns relay information concerning proprioception and two-point discrimination. The
spinothalamic tracts relay pain and temperature information. (From Ginsberg L. Lecture Notes:
Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:122. Copyright © 2005 L Ginsberg.
Reprinted by permission of John Wiley & Sons, Inc.)

The blood supply for the anterior two-thirds of the spinal cord comes
primarily from a single anterior spinal artery (ASA) running along most of
the ventral surface of the cord. The cephalad portion of the ASA arises from
branches of the two vertebral arteries. The caudal portion of the ASA
originates as aortic branches that form the artery of Adamkiewicz. The
anterior horns, spinothalamic tracts, and lateral corticospinal tracts, are
perfused by the ASA. There are two posterior arteries that perfuse the
dorsal columns.
FIGURE 22-3. The corticospinal tract from the cortex to the ventral horn. [Copyright © 2012
Dr. Juan Acosta, MD.]

The spinal cord is protected chemically by the blood–brain (or blood–

CNS) barrier and structurally by the resilient connective tissue of the dura
mater and surrounding vertebrae. Importantly, related spinal structures, such
as the intervertebral disks, can cause neurologic dysfunction when out of
place.For example, herniated disks can cause potentially serious
“extradural” compression of the cord. Compressive lesions can also occur
within the dura but outside of the spinal cord itself (“intradural,
extramedullary” lesions); examples include meningiomas and
neurofibromas. Finally, lesions within the cord itself (“intramedullary”
lesions), such as gliomas, can cause cord impingement and dysfunction.
Spinal cord compression causes weakness, incoordination, and sphincter
dysfunction below the level of the lesion and often causes a sensory level at
or below the lesion. Spinal cord compression is a neurologic emergency,
although related symptoms and signs can evolve over time.
 KEY POINTS
● The corticospinal tract is an important descending motor tract that runs in the lateral aspect
of the cord.
● The dorsal columns contain ascending sensory fibers in the posterior aspect of the cord
that convey joint position, discriminative touch, and vibration input.
● The spinothalamic tract is an ascending sensory tract in the lateral aspect of the cord,
carrying pain and temperature sensation.
● The corticospinal and dorsal column fibers cross at the medulla, while the spinothalamic
fibers cross a few levels above their level of entry into the spinal cord.
● A single anterior spinal artery supplies blood to the anterolateral aspects of the spinal cord,
whereas two posterior arteries are primarily responsible for the dorsal column’s blood
supply.
● Spinal cord compression is a neurologic emergency.

LOCALIZATION OF SPINAL CORD

DYSFUNCTION
The symptoms of spinal cord dysfunction can be protean, but the patient’s
history and a careful neurologic examination can help point to a lesion in
this region of the CNS. Patients may report sensorimotor symptoms. Bowel
and bladder dysfunction often accompanies cord dysfunction. A girdle or
band-like sensation around the torso can reflect cord dysfunction with
involvement of the dorsal columns, as can a sensation of limb swelling in
the absence of visible edema. In classic, chronic spinal cord dysfunction,
“long tract signs” such as limb spasticity and hyperreflexia may be present.
Indeed, the combination of increased reflexes and weakness in the same
somatic territory (such as a motor root distribution) are a common finding
in the setting of cord dysfunction. By performing a sensory (e.g., pinprick)
examination of the limbs and posterior trunk bilaterally, a “level”
demarcating the boundary between normal and abnormal sensation can be
sought. Such a finding indicates a cord lesion at or above the identified
level. (Because of the laminated organization of fibers in the cord, this level
can rise over time.) It is important to remember that acute cord lesions (e.g.,
spinal shock) can be associated with paralysis and a loss of, rather than
increase in, reflexes and tone. In this scenario, the more characteristic signs
of cord dysfunction may emerge only after a period of weeks.
 KEY POINTS
● Patients with spinal cord lesions may report sensorimotor symptoms, bowel or bladder
dysfunction, a tight “girdle-like” sensation, or a combination of symptoms.
● Classic, subacute to chronic cord lesions are associated with long tract signs, including
increased reflexes and spasticity together with weakness.
● Acute spinal shock can result in flaccid paralysis.
● An identified sensory level signifies a lesion at or above this location.

SPINAL CORD SYNDROMES

Spinal cord dysfunction can be characterized according to the region of the
cord involved and on the basis of the underlying cause of the impairment.
Complete cord transection, hemicord, central cord, posterior cord, conus
medullaris/cauda equina, and ASA syndromes are associated with specific
anatomic patterns of neurologic deficit. Autoinflammatory, infectious,
(para)neoplastic, traumatic, treatment-related, toxic-metabolic, vascular,
and degenerative disorders can manifest with spinal cord dysfunction that
may or may not adhere to more clear-cut distributions. Accordingly, a
working familiarity with spinal cord anatomy and etiology of lesions is
important.

COMPLETE CORD TRANSECTION

Severe trauma may cause complete transection of the spinal cord. Because
this injury disrupts all descending tracts traveling from above and all
ascending tracts coming from below, sensorimotor function is abolished
below the level of the lesion. The level of transection further dictates
specific deficits. If transection occurs above the level of the C3–C5 nerve
roots, which control the diaphragm, respiratory insufficiency may result.
Autonomic regulation and abdominal reflexes may be lost with lesions
above T6. Bowel and bladder dysfunction (e.g., constipation and urinary
urgency, retention, or incontinence) may accompany lesions above the
sacral cord level.

HEMICORD LESIONS
When one side of the spinal cord is affected, a “hemicord” or Brown-
Sequard syndrome results. In this disorder, there is weakness and impaired
proprioception and vibration sensation ipsilateral to the lesion, together
with loss of pain and temperature sensation contralateral to the lesion. This
makes sense because a lesion, involving one side of the cord will affect
descending CST fibers that have already crossed in the medulla, ascending
dorsal column fibers that have yet to cross in the medulla, and ascending
spinothalamic fibers that have already crossed from the opposite side a few
levels below the lesion. (It can help visualize involved pathways by
drawing them out!) Hemicord lesions may occur, for example, in the setting
of transverse myelitis due to infection.
Hemicord syndromes can also be caused by structural lesions such as
herniated disks. When structural lesions are associated with cord
compression, urgent treatment with dexamethasone to reduce local pressure
prior to decompressive surgery may be necessary.

FIGURE 22-4. Clinical features of syringomyelia. [LMN, lower motor neuron.] (From
Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:124. Copyright ©
2005 L Ginsberg. Reprinted by permission of John Wiley & Sons, Inc.)

CENTRAL CORD LESIONS

A structural abnormality in the center of the spinal cord tends to impact
spinothalamic tract fibers because they cross in the ventral white
commissure situated just in front of the middle of the cord. Deficits in pain
and temperature sensation are usually bilateral and span several segments.
Thus, with a central lesion in the cervical cord, there can be a “cape-like”
loss of these sensations over the shoulders and arms, with preservation of
the same sensations above and below the lesion. The sensory loss is
described as “dissociated” because pain and temperature sensation is
affected but touch and position sense are not. In addition, a variety of motor
and sensory functions can be impaired below the lesion. Syringomyelia is
one cause of a central cord syndrome (Fig. 22-4).

POSTERIOR CORD (DORSAL COLUMN) LESIONS

The posterior aspect of the cord can be affected preferentially. As one
would predict in this case, there is dysfunction of proprioception and
vibration sense. Patients can experience lancinating pain, paresthesias, gait
dysfunction, and dysuria. The classic disorder with this localization is aptly
named tabes dorsalis and is historically associated with late-stage syphilis.
Subacute combined degeneration is a condition in which the dorsal columns
are affected in combination with the lateral columns of the spinal cord—
primarily in the cervical segment. As a result, patients can have limb
spasticity, hyperreflexia, sensory ataxia, and bladder dysfunction.

CONUS AND CAUDA EQUINA LESIONS

The spinal cord ends in the conus medullaris, located at approximately the
L1 level. Lesions there can cause leg weakness (including a flaccid
paralysis), saddle anesthesia, bowel and bladder dysfunction, and
impotence. Cauda equina lesions are distal to the cord, and affect the
lumbar and sacral spinal nerve roots within the spinal canal. Patients can
have back pain that radiates asymmetrically into the legs, and they may
have bowel or bladder dysfunction, or both. On examination, weakness,
fasciculations, and a loss of reflexes in lower lumbosacral distributions may
be detected. These lesions can evolve in the setting of advanced
degenerative disk disease.

ANTERIOR SPINAL ARTERY LESIONS

The spinal cord, like the brain, can incur a stroke when the blood supply is
compromised. The most common form of cord stroke is the ASA syndrome.
Patients may present following the acute onset of back or girdle-like pain,
weakness, and loss of sphincter control. On examination, small fiber (pain
and temperature) sensory loss is prominent, with preservation of position
sense because posterior column function is unaffected in this syndrome—a
major neurologic clue to the diagnosis. Because it is a watershed region, the
thoracic cord is most vulnerable, and there is often a spinal sensory level at
about T4. Spinal cord infarction is rare, but can be seen following surgical
procedures, particularly those involving aortic surgery.

KEY POINTS
● In complete spinal cord transection, sensory and motor function is abolished below the
level of the lesion.
● A Brown-Sequard (hemicord) syndrome affects one side of the cord and causes ipsilateral
weakness and position sense loss, with contralateral deficits in pain and temperature
sensation below the level of the lesion.
● A central cord syndrome includes motor and sensory dysfunction below the lesion and
often a “cape-like” loss of pain and temperature sensation at levels near the lesion.
● Posterior column syndromes cause deficits of proprioception.
● Conus medullaris and cauda equina lesions may present with weakness, alterations in
sphincter control, and sexual dysfunction.
● The ASA syndrome affects CST and spinothalamic function while sparing dorsal column
function.

OTHER CAUSES OF SPINAL CORD

DYSFUNCTION
There are many inherited and acquired causes of spinal cord dysfunction
that fall into the categories of autoinflammatory, infectious,
(para)neoplastic, traumatic, treatment-related, toxic-metabolic, vascular,
and degenerative disorders. Potential autoinflammatory causes include
demyelinating disorders (e.g., neuromyelitis optica and multiple sclerosis,
as discussed in Chapter 20). Connective tissue diseases such as systemic
lupus erythematosus, sarcoidosis, scleroderma, and rheumatoid arthritis can
also affect the cord. Enterovirus infection has been associated with
poliomyelitis. More recently, West Nile Virus has caused anterior horn cell
dysfunction. Infections including HIV/AIDS and HTLV can be associated
with a spastic paraparesis. Particularly in patients with risk factors (e.g.,
recent invasive procedures), epidural abscess should be included on the
differential. Spinal cord tumors can cause dysfunction by compression.
Remote tumors can cause cord dysfunction via a paraneoplastic process, as
can be seen in the setting of lymphoma. Trauma (e.g., from motor vehicle
collisions and falls) is an important cause of spinal cord lesions of all sorts
and is often readily identifiable. In contradistinction, treatment-related cord
lesions can be elusive. For this reason, it is worthwhile to ask patients with
clinical signs of spinal cord dysfunction if they have ever had radiation
treatment; the emergence of radiation myelopathy can be delayed by
months or years. Vitamin deficiencies (including of B12), or copper
deficiency, and hepatic disease can be associated with spinal cord
dysfunction.
In addition to spinal cord infracts due to ASA disease, dural
arteriovenous fistulas (AVFs) and intramedullary spinal arteriovenous
malformations (AVMs) can cause cord dysfunction. AVFs can manifest
with progressive paraparesis, with leg pain or weakness, ambulation
difficulty, and sensory symptoms, sphincter dysfunction or combinations of
these deficits—often in a stepwise pattern as venous pressure builds.
Although AVFs are more common in middle-aged men, teenagers and
young adults may develop similar symptoms from bleeding or ischemia in
the cord because of intramedullary spinal AVMs. Although these causes are
relatively rare, degenerative disk disease is quite common. Spondylotic
changes or herniated disks in the cervical region are a frequent cause of a
myelopathy manifested by a spastic gait, weakness (often with hand
dysfunction and atrophy), sensory loss, and urinary urgency. Neighboring
symptoms and signs narrow the differential and inform the investigation
and treatment.
Some sporadic and inherited neurodegenerative diseases tend to affect
certain spinal cord elements. For instance, amyotrophic lateral sclerosis
(ALS) is a disease of anterior horn cells with sporadic and familial forms.
Patients present with painless, progressive weakness associated with
increased tone and hyperreflexia. Although the disease involves the anterior
horn of the spinal cord, it also affects related motor nerve roots and the end-
organ muscles innervated by these roots. As a result, upper motor neuron
findings are often accompanied by lower motor neuron findings including
atrophy and fasciculations. Importantly, many disorders that affect the
spinal cord, including ALS, occur on an upper to lower motor neuron
continuum so that there is a mixture of localizing signs. Some disorders,
like hereditary spastic paraplegia (HSP), have primarily upper motor neuron
findings; others, such as Friedreich ataxia (which affects the posterior
columns and spinocerebellar tracts) have predominantly lower motor
neuron features (e.g., weakness and areflexia).

KEY POINTS
● Acquired causes of spinal cord dysfunction are diverse; accompanying symptoms and
signs narrow the differential and direct diagnostic investigation.
● Many neurodegenerative disorders involving the spinal cord, such as ALS, have both
upper and lower motor neuron features on examination.
● Congenital abnormalities in spinal cord structure include syringomyelia,
myelomeningocele, and tethered cord syndrome.

Many congenital abnormalities affect the spinal cord. In syringomyelia, a

fluid-filled cavity in the center of the spinal cord (most common in the
cervical and thoracic regions), can be associated with a Chiari
malformation, a downward protrusion of the medulla, with or without the
cerebellum, through the foramen magnum.
FIGURE 22-5. Arnold Chiari malformation with syrinx. Sagittal T1-weighted MRI of the
cervical spine. Note the downward displacement of the cerebellar tonsils projecting through the
foramen magnum caudally to the C1 level (arrow) and the uniformly low signal intensity (of fluid) in
the syrinx cavity that enlarges the entire cervical spinal cord (arrowhead). Note also the unrelated
changes of degenerative spondylosis at C5-C6 (crossed arrow). [MRI, magnetic resonance imaging.]
(From Ginsberg L. Lecture Notes: Neurology. 8th ed. Oxford: Blackwell Publishing; 2005:123.
Copyright © 2005 L Ginsberg. Reprinted by permission of John Wiley & Sons, Inc.)

Improper closure of the neural tube can result in midline structural

deficits referred to as “dysraphisms.” Resultant structural abnormalities
range from asymptomatic (as in spina bifida occulta) to paraplegia, bladder
dysfunction, and maldevelopment of the legs, as can be seen with
myelomeningocele, in which there is protrusion of the spinal cord tissue
outside of the spinal canal. Hypertrophy of the filum terminale can produce
a “tethered cord syndrome” with pain and cord dysfunction, especially at
lower levels.
SPINAL CORD DIAGNOSTIC TESTS
The overall clinical picture helps inform the choice of diagnostic tests.
Magnetic resonance imaging (MRI) is one of the most informative studies
(Fig. 22-5); it can show the relationship of the spinal cord to surrounding
structures (including spinal elements such as bones and disks) and other
extrinsic or intrinsic abnormalities. Vascular lesions such as strokes and
hemorrhages are often demonstrated well, and can indicate a need for spinal
angiography. Cerebrospinal fluid (CSF) from a lumbar puncture can
provide evidence of infection, inflammation, or malignancy. If an epidural
abscess is a concern, blood cultures can be helpful. Additional blood work
can be done to assess for other forms of infection, connective tissue
diseases, and toxic-metabolic processes. Increasingly, genetic assays are
used to make definitive diagnoses in the appropriate clinical context.

KEY POINTS
● MRI is one of the most helpful tests in characterizing spinal cord lesions.
● CSF analysis can provide support for the presence of infection, inflammation, or
malignancy.
● Additional blood work, including genetic assays, may provide more specific diagnostic
information.

CLINICAL VIGNETTES

VIGNETTE 1
A 72-year-old man presents with lower back pain, numbness and
weakness of the legs, and urinary retention. He has a history of prostate
cancer that was treated with radical prostatectomy 4 years ago. His
exam shows a normal mental status, normal arm strength, and normal
coordination in finger–nose–finger. Upper limb reflexes are normal. He
has a sensory level to pinprick at T6, with brisk reflexes at the knees,
ankle clonus, and upgoing toes (Babinski sign) bilaterally. Both legs are
weak, but tone is increased. Vibration and joint position sense are
reduced.
1. The most likely localization of the lesion is:
a. Brainstem
b. Thoracic cord
c. Lumbar cord
d. Cauda equina
e. Conus medullaris
2. MRI of the entire spine shows an epidural spinal cord compression
at the T6 level from a metastatic lesion in the epidural space. The
best immediate step will be:
a. Take the patient to the operating room for surgical
decompression
b. Admit the patient for observation with neuro checks every 4
hours
c. Place a catheter to deal with urinary incontinence or retention
d. Administer 100 mg IV of dexamethasone
e. Pain management
3. The patient underwent decompression and radiation for a single
epidural metastasis. His symptoms resolved, and his examination
returned to normal. Four weeks later, he presents with a sudden
onset of paraplegia, numbness in the legs, and urinary retention.
The exam this time shows a sensory level to pinprick and
temperature at T8, absent knee and ankle jerks, flaccid tone, and
areflexia. Your attending physician performs one bedside test and
states that this is an anterior spinal artery syndrome. The test that
most reliably supports this diagnosis is:
a. MRI of the spine
b. Preserved proprioception when the patient’s toes are moved
c. Diminished tone on rectal exam
d. Absent abdominal reflexes
e. The scenario above is untrue. There is no way one can make a
clinical diagnosis of an ASA syndrome on examination alone.

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
Findings on exam suggest a lesion at the thoracic or cervical levels, as a
sensory level was found at T6. Conus medullaris lesions usually present
with prominent bowel or bladder problems (or both) and sexual
dysfunction, with or without associated leg weakness, but not a thoracic
sensory level. A cauda equina syndrome can produce weakness and
numbness with diminished reflexes in the legs, but not a sensory level at
T6. Lumbar cord lesions will produce signs similar to those found in
this patient, except for a sensory level at T6. Remember that a sensory
level at T6 indicates that the lesion is at or above that level.

VIGNETTE 1 QUESTION 2
2. Answer D:
In epidural metastatic cord compression, the first step in management is
the use of high-dose steroids (dexamethasone) to reduce edema and
relieve some of the pressure. This can be followed by surgical
decompression and external radiation therapy.

VIGNETTE 1 QUESTION 3
3. Answer B:
The ASA supplies blood to the anterior two-thirds of the spinal cord and
therefore the descending motor corticospinal tract and ascending
sensory spinothalamic tracts. It does not supply the posterior columns,
where joint position sense (proprioception) travels. The ASA syndrome
is a “cord infarction” with an acute onset, bilateral lower extremity
weakness, loss of sphincter control, and sensory loss below the level of
the lesion to pinprick and temperature. On examination, only
proprioception is relatively preserved. The ASA syndrome is a bedside
diagnosis. An acute cord syndrome can present with flaccid paralysis
and areflexia, and later manifest more spasticity and hyperreflexia
below the level of the lesion.
 23 Radiculopathy, Plexopathy, and
Peripheral Neuropathy

The peripheral nervous system (PNS) consists of spinal nerve roots, the
brachial and lumbosacral plexi, peripheral nerves, autonomic ganglia, the
neuromuscular junction, and muscles. This chapter focuses on the more
proximal elements of the PNS, whereas Chapter 24 discusses the
neuromuscular junction and muscle disorders. The symptoms and signs of
PNS dysfunction often form recognizable patterns that can help localize
deficits to one of these parts of the nervous system. Electrodiagnostic
studies can also be particularly helpful in characterizing contributory
lesions.

SPINAL NERVE ROOTS AND

RADICULOPATHY
ANATOMY
The vertebral bodies form the bony building blocks of the spine.
Intervertebral disks are located between the vertebral bodies. They provide
some degree of cushioning and allow movement. Together with neighboring
joints, the elements of the vertebral bodies above and below each
intervertebral disk form a bony canal called an intervertebral foramen.
Spinal nerve roots travel through the intervertebral foramina on their way to
the limbs. Each spinal nerve root is formed by a combination of a ventral
and dorsal nerve root leaving the spinal cord. Ventral nerve roots ultimately
facilitate motor function; the muscles served by a ventral nerve root make
up a myotome. Dorsal nerve roots transmit sensory information; the
cutaneous region in the distribution of a dorsal root is referred to as a
dermatome. It is important to note that there is overlap in the somatic
territories from one myotome or dermatome to the next. As a result,
strength and sensation may be relatively preserved on neurologic
examination even if there is demonstrable injury to a given nerve root.

PATHOPHYSIOLOGY
Nerve root dysfunction is referred to as radiculopathy. Radiculopathy can
result from structural or nonstructural causes. Structural causes are most
common, and there are two main sources of nerve root compression:
intervertebral disk herniation and degenerative changes in the spine. Acute
disk herniation is common in younger individuals and is more likely to
affect a single spinal nerve root. Degenerative changes include disk
desiccation, arthritic bony growth (spondylosis and osteophyte formation),
and changes in bony alignment (spondylolisthesis). Often these changes
cause narrowing of the intervertebral foramina, with secondary
impingement of nerve roots at multiple levels. Radiculopathies at the C7
and L5/S1 spinal levels are the most frequent ones in the cervical and
lumbosacral regions respectively. Thoracic radiculopathies are relatively
uncommon.
In the absence of a compressive cause, consideration must be given to
infectious, inflammatory, infiltrative, and vascular etiologies. For instance,
cytomegalovirus, herpes simplex, varicella zoster, and human
immunodeficiency viruses and Lyme disease can cause radiculopathy.
Sarcoidosis can be associated with an inflammatory radiculitis. Neoplastic
processes can damage the nerve root through infiltration. Infarction (e.g.,
from vasculitis or diabetes) is an unusual cause of radiculopathies.

SYMPTOMS AND SIGNS

Pain, sensory changes, or both, radiating in the distribution of a spinal nerve
root point to a radiculopathy. Accordingly, there can be some degree of
sensory, strength, or reflex abnormality that helps specify the nerve root of
interest (Table 23-1). When patients present with upper extremity
symptoms, Spurling’s maneuver can be performed by putting gentle
pressure on the head as it is turned toward the side of pain while the neck is
extended; the test is considered positive if symptoms are reproduced. Of
note, the assessment should be avoided in patients who could have spine
instability, as in the setting of rheumatoid arthritis. The straight leg raise test
can be helpful in corroborating a lumbosacral radiculopathy. The test is
considered positive when the patient’s symptoms are reproduced when the
leg is passively elevated, typically beyond 30 to 60 degrees, with the knee
extended and the foot dorsiflexed.

TABLE 23-1. Root Syndromes Distribution of Abnormalities

Segment Sensory Abnormality Motor Deficit / Weakness Reflex Changes
Cervical
C5 Pain in lateral shoulder; Deltoid, supraspinatus, and Decreased or lost
sensory loss over deltoid biceps biceps reflex
C6 Radial side of the arm to Biceps and brachioradialis Decreased or lost
thumb biceps reflex
C7 Between the 2nd and 4th Triceps, wrist extensors and Decreased or lost
fingers flexors, pectoralis major triceps reflex
Lumbosacral
L3 Often none; sometimes Quadriceps; possibly Decreased or lost
medial thigh and knee adductors patellar reflex
L4 Medial leg below the knee, Quadriceps and anterior Decreased or lost
to medial malleolus tibial patellar reflex
L5 Dorsum of the foot to great Extensor hallucis longus, None
toe extensor digitorum longus,
inverters and everters of the
foot
S1 Lateral side of the foot Plantar flexion, toe flexion Decreased or lost
Achilles reflex

DIAGNOSIS
A diagnosis of radiculopathy can usually be made on clinical grounds.
Immediate imaging is warranted if infection or malignancy is a concern, if
pain is accompanied by saddle anesthesia and urinary retention, or if
symptoms are acute in onset and associated with progressive deficits.
Magnetic resonance imaging (MRI) is best, when possible to obtain. Nerve
conduction studies (NCSs) and electromyography (EMG) are most helpful
in confirming the presence of a radiculopathy when performed at least 3
weeks after symptom onset and when there is clinical weakness. A lumbar
puncture (LP) may be indicated when an infiltrative or infectious process is
high on the differential. The results of investigative studies guide treatment
approaches.
 KEY POINTS
● Muscles and cutaneous regions in the distribution of a spinal nerve root are myotomes and
dermatomes, respectively.
● Structural lesions, including disk herniation and degenerative changes, are the most
common causes of radiculopathy.
● Radiculopathy is often associated with pain or sensory symptoms in the distribution of a
given nerve root. Corresponding strength, sensory, and reflex abnormalities on exam can
support clinical hypotheses.
● MRI, EMG, and LP are investigative studies that can help elucidate the cause of a
radiculopathy.

PLEXUS AND PLEXOPATHIES

ANATOMY
Multiple spinal nerve roots form an intricate network called a plexus, in the
upper and lower limbs. In the arms, roots C5-T1 form the brachial plexus.
The brachial plexus can be organized into trunks, divisions, cords, and
branches before forming the individual nerves that serve the skin and
muscles in the arms (Fig. 23-1). The brachial plexus lies behind the scalene
and pectoralis muscles and clavicle. All of the major nerves in the legs arise
from the lumbosacral plexus, a combination of the L1-S3 nerve roots. The
upper portion of this plexus, the lumbar plexus, is depicted in Figure 23-2.
The lumbosacral plexus lies behind the psoas muscles in the
retroperitoneum before continuing below the pelvic outlet.
FIGURE 23-1. The brachial plexus. (Reprinted with permission from Williams A. Massage
Mastery. 1st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Figure 5.8.)

PATHOPHYSIOLOGY
Trauma, compression, inflammation, metabolic disturbance, malignancy,
and radiation can cause plexus lesions. Trauma is the most common
etiology of brachial plexopathies in adults. Specifically, motorcycle and
other motor vehicle accidents can result in damage from abrupt traction
when the head is pulled away from the shoulder. Inflammatory brachial
plexopathies, also referred to as brachial neuritis or Parsonage-Turner
syndrome, are also often acute in onset. Triggers can include antecedent
illness, vaccination, surgical procedures, or exercise; some triggers are
difficult to identify. An apical lung (Pancoast) tumor can lead to a more
insidious development of a brachial plexopathy from local infiltration or
direct compression. Similarly, radiation therapy may be associated with a
slowly developing brachial plexopathy, even a year following the
conclusion of treatment to the shoulder or chest region. In neonates,
brachial plexopathies may result from traction injuries at birth, particularly
in the setting of shoulder dystocia.
Type 2 diabetes, in the form of diabetic amyotrophy, is the most common
cause of lumbosacral plexopathy. As with brachial plexopathies, neoplasias
can be associated with lumbosacral plexopathies. Compression (e.g., from a
neonate’s skull) in the peripartum period or from a retroperitoneal
hematoma, is also a cause of lumbosacral plexopathies.

FIGURE 23-2. The lumbosacral plexus (left), and upper (lumbar) plexus alone (right).
Reprinted with permission from Anderson MK. Foundations of Athletic Training. 5th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Figure 12.4.

SYMPTOMS AND SIGNS

Plexus lesions cause patchy pain and sensory symptoms and signs. It can be
helpful to think about brachial plexus lesions in two main etiologic
categories: (1) structural (e.g., a brachial plexopathy from a tumor, traction
injury during trauma or surgery, or laceration due to line placement) and (2)
inflammatory (e.g., as in brachial neuritis or Parsonage-Turner syndrome).
In a classic Parsonage-Turner syndrome, patients awaken from sleep in the
early hours of the morning with pain in the periscapular and shoulder girdle
regions. Typically, pain is severe and can last up to 4 weeks before abating
spontaneously. The pain is ultimately associated with weakness (sometimes
resulting in scapular winging) and muscle atrophy. If brachial neuritis is on
the differential, it is important to assess for scapular winging but also to
look for a Horner’s syndrome; the latter can be caused by an apical lung
tumor.
Typically, patients with lumbosacral plexopathies present with leg pain,
sensory change, atrophy, and asymmetric weakness. Weakness of knee
extension, adduction hip flexion, or combinations of these, points to a
lumbar plexus problem. Foot drop is more consistent with a lumbosacral
plexopathy. In diabetic amyotrophy, there is associated weight loss and
autonomic dysfunction.

DIAGNOSIS
EMGs can be very helpful in characterizing plexus lesions. In certain
situations, imaging is important to evaluate for structural compression of
the plexus. An analysis of serology for infectious, autoinflammatory, and
metabolic disturbances and, less commonly, cerebrospinal fluid analysis,
may help determine a cause and guide management. Ultimately,
plexopathies due to inflammation often recover spontaneously over months,
whereas compressive lesions may require intervention.

KEY POINTS
● Spinal nerve roots C5-T1 and L1-S3 combine to form complex networks called the
“brachial plexus” and “lumbosacral plexus,” respectively.
● Trauma is the most common cause of brachial plexus lesions, whereas type 2 diabetes is
commonly associated with a form of lumbosacral plexopathy.
● Plexus lesions present with pain and patchy sensorimotor deficits; the pattern of
abnormalities can help localize the parts of the plexus affected.
● EMG, imaging, and laboratory testing can help characterize plexopathies and guide
treatment.
PERIPHERAL NERVES AND MONO- AND
POLYNEUROPATHIES
ANATOMY AND TERMINOLOGY
In the limbs, individual peripheral nerves are derived from the brachial and
lumbosacral plexuses. The term “polyneuropathy” refers to the involvement
of many nerves. In classic polyneuropathies, the most distal aspects of the
nerves are initially and preferentially affected. A mononeuropathy is a
dysfunction of an individual nerve, as can occur in the setting of focal
compression, such as in the carpal tunnel syndrome. Cranial nerves (except
CN II) are also peripheral; their dysfunction can also be a mononeuropathy
(e.g., in the facial nerve, as can be seen in a Bell’S palsy). In the rare case
that separate individual nerves are affected simultaneously or sequentially,
the condition is characterized as a mononeuropathy multiplex.
Peripheral nerve deficits can be classified according to whether they
affect motor, sensory, autonomic, or combinations of fibers. Further,
neuropathies may preferentially affect large-diameter fibers responsible for
proprioception, or small-diameter fibers that relay pain and temperature
information. The pattern of nerve involvement can give hints to underlying
pathophysiology (Box 23-1).

PATHOPHYSIOLOGY
A myriad of acquired and genetic processes can underlie peripheral nerve
lesions. Infectious, inflammatory, toxic, and metabolic conditions may play
roles in acquired conditions; diabetes is a particularly common cause of
neuropathies (Table 23-2). Genetic variations, such as those associated with
Charcot–Marie–Tooth (CMT) disease, can be seen in hereditary disorders.
Injured nerves can react only in a limited number of ways. Accordingly, key
information gleaned from the history, exam, and investigative studies help
characterize the type of peripheral nerve lesion.

SYMPTOMS AND SIGNS

Patients may describe positive or negative sensory, motor, and autonomic
symptoms. For example, tingling and “pins and needles” sensations,
together with reduced joint position sense and reflexes suggest large fiber
dysfunction. Burning, shooting, and jabbing pain, combined with deficits in
pain and temperature sensation, often indicate a small fiber neuropathy.
Weakness can accompany sensory changes, or, less often, be the primary
symptom. Autonomic symptoms include blood pressure (BP) dysregulation
(particularly orthostatic hypotension), abnormal sweating, urinary retention,
and impotence. The temporal course (e.g., acute, subacute, or insidious) and
the pattern of progression (e.g., gradually progressive, stepwise, or
relapsing-remitting) can point to specific etiologies. It is equally important
to gather data about the patient’s medical history (e.g., the presence of
diabetes, thyroid dysfunction, malignancy, or autoimmune disease),
medication use (e.g., chemotherapy), habits (e.g., alcohol intake), and
occupational history (e.g., work that requires lots of typing) that may
inform the search for a cause.

BOX 23-1. Approach to the Classification of Peripheral Neuropathy

Functional involvement
Motor
Sensory
Small fiber
Large fiber
Small and large fiber
Autonomic
Anatomic distribution
Asymmetric
Symmetric
Upper extremity
Lower extremity
Temporal course
Acute: GBS, porphyria, diphtheria, polio, toxins (thallium, lead, arsenic, adriamycin),
paraneoplastic, uremia, vasculitis
Subacute: deficiency states (vitamins B1 and B12), toxins, uremia, diabetes, sarcoidosis,
paraneoplastic, vasculitis, toxins, drugs
Chronic: CIDP, diabetes, uremia
Relapsing: CIDP
Pathologic mechanism
 Axonal
Demyelination
Combined neuropathy

[CIDP, chronic inflammatory demyelinating polyneuropathy; GBS, Guillain–Barré syndrome.]

TABLE 23-2. Diabetic Neuropathies

Type Clinical Features
Chronic progressive distal symmetric diabetic Mixed sensory–autonomic–motor
polyneuropathy polyneuropathy; variants include small fiber
(painful, usually spontaneous burning pain),
large fiber (ataxic), and autonomic
Diabetic proximal motor neuropathy (diabetic Severe thigh pain, followed within weeks by
amyotrophy) mild-to-severe hip and thigh muscle weakness
with muscle atrophy; usually affects older type 2
diabetic patients
Acute axonal diabetic polyneuropathy (intensely Diabetic neuropathic cachexia often associated
painful acute or subacute progressive symmetric with weight loss; “insulin neuritis” (with
sensory axonal peripheral neuropathy) improved control of hyperglycemia)
Diabetic mononeuropathy, radiculopathy, and Can present with cranial neuropathy (third,
polyradiculopathy fourth, or sixth nerves), multisegmental truncal
radiculopathy, or limb mononeuropathy
Focal compression neuropathies associated with Diabetic patients are more susceptible to
diabetes compression neuropathies, such as in the median
nerve at the wrist, the ulnar nerve at the elbow,
and the peroneal nerve at the knee

On exam, distal symmetric sensory or sensorimotor deficits are the most

typical presentation of a polyneuropathy. If the presenting symptoms and
signs follow an atypical pattern, that can narrow the differential, as shown
in Table 23-3. Hammertoes and high-arched feet raise the possibility of a
genetic condition such as CMT disease. More common mononeuropathies,
such as carpal tunnel syndrome, ulnar neuropathy at the elbow, radial
neuropathy at the spiral groove (“Saturday night palsy”), lateral femoral
cutaneous neuropathy (“meralgia paresthetica”), peroneal neuropathy at the
fibular neck, and facial neuropathy (e.g., a Bell’s palsy) have sensory,
strength, and reflex abnormalities that correspond to the affected nerves
(Table 23-4). Autonomic dysfunction can be detected at the bedside with
orthostatic BP measurements and a pupil exam.
TABLE 23-3. Atypical Neuropathy Features That Narrow the
Differential Diagnosis
Atypical Feature Potential Diagnoses
Begins in proximal rather than distal limbs Sensory: porphyria, occasionally Charcot–
Marie–Tooth and Tangier disease
Motor: GBS, CIDP, diabetes
Sensory symptoms and signs predominate Autoimmune: Miller Fisher syndrome, IgM
paraproteinemia, paraneoplastic, Sjögren
syndrome
Toxic: pyridoxine, doxorubicin
Infectious: diphtheria, HIV
Nutritional: vitamin E deficiency
Motor symptoms and signs predominate GBS, porphyria, and multifocal motor
neuropathy
Cranial nerves are involved Diphtheria, sarcoidosis, diabetes, GBS, Sjögren
syndrome, polyarteritis nodosa, Lyme disease,
porphyria, Refsum disease, syphilis, arsenic
Individual nerve territories are affected in a Trauma, diabetes, vasculitis, leprosy, HIV,
stepwise, non-length-dependent manner (as in Lyme, sarcoidosis, tumor infiltration, lymphoid
mononeuritis multiplex) granulomatosis, HNPP
Peripheral nerves are palpable CMT and Dejerine–Sottas, amyloidosis, Refsum
disease, leprosy, acromegaly, neurofibromatosis
[CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMT, Charcot–Marie–
Tooth; GBS, Guillain–Barré syndrome; HIV, human immunodeficiency virus; HNPP, hereditary
neuropathy with liability to pressure palsies; IgM, immunoglobulin M.]

TABLE 23-4. Common Mononeuropathies

Nerve Clinical Features Exam Findings Etiology
Upper extremity
Median Numbness or tingling Weakness and atrophy Compression of the median
nerve: at the involving one or more of the of the thenar muscles, nerve at the wrist within the
wrist is first four digits. Symptoms particularly APB. space known as the carpal
called carpal may awaken the patient Reduced sensation in tunnel.
tunnel from sleep. the volar aspect of the
syndrome first three and a half
digits. Tinel and Phalen
signs may be present.
Ulnar nerve: Paresthesias and pain in the Weakness and atrophy Compression of the ulnar
at the elbow fifth digit and the medial in the FDI and ADM. nerve in the cubital tunnel at
is called half of the fourth. Difficulty the elbow.
cubital spreading the fingers.
tunnel
syndrome
Radial nerve Wrist drop and sensory loss Weakness includes Compression of the radial
on the dorsal aspect of the triceps, brachioradialis, nerve at the level of the
 hand. supinator, and wrist axilla (“Saturday night
and finger extensors. palsy”); in the spiral groove,
The triceps is affected or in the forearm (posterior
by axillary interosseous neuropathy).
compression but spared
by spiral groove
compression.
Weakness of wrist
extensors causes
wristdrop.
Lower extremity
Meralgia Burning sensation and Area of sensory change Entrapment of the lateral
paresthetica variable loss of sensation over the lateral aspect femoral cutaneous nerve
over the anterolateral thigh. of the thigh. near the inguinal ligament.
Tenderness upon
palpation of the
inguinal ligament. No
motor involvement.
Femoral Leg weakness on attempting Weakness of the Usually trauma from
neuropathy to stand or walk. Pain in the quadriceps muscles, surgery, stretch injury
anterior thigh is common. absent or diminished (prolonged lithotomy
patellar reflex, and position in childbirth),
sensory loss over the diabetes mellitus, and other
anterior thigh—and, inflammatory processes.
with saphenous nerve
involvement, the
medial leg or foot of
both. Adductors are
intact (differentiates
from an L2-3
radiculopathy).
Peroneal Foot drop, with minimal Weakness of extensor Entrapment of the peroneal
neuropathy sensory complaints. hallucis longus, tibialis nerve between the neck of
anterior, and the the fibula and the insertion
peroneal muscles of the peroneus longus
(eversion of the foot); muscle.
sensory loss over the
dorsal part of the foot
is mild.
[ADM, abductor digiti minimi; APB, abductor pollicis brevis; FDI, first dorsal interosseus.]

DIAGNOSIS
In general, an outpatient diagnostic evaluation for polyneuropathy starts
with lab testing for the more common causes; a panel might include HbA1c,
B12, TSH, SPEP, UPEP, IFE, ANA, and ESR. Depending on the clinical
context, additional studies designed to assess for toxic–metabolic
abnormalities (e.g., heavy metals), infection (Lyme, HIV, hepatitis B or C),
autoinflammatory processes (e.g., Ro, La, ACE, or RF levels),
paraneoplastic syndromes (e.g., anti-Hu, anti voltage-gated potassium
channel (VGKC) antibodies), and vitamin excess or deficiency (e.g., with
vitamins B6 and B1, respectively) may be performed. One of the most
helpful tests for poly- and mononeuropathies is an EMG, which can help
characterize whether multiple or individual nerves are involved and whether
the primary pathophysiology is axonal or demyelinating; this can help
narrow the differential diagnosis and guide the next steps in investigation
and management. Importantly, standard NCSs can test only large-diameter
nerve fibers. Therefore, if a patient is thought to have a small fiber
neuropathy, a skin biopsy may be necessary. In the setting of small fiber
neuropathy and significant autonomic dysfunction, a fat pad biopsy or
genetic testing may be warranted to look for amyloidosis. In the setting of
the mononeuritis multiplex, a combined nerve and muscle biopsy to assess
for the evidence of vasculitis may be considered. Genetic testing may be
worthwhile if features of the history, exam, and EMG suggest a hereditary
process. Autonomic testing can assist if dysautonomia is a prominent
element of the presentation.

KEY POINTS
● Polyneuropathy refers to a generalized process that involves many nerves, whereas a
mononeuropathy describes injury to an individual nerve, as can be seen in an entrapment
neuropathy such as carpal tunnel syndrome.
● The temporal course, the pattern of progression, medical history, medication use, and
habits can provide hints to the type and cause of neuropathy affecting a patient.
● The neurologic examination can help determine which fibers are involved, and in what
distribution, to help narrow the differential.
● Electrodiagnostic studies can characterize further the polyneuropathy as axonal or
demyelinating and detail the severity.

CONDITIONS OF NOTE
On the inpatient service, acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) or Guillain–Barré syndrome (GBS) is
relatively common. Its worldwide incidence is about 1 to 2 cases/100,000
people per year. Men are more commonly affected than women. Often,
there is an antecedent infection. Symptoms include weakness and gait
unsteadiness. The classic presentation is of ascending paralysis, but there
may be considerable variation in the pattern of weakness. Loss of power
may be accompanied by sensory changes and back or leg pain. Symptoms
typically develop quickly, often progressing over days to weeks. Signs often
include relatively symmetric weakness and decreased reflexes in at least
two limbs. Patients may also have facial, bulbar, and respiratory weakness
in addition to autonomic symptoms. The Miller-Fisher variant is
characterized by gait ataxia, areflexia, and external ophthalmoplegia,
usually without limb weakness. An EMG can be particularly helpful in this
setting, confirming the characteristic signs of demyelination. An LP should
be done to rule out an infection or inflammatory process and to assess for
an elevated protein with a normal white blood cell count, a
cytoalbuminologic dissociation. Importantly, it may take up to 3 weeks
before this finding becomes apparent—and it does not ever occur in about
25% of patients. Positive assays for campylobacter jejuni and the GQ1b
antibody provide support for the diagnosis. If the patient has a marked
functional deficit and presents within about four weeks, treatment with
plasma exchange or intravenous immunoglobulin (IVIG) is often beneficial.
GBS is a monophasic illness. In some cases, however, individuals have
symptoms that progress beyond the 4-week mark or recur after initial
resolution. In this setting, chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) should be considered as a more likely
diagnosis. In contrast to GBS, there is often no readily identifiable
antecedent trigger for CIDP. Weakness affects both proximal and distal
muscles symmetrically. Sensory symptoms may be present, and the exam
often shows more pronounced deficits in vibration and position sensation
than in pain and temperature sensation. Reflexes tend to be diminished
throughout the limbs. As in GBS, EMG plays a key role in confirming the
presence of demyelination. An LP can help exclude inflammation or
infection and provide support for the diagnosis in the form of a
cytoalbuminologic dissociation. MRI of the spine may demonstrate
enlargement or enhancement of nerve roots. Although corticosteroids are
not helpful in the setting of GBS, they may be helpful treatment for CIDP in
the absence of contraindications (e.g., diabetes).
 Thus, although there is overlap in the features of GBS and CIDP, there
are some distinguishing features, as outlined in Box 23-2. GBS and CIDP
occur on a temporal continuum; monitoring over time may be necessary to
confirm the diagnosis. Although the classic forms of these conditions are
outlined here, it is worth noting that there are many variants.

BOX 23-2. Characteristics of Acute and Chronic Inflammatory

Demyelinating Polyradiculoneuropathy

Feature AIDP (GBS) CIDP

Classic distribution of Symmetric, Symmetric,
weakness at onset: distal proximal and distal
CSF findings: Elevated protein, normal Elevated protein, normal white
white blood cell count blood cell count
Classic NCS/EMG Primary demyelination Primary demyelination
findings:
Duration of symptom Up to 3–4 wk Beyond 8 wk
progression:
Symptom No Yes
recurrence/relapse?
Treatments: IVIG, PLEX Corticosteroids, steroid-sparing
agents, IVIG, PLEX

AIDP, acute inflammatory demyelinating polyradiculoneuropathy; GBS, Guillain–Barré

syndrome; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CSF,
cerebrospinal fluid; NCS/EMG, nerve conduction study / electromyography; IVIG, intravenous
immunoglobulin; PLEX, plasma exchange.

CMT refers to a group of hereditary polyneuropathies caused by

mutations in genes important for the myelin sheath or for the axons of
peripheral nerves, or for both. The most common presentation is that of a
slowly progressive, distal, symmetric, predominantly motor neuropathy.
Patients often have high-arched feet (pes cavus) and hammertoes. In
addition to the atrophy of hand and foot muscles, there may be a loss of
muscle bulk distally in the legs, leading to a “stork leg deformity” or an
“inverted champagne bottle” appearance. Achilles tendon reflexes are
almost always absent. EMG can help characterize the pathophysiology as
primarily demyelinating or axonal, guiding the choice of genetic studies.
Treatment is supportive.

KEY POINTS
● GBS is an acute form of polyneuropathy classically associated with ascending paralysis,
areflexia, sensory disturbance, and dysautonomia, responsive to plasma exchange and
IVIG.
● CIDP is a chronic form of polyneuropathy classically associated with symmetric proximal
and distal weakness, areflexia, and large-fiber sensory disturbance, responsive to
corticosteroids, steroid-sparing agents, plasma exchange, and IVIG.
● CMT is a hereditary motor sensory neuropathy associated with high arches and
hammertoes; genetic testing can provide a diagnosis; treatment is supportive.

CLINICAL VIGNETTES

VIGNETTE 1
A 52-year-old man presents to your clinic with a few month history of
intermittent paresthesias (tingling and numbness) and mild pain on the
bottom of his feet. Examination shows a normal mental status, brisk
reflexes at the knees, but absent ankle jerks, upgoing toes and
hypoesthesia to pinprick in the bottom of his feet. Vibration sensation is
reduced in the toes.
1. You order blood work to evaluate for possible causes of peripheral
neuropathy or polyneuropathy. Which abnormal finding is most
likely?
a. Low TSH
b. High TSH
c. Low B12
d. High B6
e. High glucose
2. Your test results confirm your initial diagnostic impression. What is
the best treatment?
a. Thyroid hormone replacement
b. Vitamin B12 replacement
 c. Oral hypoglycemic agents
d. Insulin
e. Fish oil
3. If the patient were to remain untreated, what other complication
could most likely occur?
a. Seizures
b. Dementia
c. Hyperglycemia
d. Infection
e. Skin disease

VIGNETTE 2
A 49-year-old, previously healthy woman presents to the emergency
department because of difficulty walking and bilateral foot pain. This
was preceded 2 weeks earlier by a gastrointestinal syndrome with 2
days of diarrhea. She states that she developed some weakness in her
feet 4 days ago, but today she is barely able to walk. She has also
noticed reduced handgrip strength and mild dyspnea. In addition, she
describes burning pain in her feet and lancinating lower back pain. She
has no bowel or bladder symptoms. Your exam shows BP 198/105,
pulse 110, respiratory rate 28/minute. O2 sat is 98% on room air. Her
lungs are clear. She has a normal mental status, cranial nerve
examination, and finger–nose–finger testing. She has no reflexes in any
limb. Arm strength is good except for hand intrinsic muscles that are
4/5. Leg muscle strength includes 3/5 weakness of foot dorsiflexion and
plantar flexion and 4/5 hip flexion and knee extension. The sensory
exam shows some reduced vibration sense and some pinprick
hyperalgesia in the soles of her feet. She has difficulty walking and a
bilateral steppage gait.
1. Which of the following tests would you do next?
a. MRI of the lumbosacral spine
b. Lumbar puncture
c. Anti-Hu antibodies
d. Lyme serology
e. Vitamin B12 levels
 2. You get the results of a patient’s laboratory testing, showing a
normal complete blood count and differential, and a normal
comprehensive metabolic panel. An LP shows no white blood cells
(WBCs), with a protein of 115 mg/dL (normal 15 to 40 mg/dL) and
a glucose of 62 mg/dL. Your best next step is:
a. Start ceftriaxone 1 g IV q 12 hours
b. Begin a beta-2 agonist for possible obstructive airway disease
c. Obtain NCSs and EMG
d. Determine forced vital capacity (FVC) and negative inspiratory
force (NIF)
e. Start hydrocodone for treatment of pain
3. You admit the patient to the intensive care unit (ICU) where her
FVC remains 25 mL/kg and NIF −55 cm H2O. What treatment
would you start next?
a. High-dose intravenous (IV) steroids
b. Oral prednisone at 1 mg /kg per day
c. IVIG
d. No need for treatment, just observation
e. Intubate

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer C:
This patient has features suggesting a peripheral neuropathy
(paresthesias or tingling and pain in the feet) plus a myelopathy
(upgoing toes and brisk knee jerks), raising the possibility of subacute
combined degeneration, a complication of severe vitamin B12
deficiency. Thyroid disease (hypo or hyperthyroidism), B6 intoxication,
and hyperglycemia can all cause peripheral neuropathies but are
unlikely to produce signs of a myelopathy, such as those described
above. Other causes of subacute combined degeneration include
neurosyphilis, tropical myeloneuropathies, Lyme disease, multiple
sclerosis, and HIV-1-associated vacuolar myelopathy.
VIGNETTE 1 QUESTION 2
2. Answer B:
In this case, B12 replacement is the treatment of choice. All the other
therapies are appropriate for different illnesses. Fish oil has no known
benefit in the management of peripheral neuropathy.

VIGNETTE 1 QUESTION 3
3. Answer B:
Vitamin B12 deficiency can also produce psychiatric and cognitive
symptoms (including dementia), gait instability, and hematologic
abnormalities, including anemia with an increased mean corpuscular
volume. It has not been associated with an increased risk of infection or
skin disease. Hyperglycemia is a complication of diabetes. Seizures are
not associated with B12 deficiency.

VIGNETTE 2 QUESTION 1
1. Answer B:
The presentation with a painful, symmetric, ascending (motor more than
sensory) polyneuropathy, with no reflexes, is consistent with an AIDP
or a GBS. LP is important to rule out infectious and inflammatory
causes of a polyradiculopathy. It may also show a “cytoalbuminologic
dissociation” (high protein, with no or few WBCs), characteristic of
GBS—after the first week or so. MRI of the lumbosacral spine is
worthwhile if an acute lumbosacral polyradiculopathy (cauda equina
syndrome) is the initial diagnosis, but upper extremity involvement and
respiratory problems make this unlikely. Anti-Hu antibodies are
associated with paraneoplastic polyneuropathies (sensory
ganglionopathy or sensorimotor polyneuropathy) that are unlikely to
present acutely as in this case. Lyme serology is always worthwhile, but
nothing in this case points to a history of a tick bite or other typical
finding in that disease. B12 deficiency would not explain this clinical
picture.

VIGNETTE 2 QUESTION 2
2. Answer D:
This patient has signs of respiratory distress, with a respiratory rate of
28/minute and symptoms of dyspnea. Weakness may be progressing to
involve respiratory muscles (particularly the diaphragm), and
respiratory failure could occur at any time, requiring intubation. When
the FVC is less than 15 mL/kg and the NIF closer to zero (normal is at
least −60 cm H2O) or less (negative) than −25 cm H2O, prophylactic
intubation and ventilation should be considered. Also, a decrease of
more than 30% of FVC or NIF in 24 hours may indicate the need for
intubation. NCSs and EMG can help in the diagnostic evaluation of
GBS but are not a task to be done in the emergency department.
Additionally, this patient is already presenting signs of autonomic
instability (with hypertension and tachycardia) that could change to
hypotension or bradycardia at any time. ICU admission is required.

VIGNETTE 2 QUESTION 3
3. Answer C:
The use of IVIG or plasmapheresis is the first line of therapy in patients
with GBS with progressive weakness. IV steroids and oral prednisone
are not beneficial and could be potentially harmful. Intubation is not
indicated because the FVC and NIF remain stable. Observation alone is
not appropriate in patients with significant weakness and respiratory or
autonomic compromise.
 24 Disorders of the Neuromuscular
Junction and Skeletal Muscle

Disorders of the neuromuscular junction and muscle are pure motor

phenomena. The underlying pathophysiology can result in distinctive
patterns of weakness that narrow the list of potential causes. In addition to
laboratory studies including genetic assays, nerve conduction studies and
electromyography can be particularly helpful in diagnosing neuromuscular
junction and muscle disorders (see Table 24-1).

DESCRIBING THE NEUROMUSCULAR

JUNCTION
The neuromuscular junction (NMJ) is an electrical–chemical–electrical link
between nerve and muscle. More specifically, electrical action potentials in
the nerve can be communicated and then transmitted through muscle to
cause a contraction via the neurotransmitter acetylcholine in a well-
choreographed cascade. An action potential propagates down the entire
length of a motor nerve axon to the axon button. Depolarization then
triggers voltage-gated calcium channels (VGCCs) to open and, in turn, the
influx of calcium causes a proportional release of acetylcholine from the
presynaptic terminal; when more calcium is present, more acetylcholine is
released. Acetylcholine then travels across the synaptic cleft and binds to
receptors on the muscle membrane, stimulating sodium channels to open
(see Fig. 24-1). The resultant depolarization creates end-plate potentials
with amplitudes proportional to the amount of bound acetylcholine. If the
end-plate potentials are great enough, an action potential is transmitted
through the muscle fiber. Acetylcholinesterase metabolizes acetylcholine in
the synaptic cleft.
 Neuromuscular dysfunction can arise from abnormalities in key points
along this multistep path. The resultant disorders can be classified
pathophysiologically as presynaptic, synaptic, or postsynaptic. NMJ
diseases can be further characterized by their etiologies. Some are
congenital and affect the packaging, metabolism, and receptors of
acetylcholine. Toxic and metabolic causes include snake and black widow
spider venom, organophosphate poisoning, botulism, and
hypermagnesemia. The most commonly encountered disorders, however,
are immune-mediated: Lambert–Eaton myasthenic syndrome (LEMS) is a
presynaptic disorder, while myasthenia gravis (MG) is a postsynaptic
disorder of the NMJ.

KEY POINTS
● Acetylcholine plays a key role in transmitting an electrical signal from the presynaptic
motor axon terminal to the postsynaptic muscle membrane, where binding can prompt an
action potential and, ultimately, muscle contraction.
● The amount of acetylcholine released is proportional to the amount of calcium present in
the presynaptic axon terminal; the size of the postsynaptic electrical response is
proportional to the amount of acetylcholine that binds effectively to receptors on the
muscle membrane.
● NMJ disorders are pathophysiologically classified as presynaptic, synaptic, and
postsynaptic.
● LEMS is a presynaptic disorder. MG is a postsynaptic disorder. Both have immune-
mediated underpinnings.

DISORDERS OF THE NEUROMUSCULAR

JUNCTION

MYASTHENIA GRAVIS
Several identified antibodies play a role in the pathogenesis of MG. In the
most common form of antibody-positive MG, there is an IgG-directed
attack on postsynaptic nicotinic acetylcholine receptors (Fig. 24-1). The
antibody binding effectively limits the number of functioning receptors to
which acetylcholine can bind. Therefore, even though the amount of
acetylcholine released from the nerve axon button into the cleft is sufficient,
it is not ultimately sensed in adequate quantities by the motor endplate.
Patients with MG may also have elevated MuSK or LRP4 titers, although
some patients do not have any detectable antibodies. Nevertheless,
“seronegative” MG presents in a manner indistinguishable from
seropositive MG.

TABLE 24-1. Disorders of the Neuromuscular Junction and Skeletal

Muscle
Disease Common Clinical Phenotype Commonly Associated
Abnormalities
Myasthenia gravis Fatigable proximal muscle Antibodies against the muscle
weakness; prominent ocular nicotinic acetylcholine receptor
and bulbar involvement or muscle specific kinase
Lambert–Eaton myasthenic Fatigable proximal muscle Antibodies against the P/Q-type
syndrome weakness; ocular and bulbar voltage-gated calcium channel
involvement rare; prominent
autonomic symptoms
Hyperkalemic periodic Episodes of generalized Voltage-gated sodium channel
paralysis weakness lasting minutes to mutations
hours
Hypokalemic periodic paralysis Episodes of generalized Voltage-gated calcium channel
weakness lasting hours to days mutations
Duchenne and Becker muscular Childhood onset of proximal Dystrophin gene mutation
dystrophy muscle weakness, including
neck flexors; no ocular or
bulbar involvement
Emery–Dreifuss muscular Early onset of joint Emerin and lamin A/C gene
dystrophy contractures; humeroperoneal mutations
pattern of muscle weakness
Myotonic dystrophy Distal muscle weakness and Intronic tri/tetra-nucleotide
stiffness, myotonia, systemic repeat expansion in DMPK
features (ptosis, balding, etc.) (DMI) and ZNF9 (DMII) genes
Facioscapulohumeral muscular Weakness predominantly DUX4 gene mutation
dystrophy affecting the face, shoulder
girdle, and upper arms
Limb-girdle muscular Proximal muscle weakness; no Genetic mutations in
dystrophy ocular or bulbar involvement sarcoglycan and several other
structural proteins, including
calpain, caveolin, and dysferlin

The characteristic symptom is “fatigable weakness,” a loss of power that

becomes more pronounced with the use of the affected muscles, and at the
end of the day. Although some patients have symptoms limited to the ocular
region, most develop some combination of weakness involving ocular,
bulbar, respiratory, and limb muscles. On exam, patients may have
asymmetric ptosis or extraocular abnormalities, nasal voice, limited palate
elevation, impaired gag reflex, slurring of speech, head drop, proximal
weakness, or combinations of these.
Several specialized bedside examination maneuvers can be done to assess
for fatigable weakness. To test sustained up-gaze, the examiner asks the
patient to look upward at a fixed target for about 60 seconds. Findings
supportive of MG include the subjective experience of double vision or the
objective development of ptosis, eye misalignment over time, or both. If
there is detectable ptosis at baseline, ice can be applied to the affected eye
for at least 2 minutes, as tolerated; a transient decrease in the degree of
ptosis suggests MG. Checking neck muscle strength is also important,
because weakness there may be accompanied by diaphragmatic weakness;
nerve roots C3, 4, and 5 serve both neck and diaphragmatic muscles—the
latter through the phrenic nerves. Asking the patient to count as high as
possible during a single exhalation can also provide a rough idea of
respiratory function; an inability to count to 40 should raise concern, as
should shortness of breath that increases in the supine position (when the
mechanical advantage of gravity is lost). Limb strength can be checked
before and after a brief exercise task. For instance, after checking deltoid
strength, have the patient perform 20 “arm pumps” in which the arm is
repeatedly abducted to shoulder level and then adducted to the torso. A
subsequent reduction in deltoid strength indicates fatigable weakness.
FIGURE 24-1. The neuromuscular junction: key components of the NMJ are depicted,
including the motor axon and muscle endplate, the synaptic cleft, and the muscle fiber. When an
action potential reaches the terminal, ACh is released into the synapse and binds to the nicotinic ACh
receptors on the sarcolemma, triggering a muscle fiber action potential and contraction. The antigenic
targets in MG and LEMS are indicated, as is the site of action of botulinum toxin. [NMJ,
neuromuscular junction; ACh, acetylcholine; MG, myasthenia gravis; LEMS, Lambert–Eaton
myasthenic syndrome]. Reprinted with permission from Louis ED, Mayer SA, Rowland LP. Merritt’s
Neurology. 13th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015. Figure 89.1.

The diagnosis of MG is made largely on the clinical evaluation. It can be

confirmed by the identification of elevated acetylcholine receptor, MuSK,
or LRP4 antibody titers. Elevated anti-striated muscle antibody titers may
also be present and have been linked with a higher incidence of thymoma.
All patients with a new diagnosis of MG should have chest imaging to
assess for thymic tumors.
In the absence of characteristic antibodies, electrodiagnostic tests can be
very helpful. Specifically, a “decremental” (decreasing) response on slow
repetitive nerve stimulation may occur. The most sensitive electrodiagnostic
test, however, is single-fiber electromyography (SF-EMG) when performed
on a weak muscle; this test is abnormal in 95% to 99% of patients with
generalized MG. Of note, increased “jitter” on SF-EMG is not specific and
can be seen in other neuromuscular conditions, including LEMS.
 Treatment with antiacetylcholinesterase agents, such as pyridostigmine
(Mestinon), can provide relief of symptoms, but it is important to remember
that pyridostigmine does not address the underlying cause of MG. Rather,
immunomodulatory therapies such as prednisone and steroid-sparing agents
may be necessary. In the setting of myasthenic crisis, with pronounced
respiratory distress potentially requiring intubation, intravenous
immunoglobulin (IVIG) and plasmapheresis are indicated because they act
much more quickly.

KEY POINTS
● MG is a postsynaptic NMJ disorder mediated by abnormal antibodies; acetylcholine
receptor antibodies are the most common.
● The signs of fatigable weakness may be identified on the exam using specialized
techniques; transient improvement in ptosis with the application of ice can support a
diagnosis of MG.
● When performed on a weak muscle, SF-EMG is the most sensitive test for MG.
● There is an important association between MG and thymoma.
● Treatment includes pyridostigmine and immunomodulatory therapies.

LAMBERT–EATON MYASTHENIC SYNDROME

In LEMS, IgG antibodies are directed against the P/Q type of VGCC,
impeding the calcium-dependent release of acetylcholine from the
presynaptic membrane. The downstream effect can be neuromuscular
transmission failure.
Patients may develop proximal leg weakness associated with aching
muscles and cramps—particularly following exertion. For this reason, the
syndrome is sometimes misinterpreted as neurogenic claudication. Unlike
neurogenic claudication, however, LEMS is typically associated with
autonomic symptoms including dry mouth, blurred vision, and constipation.
Examination may show proximal weakness. Reflexes may be depressed or
absent at rest, but rechecking an abnormal reflex after a patient contracts a
related muscle for 10 seconds (e.g., straightening the leg by activating the
quadriceps muscle before rechecking the patellar reflex) can yield a
stronger reflex. In LEMS, strength may also improve mildly after 10
seconds of maximal voluntary contraction. This phenomenon is referred to
as “facilitation.”
 LEMS occurs more frequently in patients greater than 40 years of age. It
is more common in men than in women. Smokers are at particular risk;
small cell lung cancers are discovered in about 60% of patients.
Electrodiagnostic studies, including repetitive nerve stimulation, can aid
in diagnosis. Specifically, the combination of a “decrement” upon slow
repetitive nerve stimulation and an “increment” on rapid repetitive nerve
stimulation supports the diagnosis. Blood work can also be done to evaluate
for the presence of an elevated VGCC antibody titer. Given the link with
malignancy, cancer screening should be undertaken. Treatments are aimed
at addressing both any detected cancer and the NMJ disorder. Although 3,4
diaminopyridine is the most effective therapy, it is not widely available, so
pyridostigmine, IVIG, and other oral immunosuppressants may be tried.

KEY POINTS
● LEMS is a presynaptic NMJ disorder mediated by P/Q-type VGCC antibodies.
● The signs of “facilitation” may be identified on the strength exam, reflex assessment, and
rapid repetitive nerve stimulation during electrodiagnostic tests.
● There is an important association between LEMS and small cell lung cancer.

DISORDERS OF MUSCLE
Patients may report “weakness,” a term used to describe a variety of
symptoms ranging from fatigue to limited mobility (e.g., due to stiffness). It
is, therefore, important to elucidate if the symptom actually reflects a loss
of power. Asking what specific activities pose a challenge (e.g., standing
from low chairs, moving in or out of cars, maintaining the arms above
shoulder level) can be helpful. The exam may help characterize the
distribution of affected muscle groups further. Although there are
exceptions, many primary muscle disorders are symmetric and proximal.
Additional information may be gained through laboratory studies, including
a creatine kinase (CK) level, and electrodiagnostic studies. In certain
instances, muscle ultrasound and MRI may show pattern-specific
abnormalities or help guide the choice of a biopsy site, although biopsies
are becoming increasingly rare with advances in genetic testing.
 Muscle disorders may be acquired or inherited. Further, they can
represent a primary disease or occur in the setting of systemic illness.
Trauma or strenuous exercise can cause CK elevations in the absence of an
underlying disease. Conversely, muscle disorders can be discovered
incidentally (e.g., through CK or liver function test (LFT) abnormalities)
during routine screening. As always, the clinical context is important in
interpreting laboratory findings.

ACQUIRED MUSCLE DISORDERS

Infectious
Infectious myopathies are some of the easiest to diagnose because there is
usually an identifiable antecedent illness. Associated muscle symptoms and
signs occur along a spectrum from myalgias to demonstrable
rhabdomyolysis. In the United States, enteroviruses and influenza A and B
are most frequently linked to self-limited viral myositis. HIV is associated
with a more chronic myopathy.

Toxic
Excessive alcohol use can be associated with both acute and chronic
myopathies. The former usually occurs after a binge and results in diffuse
muscle tenderness, cramps, swelling, and weakness that may be most
pronounced in the calves. Malnourished women who suffer from alcohol
dependence are most susceptible to the chronic form of myopathy which is
gradual in onset and proximal in distribution. Abstinence can help.
Just as taking an alcohol use history is important, so is reviewing
medication lists. Lipid-lowering and antiretroviral drugs and
glucocorticoids can cause myopathies. At doses above 40 to 60 mg per day,
prednisone can lead to detectable weakness within 2 weeks. Proximal limb
weakness is most common. Muscle enzyme assays and electromyographies
(EMGs) are usually normal. Although not typically performed in this
setting, a biopsy would be likely to show atrophy of type II fibers. Strength
can improve when the glucocorticoid dose is lowered (e.g., to less than 10
mg/day of prednisone).
Skeletal muscle is also affected in the drug-related neuroleptic
malignant syndrome (NMS), although mental status changes (for example,
agitation and inattention) are often the initial symptoms. NMS is a
consideration when mental status change is accompanied by a temperature
above 38°C, generalized muscular rigidity (with CK elevations >1,000
µ/L), and autonomic instability. Dysautonomia variably manifests as
profuse diaphoresis, tachypnea, hypertension, tachycardia, and cardiac
arrhythmias. The dysautonomia accounts for most fatalities from NMS.
NMS can develop because of withdrawal from dopamine agonists used to
treat Parkinson disease but is more commonly caused by the use of
neuroleptic agents; NMS can occur after many years of neuroleptic
treatment or just after a single dose. Discontinuing the culprit medication is
one of the most important steps to take. Sometimes drugs such as
dantrolene and bromocriptine are given. In any case, supportive measures
are important during recovery, which often takes about 2 weeks. Most
patients have no chronic deficits following an episode of NMS. NMS can
be distinguished from serotonin syndrome by a few key features:
shivering, hyperreflexia, ataxia, and myoclonus are more common in
serotonin syndrome than with NMS.

Endocrine
Untreated hypo- and hyperthyroidism can be associated with weakness,
muscle aches, and cramps. An EMG can be normal or show myopathic
features in both conditions, but there are several features that can help
distinguish between them. In hypothyroidism, deep tendon reflexes (DTRs)
may have a delayed relaxation phase and CK levels are often elevated. In
hyperthyroidism, DTRs may be increased and CK levels are often normal.
Thyroid function tests can help make the diagnosis; treatment of the thyroid
dysfunction can lead to improvement in muscle symptoms within weeks to
months.

Inflammatory
Inflammatory myopathies include disorders such as polymyositis,
dermatomyositis, and inclusion body myositis. Polymyositis and
dermatomyositis generally present with symmetric, proximal limb and
neck flexor weakness and sometimes, dysphagia, myalgias, arthralgias, and
interstitial lung disease. Dermatomyositis is associated with a distinctive
purplish (or heliotrope) eyelid color and skin changes in the upper torso and
hip regions. Importantly, there is an increased risk of malignancy with
dermatomyositis. Slowly progressive leg weakness and frequent falls may
herald inclusion body myositis, which can preferentially affect proximal
legs and forearm flexors. The signs of an inflammatory myopathy on EMG,
elevated CK, aldolase, aminotransferases, lactate dehydrogenase, and
myositis-specific autoantibody titers (e.g., anti-Jo-1) help support a
diagnosis of inflammatory myopathy. Glucocorticoids are generally the
initial therapy. With a goal of lowering the cumulative dose of prednisone, a
steroid-sparing agent such as azathioprine or methotrexate may also be
started. IVIG is indicated in certain situations, including when the degree of
dysphagia poses an aspiration risk or when weakness is life-threatening.

KEY POINTS
● Enterovirus and influenza can cause a self-limited viral myositis.
● Alcohol and medications including glucocorticoids can cause myopathies.
● NMS is associated with mental status changes, fever, muscle rigidity, and dysautonomia.
● Thyroid dysfunction can lead to weakness and reflex abnormalities.
● Inflammatory myopathies include polymyositis, dermatomyositis, and inclusion body
myositis, which can be distinguished by the pattern of weakness and by the presence of
systemic symptoms and signs, such as a rash.

CONGENITAL MUSCLE DISORDERS

Congenital muscle disorders can be categorized as “nondystrophic” or
“dystrophic.” In the latter, muscle biopsies show “dystrophic” changes such
as increased connective tissue and fiber splitting. Inherited disorders are
phenotypically diverse, and the number of contributory genetic variants is
ever-expanding.

NONDYSTROPHIC

Metabolic Myopathies
Metabolic myopathies present as proximal myopathies, one element of a
more diffuse neurologic syndrome with central nervous system dysfunction,
or as intermittent myoglobinuria and cramps. The hallmark of metabolic
myopathies is exertion-related symptoms, including the development of
muscle pain and cramps during exercise. These processes reflect
dysfunction in lipid or glycogen metabolism.
An important group of metabolic myopathies is the mitochondrial
myopathies, which are related to abnormalities in the oxidative
phosphorylation pathway. They have several forms. One form is a
myopathy associated with short stature and other multisystem
abnormalities. An example of this form is mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS),
which is discussed more fully in Chapter 18. Another mitochondrial
myopathy is chronic progressive external ophthalmoplegia, a syndrome of
bilateral ptosis and weakness of extraocular muscles that worsens over time.
A third type is limited to the skeletal muscle; it presents with muscle aches,
fatigue with exercise, elevated CK, and sometimes, rhabdomyolysis. In
each of these cases, symptom exacerbations can occur because of
physiologic stressors such as cold exposure, fasting, and heavy exercise.

Channelopathies
Physiologic stressors can also precipitate symptoms in inherited muscle
disorders because of ion channel dysfunction. These “channelopathies”
include hyper- and hypokalemic periodic paralysis (PP). In both of these
rare conditions, patients have bouts of painless weakness, most pronounced
in proximal limbs. Bulbar and respiratory muscles are generally not
affected, and consciousness is preserved. During symptoms, a chemistry
panel may demonstrate a high or a low potassium level. Abortive treatments
include calcium or beta-adrenergic agonists (for hyperkalemic PP) or
potassium chloride without dextrose (for hypokalemic PP). Prophylactic
therapies include acetazolamide, but attacks may also be avoided by
limiting exercise and carbohydrate intake. During asymptomatic periods,
when strength is normal, nerve conduction studies and EMG may
demonstrate characteristic changes in motor response amplitudes and motor
unit action potentials. Further, the presence of electrical myotonia on an
EMG points to hyperkalemic, rather than hypokalemic, PP. Genetic testing
can be most helpful in identifying an underlying cause. Although
hyperkalemic PP is related to sodium channel dysfunction, hypokalemic PP
results from a calcium channel defect. Whenever PP is a diagnostic
consideration, obtaining an ECG is important because the channelopathies
and associated electrolyte abnormalities can predispose to arrhythmias,
including with a prolonged QTc. Caution with general anesthesia, and
avoidance of depolarizing agents, is recommended to avoid paralysis and
complications with extubation.

KEY POINTS
● The hallmark of metabolic myopathies is exertion-related symptoms, including the
development of muscle pain and cramps during exercise.
● In hyper- and hypokalemic PP, patients experience episodes of painless weakness most
pronounced in proximal limbs.
● Physiologic stressors can cause symptom exacerbations in these inherited muscle
disorders.

DYSTROPHIC

Duchenne and Becker Muscular Dystrophies

Muscular dystrophies, congenital causes of weakness, are a heterogeneous
group of disorders with variable ages of onset and phenotypic expression.
Duchenne and Becker muscular dystrophies are X-linked disorders that lead
to progressive weakness in young boys. Duchenne muscular dystrophy
(DMD) is more severe; weakness develops by 2 to 3 years of age. Affected
individuals may have trouble navigating stairs, running, and jumping. Use
of the arms to rise from the floor to a standing position (Gower’s sign), a
waddling gait, decreased reflexes, lumbar lordosis, and calf enlargement are
characteristic findings. Cardiac involvement (e.g., conduction abnormalities
and a dilated cardiomyopathy) is common. Becker muscular dystrophy
(BMD) has similar manifestations, but onset is later and life expectancy is
longer. Individuals with DMD tend to die of respiratory insufficiency or
cardiac complications in their teens or 20s, but those with BMD can live
beyond 30 years of age. Genetic testing is key in establishing a diagnosis. If
genetic testing is negative, a muscle biopsy can be diagnostic.
Glucocorticoids are generally prescribed after the age of 4 when motor
skills stop progressing or start to decline.
Emery–Dreifus Muscular Dystrophy
Emery–Dreifus muscular dystrophy (EDMD) is genetically heterogeneous
and can be autosomal recessive, autosomal dominant, or X-linked recessive.
In general, children present with weakness in a humeroperoneal distribution
(with preferential involvement of biceps, triceps, and tibialis anterior).
Contractures of the Achilles tendons and elbow flexors are characteristic.
Dilated cardiomyopathy and cardiac conduction abnormalities are common.
For this reason, cardiac status should be evaluated when EDMD is on the
differential. Genetic testing can provide a definitive diagnosis. Treatment is
supportive.

Myotonic Dystrophy
Myotonic dystrophy is an autosomal dominant, multisystem disorder
associated with myotonia, or delayed muscle relaxation after activation.
Individuals with myotonic dystrophy types I (DMI) and II (DMII) tend to
have a narrow, elongated face, frontal balding, temporal wasting, ptosis, and
a horizontal smile (due to facial weakness). In both forms of the disorder,
sleep and endocrine disturbances, cataracts, and cardiac conduction
abnormalities typically develop. Although similar in many ways, the two
forms of the disorder can be distinguished by the time of symptom onset,
the distribution of weakness, and the presence of pain. Patients with DMI
usually present in their late teens with distal weakness and wasting, whereas
DMII usually presents in adults in their 40s or older with proximal
weakness. Pain in the arms, thighs, and back is more frequent in DMII.

Facioscapulohumeral Muscular Dystrophy

Chronic pain can also be a component of facioscapulohumeral muscular
dystrophy (FSHD). A typical early finding of FSHD is scapular winging.
As suggested by its name, however, patients with this disorder may also
have facial and upper arm weakness; legs and abdominal muscles are
variably affected. FSHD is linked with a mutation in the double homeobox
protein 4 (DUX4) gene.

Limb-girdle Muscular Dystrophy

There is no single gene responsible for the limb-girdle muscular
dystrophies, which encompass a growing group of disorders characterized
by progressive loss of power and muscle bulk primarily in the shoulder and
pelvic girdle regions. The severity of symptoms and signs, the age of onset,
and the phenotype for these disorders is variable—even in the setting of a
common genetic mutation. CK levels are often at least mildly elevated.
EMG generally shows myopathic changes. Genetic testing is required for
definitive diagnosis. Therapy is supportive, with help from members of a
multidisciplinary team, for example from genetics, orthopedics, cardiac,
pulmonary, nutrition, occupational therapy, and physical therapy.

KEY POINTS
● Duchenne and Becker muscular dystrophies are X-linked disorders that lead to progressive
weakness in young boys.
● EDMD is characterized by humeroperoneal weakness, contractures, and cardiac
conduction abnormalities.
● Individuals with DMI and DMII tend to have narrow, elongated faces, frontal balding,
temporal wasting, ptosis, and a horizontal smile, in addition to myotonia.
● FSHD can present with scapular winging and facial weakness.
● Limb-girdle muscular dystrophies are multiple disorders associated with progressive loss
of power and muscle bulk in the shoulder and pelvic girdle regions.

CLINICAL VIGNETTES

VIGNETTE 1
A 63-year-old man with hypertension (on a thiazide diuretic) and high
cholesterol (on an HMG CoA reductase inhibitor) is seen in the
Neurology clinic with symptoms of generalized weakness and difficulty
getting up from a low-seated position. There is no clear diurnal
fluctuation in the severity of symptoms. He reports no ocular or bulbar
symptoms and no muscle pain. He has, however, noticed that he feels a
little light-headed if he stands up quickly from the lying or seated
position. He reports a 10-pound weight loss. Examination shows very
mild weakness of hip flexion and hip abduction. He seems weaker
initially and then gets stronger. DTRs are absent.
1. Which of the following diagnoses do you suspect is the most
likely?
 a. Myasthenia gravis
b. LEMS
c. Polymyositis
d. Statin-induced myositis
e. Hypokalemic PP due to potassium wasting from
hydrochlorothiazide (HCTZ)
2. Clinically you suspect LEMS, but your differential diagnosis
includes MG. Which of the following test results would be most
helpful in differentiating the two?
a. Normal acetylcholine receptor antibody titers
b. A decremental response on slow repetitive nerve stimulation
(RNS)
c. Elevated jitter on SF-EMG
d. An incremental response on fast RNS
e. A negative ice pack test
3. You confirm the diagnosis of LEMS on the basis of an incremental
response following fast RNS and the presence of anti-P/Q VGCC
antibodies. Which of the following is not relevant to the
management of patients with LEMS?
a. Pyridostigmine
b. 3,4-diaminopyridine
c. Prednisone
d. Chest computed tomography (CT) to exclude underling small
cell lung cancer
e. Thymectomy

VIGNETTE 2
A 37-year-old African American woman is seen in the Neurology clinic
with a 2-month history of diplopia, ptosis, dysarthria, and shortness of
breath. Her symptoms fluctuate somewhat: worse in the evening than in
the morning. Examination shows fatigable ptosis bilaterally, diffuse
ophthalmoplegia, mild bifacial weakness, and moderate weakness of
neck flexion. Her primary care physician thought she likely had MG
despite negative acetylcholine receptor antibody titers but found that her
symptoms responded only minimally to treatment with pyridostigmine.
1. The most likely diagnosis is:
 a. botulism
b. LEMS
c. MG
d. polymyositis
e. Guillain–Barré syndrome
2. On further review of medical records, you discover that she has
elevated anti-MuSK antibody titers, supporting a diagnosis of MG.
The most appropriate next step is:
a. obtain a CT scan of the chest
b. check antistriated muscle antibody titers
c. refer for electrophysiologic studies (repetitive nerve stimulation
and SF-EMG)
d. check respiratory muscle function with a forced vital capacity
(FVC)
e. perform an ice pack test

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer B:
The history of mild proximal weakness and autonomic symptoms
(orthostatic hypotension) along with the finding of absent DTRs and
weakness that facilitates (i.e., improves over a period of seconds while
testing muscle strength), all point strongly to a diagnosis of LEMS. MG
may also produce proximal weakness, but reflexes are typically
preserved and autonomic symptoms are absent. Polymyositis and statin-
induced myositis may both cause proximal weakness, but there is often
some degree of muscle pain (myalgia), and the reflexes should not be
absent in the face of relatively mild weakness. Neither of these
disorders is associated with orthostatic hypotension, and neither should
produce weakness that facilitates. Although HCTZ does cause
potassium wasting, the history of static weakness is not characteristic of
hypokalemic PP, which typically causes episodes of severe weakness
with complete recovery between attacks. Also, it would be highly
unusual for an inherited ion channelopathy such as PP to manifest at
this late age.

VIGNETTE 1 QUESTION 2
2. Answer D:
LEMS is characterized both by a decremental response following slow
RNS and an incremental response following fast RNS or tetanic muscle
contraction. A decremental response following slow RNS is also seen in
myasthenia and so would not help differentiate the two diagnoses.
Increased jitter on SF-EMG may be seen in both disorders. Although
elevated acetylcholine receptor antibodies help confirm the diagnosis of
myasthenia, negative antibody titers do not preclude the diagnosis, as
about 20% of people with generalized myasthenia do not have elevated
acetylcholine receptor antibodies. A negative ice pack test similarly
does not exclude the diagnosis of MG (particularly if there is no ptosis)
and so is not helpful in differentiating myasthenia from LEMS.

VIGNETTE 1 QUESTION 3
3. Answer E:
3,4-diaminopyridine and pyridostigmine are frequently used together
for symptomatic management of muscle weakness in LEMS.
Prednisone may also be helpful. Because about 60% of patients with
LEMS have an underlying cancer (most often a small cell lung cancer),
a chest CT should always be performed. Thymectomy has no role in the
management of LEMS except in the rare circumstance when a thymoma
represents the underlying malignancy (rather than a small cell lung
carcinoma).

VIGNETTE 2 QUESTION 1
1. Answer C:
The most likely diagnosis is still MG, but probably with elevated anti-
MuSK (muscle specific kinase) antibodies, rather than acetylcholine
receptor antibodies. MuSK-positive myasthenics are typically young
(<40 years old) women, often African American, who typically present
with early respiratory dysfunction and often do not respond well to
treatment with cholinesterase inhibitors such as pyridostigmine. The
clinical presentation could be consistent with botulism, but the diurnal
fluctuation in symptom severity suggests MG, and there is no history of
environmental exposure to food containing botulism and no history of a
wound that might have been contaminated by the Clostridium
bacterium. Polymyositis should not cause ophthalmoplegia and
typically is more subacute in onset. The constellation of symptoms is
compatible with Guillain–Barré syndrome, but the temporal course of
her illness (2 months) and the diurnal fluctuation argue against this
diagnosis.

VIGNETTE 2 QUESTION 2
2. Answer D:
It is essential to quantify the severity of her respiratory muscle
weakness, and a bedside test such as the FVC or negative inspiratory
force is appropriate. The ice pack test and electrodiagnostic studies are
unnecessary because the diagnosis of MG has already been confirmed.
CT scan of the chest is not necessary, because thymoma and thymic
hyperplasia are associated with acetylcholine receptor antibody-positive
myasthenia and not anti-MuSK myasthenia. Antistriated muscle
antibodies are similarly unnecessary, because they have no diagnostic
value in this context.
 25 Pediatric Neurology

Neurologic disorders in children are encountered commonly by

pediatricians and family physicians. Although many neurologic illnesses
that affect infants and children also affect adults (such as infection, epilepsy,
inflammatory and demyelinating diseases, peripheral neuropathies, and
myopathies), some, including developmental disorders, malformations, and
many genetically determined conditions, are especially characteristic of the
pediatric population.
The history is the most important component of the evaluation of a child
with a neurologic problem. It shares the same principles as described for the
adult history but also requires a complete review of the pregnancy, labor,
and delivery (especially in cases of perinatal injury), congenital infection,
and family history.

DEVELOPMENT AND MATURATION

One of the most important elements of the neurologic history is a
developmental assessment of the child. The Denver Developmental
Screening Test is an efficient and reliable method to assess achievement of
developmental milestones. It evaluates four components of development:
gross motor skills, fine motor adaptive skills, language, and personal–social
interaction. Table 25-1 summarizes developmental milestones by age. This
is based on averages and therefore can be used only with an understanding
of the variability among children. Table 25-2 gives a brief description of
primitive reflexes and their significance.

CEREBRAL PALSY
Cerebral palsy (CP) is a static (nonprogressive) disorder due to pre- or
perinatal damage to cerebromotor pathways. It is the most common motor
disability in childhood, affecting about 2.7 per 1,000 live births. Risk
factors for CP include hypoxic–ischemic insult to the brain in the perinatal
period, prematurity, low birth weight, chorioamnionitis, prenatal viral
infections, and prenatal strokes.

CLASSIFICATION
The most commonly used classification of CP is based on the distribution
of the affected motor dysfunction:
• Hemiparetic: Weakness and spasticity are seen on one side of the body.
Signs include fisting on the affected side, early hand preference, and
increased reflexes on the affected side.
• Diparetic: There is spasticity of all four limbs but affecting the legs
much more than the arms. The children are often of normal intelligence
and are less likely to have seizures than children with other forms of CP.
• Spastic quadriplegic: All four limbs are affected. Seizures often occur
within the first 48 hours of life. The infant may show signs of cerebral
hypotonia (see later discussion).

CLINICAL MANIFESTATION
CP may be diagnosed as early as the first week of life: infants may have
flaccid weakness, asymmetric limb movements, or seizures. In older
children, spasticity, dystonia, and developmental delay are common
presentations.

DIAGNOSTIC EVALUATION
The diagnosis of CP is based on the clinical symptoms and signs. The time
course of symptoms should be static, rather than progressive. Other entities
that may present with dystonia, ataxia, or spasticity but that progress with
time (e.g., metabolic disorders and leukodystrophies) must be excluded.
Magnetic resonance imaging (MRI) is indicated to exclude the structural
causes of the symptoms and signs, such as tumor, stroke, or vascular
malformations.
TABLE 25-1. Developmental Milestones
Age Adaptive/Fine Gross Motor Language Personal/Social
Motor Skills Skills
1 mo Grasp reflex; hand Raises head Facial response to Stares at face
fisted slightly when sounds
prone
2 mo Follows objects with Lifts head from Coos Smiles in
eyes past midline prone to 45 response to
degrees others
4 mo Hands open; brings Sits, head steady; Laughs and squeals; Smiles
objects to mouth rolls to supine toward voice spontaneously
6 mo Palmar grasp of Sits Babbles (consonant Reaches for toys;
objects; starts transfer independently; sounds); mimics recognizes
of objects stands with hands sounds strangers
held
9 mo Pincer grasp; claps Pulls to stand Says “mama,” “dada,” Finger-feeds self;
hands nonspecifically; waves bye-bye
comprehends “no”;
associates word and
action (“bye-bye,”
“no,” etc.)
1y Helps to turn pages of Stands 2–4 words; follows Points to indicate
book; tower of two independently; command with wants
blocks walks with one gesture
hand held
18 mo Turns pages of book; Walks up steps 10–20 words; points Feeds self with
imitates vertical lines to four body parts; spoon; uses cup
obeys simple
commands
2y Solves single-piece Jumps; kicks ball Combines 2–3 words; Removes coat;
puzzles uses I and you; 50– verbalizes wants
300 words
3y Copies circle; draws Throws ball Gives full name, age, Toilet trained;
person with three overhand; walks and sex; names two puts on shirt and
body parts; imitates up stairs, colors knows front from
horizontal lines; alternating feet back
towers of six cubes;
draws circles
4y Counts four objects; Hops on one foot Understands Dresses with
identifies some prepositions (under, little assistance;
numbers and letters; on, behind, in front shoes on correct
uses scissors of); asks “how” and feet
“why”
5y Prints first name; Skips, alternating Asks the meaning of Ties shoes
counts 10 objects; feet words; understands
draws triangle; draws conjunctions and past
tenses; knows colors
 person with several
parts
DENVER II Technical Manual © 1990 William K Frankenburg and Josiah B Dodds © 2009
Wilhelmine R. Frankenburg
Adapted from Frankenburg WK, Dodds J, Archer P, et al. The DENVER II Technical Manual.
Denver, CO: Denver Developmental Materials Inc.; 1996.

TREATMENT
In general, a multidisciplinary approach is necessary, with early infant
stimulation, physical and occupational therapy, orthopedic and psychologic
evaluation, and speech therapy.

KEY POINTS
● CP is a static disease. If the disease is progressing, it is not CP.
● It occurs in almost 3 in 1,000 births worldwide.
● The most common neurologic abnormality is spasticity.

TABLE 25-2. Primitive Reflexes

Reflex Significance Appears Disappears
Moro (startle reflex) Elicited by head Term newborns 3 mos
extension. Two phases:
extension and
abduction of arms and
leg extension, followed
by slower abduction of
arms. Asymmetry
indicates central
nervous system
dysfunction such as
hemiparesis, spinal
cord lesion, or brachial
plexus injury.
Tonic neck Turning head: arm and 1 month 5 mos
leg extended on the
side of the turn, with
flexion on the other
side (fencing posture).
If an infant is unable to
move out of posture,
implies possible brain
pathology.
 Traction response Lift baby by traction in Birth to 6 mos Persists throughout life
both hands. Head lag
after 6 mo is pathologic
and indicates
hypotonia.
Parachute Elicited by plunging 6 mos Persists throughout life
suspended infant
downward. Arms
should thrust forward
symmetrically as if
breaking the fall. Also
elicited with baby in
sitting position and
pushed forward. Arms
should try to break the
fall. Asymmetry
suggests hemiparesis,
spinal cord lesion, or
brachial plexus
pathology.

INTELLECTUAL DISABILITY AND

DEVELOPMENTAL DELAY
Intellectual disability (ID) is the term used to describe impairment in the
ability to achieve an expected level of cognitive function. The disorder can
vary significantly in severity but manifests prior to adulthood. It can be
classified by the results of standard intelligence tests such as the Stanford–
Binet IQ and the Wechsler Preschool and Primary Scale of Intelligence—
Revised. Normal IQ is 100 with a standard deviation of 15. ID is
categorized as follows:
• Mild: IQ between 55 and 70
• Moderate: IQ between 40 and 55
• Severe: 25 to 40
• Profound: less than 25
For most children with ID, the cause is not known. There are many
known causes of ID, including prenatal and postnatal trauma (e.g.,
intracerebral hemorrhage and hypoxic–anoxic encephalopathy); congenital
and postnatal infection (e.g., congenital rubella, syphilis, cytomegalovirus,
toxoplasmosis, and HIV infection); chromosomal abnormalities (e.g., Down
syndrome, fragile X syndrome, Angelman syndrome, Prader–Willi
syndrome); chromosomal translocations (e.g., cri du chat syndrome);
inherited metabolic disorders (e.g., hypothyroidism, galactosemia, Tay–
Sachs disease); and toxic, nutritional, and environmental causes. Table 25-3
summarizes some important chromosomal abnormalities associated with
ID.
Developmental delay is the failure to acquire age-appropriate cognitive,
language, fine or gross motor skills, or social skills. The Denver
Developmental Assessment is a standard test that can help establish the
diagnosis. Many of the etiologies of developmental delay are similar to
those responsible for ID and include intrauterine toxins and infections,
genetic abnormalities, neuronal migrational disorders, hypoxic–ischemic
encephalopathy, and inborn errors of metabolism. Most often, though, no
cause for developmental delay is found, in which case it is labeled
“idiopathic” (or more appropriately, cryptogenic).
The treatment for both ID and developmental delay includes referral to
early intervention programs for special education and training.

KEY POINTS
● ID implies a substantially below-average cognitive ability and impaired adaptive behavior.
● Developmental delay implies the inability to achieve developmental milestones at the
usual age. It is not synonymous with ID.

AUTISTIC SPECTRUM DISORDERS

Autism is a developmental disorder of brain function. Usually, the etiology
is unknown. Autism is the most common of the disorders that fall under the
rubric of pervasive developmental disorders.

TABLE 25-3. Intellectual Disability Syndromes Associated with

Chromosomal Abnormalities
Condition Epidemiology Genetic Defect Clinical
Characteristics
Down syndrome Most common Trisomy 21 ID; upslanting
 inherited ID palpebral fissures;
protruding tongue;
simian crease;
Brushfield spots
Fragile X syndrome Relatively common Defect in the X 20% of boys are
form of ID; affects chromosome; mutation normal; 30% of carrier
boys more than girls in the 5' end of the girls are mildly
gene with amplification affected; moderate ID;
of a CGG repeat (200 behavioral problems;
or more copies) somatic abnormalities:
long face, enlarged
ears, and
macroorchidism
Prader–Willi syndrome Uncommon inherited The absence of ID, reduced muscle
disorder segment 11–13 on the tone, short stature,
long arm of the emotional lability, and
paternally derived insatiable appetite
chromosome 15 (obesity)
Angelman syndrome Uncommon Deletion of segment ID; abnormal gait;
neurogenetic disorder 11–13 on the speech impairment;
maternally derived seizures; inappropriate
chromosome 15 happy behavior that
includes laughing,
smiling, and
excitability (“happy
puppet” syndrome)
Rett syndrome Progressive Causal gene is MeCP2, Normal development
neurodevelopmental found on the long arm until 6–18 mo; a first
disorder; generally of chromosome X (X sign is hypotonia;
affects girls only; 28) autistic-like behavior;
incidence of 1 in stereotyped hand
10,000 births movements (wringing
and waving); lag in
brain and head growth;
gait abnormalities;
seizures
ID, intellectual disability.

CLINICAL MANIFESTATIONS
Autism is characterized by a combination of social, behavioral, and
language abnormalities with onset before age 3. Marked deficiencies in
social and communication skills manifest as a lack of attachment to other
members of the family and poor social interactions. A restricted range of
behaviors, interests, and activities is demonstrated and may include
repetitive and stereotyped behaviors such as toe walking, rocking, flapping,
banging, and licking. Abnormal language features include echolalia and
stereotyped speech.

DIAGNOSTIC EVALUATION
The diagnosis of autism is clinical. Differential diagnosis includes other
causes of speech and language problems, such as deafness, ID, and seizures
(e.g., in Landau–Kleffner syndrome). Asperger syndrome can be
considered a variant of autism characterized by social isolation and
eccentric behavior with normal intelligence and language development.

TREATMENT
The treatment of autism includes support and behavior modification. No
cures are available at present.

KEY POINTS
● Autism is characterized by a combination of social, behavioral, and language
abnormalities. Asperger syndrome is an autism variant with normal intelligence and
language development.

DEVELOPMENTAL REGRESSION AND

INHERITED NEURODEGENERATIVE
DISORDERS
Developmental regression is defined as a loss of previously attained
developmental milestones. It is often related to an inherited
neurodegenerative disorder. It is one of the most distressing complaints
confronted by pediatricians and neurologists. An extensive battery of
diagnostic tests is the wrong approach. Rather, a complete history, physical
and neurologic examination, and additional tests based on those findings,
are fundamental in reaching an accurate diagnosis. It is important to
differentiate regression from developmental delay (see previous section).
Table 25-4 shows common causes of progressive encephalopathy at
different ages that can produce developmental delay or regression.
The inherited neurodegenerative diseases are classified according to the
involved intracellular structure: the lysosome, peroxisome, mitochondria,
Golgi apparatus, and cell membrane. Whatever the cellular and molecular
mechanism responsible, it is often more productive to recognize the
common patterns of disease expression according to the age of onset,
symptoms, and systems involved. The most common clinical features of
neurometabolic diseases presenting in infancy and childhood are
developmental delay or regression.

TABLE 25-4. Causes of Progressive Encephalopathy

Onset Before Age 2 Onset After Age 2
Mitochondrial disorders AIDS
Hypothyroidism Congenital syphilis
Neurocutaneous syndromes Subacute sclerosing panencephalitis
Tuberous sclerosis complex Enzymatic lysosomal disorders
Neurofibromatosis Gaucher disease
Gray matter disorders Gangliosidosis
Infantile ceroid lipofuscinosis Late-onset Krabbe disease
Rett syndrome Metachromatic leukodystrophy
White matter disorders Other gray matter disorders
Alexander disease Ceroid lipofuscinosis
Canavan disease Huntington disease
Neonatal adrenoleukodystrophy Mitochondrial disorders
Pelizaeus–Merzbacher disease (peroxisomal Other white matter disorders
disorders)
Disorders of amino acid metabolism Adrenoleukodystrophy
Homocystinuria Alexander disease
Maple syrup urine disease
Phenylketonuria
Enzymatic disorders
Gangliosidosis
Gaucher disease
Krabbe disease
Mucopolysaccharidoses
Metachromatic leukodystrophy
 Lysosomal disorders are caused by the genetic defects of lysosomal
enzymes and cofactors that result in the accumulation of undegraded
substrates in lysosomes. They are classified according to the accumulated
material: sphingolipidoses, mucopolysaccharidoses, mucolipidoses,
glycogen storage disease type II, sialidoses, and neuronal ceroid
lipofuscinosis. Some of the most important characteristics of these clinical
entities are reviewed in Table 25-5.

TABLE 25-5. Inherited Neurodegenerative Disorders

Disorder Metabolic Defect Chromosome and Notes
Inheritance
Tay–Sachs disease Hexosaminidase A 15, autosomal Cherry-red spot. More
recessive common in Ashkenazi
Jews.
Niemann–Pick disease Sphingomyelinase 11, autosomal recessive Cherry-red spot. More
common in Ashkenazi
Jews.
Gaucher disease Glucocerebrosidase 1, autosomal recessive Cherry-red spot.
Gaucher cells in bone
marrow.
Krabbe disease Galactosylceramide P- 14, autosomal Globoid cells with
galactosidase recessive PAS-positive granules.
Hurler syndrome a-L-iduronidase 4, autosomal recessive Clouding of the cornea.
Characteristic facies
and dwarfism.
Hunter syndrome Iduronate sulfatase X-linked Hurler phenotype
without corneal
clouding.
Metachromatic Arylsulfatase A 22, autosomal Cherry-red spot.
leukodystrophy recessive Demyelinating
disorder. Can present
as schizophrenia in
adults. Positive urine
sulfatides.
Adrenoleukodystrophy Very long chain fatty X-linked White matter
acid oxidation hyperintensity on MRI.
May present as a
neuropathy or
myelopathy in adults.
Alexander disease Glial fibrillary acidic 11 or 17, autosomal Rosenthal fibers on
protein recessive biopsy. Macrocephaly.
Dysmyelination of the
CNS.
Canavan disease Aspartoacylase 17, autosomal Macrocephaly.
 recessive Dysmyelination of the
CNS.
Pelizaeus–Merzbacher Proteolipid protein X-linked Pendular nystagmus.
disease Dysmyelination of the
CNS.
Leigh disease Mitochondrial Autosomal recessive or Bilateral putaminal
X-linked hyperintensity on MRI.
Rett syndrome Methyl-CpG-binding X-linked Occurs exclusively in
protein-2 girls. Microcephaly,
autism, and hand-
wringing.
Neuronal ceroid Excess lipofuscin Variety of mutations, Dementia, myoclonus,
lipofuscinosis storage autosomal recessive ataxia, retinitis
pigmentosa. Variety of
forms with different
ages of onsets and
severities.
[CNS, central nervous system; MRI, magnetic resonance imaging; PAS, periodic acid–Schiff.]

Peroxisomal disorders are a heterogeneous group of syndromes

characterized by abnormalities in lipid metabolism. Multiple enzyme
deficiencies have been characterized. These disorders are rare. The most
important of these disorders to diagnose is X-linked adrenoleukodystrophy
as it has potentially life-saving therapies. Most of the degenerative diseases
of infancy and childhood are not treatable (see Table 25-5). Attempts to
reach a final diagnosis are still important in order to provide parents with
genetic counseling, prognosis, and further management advice.

KEY POINTS
● Neurodegenerative diseases involving the white matter include metachromatic
leukodystrophy, Krabbe disease, adrenoleukodystrophy, Pelizaeus–Merzbacher disease,
Canavan disease, and Alexander disease.
● Peripheral nerve involvement is found in metachromatic leukodystrophy, Krabbe disease,
Canavan disease, and adrenoleukodystrophy.
● Congenital macular cherry-red spots (red color of the macula compared with a pale retina)
are found in Tay–Sachs disease, Sandhoff disease, Niemann–Pick disease, Gaucher
disease, metachromatic leukodystrophy, and the sialidoses.
NEUROCUTANEOUS DISORDERS
Neurocutaneous disorders (phakomatoses) are characterized by lesions in
the central nervous system (CNS) and peripheral nervous system (PNS),
skin, eyes, and other organs. A summary of neurocutaneous disorders and
their clinical features is given in Table 25-6.

TABLE 25-6. Neurocutaneous Syndromes

Inheritance Neurologic Cutaneous Other Findings
Findings Findings
Neurofibromatosis Autosomal Optic nerve gliomas Café-au-lait Lisch nodules in
1 dominant; spots, the iris
chromosome 17 neurofibromas,
axillary or
inguinal freckles
Neurofibromatosis Autosomal Bilateral acoustic Neurofibromas
2 dominant; neuromas and café-au-lait
chromosome 22 spots are less
common than in
NF-1
Tuberous sclerosis Autosomal Cortical tubers, Adenoma Angiomyolipomas
dominant; TSC subependymal sebaceum, ash- of kidneys, cardiac
1–chrom 9; TSC nodules and leaf spots, rhabdomyoma
2–chrom 16 astrocytomas, ID, shagreen patches
seizures
Ataxia- Autosomal Truncal ataxia, Telangiectasias Immunodeficiency
telangiectasia recessive; progressive and susceptibility
chromosome 11 dementia to infections,
leukemia,
lymphoma
von Hippel– Autosomal Cerebellar Café-au-lait Renal lesions
Lindau dominant; hemangioblastomas, spots including
chromosome 3 ataxia hemangiomas and
carcinomas,
pheochromocytoma
Sturge–Weber Sporadic Venous angioma of Port-wine stain
the pia mater, in the
seizures, distribution of
hemiparesis, ID the ophthalmic
nerve
[ID, intellectual disability; NF, neurofibromatosis; TSC, tuberous sclerosis complex.]
THE HYPOTONIC INFANT
Hypotonia is diminished resistance of muscles to passive stretching.
Although weak infants are always hypotonic, hypotonia can present with
normal strength. It may be the manifestation of a CNS or PNS disorder or
both.
The most common cause of hypotonia is cerebral hypotonia, a static
encephalopathy from pre- or perinatal brain injury. The most useful
diagnostic finding in this group of disorders is not the hypotonia but the
other signs of CNS dysfunction. Seizures, microcephaly, dysmorphic facies,
and ID point to the brain as the source of hypotonia.
The other causes of hypotonia include spinal cord disease (e.g.,
transection during breech presentation), anterior horn cell lesions (spinal
muscular atrophy), neuromuscular junction abnormalities (congenital
myasthenia), and myopathies (congenital muscular dystrophies, congenital
myopathies). The physical and neurologic examinations and the presence or
absence of “central” signs, such as increased reflexes, may help localize the
site of disease.

KEY POINTS
● Hypotonia can be caused by central or peripheral causes, or by both.
● Severe hypotonia but only marginal weakness is usually not due to a peripheral or lower
motor neuron cause.
● Cerebral hypotonia is usually associated with the other signs of CNS dysfunction
(seizures, developmental delay, etc.).

ATTENTION DEFICIT–HYPERACTIVITY
DISORDER
CLINICAL MANIFESTATION
The essential features of attention deficit–hyperactivity disorder (ADHD)
are inappropriate inattention, impulsivity, and hyperactivity for age.
Children with the hyperactive–impulsive subtype are fidgety, leave their
seats in the classroom, and have difficulty playing quietly. Children with the
inattentive–distractible subtype do not pay close attention to details, have
difficulty organizing tasks, and are forgetful in daily activities. Often, there
is a family history of ADHD, implying a genetic etiology.

DIAGNOSTIC EVALUATION
A diagnosis is made by clinical history and neuropsychological screening
tests. Children usually have normal IQs but low scores on tests of sustained
attention. Imaging and laboratory tests are generally not helpful.

TREATMENT
The standard medical treatment of ADHD includes the use of stimulant
drugs like methylphenidate and dextroamphetamine. It is important to
emphasize parent participation in the treatment program, which must also
incorporate behavioral modifications like goal setting and incentives.

KEY POINTS
● Children with ADHD often have a positive family history for the disorder.
● Stimulants like methylphenidate and dextroamphetamine are often effective treatments for
ADHD.

CLINICAL VIGNETTES

VIGNETTE 1
A 4-year-old boy is evaluated for mild developmental delay. On
dermatologic examination, you find multiple café-au-lait spots,
neurofibromas, and a freckle in the left axilla.
1. What is the most likely diagnosis?
a. Neurofibromatosis type 1
b. Neurofibromatosis type 2
c. Sturge–Weber syndrome
d. Tuberous sclerosis
 e. Von Hippel–Lindau disease
2. You learn that there is a family history of a similar but milder
disorder in the patient’s father and older sister. You decide to pursue
genetic testing to confirm the diagnosis. What is the inheritance
pattern and location of the gene responsible for this disorder?
a. Autosomal dominant, chromosome 3
b. Autosomal dominant, chromosome 16
c. Autosomal dominant, chromosome 17
d. Autosomal dominant, chromosome 22
e. Autosomal recessive, chromosome 11
3. In the course of your evaluation, you obtain an MRI of this patient’s
brain. Which of the following tumors is associated with this
condition?
a. Acoustic neuroma
b. Cerebellar hemangioblastoma
c. Hypothalamic hamartoma
d. Optic glioma
e. Subependymal giant cell astrocytoma

ANSWERS

VIGNETTE 1 QUESTION 1
1. Answer A:
The finding of multiple café-au-lait spots, neurofibromas, and axillary
or inguinal freckling is diagnostic of neurofibromatosis type 1. Café-au-
lait spots and neurofibromas are also seen in neurofibromatosis type 2,
but they are less common than in neurofibromatosis type 1. Patients
with tuberous sclerosis may also have café-au-lait spots, but other
characteristic dermatologic findings including adenoma sebaceum, ash-
leaf spots, and shagreen patches are also present. Von Hippel–Lindau
disease is also associated with café-au-lait spots, but patients do not
have any of the other listed dermatologic features. The expected
dermatologic finding in Sturge–Weber syndrome is a port-wine stain in
the distribution of the ophthalmic nerve.
VIGNETTE 1 QUESTION 2
2. Answer C:
Neurofibromatosis type 1 is an autosomal-dominant disorder associated
with a mutation on chromosome 17. Von Hippel–Lindau disease is an
autosomal-dominant disorder associated with a mutation on
chromosome 3. Neurofibromatosis type 2 is also an autosomal-
dominant disorder and is associated with mutations on chromosome 22.
Tuberous sclerosis is inherited in an autosomal-dominant fashion as
well and is produced by mutations on chromosome 9 and chromosome
16. Ataxia-telangiectasia is an autosomal-recessive neurocutaneous
disorder due to a mutation on chromosome 11.

VIGNETTE 1 QUESTION 3
3. Answer D:
Optic glioma is associated with neurofibromatosis type 1. Acoustic
neuroma (usually bilateral) is associated with neurofibromatosis type 2;
cerebellar hemangioblastoma with von Hippel–Lindau disease; and
subependymal giant cell astrocytoma with tuberous sclerosis.
Hypothalamic hamartoma is not associated with any of the
neurocutaneous disorders.
 Questions

1. A 78-year-old woman with dementia and rigidity is hospitalized

with dehydration. During her hospitalization, she becomes agitated
and has prominent visual hallucinations. After a dose of
haloperidol, she becomes very rigid and mute. The most likely type
of dementia in this patient is:
a. Alzheimer disease
b. Parkinson disease
c. Dementia with Lewy bodies
d. Pick disease
e. Vascular dementia
2. A 32-year-old woman presents to the emergency room (ER)
complaining of blurred vision and pain in the right eye. Your
evaluation shows decreased visual acuity in the right eye that does
not correct with pinhole testing. There is a relative afferent
pupillary defect on the right, and testing of the right visual field
shows a small central scotoma. The most likely localization of the
lesion is the:
a. Optic chiasm
b. Optic nerve
c. Optic tract
d. Occipital cortex
e. Optic radiations
3. In the course of evaluating an infant with developmental regression,
a pediatric neurologist notes a cherry-red spot on funduscopic
examination. Which of the following diagnoses is consistent with
that finding?
a. Alexander disease
b. Hurler syndrome
c. Krabbe disease
 d. Niemann–Pick disease
e. Canavan disease
4. A 62-year-old woman presents with progressive distal symmetric
paresthesias and dysesthesias, with preserved muscle strength. She
smokes cigarettes. Your electrodiagnostic study indicates that this is
likely a sensory neuronopathy. Which one of the following tests
will help find the possible etiology?
a. Anti-GM1 antibodies
b. Anti-DNA antibodies
c. Anti-Hu antibodies
d. MRI of the spine
e. CT myelogram
5. A 40-year-old woman is evaluated in the ER after a motor vehicle
accident resulting in left facial injuries. Subsequent examination
shows that her left seventh and eighth cranial nerves remain
dysfunctional. Which of the following skull structures may have
been affected by her injury?
a. Cribriform plate
b. Optic canal
c. Superior orbital fissure
d. Internal auditory meatus
e. Jugular foramen
6. A 54-year-old woman is seen in the ER complaining of a severe
headache. Head CT was normal. A lumbar puncture (LP) was
performed. The opening pressure was 14 cm H2O, and
cerebrospinal fluid (CSF) analysis showed the following: 150
RBC/mm3, xanthochromic fluid, protein 55 mg/dL (slightly
increased), 3 WBC/mm3 (90% lymphocytes), and normal glucose.
Which of the following is true?
a. The xanthochromia may have been caused by a traumatic tap.
b. The lymphocytic pleocytosis indicates an active infectious
process.
c. Viral meningitis is unlikely because of the normal CSF glucose.
d. This patient should undergo a vascular imaging study of the
brain.
 e. The opening pressure is elevated and reflects pseudotumor
cerebri.
7. A 29-year-old woman is brought into the ER in an unresponsive
state. Her temperature is 37°C (98.6°F), heart rate 84/minute,
respiration 10 breaths per minute, and blood pressure 152/84 mm
Hg. On examination, she withdraws to noxious stimulation only.
Her right pupil is 10 mm and does not constrict to light. Her left
pupil is 5 mm and reacts normally. Which of the following is
clinically contraindicated?
a. Raising the head of the bed
b. Intravenous administration of mannitol
c. Hyperventilation
d. Lumbar puncture
e. Neurosurgical consultation
8. A patient presents with gradually worsening weakness of the
proximal arm and leg muscles symmetrically over several months.
On examination, weakness is identified in neck flexors and
extensors, and there is mild diffuse atrophy with preserved reflexes.
There is no muscle pain or tenderness. What is the most likely site
of dysfunction in the nervous system?
a. Peripheral nerve
b. Brachial plexus
c. Spinal nerve root
d. Internal capsule
e. Muscle
9. An 8-year-old boy is brought to a child psychiatrist for evaluation
of potential attention deficit/hyperactivity disorder. His mother
states that his teachers have been concerned about his attention
because they frequently have to repeat instructions to him. At
home, his brother has noticed that he will stare for several seconds
at a time, during which he does not respond to questions. An EEG
demonstrates a 3-Hz spike-and-wave pattern. Which of the
following is the most appropriate treatment?
a. Methylphenidate (Ritalin)
b. Ethosuximide (Zarontin)
c. Clonidine (Catapres)
 d. Fluoxetine (Prozac)
e. Carbamazepine (Tegretol)
10.A 28-year-old woman comes to the ER with a severe unilateral
throbbing headache accompanied by photophobia and
phonophobia. These headaches started in her teens and she has one
every month. Which of the following medications is effective as
abortive treatment?
a. Propranolol
b. Sumatriptan
c. Verapamil
d. Amitriptyline
e. Valproic acid
11. A 42-year-old man is brought to the neurologist for evaluation of a
few months’ history of personality changes. His family indicates
that, over the previous year, he has made unusual movements with
his hands, and he seems to have some memory difficulties. His
father died in his 50s with a similar clinical syndrome, including
prominent chorea and dementia. The most likely genetic
abnormality will be localized on chromosome:
a. 19
b. 6
c. 4
d. 11
e. 21
12.A 55-year-old woman with a history of ovarian cancer and
moderate alcohol consumption is seen in the Neurology ambulatory
clinic with a 1-month history of progressive unsteadiness of gait
and dysarthria. Examination confirms the presence of gait and limb
ataxia as well as nystagmus. These symptoms were fairly abrupt in
onset, progressed over a period of a few weeks, and now appear to
have stabilized, but there has been no sign of spontaneous
improvement. Which of the following statements is correct?
a. The findings of gait ataxia, dysarthria, and nystagmus indicate
diffuse involvement of the cerebellum and suggest that alcohol
consumption is the likely cause.
 b. The constellation of symptoms and their temporal evolution are
most consistent with paraneoplastic cerebellar degeneration, a
disorder associated with underlying gynecologic malignancy.
c. The constellation of symptoms and their temporal evolution are
most consistent with a spinocerebellar ataxia.
d. The symptoms and signs indicate cerebellar hemisphere
dysfunction and are most suggestive of a metastasis from an
underlying ovarian cancer.
e. The sudden onset of symptoms and diffuse cerebellar
involvement suggest midline cerebellar hemorrhage as the
cause.
13.A 45-year-old man with multiple sclerosis (MS) comes to the
Neurology clinic complaining of urinary incontinence. He indicates
that he experiences increased urgency and frequency of urination.
The most likely urodynamic finding in this patient is:
a. An atonic bladder
b. A spastic bladder
c. Stress incontinence
d. Absence of abnormalities
e. Overflow incontinence
14.A 65-year-old man complains of a 3-month history of intermittent
urinary incontinence. Urodynamic studies show an atonic bladder.
Which of the following is most likely responsible for his problem?
a. Diabetes
b. Old stroke
c. Multiple sclerosis
d. Right parietal tumor
e. Pineal tumor
15.A 35-year-old man is seen in the Neurology outpatient clinic with
the complaint that his fingers occasionally “get stuck” when he tries
to open jars. On examination, you find subtle weakness of the
fingers and toes as well as percussion myotonia. You suspect the
diagnosis of myotonic dystrophy. Which of the following
statements is true?
a. Myotonic dystrophy is a systemic disorder that may also cause
cataracts, diabetes, mental retardation, and cardiac arrhythmias.
 b. Myotonic dystrophy is a disorder affecting skeletal muscles
alone.
c. Myotonic dystrophy should not be considered in the differential
diagnosis because it is an inherited disorder that typically
manifests itself either at birth or early in life.
d. Myotonic dystrophy is an autosomal recessive disorder caused
by a triplet expansion in the DMPK gene.
e. Electromyography is usually normal in myotonic dystrophy and
genetic testing is essential to confirm the diagnosis.
16.An 18-year-old woman is brought to the Neurology clinic by her
mother, who explains that her daughter has been behaving strangely
recently and appears to have paranoid delusions. She has a slight
tremor of both hands and the examiner notes that there is a
brownish discoloration of the cornea in the vicinity of the limbus.
Laboratory studies show a mild transaminitis. Which of the
following test results are most likely?
a. Increased serum free copper, increased ceruloplasmin, and
decreased 24-hour urinary copper excretion
b. Increased serum free copper, decreased serum ceruloplasmin,
and increased 24-hour urinary copper excretion
c. Decreased serum free copper, increased serum ceruloplasmin,
and increased 24-hour urinary copper excretion
d. Decreased serum free copper, increased ceruloplasmin, and
decreased 24-hour urinary copper excretion
e. Decreased serum free copper, decreased serum ceruloplasmin,
and decreased 24-hour urinary copper excretion
17.A 40-year-old woman with systemic lupus erythematosus develops
weakness of her right finger and wrist extensors and pain on the
right dorsum of her hand several months after being diagnosed with
left carpal tunnel syndrome and right sciatic neuropathy. What is
the most likely diagnosis?
a. Mononeuropathy multiplex
b. Axonal polyneuropathy
c. Demyelinating polyneuropathy
d. Neuromuscular junction disease
e. Polyradiculopathy
18.A 70-year-old man develops acute onset of an inability to speak.
Examination reveals that he struggles to pronounce a complete
word and cannot string words together. He is unable to repeat a
sentence, but can follow simple and multistep commands. What is
the most likely diagnosis?
a. Global aphasia
b. Conduction aphasia
c. Broca’s aphasia
d. Wernicke’s aphasia
e. Transcortical motor aphasia
19.A 28-year-old woman is brought to the ER by her husband. In
addition to having neck stiffness, she has had a fever for several
days, has been somewhat confused, and has not been “acting like
herself.” A lumbar puncture shows 9 WBCs with a lymphocytic
predominance, 32 RBCs, protein = 63, and glucose = 65. Gram
stain is negative. What is the most likely diagnosis?
a. Bacterial meningitis
b. Viral meningitis
c. Fungal meningitis
d. Meningitis from tuberculosis
e. Subarachnoid hemorrhage
20.A healthy 32-year-old man is brought to the ER after he stopped
speaking suddenly, fell to the ground, lost consciousness, and shook
for 2 minutes. After the event, he was noted to have a tongue
laceration and urinary incontinence. He has no history of similar
events. His physical examination shows a mild right hemiparesis.
Routine laboratory studies and a head CT are normal. An EEG
performed the next day is normal. The normal EEG suggests that
this man:
a. Had a pseudoseizure and does not require anticonvulsants
b. Needs admission for long-term video-EEG monitoring
c. Probably had a seizure, and the normal EEG result is not
surprising
d. Requires hyperventilation to elicit an absence seizure on EEG
e. Has actually had an ischemic stroke rather than a seizure
21.Two days after coronary artery bypass surgery, a 62-year-old man
with hypertension complains that “there is another man’s arm in
bed” with him. When asked to hold up his arms, the patient raises
his right arm only. When asked about his left arm, he claims it is the
examiner’s or another patient’s. What is the most likely diagnosis?
a. Right hemisphere stroke with neglect
b. Left hemisphere stroke with neglect
c. Conversion disorder
d. Adjustment disorder
e. Alien-limb phenomenon
22.A 35-year-old man with no known history of seizures is brought in
by paramedics in status epilepticus. Which of the following
medications or medication classes is used as initial therapy for this
condition?
a. Benzodiazepines
b. Barbiturates
c. Propofol
d. Carbamazepine
e. Lamotrigine
23.Subfalcine herniation most often results in which of the following?
a. Ipsilateral third nerve palsy
b. Contralateral third nerve palsy
c. Contralateral hemiparesis
d. Small, reactive pupils
e. Bilateral leg weakness
24.A 23-year-old woman presents with loss of vision in the right eye
accompanied by slight pain in that eye over a period of 3 days. She
has 20/200 acuity, red desaturation, and an afferent pupillary defect
in the right eye. The remainder of her examination and MRI are
normal. A diagnosis of optic neuritis is made. Which of the
following is true about treatment?
a. Interferon β-1b will hasten recovery from this episode.
b. Natalizumab is the most effective treatment.
c. Medical treatment is not likely to help optic neuritis.
d. Oral corticosteroids are preferred for the treatment of optic
neuritis.
 e. Corticosteroids may delay the development of MS.
25.A 22-year-old right-handed woman develops horizontal diplopia
acutely. Your evaluation shows normal right lateral gaze but
difficulty with adduction of the right eye while looking to the left
and nystagmus in the abducting left eye. What is the most likely
anatomic localization?
a. Left paramedian pontine reticular formation (PPRF) producing a
right internuclear ophthalmoplegia (INO)
b. Right PPRF producing a right one-and-a-half syndrome
c. Right medial longitudinal fascicle (MLF) producing a right INO
d. Left MLF producing a right INO
e. Lateral geniculate nuclei
26.A 55-year-old man with a history of tick bite and erythema
chronicum migrans is diagnosed with Lyme disease. He asks his
primary care physician about neurologic symptoms he should watch
for. Which of the following is an early neurologic manifestation of
Lyme disease?
a. Facial nerve palsy
b. Painful polyradiculopathy
c. Spinal cord compression
d. Leukoencephalopathy
e. Generalized epilepsy
27.A 34-year-old man is seen in the Neurology outpatient clinic with
symptoms of headache and bilateral lower motor neuron (LMN)
facial weakness. There is no history of a skin rash. Neurologic
examination shows a relative afferent papillary defect in the right
eye and the bilateral facial weakness.
a. Guillain–Barré syndrome is the most likely diagnosis, and he
should have an LP to help confirm the diagnosis.
b. Lyme disease is the most likely diagnosis, and Borrelia serology
should be sent to confirm the diagnosis.
c. Sarcoidosis is likely the correct diagnosis, and appropriate
investigations include MRI of the brain, LP, and chest X-ray.
d. Multiple sclerosis is most likely the correct diagnosis, because
bilateral facial weakness and optic neuropathy are both common
manifestations of this disease.
 e. Mononeuritis multiplex secondary to vasculitis is the most likely
diagnosis, so the patient should be referred for rheumatologic
evaluation.
28.A 64-year-old man with a history of hypertension presents to the
ER with the sudden onset of numbness of his left leg, arm, and face.
His motor examination is normal. What is the most likely site of his
lesion?
a. Right thalamus
b. Right internal capsule
c. Right precentral gyrus
d. Right occipital lobe
e. Right corona radiata
29.While playing baseball, a 15-year-old boy was hit on the side of the
head with a ball. He was knocked unconscious briefly, but
recovered fully. Two hours later he became increasingly lethargic,
so his parents brought him to the ER. When you evaluate the
patient, he is barely rousable to voice. He has mild weakness on the
left side of his body, and his right pupil is slightly larger than the
left pupil; the right pupil does not appear to react to light. What is
the most likely cause of the patient’s symptoms and signs?
a. Concussion
b. Epidural hematoma
c. Diffuse axonal injury
d. Ischemic infarct
e. Drug intoxication
30.Which of the following syndromes or diseases could cause bilateral
weakness and loss of pain and temperature sensation with
preservation of joint position sense in both legs?
a. Amyotrophic lateral sclerosis
b. Vitamin B12 deficiency
c. Brown-Séquard syndrome
d. Anterior spinal artery syndrome
e. Tabes dorsalis
31.A 2-year-old child presents with new seizures. Her mother tells you
that the child is not walking yet. SHe has a 5-year-old brother with
 a seizure disorder and mental retardation. On examination, using
the Wood’s lamp, you find hypomelanotic lesions. The most
appropriate next test is:
a. Skeletal surveillance
b. Skin biopsy
c. Head CT or MRI
d. No need for further tests
e. Lumbar puncture
32.A 3-year-old boy is brought to his pediatrician for evaluation of
repetitive behaviors, delay of language development, and social
isolation. He has normal motor development otherwise. Which of
the following is a feature of autism, but not of Asperger syndrome?
a. Abnormal language development
b. Social isolation
c. Restricted, repetitive patterns of behavior
d. Failure to meet milestones for gross motor development
e. Failure to meet milestones for fine motor development
33.A 62-year-old woman with a history of small cell lung carcinoma
presents to the Neurology clinic complaining of bilateral
paresthesias of the legs. She has no history of diabetes or family
history of polyneuropathy. She describes severe pain in the soles of
her feet when standing and has difficulty walking. On examination,
there is severe pain to light touch over both soles. On your sensory
examination description, you will state that this patient has:
a. Hyperesthesia
b. Paresthesia
c. Allodynia
d. Sensory loss
e. Hypesthesia
34.A 38-year-old man presents to the ER complaining of a mild
headache. He had neck trauma a week earlier. The examination
shows anisocoria, with the right pupil being 3 mm and the left 5
mm, both reactive to light. What other findings will help localize
the lesion?
a. Look at the pupils in the dark and check tongue deviation.
 b. Look for evidence of ptosis in the left eye and anhidrosis on the
left face.
c. Look for evidence of ptosis in the right eye and anhidrosis in the
right face.
d. Look for evidence of horizontal diplopia and a cut in the right
visual field.
e. Look for evidence of dysarthria and hemiparesis.
35.A 35-year-old woman presents to the ER reporting 10 days of
progressive ascending muscle weakness. She had a viral infection a
few weeks earlier. On examination, you find diffuse weakness and
areflexia. The most likely finding in the CSF is:
a. High protein–high cell count
b. High protein–low cell count
c. Low protein–high cell count
d. Low protein–low cell count
e. Normal CSF
36.A 33-year-old man is seen in the ER for difficulty walking. He has
paresthesias in his feet and a left foot drop. Initial physical
examination shows mild distal weakness in both legs, with absent
ankle jerks and reduced reflexes throughout. While the patient is
waiting in the ER, his weakness worsens, involving the arms, but he
has no difficulty breathing. You want to admit the patient to the
intensive care unit. What will be your best argument to convince
your ER attending to do so?
a. Absence of reflexes in the arms
b. Decreased gag reflex
c. A forced vital capacity below 25 mL/kg
d. The patient’s weakness is worsening very quickly, and you fear
that he may need mechanical ventilation.
e. The presence of a left foot drop
37.A 35-year-old man who is HIV-positive presents with radicular pain
in the legs and associated bladder distension. The most likely agent
responsible for these symptoms is:
a. Cytomegalovirus
b. Clostridium
c. Toxoplasma
 d. Cryptococcus
e. Pneumocystis carinii
38.A 45-year-old woman presents to the ER with “dizziness,” by
which she means that she feels a spinning sensation. The sensation
is intermittent and seems to be exacerbated by head movement. She
has some nausea with the episodes, but otherwise has no other
symptoms such as double vision, weakness, hearing loss, tinnitus,
or difficulty swallowing. What diagnosis is most likely?
a. Vestibular neuronitis
b. Ménière disease
c. Brainstem infarction
d. Benign positional paroxysmal vertigo
e. Cerebellar infarction
39.A 32-year-old woman is seen in the neurology outpatient clinic
with symptoms of diplopia and ptosis that fluctuate during the
course of the day. Examination shows fatigable proximal weakness.
You suspect that she has myasthenia gravis (MG). Which of the
following statements concerning MG is true?
a. It is an autoimmune disorder caused by antibodies that are
directed against presynaptic nicotinic acetylcholine receptors.
b. It is an autoimmune disorder caused by antibodies directed
against postsynaptic muscarinic acetylcholine receptors.
c. It is an autoimmune disorder caused by antibodies directed
against presynaptic voltage-gated calcium channels.
d. It is an autoimmune disorder caused by antibodies directed
against postsynaptic nicotinic acetylcholine receptors.
e. It is an autoimmune disorder caused by antibodies directed
against the synaptic enzyme acetylcholinesterase.
40.A patient complains of difficulty chewing. On examination, he is
found to have decreased strength of his muscles of mastication.
Which of the following cranial nerves is responsible for this motor
function?
a. Trigeminal
b. Facial
c. Oculomotor
d. Glossopharyngeal
 e. Hypoglossal
41.The following patients are being evaluated in a neurologic intensive
care unit. For which patient would the Glasgow Coma Scale be
used most commonly to follow his or her clinical status?
a. A 75-year-old man in coma after cardiac arrest
b. A 29-year-old woman with delirium after medication overdose
c. A 69-year-old woman with a thromboembolic stroke and Broca
aphasia
d. A 20-year-old man who is unresponsive after head trauma
e. A 59-year-old man with subarachnoid hemorrhage after
aneurysm rupture
42.A 68-year-old man taking dabigatran falls while in the hospital, is
found on the floor, and is difficult to rouse. He has a new right
hemiparesis. You order a CT of the head without contrast. Which of
the following possible etiologies for his presentation will be
assessed with the CT?
a. Subdural hematoma
b. Epidural hematoma
c. Intraparenchymal hemorrhage
d. Large territory cerebral infarction
e. All of these
f. None of these
43.A 75-year-old man presents to your office with a 1-month history of
progressive pain in the left temporal area and pain in his jaw while
eating. On laboratory testing, the patient is found to have an
elevated erythrocyte sedimentation rate of 94. What is the treatment
of choice?
a. Sumatriptan
b. Carbamazepine
c. Verapamil
d. Surgical resection of brain tumor
e. Prednisone
44.A 35-year-old man presents to your office for difficulty
concentrating. He has fallen asleep while driving and also in the
middle of important business meetings, despite sleeping at least 8
 hours each night. He denies hallucinations or a history of his knees
buckling while laughing. His wife reports that he snores loudly
during sleep. His examination is normal except for moderate
obesity. Which of the following tests would be most helpful in
diagnosing this patient’s disorder?
a. Multiple sleep latency test
b. EEG
c. MRI of the brain
d. Lumbar puncture
e. Polysomnography
45.A previously healthy 21-year-old man presents to the ER after
being involved in a high-speed motor vehicle accident. You note
that he is unresponsive, makes no spontaneous movement, and has
a dilated pupil on the right that is nonreactive to light. What is the
best explanation for these signs?
a. Infarction of the left occipital lobe
b. Concussion from the motor vehicle accident
c. Uncal herniation
d. Cervical spine fracture
e. Diffuse axonal injury
46.An 84-year-old man is transferred from another hospital with a
reported hypertensive hemorrhage. The films from that hospital are
not available, and no further details are available. Which of the
following is the most likely location of his hemorrhage?
a. Basal ganglia
b. Midbrain
c. Internal capsule
d. Frontal lobe
e. Corpus callosum
47.A 28-year-old man has been diagnosed with obstructive sleep
apnea. Of the following choices, which is the most appropriate
treatment?
a. Sodium oxybate
b. Methylphenidate
c. Continuous positive airway pressure
d. Clonazepam
 e. Clomipramine
48.A 45-year-old man with a prior history of migraine headaches with
aura presents to the ER complaining of a progressively worsening
headache for the past month that is different from his usual
migraine. There is no associated nausea or vomiting. His neurologic
examination is completely normal. Your next step in management
should be:
a. Brain imaging study
b. Abortive migraine treatment
c. Preventive migraine treatment
d. Reassurance and discharge home
e. Administration of pure oxygen
49.Which of the following features is most commonly associated with
a pituitary adenoma?
a. Homonymous hemianopia
b. Bitemporal hemianopia
c. Ring enhancement on brain imaging with contrast
d. Seizures
e. Hemiparesis
50.A 24-year-old construction worker falls from a ladder and fractures
his cervical spine with resulting signs of upper motor neuron
(UMN) dysfunction. Which of the following signs is characteristic
of a UMN lesion?
a. Hypotonia
b. Decreased reflexes
c. Flexor plantar response
d. Spasticity
e. Absent reflexes
51.A 67-year-old woman presents to the ER with a new onset of
headache, nausea, vomiting, and unsteadiness of gait. Her history is
significant for atrial fibrillation, for which she is chronically
anticoagulated with rivaroxaban. She also has a pacemaker in place.
You are concerned about the possibility of a cerebellar hemorrhage.
The imaging modality of choice is:
 a. A CT scan without contrast, because this is the imaging test
most sensitive to the presence of acute intracranial blood and
can be obtained rapidly
b. An MRI, because blood in the posterior fossa will not be
visualized on CT
c. An MRI, because CT is contraindicated by the presence of a
pacemaker
d. A CT scan with contrast, because it provides the best images of
the contents of the posterior fossa
e. A single-photon emission computed tomography scan to show
metabolic activity in the cerebellum
52.A 22-year-old woman presents with acute bilateral facial nerve
palsy and intermittent peripheral nerve symptoms for over 3 weeks.
You find elevated Lyme titers in serum and CSF. What treatment
would you choose first?
a. Oral doxycycline
b. Intravenous ceftriaxone
c. Oral amoxicillin
d. Oral amoxicillin and doxycycline
e. Fluconazole
53.A 58-year-old man is seen in the Neurology ambulatory clinic with
a 3-month history of right-sided resting tremor. On examination, he
is noted to have mild masking of facial expression and there is
diminished swing of the right arm when he walks. You suspect that
he may have early idiopathic Parkinson disease. Which of the
following statements concerning this disorder is true?
a. Most cases are familial with mutations in the α-synuclein or
parkin genes.
b. It is characterized by the death of dopaminergic neurons in the
substantia nigra pars reticulata.
c. The four cardinal features of this disorder are tremor, rigidity,
bradykinesia, and postural instability.
d. Impairment of vertical gaze is a common manifestation of this
disorder.
e. Early falls are a common problem in this disorder.
54.A 5-year-old boy is seen in the Pediatric Neurology clinic. His
motor milestones have been delayed, and examination shows
proximal muscle weakness with difficulty arising from the floor.
There is pseudohypertrophy of his calf muscles. He has an older
brother with Duchenne muscular dystrophy (DMD) who is confined
to a wheelchair. Which of the following statements concerning
DMD is true?
a. It is an autosomal recessive disorder caused by mutation in the
dystrophin gene.
b. It is an autosomal dominant disorder caused by mutation in the
dystrophin gene.
c. DMD and limb-girdle muscular dystrophy are allelic disorders,
both being due to mutations in the dystrophin gene.
d. It is a disorder caused by mutation in the dystrophin gene, which
is located on the X chromosome.
e. DMD and Becker muscular dystrophy are allelic disorders, due
to mutations in the dystrophin gene on chromosome 4.
55.A 9-year-old boy presents with difficulty walking. Neurologic
examination demonstrates, among other things, that he performs
rapid alternating movements poorly, with a lack of proper rhythm
and coordination. This finding, called dysdiadochokinesis, is most
typically associated with dysfunction of which of the following
brain structures?
a. Basal ganglia
b. Medulla
c. Cerebellum
d. Parietal lobe
e. Thalamus
56.An ischemic stroke involving the right side of the pons could lead
to which of the following patterns of weakness?
a. Left facial weakness and right body weakness
b. Right facial weakness and left body weakness
c. Right facial weakness and right body weakness
d. Left arm weakness and right leg weakness
e. Right arm weakness and left leg weakness
57.A 27-year-old woman with complex partial seizures is well
controlled on carbamazepine. Which of the following is a
characteristic side effect of this medication?
a. Thrombocytopenia
b. Agitation
c. Diabetes insipidus
d. Nephrolithiasis
e. Hyponatremia
58.A 53-year-old construction worker is brought to the ER with a
severe, sudden-onset headache accompanied by vomiting. A CT
scan of his head demonstrates a subarachnoid hemorrhage. Which
of the following is the most common cause of subarachnoid
hemorrhage?
a. Tearing of bridging veins
b. Laceration of the middle meningeal artery
c. Aneurysmal rupture
d. Amyloid angiopathy
e. Arteriovenous malformation rupture
59.A 45-year-old woman has an MRI scan of the brain for evaluation
of progressive headaches. The scan shows a lesion that enhances in
a homogeneous manner with contrast administration. Which of the
following lesions is most likely to account for the appearance of the
MRI scan?
a. Glioblastoma multiforme
b. Meningioma
c. Brain abscess
d. Toxoplasmosis
e. Granuloma
60.A 75-year-old man is brought to the ER after having lost
consciousness briefly in his bathroom. By the time he arrives he is
feeling fine and is able to give a clear account of what happened.
He recalls walking to the bathroom to urinate. Shortly thereafter he
became light-headed and felt as if his vision were graying out.
These symptoms lasted for about 30 seconds. The next thing he
recalls is awakening on his bathroom floor. His wife notes that he
 was unconscious only briefly. Which of the following descriptions
pertinent to this clinical scenario is correct?
a. The symptoms of light-headedness and graying out of vision are
atypical symptoms described by patients with syncope.
b. He has micturition syncope.
c. Orthostatic hypotension is the likely explanation for his
syncopal episode.
d. Vasovagal syncope is the likely explanation for his syncopal
episode.
e. Vestibular neuronitis is the likely explanation for his symptoms.
61.A 36-year-old man comes to the ER with a 4-day history of fever
and a generalized convulsion 2 hours earlier. He has been on long-
standing immune suppression for treatment of ulcerative colitis and
is mildly pancytopenic at baseline. His CT scan of the head shows
no focal lesions, and a nontraumatic LP shows 5,000 RBCs and 25
WBCs. Which of the following is the most appropriate clinical
management?
a. MRI of the brain
b. Treatment with an anti-seizure drug
c. Empiric treatment with broad spectrum antibiotics
d. Empiric treatment with acyclovir
e. All of the above
62.A 55-year-old woman comes to the Neurology clinic complaining
of numbness in the fourth and fifth fingers of her right hand; it
tends to worsen at night. On examination, you find a positive Tinel
sign at the right elbow (percussion of the ulnar nerve at the right
elbow produces a tingling sensation in the fourth and fifth fingers).
You are convinced that this is an ulnar neuropathy at the right
elbow and perform electrodiagnostic studies. Why do you think that
this is a peripheral nerve problem?
a. The acuteness of presentation
b. The physical examination findings
c. The symptoms described by the patient
d. You do not think this is a peripheral nerve problem.
e. There is no central nervous system complaint.
63.A 25-year-old man is now comatose after suffering blunt force
trauma to the head. On the basis of the clinical history, neurologic
examination, and head CT scan, he is diagnosed with an epidural
hematoma. Of the following choices, which is the best treatment
option?
a. Neurosurgical decompression
b. Hyperventilation
c. Administration of mannitol
d. Conservative management with close monitoring of vital signs
and neurologic status
e. Administration of tissue plasminogen activator
64.A 19-year-old man is admitted to a Neurology service with an
episode of transverse myelitis. Workup includes an MRI of his head
and LP. Which of the following distinguishes acute disseminated
encephalomyelitis (ADEM) from MS?
a. Presence of oligoclonal bands in the CSF
b. Pleocytosis with neutrophilic predominance
c. Monophasic course
d. Multiple lesions on MRI
e. A positive family history of ADEM
65.A 55-year-old man with type 2 diabetes presents with a 5-week
history of pain in his right knee, followed by weakness and atrophy
of his right quadriceps. Examination shows weakness of the right
quadriceps and iliopsoas muscles and an absent right knee jerk.
This presentation is most characteristic of which of the following
conditions?
a. Diabetic distal symmetric polyneuropathy
b. Diabetic amyotrophy
c. Mononeuropathy multiplex
d. Stroke
e. Herniated intervertebral disk at L5-S1
66.A 19-year-old man is accidentally hit on the left side of the head
with a baseball bat. He loses consciousness and is taken to an ER.
A head CT scan showed a lenticular-shaped hyperdensity over the
left temporal region that is exerting some mild mass effect on the
 brain. Which of the following mechanisms best explains the
patient’s head CT scan results?
a. Tearing of bridging veins
b. Laceration of the middle meningeal artery
c. Contact of the frontal poles of the brain with the skull
d. Rotational acceleration and deceleration of the head
e. Rupture of a cerebral aneurysm
67.A 56-year-old woman is referred to the Neurology clinic by her
optometrist, who noted that she had limited movement of her eyes.
The patient herself notes only that she has fallen a few times in
recent months. Examination confirms that there is marked
limitation of vertical eye movements (both up and down gaze).
There is mild rigidity in both arms and legs but no tremor. Her
postural reflexes are poor. Which of the following is the most likely
diagnosis?
a. Parkinson disease
b. Progressive supranuclear palsy
c. Corticobasal ganglionic degeneration
d. Miller–Fisher syndrome
e. Chronic progressive external ophthalmoplegia
68.A 65-year-old obese woman is referred to the Neurology clinic with
complaints of burning pain in both feet, which has been present for
several months. You suspect that she may have a small fiber
peripheral neuropathy. The most likely findings on examination are:
a. Symmetric weakness and atrophy of intrinsic muscles of the feet
with loss of ankle reflexes
b. Symmetric stocking pattern diminution of pinprick and
temperature sensation
c. Symmetric stocking pattern diminution of vibration and joint
position sense with absent ankle reflexes
d. Symmetric stocking pattern diminution of all sensory modalities
with absent deep tendon reflexes in the arms and legs
e. Symmetric stocking pattern diminution of vibration and joint
position sense with retained ankle reflexes
69.A 45-year-old man presents with a several-month history of
weakness in his arms and legs. On examination, in addition to
 weakness in multiple muscle groups, he has atrophy, hyperreflexia,
spasticity of the legs, and bilateral Babinski signs. Fasciculations in
multiple muscles are also noted. His sensation of pain, temperature,
and joint position are intact. What is his most likely diagnosis?
a. Amyotrophic lateral sclerosis
b. Vitamin B12 deficiency
c. Anterior spinal artery syndrome
d. Central cord syndrome
e. Brown-Séquard syndrome
70.A 60-year-old woman presents with a primary complaint of
insomnia. She feels fatigued during the day and needs to take a nap
each afternoon. She goes to sleep at 7:00 PM and awakens at 3:00
AM each day. What is the most appropriate treatment for this
patient?
a. Continuous positive airway pressure
b. Behavioral modification therapy
c. Modafinil in the morning
d. Zolpidem at bedtime
e. Bright light therapy
71.A 54-year-old man is seen in the Neurology clinic with complaints
of resting tremor of the left hand and a general feeling of slowing
down. As an example, he explains that it takes him at least 20
minutes to get dressed in the morning. You suspect that he has
idiopathic Parkinson disease. If you are correct, examination would
be most likely to show which of the following combinations of
physical signs?
a. Asymmetric rest tremor, asymmetric rigidity, and poor postural
reflexes
b. Symmetric rest tremor, asymmetric rigidity, and poor postural
reflexes
c. Asymmetric rest tremor, symmetric rigidity, and poor postural
reflexes
d. Symmetric rest tremor and rigidity and poor postural reflexes
e. Asymmetric rest tremor, symmetric rigidity, and impairment of
vertical gaze
72.A 55-year-old man with a history of hypertension is seen in the ER
with complaints of clumsiness and incoordination; they began 2
days earlier and have increased in severity. He also reports double
vision on lateral gaze, which resolves when one eye is covered. He
is awake, alert, and oriented. Examination shows restricted eye
movements in all directions, with eye abduction in both directions
most limited. Deep tendon reflexes are absent, and there is impaired
joint position sense. The most likely diagnosis is:
a. Brainstem stroke
b. Cerebellar infarction with compression of the brainstem
c. Miller–Fisher syndrome
d. Mysathenia gravis
e. Alcoholic cerebellar degeneration
73.A 44-year-old woman presents to the ER complaining of urinary
incontinence and lower back pain. What will be the most useful
diagnostic procedure to try in the effort to find the etiology of her
problem?
a. Urodynamic studies
b. Blood testing including glucose level
c. MRI of the spine
d. Post-void residual
e. Lumbar puncture
74.A 48-year-old woman reports recurrent episodes of stabbing
unilateral head pain associated with tearing and conjunctival
injection. Which of the following is characteristic of chronic
paroxysmal hemicranias, and not of cluster headache?
a. Unilateral pain
b. Conjunctival injection
c. Male predominance
d. Indomethacin responsivity
e. Headache duration of hours
75.A 75-year-old right-handed man with hypertension, diabetes, and
hypercholesterolemia is seen in the ER. His family explains that he
has had difficulty doing things around the house for the past few
days. The patient himself admits that he has found it difficult to get
dressed and to prepare his breakfast, but he feels healthy otherwise.
 On examination, his speech is fluent, and he is able to name objects
and repeat short phrases without difficulty. He is, however, unable
to mimic certain activities described by the examiner, although he
seems to have no difficulty understanding what it is that he is
supposed to do.
a. He likely has a form of Wernicke aphasia due to a lesion in the
left superior temporal lobe.
b. He likely has a form of apraxia due to a lesion in the right
frontal lobe.
c. He likely has a form of Wernicke aphasia due to a lesion in the
left inferior frontal lobe.
d. He likely has a form of apraxia due to a lesion in the right
parietal lobe.
e. He likely has a form of apraxia due to a lesion in the left parietal
lobe.
76.The most reliable method for distinguishing between a
subarachnoid hemorrhage and a “traumatic” spinal tap (LP) is the
presence of:
a. Increased opening pressure
b. Increased red cell count
c. Increased white cell count
d. Xanthochromia
e. Pain upon needle insertion
77.The MRI sequence that is most sensitive for the presence of blood
breakdown products (e.g., after a hemorrhage) is:
a. T1
b. T2
c. Contrast-enhanced T1
d. Fluid-attenuated inversion recovery (FLAIR)
e. Susceptibility
78.Which of the following disorders is most closely associated with
rapid eye movement sleep behavior disorder?
a. Alzheimer disease
b. Multiple sclerosis
c. Multiple system atrophy
d. Myasthenia gravis
 e. Primary lateral sclerosis
79.Which of the following vascular malformations is the most likely to
result in an intracranial hemorrhage?
a. Arteriovenous malformation
b. Capillary telangiectasia
c. Cavernous hemangioma
d. Developmental venous anomaly
e. Vein of Galen
80.An 81-year-old right-handed man with hypertension and
hypercholesterolemia presents with sudden onset of a dense right
hemiplegia. His language is normal, and he has normal eye
movements and pupillary reactions. He has no sensory deficits.
What is the most likely localization of his stroke?
a. Left motor cortex
b. Left internal capsule
c. Left thalamus
d. Left lateral medulla
e. Left cerebellar hemisphere
81.In which of the following disorders would the highest elevation of
creatine kinase be expected?
a. Becker muscular dystrophy (BMD)
b. Duchenne muscular dystrophy (DMD)
c. Lambert–Eaton myasthenic syndrome
d. Limb-girdle muscular dystrophy
e. Myotonic dystrophy
82.A 68-year-old man with no major medical problems has his annual
visit with his primary care physician. The doctor wishes to perform
a brief screening neurologic examination. Which of the following
parts of the neurologic examination would be the most sensitive for
the detection of potential abnormalities in multiple different parts of
the nervous system?
a. Deep tendon (muscle stretch) reflexes
b. Gait evaluation
c. Visual field examination
d. Joint position sense testing
 e. Total weight-lifting capacity
83.A 78-year-old woman with a history of coronary artery disease and
hypercholesterolemia develops sudden onset of paralysis of all four
limbs. On examination, her eyes are open, she appears alert, and
she can consistently respond to complex questions and commands
by blinking her eyes, but otherwise has minimal facial movement
and no movement of the limbs. This condition is best described as:
a. Locked-in syndrome
b. Persistent vegetative state
c. Brain death
d. Coma
e. Stupor
84.A 30-year-old man is found to have increased intracranial pressure
after a head injury. Which of the following treatments can serve to
lower intracranial pressure?
a. Lowering the head of the bed
b. Intravenous fluid load
c. Depression of respiratory rate
d. Mannitol
e. Basilar artery stent
85.An 80-year-old man has developed gradually worsening memory
over the past several years. His wife also reports that he appears to
have vivid visual hallucinations at times, and his alertness has been
fluctuating on a day-to-day basis. Examination shows bradykinesia
and rigidity in the limbs, without any dyskinesias. What is the most
likely diagnosis?
a. Alzheimer disease
b. Dementia with Lewy bodies
c. Vascular dementia
d. Huntington disease
e. Progressive supranuclear palsy
86.A 71-year-old with a clinical diagnosis of Alzheimer disease comes
to autopsy after a fatal motor vehicle accident. Which of the
following is a neuropathologic hallmark of Alzheimer disease?
a. Lewy bodies in the substantia nigra
 b. Lewy bodies in cortical neurons
c. Prominent atrophy of caudate
d. Spongiform changes in cortex
e. Neurofibrillary tangles
87.A 34-year-old man comes in for neurologic consultation because of
paroxysmal episodes of speech difficulty that have occurred
recently. The best way to distinguish whether these are seizures or
other types of events is:
a. History
b. Neurologic examination
c. Brain MRI
d. Routine EEG
e. Empiric anticonvulsant trial
88.An 18-year-old college student is seen in the ER because of fever,
confusion, and headache. LP is performed. Which of the following
CSF profiles is most consistent with acute bacterial meningitis?
a. Normal WBC count, high protein, low glucose
b. Normal WBC count, high protein, high glucose
c. Elevated WBC count, high protein, low glucose
d. Elevated WBC count, high protein, high glucose
e. Decreased WBC count, high protein, high glucose
89.A 55-year-old man presents with headache and right hand
weakness. On examination, you find bilateral papilledema and
UMN weakness in the right arm and leg. MRI with contrast shows
an enhancing mass in the left frontal region, crossing the corpus
callosum in a “butterfly” pattern with surrounding edema. Before
requesting a biopsy, you discuss with your resident that this is most
likely a:
a. Meningioma
b. Astrocytoma
c. Glioblastoma
d. Ependymoma
e. Schwannoma
90.You evaluate a 22-year-old woman complaining of visual problems.
Your examination shows bitemporal visual field defects. Where is
 the lesion?
a. Right optic nerve
b. Right occipital lobe
c. Left optic radiation
d. Optic chiasm
e. This visual field defect is nonphysiologic, suggesting a
psychiatric explanation.
91.You are asked to evaluate a 33-year-old construction worker who is
complaining of paresthesias in the first and second digits of his
right hand. Your physical examination shows no weakness, but he
has a mild decrease in light touch over the thumb. You request a
nerve conduction study to rule out carpal tunnel syndrome, and it
turns out to be normal. On repeated history, the patient indicates
that on occasion, he gets a sharp, “electric” pain travelling from his
neck to the right hand. What are you missing?
a. A median neuropathy at the wrist
b. A neuromuscular junction disorder affecting distal hand muscles
c. A C8-T1 radiculopathy
d. A lower trunk brachial plexopathy
e. A C6–C7 radiculopathy
92.A 75-year-old man underwent surgery to correct a large abdominal
aortic aneurysm. The procedure appeared to go well, but you are
called in a few hours later to evaluate the patient who states that he
cannot move or feel his legs. On the way to the ICU, you consider
the possible causes of his symptoms and plan your physical
examination. Which of the following neurologic examination signs
do you expect to be normal?
a. Pinprick sensation in the legs
b. Leg strength
c. Cold sensation in the legs
d. Pinprick sensation over the posterior trunk
e. Toe position sense
93.A 19-year-old man presents to the emergency department with 2
days of ascending weakness. He denies associated pain, sensory
changes, and bowel or bladder dysfunction. He had diarrhea 3
weeks earlier. He looks comfortable. On examination, you find
 moderate weakness in all limbs, and mild weakness of neck
muscles. Facial strength is full. There is no sensory level. You
suspect Guillain Barré syndrome and recommend admission to the
neurology unit. What should be done first?
a. Do an LP to look for albumin-cytologic dissociation.
b. Call for an emergency EMG to verify diagnosis.
c. Send the patient for a whole spine MRI to rule out cord
compression.
d. Obtain pulmonary function tests, including forced vital capacity.
e. Start high-dose steroids and then move to the floor.
94.A 55-year-old woman is seen in the ER with the complaint that
when she rolled over in bed in the morning she felt acutely
vertiginous for about 30 seconds, with associated nausea and
vomiting. Over the course of the day, the vertigo has recurred, each
time precipitated by turning her head. She has no other symptoms
and feels well in between the episodes of vertigo. She has poorly
controlled diabetes and hypertension. When examined in the ER,
she has rotatory and down-beating nystagmus during the Dix–
Hallpike maneuver with the head tilted one way but not the other.
The neurologic examination is otherwise entirely normal. Which of
the following is the most likely diagnosis?
a. Ménière disease
b. Cerebellar stroke
c. Benign positional paroxysmal vertigo
d. Perilymph fistula
e. Vestibular neuronitis
95.A 77-year-old woman with a history of migraine in her 20s and 30s
is seen by her primary care physician with the complaint that she
has headaches again for the first time in many years. Upon further
enquiry she reports a sense of generalized fatigue and notes that
there is discomfort over her right temple when she brushes her hair.
The neurologic examination is normal. Which of the following
would be the most appropriate clinical course?
a. Reassurance that her headaches are probably a recurrence of her
old migraine. No further investigations are needed.
 b. MRI of the brain to rule out an intracranial mass lesion, because
new-onset headaches in the elderly are commonly caused by
raised intracranial pressure.
c. LP to rule out high or low pressure headaches
d. Erythrocyte sedimentation rate, C-reactive protein, and temporal
artery biopsy, because giant cell arteritis is the most likely
diagnosis.
e. Explanation that she likely has trigeminal neuralgia, given the
distribution of her symptoms over the right temporal region
96.A 63-year-old man with poorly controlled hypertension is brought
to the ER after being found by his wife, struggling to speak. When
you examine him you find that his naming is impaired and his
verbal fluency is reduced, but other language functions, including
comprehension and repetition, are intact. Which of the following
conclusions is most accurate?
a. The reduced verbal fluency, together with an anomia, is most
suggestive of a posterior (Wernicke) aphasia.
b. The pattern of language impairment suggests a transcortical
motor aphasia.
c. He does not have aphasia given that his language functions other
than verbal fluency and naming are intact.
d. The impaired ability to name objects (anomia) is most
suggestive of a conduction aphasia.
e. This is likely a confusional state rather than an aphasia.
97.A 27-year-old African-American woman with diabetes presents to
the outpatient Neurology clinic with subacute onset of bilateral
facial weakness. She explains that the symptoms have developed
over the course of the past few days. She also reports having a
slightly raised and tender rash over the anterior aspects of both
shins. On examination, you find bilateral LMN facial weakness as
well as tender erythematous nodules over both shins. Which of the
following is the most likely diagnosis?
a. Guillain Barré syndrome
b. Lyme disease
c. Neurosarcoidosis
d. Diabetes
 e. Tuberculosis
98.Ataxia may be a manifestation of which vitamin deficiency?
a. Vitamin A
b. Vitamin B12
c. Vitamin C
d. Vitamin D
e. Vitamin E
99.Which of the following are features most consistent with essential
tremor?
a. Asymmetry from left to right
b. Worse with rest than with action
c. Sporadic (i.e., nonfamilial) pattern of onset
d. Worsening with alcohol
e. Otherwise normal neurologic examination
100.Which of the following statements regarding higher cortical
function is true?
a. Aphasia is characterized by a problem with articulation of
words.
b. Apraxia is defined by the inability to carry out an automatic or
unlearned motor task.
c. Agnosia is an inability to recognize objects through a sensory
modality even when the primary sensory modality is
unimpaired.
d. Neglect is a form of apraxia in which there is insufficient
attention paid to one hemispace.
e. Agraphia is a disorder in which affected individuals are unable
to draw pictures.
 Answers

1. c (Chapter 12)
The presence of visual hallucinations is an early symptom of dementia
with Lewy bodies (DLB). Other characteristics include cognitive
decline, fluctuations of alertness, extrapyramidal symptoms, and an
extraordinary sensitivity to neuroleptics. Visual hallucinations and
sensitivity to neuroleptics are not early signs of Alzheimer disease,
Parkinson disease (PD), Pick disease, or vascular dementia.

2. b (Chapter 4)
Decreased visual acuity that does not correct with pinhole testing, a
relative afferent pupillary defect, and a central scotoma are
characteristic of optic nerve disease. A lesion affecting the optic chiasm
will produce a bitemporal heteronymous hemianopia. If a lesion affects
the optic tract, the optic radiations (in both temporal and parietal areas)
or the occipital cortex (unilaterally), it will produce a homonymous
hemianopia that in the occipital cortex may be “macular sparing.”

3. d (Chapter 25)
Niemann–Pick disease, Gaucher disease, and Tay–Sachs disease are all
associated with cherry-red spots in the macula. Niemann–Pick disease is
an autosomal recessive disorder caused by sphingomyelinase
deficiency. Alexander disease and Canavan disease are dysmyelinating
disorders with prominent macrocephaly, but not cherry-red spots. The
classic ophthalmologic finding of Hurler syndrome is clouding of the
cornea rather than a cherry-red spot in the macula. Krabbe disease is an
autosomal recessive disorder caused by galactosylceramide β-
galactosidase deficiency. It does not produce a cherry-red spot in the
macula.

4. c (Chapter 23)
One possible etiology of sensory neuronopathies is a paraneoplastic
disorder, in particular one caused by small cell lung cancer. This is
generally associated with positive anti-Hu antibodies (antineuronal
antibodies) and can also be associated with paraneoplastic
encephalomyelitis, ataxia, and autonomic neuropathy. Anti-GM1 has
been associated with multifocal motor neuropathy with conduction
block. MRI of the spine would not help at this stage. Other causes of
sensory neuronopathy include Sjögren syndrome, pyridoxine
intoxication, and chemotherapy (cisplatin). Chest CT to search for
occult malignancy is also recommended.

5. d (Chapter 1)
Each cranial nerve courses through a particular foramen, or opening, in
the skull. Skull base fractures and other such injuries can result in
damage to these structures and injury to the associated cranial nerves.
The seventh (facial) and eighth (vestibulocochlear) nerves both course
through the internal auditory meatus, which may have been damaged in
this woman’s case.

6. d (Chapter 2)
Despite the normal head CT, this woman has had a subarachnoid
hemorrhage. She should undergo a vascular imaging study of the brain
such as a conventional angiogram, CT angiogram, or MR angiogram to
investigate for a cerebral aneurysm. Xanthochromia is the result of
breakdown of blood within the subarachnoid space. Its presence in a
bloody cerebrospinal fluid (CSF) sample helps distinguish intrathecal
hemorrhage from a traumatic tap. This patient’s CSF contains relatively
few WBCs, and thus does not suggest an active infection. The CSF
glucose is typically normal in both subarachnoid hemorrhage and viral
meningitis; it is frequently low in bacterial, mycobacterial, and
carcinomatous meningitis. An opening pressure of 14 cm H2O is within
the normal range of 6 to 15 cm H2O.

7. d (Chapter 3)
This patient’s clinical presentation suggests increased intracranial
pressure (ICP) from a right hemisphere lesion. The “blown” right pupil
suggests that herniation of the right hemisphere has compressed the
right oculomotor nerve. Choices A through C are all measures that
acutely decrease ICP, whereas neurosurgery may be needed as a more
definitive intervention. Performing a lumbar puncture in this situation
could be dangerous and could cause worsening herniation.

8. e (Chapter 5)
Symmetric proximal weakness usually suggests a primary muscle
problem, as does weakness of neck flexors and extensors. The absence
of muscle pain and tenderness does not argue against primary muscle
pathology. The other listed choices would not usually result in this
pattern of weakness.

9. b (Chapter 15)
This child likely has absence seizures, which are frequently diagnosed
after a teacher or parent notices inattention, “daydreaming,” or staring
episodes. Absence seizures often last a few seconds each, can occur
many times a day, and have a classic EEG appearance. Ethosuximide
and valproic acid are typical drugs of choice.

10. b (Chapter 10)

This woman is suffering from a migraine headache. Sumatriptan is
effective as abortive treatment. The other medications are effective in
decreasing the severity and frequency of attacks and are used as
preventive therapy.

11. c (Chapter 12)

This case represents an early onset of dementia with associated
personality changes and movement disorder (chorea)—the classic triad
of Huntington disease (HD). HD is linked to chromosome 4p16.3, also
known as the HD gene, encoding for a protein called huntingtin. This
gene normally contains a CAG repeat sequence that, when expanded
beyond 40 repeats, causes an abnormally long and neurotoxic version of
the huntingtin protein. HD is not linked to the other chromosomes
listed.

12. b (Chapter 8)
Paraneoplastic cerebellar degeneration is typically a pancerebellar
syndrome with clinical manifestations including ataxia, dysarthria, and
nystagmus. The underlying malignancy is typically a gynecologic one
or breast cancer. The temporal evolution is typically that of acute or
subacute onset with fairly rapid progression over weeks to months,
followed by stabilization. Spinocerebellar ataxia would be present
earlier in life and progress more slowly. Metastatic cerebellar disease
would more likely affect a cerebellar hemisphere and produce
lateralized cerebellar dysfunction. Alcoholic cerebellar degeneration
typically affects the vermis, and the characteristic manifestation is that
of a gait ataxia. Stroke (ischemic or hemorrhagic), although abrupt in
onset, would not be expected to progress over a period of weeks to
months.

13. b (Chapter 9)
Multiple sclerosis (MS) characteristically produces an upper motor
neuron (UMN) bladder or spastic bladder with increased frequency and
urgency. Stress incontinence is an involuntary loss of urine during
coughing, sneezing, laughing, or other physical activities that increase
intra-abdominal pressure. An atonic bladder is characterized by
overflow incontinence and increased capacity and compliance.

14. a (Chapter 9)
Atonic bladder implies a lower motor neuron (LMN) lesion at the level
of the conus medullaris, cauda equina, sacral plexus, or peripheral
nerves. It is characterized by overflow incontinence and increased
capacity and compliance. Diabetes is the only one in the group likely to
produce that type of deficit.

15. a (Chapter 24)

Myotonic dystrophy is a multisystem disorder that may also cause
frontal balding, diabetes, and gastrointestinal symptoms. It is the most
common adult-onset muscular dystrophy. It is inherited in an autosomal
dominant manner and is caused by a triplet repeat expansion in the
DMPK gene. EMG typically shows myotonic discharges.

16. b (Chapter 16)

She likely has Wilson disease, an autosomal dominant disorder of
copper metabolism that presents with neuropsychiatric symptoms as
well as a movement disorder. The pigment changes in the cornea are
Kayser–Fleischer rings and are characteristic of Wilson disease. The
most common pattern of laboratory abnormalities is increased serum
free copper, decreased serum ceruloplasmin, and increased 24-hour
urinary copper excretion.

17. a (Chapter 5)
The patient’s current symptoms are suggestive of a right radial
neuropathy. Multiple sequential mononeuropathies, each affecting a
single peripheral nerve, are known as mononeuropathy multiplex. Pain
is a typical feature. Patients with rheumatologic conditions are
susceptible; vasculitis may be involved.

18. c (Chapter 11)

Broca’s aphasia is characterized by effortful nonfluent speech and an
inability to repeat, with relatively preserved comprehension.
Transcortical motor aphasia is similar but has preserved repetition.

19. b (Chapter 21)

Along with the clinical picture, a CSF profile of lymphocytic
pleocytosis, elevated protein, normal glucose, and a negative Gram stain
point to viral or aseptic meningitis. The clinical presentations of
illnesses (a) through (d) could appear very similar, but the CSF analysis
is crucial in identifying the responsible organism. This patient’s CSF
should still be screened for herpes simplex virus (HSV), and empiric
acyclovir should be considered because the morbidity and mortality
from untreated HSV meningitis is high. Bacterial meningitis tends to
produce a granulocytic pleocytosis. Fungal meningitis is usually
associated with hypoglycorrhachia (defined as a CSF-serum glucose
ratio below 0.4). Subarachnoid hemorrhage characteristically produces a
large number (thousands) of RBCs.

20. c (Chapter 2)
About 50% of patients with epilepsy have normal routine EEGs. A
seizure is a clinical diagnosis, and this patient’s convincing history
supersedes the normal EEG. Long-term video-EEG monitoring is not
required to prove the diagnosis of seizure. Although hyperventilation
can help elicit absence seizure activity on EEG, his history and age
make an absence seizure unlikely. Although an ischemic stroke can
precipitate a seizure, this man’s history is most suggestive of seizure.
The mild right hemiparesis is more likely a Todd’s paralysis rather than
due to an ischemic stroke.

21. a (Chapter 11)

This patient exhibits a form of neglect, in which he does not recognize
his left arm as his. Right frontal or parietal lesions are the most common
causes. In the alien-limb phenomenon, patients retain awareness of the
limb but feel that it is not under their control.

22. a (Chapter 15)

Benzodiazepines are the first agents used in the treatment of status
epilepticus. Typically, phenytoin and then phenobarbital are used
subsequently. Propofol is used if status epilepticus becomes refractory,
while carbamazepine and lamotrigine are anti-seizure drugs not often
used in the early treatment of status epilepticus, as they have no
intravenous preparation.

23. e (Chapter 17)

Subfalcine herniation may result in compression of the anterior cerebral
arteries, and therefore bilateral leg weakness. Ipsilateral third nerve
palsy is the first sign of uncal (not subfalcine) herniation. Continued
uncal herniation may result in compression of the contralateral cerebral
peduncle against the free edge of the tentorium, leading to ipsilateral
hemiparesis (the “Kernohan’s notch” phenomenon). Small, reactive
pupils are seen in early transtentorial (central) herniation.

24. e (Chapter 20)

Intravenous corticosteroids may delay, but not prevent, the development
of MS in a patient with optic neuritis. They are preferred to oral
corticosteroids. Interferon β-1b and natalizumab are used for the longer
term treatment of MS, but not in the treatment of isolated optic neuritis.

25. c (Chapter 4)
Lesions of the medial longitudinal fascicle (MLF) produce an
internuclear ophthalmoplegia (INO). The clinical characteristics of a
right INO include inability to adduct the right eye in left lateral gaze
plus nystagmus of the abducting left eye. (Adduction during
convergence is maintained because this action does not depend on the
MLF.) “One-and-a-half syndrome” occurs as a consequence of a lesion
involving the PPRF or sixth-nerve nucleus and the adjacent ipsilateral
MLF. This produces an ipsilateral gaze palsy and INO on the
contralateral side; the only eye movement present in the lateral plane is
abduction of the contralateral eye.

26. a (Chapter 21)

Aseptic meningitis and cranial nerve palsies (such as facial nerve palsy)
are among the early manifestations when the nervous system becomes
involved in Lyme disease. Painful polyradiculopathy or
leukoencephalopathy are two (typically later) neurologic complications
of Lyme disease. Spinal cord compression and generalized epilepsy are
unlikely to occur due to Lyme disease.

27. c (Chapter 18)

Sarcoidosis is one of the most common causes of bilateral LMN facial
weakness. It is also an important cause of a lymphocytic meningitis
(hence the headache) and may cause a variety of other cranial
neuropathies, including optic neuropathy (hence the relative afferent
papillary defect). MS is another important cause of optic neuritis, but
bilateral facial weakness would be unusual. Guillain–Barré syndrome
(GBS) may cause bilateral facial weakness, but typically in the context
of areflexia and generalized weakness; a relative afferent papillary
defect is not likely to occur in GBS. Lyme disease may cause bilateral
facial weakness similarly (although unilateral facial weakness is more
common); the afferent papillary defect would not be expected.
Vasculitis is an extremely unusual cause of bilateral facial weakness.

28. a (Chapter 14)

The sudden onset of symptoms in the context of the patient’s stroke risk
factors makes a pure sensory stroke in the contralateral thalamus the
most likely diagnosis. Lesions of the internal capsule, precentral gyrus,
or corona radiata would be more likely to produce predominantly motor
deficits. A lesion in the right occipital lobe would usually produce a
visual field deficit, but not somatosensory numbness.

29. b (Chapter 17)

The middle meningeal artery travels between the skull and the dura.
When it is damaged (typically due to trauma resulting in a skull fracture
that lacerates that artery), blood accumulates in the epidural space,
resulting in an epidural hematoma. Patients often have a brief episode of
loss of consciousness at the time of trauma, followed by a “lucid
interval,” and then clinical deterioration as the bleeding continues. If
untreated, the blood will continue to collect and may cause brain
herniation, as in this case. An ischemic infarct would be expected to
have a sudden onset, without a progressive decline in function.
Likewise, a concussion should not cause progressive neurologic decline
and, similar to drug intoxication, would not result in the physical signs
seen in this patient. Diffuse axonal injury should not produce lateralized
deficits.

30. d (Chapter 22)

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with
involvement of the LMNs and corticospinal tracts. Weakness, muscle
atrophy, and muscle fasciculations are prominent features. Sensory
findings almost never occur in ALS. Vitamin B12 deficiency classically
results in degeneration of the dorsal columns and corticospinal tracts.
Therefore, joint position sense loss and weakness are typical features,
but pain and temperature sensation are spared. Brown-Séquard
syndrome results from hemisection of the spinal cord. The classic
features are ipsilateral weakness and loss of joint position sense, with
contralateral loss of pain and temperature sensation below the lesion.
Tabes dorsalis is a late complication of neurosyphilis and is
characterized by isolated dorsal column dysfunction resulting in loss of
joint position sense. Anterior spinal artery syndrome usually results
from infarction of the anterior spinal artery, causing ischemia to the
anterior two-thirds of the spinal cord. Therefore, dorsal columns are
spared, but weakness and loss of pain and temperature sensation result
because of involvement of the ventral horns and spinothalamic tracts.

31. c (Chapter 25)

This patient has features suggestive of tuberous sclerosis complex
(TSC). A head CT or MRI may identify cortical tubers, subependymal
giant cell astrocytomas, or other lesions. The other tests do not help in
the evaluation of TSC.

32. a (Chapter 25)

A diagnosis of autism requires a combination of social, behavioral, and
language abnormalities. Asperger syndrome shares social isolation and
eccentric behavior with autism, but language is normal. Gross and fine
motor delays are not required features of either condition.

33. c (Chapter 6)
Allodynia is pain provoked by normally innocuous stimuli;
hyperesthesia is increased sensitivity to sensory stimuli, and
paresthesias are abnormal spontaneous sensations. “Hypesthesia” refers
to decreased sensation.

34. c (Chapter 4)
This patient appears to have a Horner’s syndrome on the right, likely
produced by a carotid dissection as a consequence of neck trauma.
Horner’s syndrome is characterized by unilateral miosis, ptosis, and
(sometimes) ipsilateral facial anhidrosis as a result of impaired
sympathetic innervation. Examine the pupils in the dark (turn the lights
off and look at the pupils during the first 5 to 10 seconds). A dilation lag
in the small pupil and anisocoria greater in darkness means a
sympathetic defect in the smaller pupil and will help with the diagnosis.

35. b (Chapter 23)

This patient appears to have a Guillain Barré syndrome.
Albuminocytologic dissociation means high protein with almost no cells
in the CSF, which is characteristic of this syndrome. Immediately after
the onset of weakness, however (the first 3 to 4 days), the CSF could be
completely normal. Additional studies to corroborate the diagnosis
include nerve conduction studies and EMG to demonstrate slowing of
conduction velocities, prolongation of F-wave latency, and possible
conduction block.

36. d (Chapter 23)

This patient appears to have acute ascending weakness with loss of
reflexes characteristic of Guillain Barré syndrome or acute
inflammatory demyelinating polyradiculoneuropathy. His examination
worsens while in the emergency room, and that should be an indication
that he is deteriorating quickly and needs to be admitted to the ICU for
close observation. A forced vital capacity (FVC) below 15 mL/kg is an
indication for intubation and mechanical ventilation. The presence of a
foot drop should not factor into decisions about ICU admission.

37. a (Chapter 23)

Cytomegalovirus (CMV) infection is the most common cause of
polyradiculitis or cauda equina syndrome in an immunocompromised
individual. The other agents do not affect the nerve roots or cauda
equina primarily. CMV polyradiculitis occurs in about 2% of AIDS
cases and is characterized by the subacute onset of a flaccid paraparesis,
sacral pain, paresthesias, and sphincter dysfunction. Polymerase chain
reaction evaluation of the CSF for CMV can provide a definitive
diagnosis. Treatment is with ganciclovir or foscarnet or, in severe cases,
both drugs.

38. d (Chapter 7)
Her symptoms consist of a feeling of movement—which is vertigo. The
intermittent nature of her vertigo, the exacerbation with head
movement, and the absence of brainstem signs are consistent with
benign positional paroxysmal vertigo (BPPV). To confirm the
diagnosis, one can perform the Dix–Hallpike maneuver at the bedside.
Brainstem and cerebellar infarctions rarely present with isolated vertigo,
and Ménière disease is characterized by hearing loss and tinnitus along
with episodic vertigo.

39. d (Chapter 24)

The primary antigenic target in autoimmune myasthenia gravis (MG) is
the postsynaptic nicotinic acetylcholine receptor. Presynaptic voltage-
gated calcium channels are the target of the Lambert–Eaton myasthenic
syndrome.

40. a (Chapter 1)
The trigeminal nerve is responsible for the muscles of mastication. The
facial nerve innervates the muscles of facial expression, the oculomotor
nerve subserves eye movements, the glossopharyngeal nerve innervates
some pharyngeal muscles, and the hypoglossal nerve moves the tongue.

41. d (Chapter 3)
The Glasgow Coma Scale (GCS)—which provides a composite
assessment of unresponsive patients depending on their eye movements,
motor function, and language ability—is typically used for patients after
head trauma. It has prognostic value for patients with head injuries and
is easy for nonphysicians to use.

42. e (Chapter 3)
A noncontrast head CT is the imaging study of choice in suspected
intracranial hemorrhage. This allows for the easiest delineation of acute
blood, which should appear hyperdense (bright) on this study—whether
subdural, epidural, or intraparenchymal hemorrhage. A CT scan might
not show a small cerebral infarction, but it would probably show a large
infarction compatible with the patient’s poor responsiveness.

43. e (Chapter 10)

The patient’s clinical presentation is typical of temporal arteritis: age
over 50, pain over the temporal arteries, jaw claudication, and an
elevated erythrocyte sedimentation rate (ESR). Definitive diagnosis is
made by temporal artery biopsy. Treatment with prednisone for several
months must be initiated early, because involvement of the ophthalmic
artery can lead to blindness if diagnosis and treatment are delayed.

44. e (Chapter 13)

The history and examination suggest a diagnosis of obstructive sleep
apnea. Polysomnography is the best test to confirm the diagnosis.
Although narcolepsy is also associated with excessive daytime
sleepiness, patients often have associated hypnagogic hallucinations or
cataplexy, which are absent in this patient. The multiple sleep latency
test (MSLT) is useful for diagnosing narcolepsy, whereas MRI of the
brain, LP, and EEG are unlikely to be of diagnostic value in this patient.

45. c (Chapter 17)

Uncal herniation results from mass lesions of the middle cranial fossa.
This patient most likely has a hemorrhage in the middle cranial fossa
from head trauma. If large enough, the mass lesion causes displacement
of the medial portion of the temporal lobe (uncus) downward over the
tentorium cerebelli, typically resulting in entrapment of the ipsilateral
third cranial nerve and compression of the brainstem. This compression
can cause coma due to disruption of the ascending arousal system in the
brainstem. It causes an ipsilateral dilated pupil due to compression of
the parasympathetic nerve fibers (traveling with the third cranial nerve)
that normally cause pupillary constriction. Diffuse axonal injury can
result in coma, but would not be expected to cause the dilated,
unreactive pupil. Infarction of the occipital lobe should produce a
homonymous hemianopia, not a loss of consciousness. Cervical spine
fracture may lead to weakness below the level of the lesion but should
not impair consciousness.

46. a (Chapter 14)

Intracerebral hemorrhages caused by hypertension are most often found
in the basal ganglia, thalamus, pons, and cerebellum, in order of
decreasing frequency.

47. c (Chapter 13)

Continuous positive airway pressure is the treatment of choice for
patients with obstructive sleep apnea. Sodium oxybate,
methylphenidate, and clomipramine are used for patients with
narcolepsy and cataplexy. Sedating drugs such as clonazepam and other
benzodiazepines can decrease upper airway tone, leading to worsened
symptoms of obstructive sleep apnea.

48. a (Chapter 19)

A headache that is either different from the normal pattern or
progressive deserves to be investigated further with a brain imaging
study. Slowly progressive brain tumors can be associated with a normal
neurologic examination or minor abnormalities. Nausea and vomiting
need not be present, especially in the early stages of a tumor.
Administration of pure oxygen is an effective treatment for cluster
headaches, but the patient’s description is not consistent with that
diagnosis.

49. b (Chapter 19)

Seizures or hemiparesis are not usual features of pituitary adenoma.
Varying degrees of bitemporal hemianopia (a visual field deficit in the
temporal visual fields bilaterally) may be caused by compression of the
optic chiasm. A homonymous hemianopia results from dysfunction of
the optic radiations or visual cortex posterior to the chiasm. On brain
imaging with contrast, pituitary adenomas usually enhance in a
homogeneous manner and do not typically exhibit ring enhancement.

50. d (Chapter 22)

Signs of UMN or corticospinal tract dysfunction include hypertonia,
spasticity, increased reflexes, and an extensor plantar response
(Babinski sign). Signs of LMN dysfunction include hypotonia,
decreased or absent reflexes, and a flexor plantar response (downgoing
toe). Weakness may be present with either UMN or LMN dysfunction.
Hypotonia is not characteristic of a UMN lesion, but it is fair to note
that a flaccid paralysis may follow an acute, severe insult, such as in
“spinal shock.”

51. a (Chapter 2)
CT without contrast is the imaging modality of choice for
demonstrating acute intracranial bleeding. Although it is true that MRI
provides better visualization of the contents of the posterior fossa, a
cerebellar hemorrhage usually will be visible on CT. Patients with
pacemakers and most other implanted metal objects cannot undergo
MRI. Although MRI with diffusion-weighted imaging is the most
sensitive test for ischemic stroke, a susceptibility-weighted MRI
sequence is preferred for detecting intracranial blood. A single-photon
emission computed tomography (SPECT) scan may help in the
evaluation of dementia or epilepsy, but will not be useful in this
scenario.

52. b (Chapter 21)

In the presence of severe Lyme disease with central nervous system
(CNS) involvement, as in this case, intravenous antibiotics followed by
oral therapy are the first choice. Intravenous ceftriaxone is the first
choice here. The combination of oral amoxicillin and doxycycline is the
most common treatment for uncomplicated Lyme disease. Fluconazole
is an antifungal agent and has no value in the treatment of Borrelia
burgdorferi infection.

53. c (Chapter 12)

Pathologically, PD is characterized by progressive death of
dopaminergic neurons of the substantia nigra pars compacta. Most cases
of PD are sporadic, but there are reports of familial cases in which
mutations in the parkin and α-synuclein genes have been described.
Impairment of vertical gaze is a common feature of progressive
supranuclear palsy (PSP), a neurodegenerative disorder that also has
parkinsonian features. Despite the gait manifestations of PD, early falls
are actually uncommon (but are common in PSP).

54. d (Chapter 24)

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy
(BMD) are allelic disorders due to mutations in the dystrophin gene,
located on the X chromosome. The inheritance pattern is X-linked. The
limb-girdle muscular dystrophies are a heterogeneous group of
disorders, some with autosomal dominant and some with autosomal
recessive inheritance. Mutations in a wide variety of genes have been
reported in patients with limb-girdle muscular dystrophy, including the
sarcoglycan genes.

55. c (Chapter 1)
The cerebellum is the primary brain structure involved in coordination,
although other components of the motor pathways are involved as well.
Testing for rapid alternating movements is part of the coordination
examination. The other choices listed have less, or no, primary role in
coordination.

56. b (Chapter 5)
“Crossed signs” can occur with unilateral lesions in the pons if
descending motor fibers heading for the ipsilateral facial nucleus are
affected, with the descending fibers heading for the contralateral spinal
cord. With right pontine lesions, the right face and left body could be
weak.

57. e (Chapter 15)

Characteristic side effects of carbamazepine include hyponatremia,
agranulocytosis, and a risk for Stevens–Johnson syndrome. Except for
the hyponatremia, these side effects are rare, and the hyponatremia may
not cause symptoms.

58. c (Chapters 14 and 17)

Aneurysmal rupture is the most common cause of (nontraumatic)
subarachnoid hemorrhage. Tearing of bridging veins produces a
subdural hematoma. Laceration of the middle meningeal artery causes
an epidural hematoma. Amyloid angiopathy is a cause of lobar
hemorrhage in the elderly. Although rupture of an arteriovenous
malformation may lead to a subarachnoid hemorrhage, aneurysmal
rupture is a more common cause.

59. b (Chapter 19)

Meningiomas enhance in a bright and mainly homogeneous manner.
Certain tumors (particularly glioblastoma multiforme and metastatic
lesions), brain abscesses, toxoplasmosis, granulomas, and active
demyelinating lesions typically show ring enhancement after contrast
administration. Although lymphomas can enhance in a homogeneous
manner, they can also be ring enhancing.

60. b (Chapter 7)
Micturition syncope is a form of reflex or neurogenic syncope that
involves the triggering of cardioinhibitory or vasodepressor responses
or both. The symptoms of light-headedness and graying of vision are
typically reported by patients with syncope. Other symptoms might
include a heavy feeling at the base of the neck, buckling at the knees,
and tinnitus. Although orthostatic hypotension is a common cause of
syncope, the occurrence of syncope after micturition, rather than upon
standing, suggests that this is not the cause in this case. Vasovagal
syncope is another common cause of syncope but typically occurs in the
setting of acute pain or with a strong emotional response. Vestibular
neuronitis is characterized by vertigo, and there is no associated loss of
consciousness. (Older patients with syncope should be screened
carefully for cardiogenic causes as well.)

61. e (Chapter 21)

HSV infection is the leading diagnostic consideration. In HSV, the
magnetic resonance imaging often shows contrast enhancement and
edema of the temporal lobes, helping to establish the diagnosis and
ruling out some other concerns. Treatment for viral meningitis is mainly
supportive, because there are no specific treatments for most viral
infections. If HSV infection is suspected, however, treatment should
begin promptly with intravenous acyclovir even while tests are pending,
because mortality is close to 70% in untreated cases. In immune
suppressed patients, it is appropriate to cover for bacterial infections as
well until the preliminary cultures return.

62. b (Chapter 23)

Physical examination is the most important information to define
symptoms as belonging to the peripheral nervous system (PNS).
Sensory symptoms can have a central or peripheral origin. The
acuteness of the presentation does not help localization in this case.
Paresthesias may be seen in both PNS and CNS dysfunction.

63. a (Chapter 17)

Neurosurgical decompression is the proper treatment for an epidural
hematoma causing coma. This is a neurosurgical emergency, so
conservative management would only result in further neurologic
decline. Although hyperventilation and administration of mannitol may
help to decrease ICP, these are temporizing measures; neurosurgical
decompression is necessary to remove the accumulating blood. Because
the patient has a hemorrhage, tissue plasminogen activator, which is
used in acute ischemic strokes, would be contraindicated.

64. c (Chapter 20)

Acute disseminated encephalomyelitis (ADEM) is a monophasic
demyelinating illness. MS is characterized by multiple white matter
lesions separated in space and time; it is not monophasic (although, of
course, the monophasic nature of the course will not be clear at the
onset of this illness). Oligoclonal bands in the CSF are more common in
MS than in ADEM. The pleocytosis of ADEM is usually lymphocytic.
It may be neutrophilic in neuromyelitis optica. Both MS and ADEM can
produce multiple lesions on MRI. ADEM is acquired and commonly
occurs after viral infections or vaccinations. A positive family history is
more likely to be relevant for a patient with MS.

65. b (Chapter 23)

This presentation is most consistent with diabetic amyotrophy, a
condition that affects the lumbosacral plexus and tends to resolve
spontaneously over months to years. Diabetes predisposes to both
diabetic amyotrophy and peripheral neuropathy. Peripheral neuropathy,
or polyneuropathy, is a more common manifestation of diabetes and
often causes painful sensory symptoms distally in both legs. Patients
with mononeuritis multiplex, a vasculitic neuropathy, often report the
stepwise development of painful sensorimotor deficits in several
individual nerve territories; nerves in watershed regions (e.g., peroneal
in the leg, ulnar in the arm) are more vulnerable given the lack of
overlapping blood supply. Strokes are unlikely to produce pain. An
intervertebral disk herniation at L5–S1 would not cause weakness of
iliopsoas or quadriceps.

66. b (Chapter 17)

The patient’s symptoms and head CT findings are consistent with an
epidural hematoma, which results from laceration of the middle
meningeal artery. The classic head CT finding of an epidural hematoma
is a hyperdense region with a biconvex or lenticular shape. Tearing of
bridging veins leads to subdural hematoma. Contact of the brain’s
frontal poles with the skull leads to cerebral contusions. On head CT,
these areas appear as hyperdensities within the brain parenchyma and
not in the epidural or subdural spaces. Diffuse axonal injury results from
rotational acceleration and deceleration of the brain can be associated
with either a normal head CT scan or hemorrhages within the deep
white matter of the brain. Rupture of a cerebral aneurysm results in
subarachnoid hemorrhage, not an epidural hematoma.

67. b (Chapter 16)

Progressive supranuclear palsy is a disorder characterized by
parkinsonism, supranuclear impairment of eye movements (vertical
gaze typically affected more prominently than horizontal gaze), and
impaired postural reflexes. Corticobasal ganglionic degeneration and
Parkinson disease may also cause rigidity and poor postural reflexes,
but are not typically associated with eye movement abnormalities.
Miller–Fisher syndrome and chronic progressive external
ophthalmoplegia are both associated with eye movement abnormalities,
but these disorders affect the external ocular muscles rather than the
supranuclear gaze centers and are not associated with extrapyramidal
features.

68. b (Chapter 18)

Small-fiber neuropathy typically produces symptoms of neuropathic
pain, and examination shows impaired temperature and pinprick
sensation. Other sensory modalities are mediated by large fibers.
Weakness and atrophy reflect involvement of motor fibers rather than
small-fiber sensory function.

69. a (Chapter 22)

The patient exhibits both UMN signs (hyperreflexia, spasticity, and
Babinski signs) and LMN signs (atrophy and fasciculations), which are
the hallmark of ALS. Weakness can occur with either LMN or UMN
dysfunction. None of the other options listed would cause widespread
UMN and LMN signs. Vitamin B12 deficiency classically results in
degeneration of the dorsal columns (loss of joint position sense) and
corticospinal tracts (UMN signs). Anterior spinal artery syndrome
usually results from infarction of the anterior spinal artery, causing
ischemia to the anterior two-thirds of the spinal cord; therefore, dorsal
columns are spared, but weakness and loss of pain and temperature
sensation result because of involvement of the ventral horns and
spinothalamic tracts. Central cord syndrome is most common in the
cervical cord and typically results in loss of pain and temperature
sensation in a capelike distribution. Brown-Séquard syndrome results
from hemisection of the spinal cord. The classic features are ipsilateral
weakness and loss of joint position sense with contralateral loss of pain
and temperature sensation below the lesion.

70. e (Chapter 13)

This patient has a history consistent with advanced sleep phase disorder.
It is most appropriately treated with bright light therapy in the evening
and melatonin to help reset her circadian rhythms. Continuous positive
airway pressure is used to treat obstructive sleep apnea. Behavioral
modification is useful for many forms of insomnia, but bright light
therapy is more effective for advanced sleep phase disorder. Modafinil
is more appropriate for narcolepsy. The patient sleeps 8 hours each
night, and zolpidem is not likely to help her.

71. a (Chapter 16)

The extrapyramidal features of idiopathic PD are typically asymmetric.
Postural reflexes may be impaired in a number of extrapyramidal
disorders including idiopathic PD. Impaired vertical gaze is more
typical of PSP than of idiopathic PD.

72. c (Chapter 8)
Miller–Fisher syndrome (MFS) is a disorder characterized by ataxia,
ophthalmoplegia, and areflexia. It is considered a variant of the Guillain
Barré syndrome and is associated with the finding of anti-GQ1b
antibodies in the serum. Stroke (involving either the brainstem or
cerebellum) should be sudden in onset, not typically progressing over
several days. Ophthalmoplegia may be seen in both myasthenia gravis
(MG) and MFS, but areflexia is not a feature of MG. Alcoholic
cerebellar degeneration may be associated with a peripheral neuropathy
and loss of joint position sense and deep tendon reflexes, but should not
produce ophthalmoplegia (unless associated with Wernicke’s
encephalopathy, in which case confusion should also be present).

73. c (Chapter 9)
Acute urinary incontinence is an emergency. MRI of the spine will help
determine whether an acute lesion is responsible for the incontinence
(cauda equina or conus medullaris syndrome, spinal cord compression,
etc.). Determination of the post-void residual would not help in this
situation, and urodynamic studies are not indicated in the acute setting.
LP is not indicated in this situation.

74. d (Chapter 10)

Both chronic paroxysmal hemicrania and cluster headache are unilateral
and can produce conjunctival injection. Chronic paroxysmal headache is
more common in women, whereas cluster headache is more common in
men. Response to indomethacin is seen in chronic paroxysmal
hemicrania, but not in cluster headache. Episodes of chronic paroxysmal
hemicrania typically last for 20 minutes rather than hours.

75. e (Chapter 11)

Although the patient’s symptoms are somewhat nonspecific,
examination shows that he has normal language function but with
inability to perform certain actions described by the examiner.
“Apraxia” refers to the inability to perform a learned motor task and it is
typically caused by lesions in either the frontal or parietal lobe of the
(language) dominant hemisphere.

76. d (Chapter 2)
Xanthochromia is a yellow discoloration of the supernatant in a spun
sample of CSF. It signifies the presence of blood due to a subarachnoid
hemorrhage (if blood has been present for a few hours). In a traumatic
tap, the red cells precipitate, and the supernatant is colorless. Increased
opening pressure, increased white cell count, and pain upon needle
insertion may or may not be present in either condition. Increased red
cell count is seen both in a subarachnoid hemorrhage and in a traumatic
tap.

77. e (Chapter 2)
Although T1 and T2 images may detect blood breakdown products,
susceptibility imaging or gradient-echo imaging is the most sensitive
technique for determining the presence of intracranial hemorrhage.
Contrast-enhanced T1 is more useful for detecting the presence of a
brain tumor. Fluid-attenuated inversion recovery (FLAIR) imaging is
the single best MRI technique for screening for most types of
intracranial lesions, particularly demyelinating ones.

78. c (Chapter 13)

Rapid eye movement (REM) sleep behavior disorder often predates the
development of synucleinopathies by years or even decades. Examples
of synucleinopathies include Parkinson disease, Lewy body dementia,
and multiple system atrophy. Alzheimer disease, multiple sclerosis,
myasthenia gravis, and primary lateral sclerosis are not
synucleinopathies and are not associated with REM sleep behavior
disorder.

79. a (Chapter 14)

Of the vascular malformations, arteriovenous malformations are at the
greatest risk for bleeding, with a rate of bleeding of approximately 2%
to 3% per year. Capillary telangiectasias, cavernous hemangiomas, and
developmental venous anomalies are vascular malformations that
rupture much less frequently. The vein of Galen is a normal anatomic
structure.

80. b (Chapter 14)

The patient has a pure motor stroke involving the right hemibody.
Possible localizations for this syndrome include the left corona radiata,
left internal capsule, and the left side of the base of the pons. Infarction
of the motor cortex capable of producing a right hemiplegia would also
likely cause aphasia. Thalamic strokes produce more prominent sensory
deficits. The lateral medullary (Wallenberg) syndrome is associated with
ipsilateral ataxia, ipsilateral Horner’s syndrome, and ipsilateral facial
sensory loss, with contralateral impairment of pain and temperature in
the arm and leg, nystagmus, and vertigo; weakness is absent in a
Wallenberg syndrome because motor fibers travel more anteriorly
within the medulla. Cerebellar hemisphere infarctions produce limb
ataxia but not a dense hemiplegia.

81. b (Chapter 24)

DMD is associated with a marked elevation of the serum creatine kinase
(CK) level. BMD and limb-girdle muscular dystrophy are associated
with less markedly elevated CK levels. Myotonic dystrophy may be
associated with a normal CK or only mild elevation. Lambert–Eaton
myasthenic syndrome is a neuromuscular junction disorder, not
typically associated with elevations in CK levels.

82. b (Chapter 1)
The ability to walk in a steady, coordinated manner requires the
concerted functioning of multiple parts of the nervous system, including
motor pathways, sensory tracts, and the cerebellum, among other
systems. Testing for gait abnormalities is thus a sensitive way to detect
abnormalities in many different nervous system functions.

83. a (Chapter 3)
Locked-in syndrome (or a “de-efferented” state) that generally occurs
with large lesions in the base of the pons, such as infarcts from cardiac
embolism or basilar artery stenosis, is characterized by loss of all
significant motor function except eye blinking or perhaps vertical eye
movements, with preservation of awareness and cognitive function. A
large pontine lesion will typically affect corticobulbar and corticospinal
fibers bilaterally, but blinking and vertical eye movements are preserved
because of intact midbrain function.

84. d (Chapter 3)
Mannitol is an osmotic diuretic that can be used to lower increased ICP,
although the benefit may be transient. Lowering the head of the bed,
loading intravenous fluids, or decreasing the respiratory rate would raise
ICP. Basilar artery stenting is not an appropriate intervention for
increased ICP.

85. b (Chapter 12)

Dementia with Lewy bodies may be the second most common type of
dementing illness after Alzheimer disease. It is characterized by a
parkinsonian motor syndrome, visual hallucinations, and marked
fluctuations in alertness, as well as an exquisite sensitivity to
neuroleptic medications.

86. e (Chapter 12)

The two neuropathologic hallmarks of Alzheimer disease are amyloid
plaques and neurofibrillary tangles. The presence of Lewy bodies in the
substantia nigra suggests Parkinson disease and in cortical neurons
suggests dementia with Lewy bodies. Prominent atrophy of the caudate
is seen in Huntington disease. Spongiform changes in cortex suggest the
possibility of Creutzfeldt–Jakob disease.

87. a (Chapter 15)

The diagnosis of seizures is a clinical one. Except on the rare occasion
when a paroxysmal event is directly observed by the physician, the best
way to distinguish a seizure from other episodes of neurologic
dysfunction such as syncope, migraine, or transient ischemic attack is
by detailed characteristics obtained from the history. The other listed
choices may contribute to the diagnostic workup, but none is as
important as the history in making the diagnosis.

88. c (Chapter 21)

A CSF leukocytosis, elevated protein, and depressed glucose level form
the characteristic profile in acute bacterial meningitis. Viral
meningitides typically do not depress the CSF glucose. Fungal and
tuberculous meningitides can share a common profile with bacterial
meningitis except that the leukocytosis predominantly involves
lymphocytes rather than neutrophils (except initially).

89. c (Chapter 19)

The typical “butterfly” pattern is characteristic of glioblastoma
multiforme. There are other tumors that can cross white matter tracts,
such as lymphoma. The other options are very unlikely to produce this
radiologic pattern. Moreover, the usual location of meningiomas,
ependymomas, and schwannomas is not those found on this MRI.

90. d (Chapter 4)
Bitemporal visual field defects are seen in conditions affecting the optic
chiasm, such as suprasellar tumors. Lesions in the left optic radiation
produce a right homonymous hemianopia, and lesions of the right
occipital lobe a left homonymous hemianopia. Optic nerve lesions
produce unilateral visual field defects.

91. e (Chapter 6)
Sensory symptoms in the thumb can be related to median neuropathies
(as in a carpal tunnel syndrome) but also to higher lesions such as those
seen in a C6 radiculopathy. Lower trunk brachial plexopathy or C8 or
T1 radiculopathies would involve the fourth and fifth digits and intrinsic
muscles of the hand (including those innervated by the median nerve).
The fact that the EMG did not show median neuropathy at the wrist,
plus the history of radicular pain, makes a C6 or C7 radiculopathy the
most likely cause. Neuromuscular junction disorders do not present with
pain or sensory symptoms.
92. e (Chapter 22)
The patient appears to have an anterior spinal artery syndrome (ASAS),
a well-recognized complication of abdominal aortic surgery. The
anterior two-thirds of the spinal cord is perfused by the ASA, while the
posterior third (posterior columns) is perfused by posterior spinal
arteries. Therefore, the corticospinal and spinothalamic tracts are
affected in ASAS, but the posterior columns remain intact. Leg strength,
pinprick appreciation, and cold sensation should be impaired, whereas
joint position sense should be preserved (a dissociated sensory loss). A
sensory level should be present over the torso, reflecting a spinal cord
injury.

93. d (Chapter 23)

The patient has ascending weakness, and the preceding gastrointestinal
syndrome makes GBS likely. Other tests need to be considered to
confirm the diagnosis, but it is important to know the current respiratory
status before any other test, particularly because neck weakness may be
accompanied by diaphragm weakness. If the FVC is less than 15 mL/kg,
the patient should be transferred to the ICU and intubated. If the FVC is
normal, the patient should have frequent FVC checks early during the
hospitalization, because a rapid deterioration can occur. Steroids are not
a treatment option for Guillain–Barré, which is treated with intravenous
immunoglobulin or plasmapheresis.

94. c (Chapter 8)
This is a very characteristic history of BPPV. Typically, episodes of
vertigo are brief, lasting 10 to 30 seconds, with no symptoms in
between attacks. The absence of any other associated symptoms, the
normal neurologic examination, and the characteristic nystagmus when
the affected ear is closer to the ground during the Dix–Hallpike
maneuver, are distinguishing features. Ménière disease is associated
with tinnitus and hearing loss. A cerebellar stroke would not produce
recurrent positional symptoms and would likely be associated with other
neurologic deficits.

95. d (Chapter 10)

This history is very characteristic of giant cell (temporal) arteritis
(GCA). Other symptoms might include jaw claudication. Testing the
ESR and C-reactive protein and proceeding to temporal artery biopsy
are critical if the feared complication of blindness from an anterior
ischemic optic neuropathy is to be avoided. Migraine is very unlikely; it
would be a mistake to assume that a new headache in a 77-year-old
woman represents recurrence of an old problem. MRI and LP are of no
value in suspected GCA (although they may be helpful if the diagnosis
of GCA is ruled out).

96. b (Chapter 11)

The anomia (impaired naming) and reduced verbal fluency indicate the
presence of an aphasia (language disorder). The preservation of
repetition and comprehension points to a transcortical motor aphasia.
Wernicke’s aphasia should be associated with normal or increased
fluency. All aphasias impair naming to some degree. This patient’s
history is not consistent with a confusional state.

97. c (Chapter 18)

The rash on her shins likely represents erythema nodosum. Sarcoidosis
is one of the most common causes of bilateral LMN facial weakness,
especially in the African-American population.

98. e (Chapter 18)

Vitamin E deficiency may cause ataxia, myelopathy, and
polyneuropathy. Vitamin B12 deficiency may cause subacute combined
degeneration of the spinal cord and dementia.

99. e (Chapter 16)

Essential tremor is usually symmetric, present with posture and action,
may have a familial component, and improves with alcohol
consumption. Besides the tremor, the neurologic examination is
otherwise normal.

100. c (Chapter 11)

Aphasia is a language (not a speech) disorder. Apraxia is the inability to
carry out a learned motor task. Neglect is not a form of apraxia.
Agraphia is an inability to write.
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Schmutzhard E. Viral infections of the CNS with special emphasis on herpes simplex infections.
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van de Beek D, de Gans J, McIntyre P, et al. Steroids in adults with acute bacterial meningitis: a
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2017;3:170–171.
Li XY, Xiao HB, Pai P. Myelitis in systemic lupus erythematosus. J Clin Neurosci. 2017;44:18–
22.

CHAPTER 23
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American Association of Neuromuscular and Electrodiagnostic Medicine, and American
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England JD, Gronseth GS, Franklin G, et al., American Academy of Neurology. Practice
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biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of
Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and
American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72:177–184.
Koller HB, Kieseier C, Jander S, et al. Chronic inflammatory demyelinating polyneuropathy. N
Engl J Med. 2005;352:1343–1356.
van Alfen N, van Engelen BG. The clinical spectrum of neuralgic amyotrophy in 246 cases.
Brain. 2006;129(Pt 2):438–450.

CHAPTER 24
Dalakas MC. Inflammatory muscle diseases. N Engl J Med. 2015;372:1734–1747.
Emery AE. The muscular dystrophies. Lancet. 2002;359:687–695.
Sanders DB. Lambert-Eaton myasthenic syndrome: diagnosis and treatment. Ann N Y Acad Sci.
2003;998:500–508.
Vincent A, Palace J, Hilton-Jones D. Myasthenia gravis. Lancet. 2001;357:2122–2128.

CHAPTER 25
Colver A, Fairhurst C, Pharoah PO. Cerebral palsy. Lancet. 2014;383(9924):1240–1249.
Froehlich TE, Lanphear BP, Epstein JN, et al. Prevalence, recognition, and treatment of
attention-deficit/hyperactivity disorder in a national sample of US children. Arch Pediatr
Adolesc Med. 2007;161(9):857–864.
Moeschler JB, Shevell M; Committee on Genetics. Comprehensive evaluation of the child with
intellectual disability or global developmental delays. Pediatrics. 2014;134(3):e903–e918.
Rappley MD. Clinical practice. Attention deficit–hyperactivity disorder. N Engl J Med.
2005;352:165–173.
Spence SJ, Sharifi P, Wiznitzer M. Autism spectrum disorder: screening, diagnosis, and medical
evaluation. Semin Pediatr Neurol. 2004;11:186–195.
Vernon HJ. Inborn errors of metabolism: Advances in diagnosis and therapy. JAMA Pediatr.
2015;169(8):778–782.
 Index

Note: Page numbers followed by f and t indicates figures and tables respectively.

A
Abducens nerve root, 30f
Abducens nucleus, 30f
Abnormal gaits, 69t
Absence seizures, 124–125, 124f
ACA (anterior cerebral), 112
Acoustic neuroma, 59–60
Acquired muscle disorders
endocrine, 212
infectious, 211
inflammatory, 212
toxic, 211–212
Acute bacterial meningitis
clinical findings, 174
diagnostic workup, 175–176
etiology, 174–175
treatment, 176
Acute confusional state, 25
definition, 25
diagnostic evaluation, 25–26
differential diagnosis of, 25
treatment and prognosis, 26
Acute disseminated encephalomyelitis (ADEM)
clinical and radiologic manifestations, 170–171
diagnostic evaluation, 171
prognosis and treatment, 171
Acute dystonic reactions, 135
Acute onset, 67–68
AD. See Alzheimer disease
ADEM. See Acute disseminated encephalomyelitis
Agnosia, 94
AION (anterior ischemic optic neuropathy), 35
Airway, breathing, and circulation (ABC), 18
Akinetic-rigid gait, 69
Alcoholic cerebellar degeneration, 68
Alemtuzumab (Lemtrada), 169t
Alexia without agraphia, 94
Allodynia, 51
Alzheimer disease (AD), 99–101, 101t
Ambulation, 8
Amyloid PET imaging, 15
Aneurysm in circle of Willis, 118f
Anomia, 91
Anterior cerebral (ACA), 112
Anterior circulation, 115
Anterior ischemic optic neuropathy (AION), 35
Anterolateral system, 49, 50f
Antiphospholipid antibody syndrome (APS), 153
Antiseizure drugs, 128t
and pregnancy, 131
Aphasia
Broca aphasia, 91–93
conduction aphasia, 94
diagnosis, 91
disorders of written communication, 94
examination of language function, 93t
global aphasia, 94
mixed transcortical aphasia, 94
subcortical aphasias, 94
transcortical motor aphasia, 94
transcortical sensory aphasia, 94
Wernicke aphasia, 93
Aphemia, 94
Apperceptive agnosia, 95
Apraxia, 3, 94–95
APS (antiphospholipid antibody syndrome), 153
Argyll Robertson pupil, 34
Arnold Chiari malformation with syrinx, 194f, 195
Arousal disorders, 109
Arterial dissection, 116
Arteries of circle of Willis, 114f
Arteriovenous malformations (AVMs), 119
Asperger syndrome, 220
Associative agnosia, 94
Ataxia
acute onset, 67–68
alcoholic cerebellar degeneration, 68
autosomal dominant spinocerebellar ataxia, 68
diagnostic approach, 66
differential diagnosis of, 67, 67t
disorders, 66
episodic ataxia, 68
Friedreich ataxia, 68
of gait, 8
Ataxic hemiparesis, 116
Attention, 2
Atypical neuropathy, 202t
Aubagio. See Teriflunomide
Autism, 220
Autistic spectrum disorders, 219
clinical manifestations, 220
diagnostic evaluation, 220
treatment, 220
Autonomic dysfunction, 134
Autosomal dominant spinocerebellar ataxia, 68
AVMs (arteriovenous malformations), 119
Axonal neuropathies, 17t

B
Babinski sign, 7, 21
Bacterial infections
acute bacterial meningitis. See Acute bacterial meningitis
brain abscess. See Brain abscess
Ballism, 137
Bladder continence
anatomy and physiology, 72
classification, 74
control of bladder function, 73f
diagnostic evaluation, 72–73
neurogenic bladder, 74t
Bladder function, control of, 73f
Blepharospasm, 138
Blood testing, 22
Brachial plexus, 198, 199f
Brachial plexus anatomy, 44, 45f
Brain abscess, 176t
clinical findings, 176
diagnostic workup, 176–177
etiology, 176
presentation of, 177f
treatment, 177
Brain, contrast-enhanced computed tomographic scan of, 162f
Brain death, 24–25
clinical diagnosis of, 25
Brain ischemia
embolism, 114
systemic hypoperfusion, 114
thrombosis, 113–114
Brainstem dysfunction, 16
Brainstem lesion, 38
Brainstem reflexes, 19, 20t
Broca aphasia, 91–93
Brudzinski sign, 174, 174f
Bruxism, 109

C
Calculation ability, 3
Carbamazepine (Tegretol), 128t
Cardiac arrhythmias, 62–63
Carotid dissection, 116
Carotid hypersensitivity, 63
Caudal basilar pontine lesion, 30f
Central cord lesions, 192
Central (transtentorial) herniation, 145
Central nervous system empyema, 177
Central nervous system tumors
causes and genetics, 156–157
clinical features, 157
demyelinating diseases of, 165–170
diagnostic evaluation, 157
epidemiology, 156
primary brain tumors. See Primary brain tumors
secondary (metastatic) brain tumors, 162–163
Central pontine myelinolysis (CPM), 150
Central vertigo, 60
cerebral infarct or hemorrhage, 60–61
demyelinating lesions, 61
migraine, 61
Cerebellar ataxia, 68
symptoms and signs in, 67t
Cerebellar herniation, 10
Cerebellar lesion, 38
Cerebellar strokes, 67
Cerebral hemispheres and brainstem disorders
associated signs and symptoms, 48
differential diagnosis, 48
imaging studies, 48
pattern of weakness, 47, 47f
Cerebral herniation, 10
Cerebral hypotonia, 223
Cerebral infarct or hemorrhage, 60–61
Cerebral palsy (CP), 217
classification, 217
clinical manifestation, 217
diagnostic evaluation, 217
primitive reflexes, 219t
treatment, 218
Cerebral vasculitis, 87
Cerebrospinal fluid (CSF) analysis, 26
findings in common neurologic diseases, 11t
findings, interpretation of, 11t
interpretation of results, 10
safety, tolerability, and complications, 10–11
technique, 10
Cerebrovascular disease, 74
Cervicogenic headaches, 89
Channelopathies, 213
Charles Bonnet syndrome, 32–33
Chorea, 6, 137
Chronic migraine, 81
Circadian rhythms, 108
Clobazam (Onfi), 128t
Clonazepam, 138
Clumsy hand syndrome, 116
Cluster headache, 84, 84f
abortive treatments, 84
preventive treatments, 84
CMAP (compound muscle action potential), 16
CN III deficit, 36
CN IV deficit, 37
CNs. See Cranial nerves
CN VI deficit, 37–39
Color vision, 35
Coma
approach to, 19f
clinical approach, 18–19
definition, 18
differential diagnosis, 21–22
examination, 20–21
laboratory and radiologic studies, 22–23
treatment and prognosis, 23–24
Common ischemic stroke syndromes, 115
anterior circulation, 115
arterial dissection, 116
lacunar syndromes, 115–116
posterior circulation, 115
Complete cord transection, 192
Complex partial seizures, 25
Compound muscle action potential (CMAP), 16
Computed tomography and magnetic resonance imaging
clinical utility, 12–13
safety, tolerability, and complications, 13
technical considerations, 12
Concussion, 143
Conditions of note, 204–205
Conduction aphasia, 94
Conduction velocity, 16
Confusion, 25
Confusional arousals, 109
Congenital muscle disorders, 212
dystrophic
Duchenne and Becker muscular dystrophies, 213–214
Emery-Dreifus muscular dystrophy, 214
facioscapulohumeral muscular dystrophy, 214
limb-girdle muscular dystrophy, 214
myotonic dystrophy, 214
nondystrophic
channelopathies, 213
metabolic myopathies, 213
Conscious state, 24t
Constipation, 134
Conus and cauda equina lesions, 193
Conventional angiography, 14
Conventional cerebral angiogram, 14f
Coordination, 21
Coordination of limbs, 8
Copaxone. See Glatiramer acetate
Cortical (language) centers, 92f
Cranial nerves (CNs), 4–5, 4t, 20
Creutzfeldt-Jakob disease, 10
CSF analysis. See Cerebrospinal fluid analysis
CT angiography (CTA), 14
CT scanning, 13
Cystometry, 73
Cystourethroscopy, 73

D
Deep tendon reflexes, 7
Deep venous sinus thrombosis, 87f
Deficits, 2
Delirium, 25
Dementia
Alzheimer disease, 99–101
causes of, 99
clinical manifestations, 96
diagnostic evaluation, 96–97
epidemiology, 96
frontotemporal lobar degeneration, 102–103
human immunodeficiency virus, 104
Huntington disease, 103
Lewy body dementia (LBD), 102
metabolic causes of, 104
Parkinson disease, 103
prion-related diseases, 103–104
progressive supranuclear palsy, 103
vascular dementia, 101
Demyelinating diseases of central nervous system, 165
clinical course and prognosis, 167
clinical manifestations of, 165–166
diagnostic evaluation, 167–168, 168f
epidemiology of, 165
multiple sclerosis, 166t, 167f
pathology, 169
treatment, 169–170
Demyelinating lesions, 61
Demyelinating neuropathies, 17t
Demyelinating plaque, 168f
Depakote. See Valproic acid
Depressed consciousness, 23
 diffuse causes of, 22
structural causes of, 21
Dermatome, 197
Detrusor hyperreflexia, 74
Developmental venous anomalies (DVAs), 119
Diabetic neuropathies, 148, 202t
Diffuse axonal injury, 144, 144f
Diffusion-weighted imaging (DWI), 12
Dilantin. See Phenytoin
Dimethyl fumarate (Tecfidera), 169t
Diplopia, 32
Direct visualization of optic nerve, 3
Dissociated sensory loss, 52
Dix-Hallpike maneuver, 57, 57f
Dopamine transporter SPECT (DaT scan), 15
Dorsal columns, 49
Double vision, 32
Drowsiness, 18
Droxidopa, 63
Drug-induced movement disorders, 135–136
Duchenne and Becker muscular dystrophies, 213–214
DVAs (developmental venous anomalies), 119
DWI (diffusion-weighted imaging), 12, 13f
Dysarthria, 66, 116
Dysdiadochokinesia, 66
Dysdiadochokinesis, 8
Dysesthesias, 51
Dysmetria, 66
Dystonia, 137–138
DYT-TOR1A dystonia, 138

E
Edinger-Westphal nucleus (EWN), 28, 31f
EEG. See Electroencephalogram/electroencephalography
18-fluorodeoxyglucose positron emission tomography (FDG-PET) scans, 15
Electroencephalogram/electroencephalography
clinical utility, 15–16
frequencies, 15f
technique, 15
Electrographic seizures, 16
Electrolyte, mineral, and nutritional factors, 150
Electromyography (EEG), 23
clinical utility, 17
in neurogenic and myopathic disorders, 17t
technique, 16–17
Emery-Dreifus muscular dystrophy (EDMD), 214
Encephalopathy, 25
Endocrine dysfunction, 148–149
Ependymoma, 160
Epidural hematoma, 142, 142f
Epilepsy syndromes, 126t
Epileptic myoclonus, 138
Episodic ataxia, 68
Epley maneuver, 58f
Erythema migrans, 180f
Essential myoclonus, 138
Ethosuximide (Zarontin), 128t
Evoked potentials, 16
Extracranial Doppler sonography, 14
Extraocular movements, 3
Eye alignment, 35–36
Eyelid abnormalities, 33
Eye misalignment, 37t
terms used to define, 37
Eye movements, 38
abnormalities, 30f

F
Facial pain, 88
head and neck disorders, 89
trigeminal neuralgia, 89
Facial sensation, 49
Facial weakness, 180, 180f
Facioscapulohumeral muscular dystrophy (FSHD), 214
Fingolimod (Gilenya), 169t
First aid for seizures, 129–130
FLAIR (fluid-attenuated inversion recovery), 12
Fludrocortisones, 63
Fluid-attenuated inversion recovery (FLAIR), 12
Focal brain disorders, 25
Focal seizures, 122–123, 123f
characteristics of, 127t
with impaired awareness, 123–124
Focal signs, presence of, 21
Fortification spectrum, 81
Foster-Kennedy syndrome, 34–35
Friedreich ataxia (FRDA), 68
Frontal gait, 69
Frontal lobe function, 3
Frontal sinusitis, 177f
Frontotemporal lobar degeneration (FTLD), 102–103
Fundoscopy, 3
Fungal infections, 182–183
CNS signs of, 183t
cryptococcal meningitis, 183

G
Gabapentin (Neurontin), 128t
Gait ataxia, 8, 66
Gait disorders, 68–69
 akinetic-rigid gait, 69
frontal gait, 69
psychogenic gait, 69–70
sensory ataxia, 69
spastic gait, 69
waddling gait, 69
Gaits, abnormal, 69t
Ganglioglioma, 161
GCA (giant cell arteritis), 35, 87
GCS (Glasgow Coma Scale), 18, 145, 145t
Generalized motor seizures, 124
Generalized seizures
absence seizures, 124–125
generalized motor seizures, 124
Gerstmann syndrome, 95–96
Giant cell arteritis (GCA), 35, 87
Gilles de la Tourette syndrome, 139
Glasgow Coma Scale (GCS), 18, 145, 145t
Glatiramer acetate (Copaxone), 169t
Glioblastoma multiforme, 157–158
Gliomas, 157
Global aphasia, 94
Guillain-Barré syndrome, 41, 67

H
Headache
cluster. See Cluster headache
diagnosis, 78
features of, 80t
history, 78
management, opioids in, 85
migraine. See Migraine
neurologic exam, 79
short-lasting unilateral neuralgiform headaches. See Short-lasting unilateral neuralgiform
headaches
tension-type. See Tension-type headache
trigeminal autonomic cephalalgias, 83–84
Head imaging, 23
Head impulse test (HIT), 59f
Head trauma
computed tomographic scan of, 142f, 143f
epidemiology, 142
Glasgow Coma Scale, 145, 145t
herniation syndromes, 144
central (transtentorial) herniation, 145
subfalcine herniation, 145
uncal herniation, 145
increased intracranial pressure, 145–146
initial assessment of, 145
types of
 concussion, 143
diffuse axonal injury, 144, 144f
epidural hematoma, 142, 142f
postconcussion syndrome, 143–144
posttraumatic seizures and epilepsy, 144
subdural hematoma, 142–143, 143f
Hearing, 3
Hemangioblastoma, 161
Hemicord lesions, 192
Hemicrania, 85
abortive and preventive treatment, 85
Hemispheric syndromes, 96
Hereditary syndromes, 156t
Herniation syndromes, 144
central (transtentorial) herniation, 145
subfalcine herniation, 145
uncal herniation, 145
Histoplasma, 183
HIT (head impulse test), 59f
HIV-associated dementia, 184–185
Homunculus of motor strip, 47f
Horizontal gaze center, 30f
Horners syndrome (HS), 34
HSV encephalitis, 182f
Human immunodeficiency virus (HIV), 104
Huntington disease (HD), 103
clinical manifestations, 136–137
diagnostic evaluation, 137
pathology, 137
therapeutic strategies in, 134t
treatment, 137
Hyperesthesia, 51
Hyperventilation, 16
Hypoesthesia, 51
Hypoglycemia, 64
Hypothalamic fibers, 37f
Hypothyroidism, 149, 150
Hypovolemia, 62

I
Individual movements, power testing of, 6f
Indomethacin trial, 85
INO (internuclear ophthalmoplegia), 30f
Intention tremor, 66
Interferon beta-1a (Avonex), 169t
Interferon beta-1b (Betaseron), 169t
Interictal epileptiform, 16
Internuclear ophthalmoplegia (INO), 30f
Intracerebral hemorrhages, 86, 86f, 113, 116f
Intracerebral hypotension, 88
Intracranial hemorrhage, 22
intracerebral hemorrhage (ICH), 119
subarachnoid hemorrhage (SAH), 118, 118f
Intracranial hypotension, 88, 88f
Intracranial tuberculoma, 179
Intravenous immunoglobulin (IVIG), 67
Ischemic optic neuropathies, 35
IVIG (intravenous immunoglobulin), 67

J
Jerk nystagmus, 39

K
Keppra. See Levetiracetam
Kernig sign, 174, 174f
Ketogenic diet, 129
Korsakoff syndrome, 151

L
Labyrinthitis, 58
Lacosamide (Vimpat), 128t
Lacunar syndromes, 115–116
Lambert-Eaton myasthenic syndrome, 211
Lamictal. See Lamotrigine
Lamotrigine (Lamictal), 128t
Landau-Kleffner syndrome, 220
Language, 2
LBD (Lewy body dementia), 102
Lemtrada. See Alemtuzumab
Lethargyx, 18
Leukoencephalopathies, 171
Levetiracetam (Keppra), 128t
Lewy body dementia (LBD), 102
Lightheadedness, 62
autonomic causes, 63
cardiac arrhythmias, 62–63
hypovolemia, 62
metabolic causes, 64
postural tachycardia, 63–64
Limb-girdle muscular dystrophy, 214
LMN (lower motor neuron), 46f
Locked-in syndrome, 24
Lower motor neuron (LMN), 46f
Low-grade gliomas, 158–159
Lumbar puncture (LP), 10, 23, 41
optimal positioning, 10
radiologic contraindications to, 10
Lumbosacral plexus, 200f
anatomy, 44
Lumbosacral spine, 178f
Lyme disease, 179
clinical findings, 180
diagnostic workup, 180
serologic testing for, 181f
treatment, 180–181
Lyrica. See Pregabalin

M
Magnetic resonance angiography (MRA), 14, 14f
Magnetic resonance imaging (MRI), 12, 12f
Magnetic resonance spectroscopy, 15
Magnetic resonance venography (MRV), 14
Marchiafava-Bignami disease, 151
Marcus Gunn pupil, 34
MCA (middle cerebral arteries), 112
MCS (minimally conscious state), 24
Medial lemniscal system, 51f
Medial longitudinal fasciculus (MLF), 29, 30f
Medical Research Council (MRC) scale, 6, 6t
Medication overuse headache (MOH), 89
Medulloblastoma, 160–161, 160f
Memory, 2
Ménière disease, 58–59
Meningioma, 159–160
Meningitis
causes of, 175t
forms of, 175t
Menses, 81
Mental status
formal, 25
neurologic examination, 2–4
testing, 20
Metabolic causes, 64
Metabolic derangements, 64
Metabolic disorders, 150–151
Metabolic myopathies, 213
MFS (Miller Fisher syndrome), 67
Middle cerebral arteries (MCA), 112
Midodrine, 63
Migraine, 61
with aura, 81
chronic, 81
complications associated with, 81
and menses, 81
prophylaxis oral medications, 82t
status migrainosus, 81
stroke risk associated with, 81
without aura, 79–81
Migraine with brainstem aura, 61
Miller Fisher syndrome (MFS), 67
Minimally conscious state (MCS), 24
Miosis, 34
Mixed incontinence, 74
Mixed transcortical aphasia, 94
MOH (medication overuse headache), 89
Mononeuropathies, 10, 43, 203t
Motor exam, neurologic examination, 5–6
Motor tone, 20
Movement disorders
ballism, 137
drug-induced movement disorders, 135–136
dystonia, 137–138
Huntington disease. See Huntington disease
myoclonus, 138
Parkinson disease. See Parkinson disease
paroxysmal dyskinesias, 140
Stiff-person syndrome, 140
tics, 138–139
tremor, 136
Wilson disease, 139
Movements, 10, 43t
Multiple periventricular hyperdensities, 168f
Multiple sclerosis, 166t, 167f
clinical course of, 167f
clinical features of, 166t
treatment of, 169t
Muscles of mastication, 3
Muscle stretch reflexes, 7, 7f, 21, 44t
Myasthenia gravis, 208–210
Myoclonus, 138
Myotome, 197
Myotonic dystrophy, 214

N
Natalizumab (Tysabri), 169t
NCS. See Nerve conduction studies
Neglect, 2, 96
Nerve conduction studies (NCS)
clinical utility, 17
technique, 16–17
Nerve root disorders, 44
Nervous system
complications of HIV infection, 183–184
effects of alcohol on, 151t
Neurally mediated syncope, 63
Neurocysticercosis, 184, 185t
Neurogenic bladder, 74t
Neuroleptic malignant syndrome, 136
Neurologic examination, 1
commonly performed elements of, 3t
 coordination, 7
cranial nerves, 4–5
gait, 8
mental status, 2–4
motor exam, 5–6
patterns of sensorimotor abnormalities, 2t
principles, 1–2
reflexes, 7
sensory exam, 7–8
Neurologic manifestations, 148
diabetic neuropathies, 148
electrolyte, mineral, and nutritional factors, 150
endocrine dysfunction, 148–149
examples of, 149
of hypothyroidism, 150
metabolic disorders, 150–151
paraneoplastic phenomena, 152
rheumatologic diseases, 153
toxic metabolic encephalopathy, 153–154
toxins, 151
Neuromuscular junction (NMJ), 16
acquired muscle disorders. See Acquired muscle disorders
associated signs and symptoms, 42
describing, 208
differential diagnosis, 42
laboratory studies, 42
Lambert-Eaton myasthenic syndrome, 211
myasthenia gravis, 208–210
pattern of weakness, 42
Neuromyelitis optica (NMO), 171
Neurontin. See Gabapentin
Neuro-ophthalmology, 28
anatomy of visual paths, pupils, and oculomotor nerves, 28–31, 28f–30f
causes of visual loss, 36t
CN III deficit, 36
CN IV deficit, 37
CN VI deficit, 37–39
diplopia, 32
eye alignment and movements, 35–36
eyelid abnormalities, 33
eye misalignment, 37t
history of, 32
nystagmus, 38t
optic disc, 34–35
peripheral nystagmus, 39t
positive and negative visual phenomena, 32–33
pupil, 33–34
vision, 35
Neurophysiologic studies, 73
Nightmares, 109
NMJ. See Neuromuscular junction
NMO (neuromyelitis optica), 171
Nystagmus, 38t, 39, 57, 66

O
Obstructive sleep apnea (OSA), 109
Obtundation, 18
Ocrelizumab (Ocrevus), 169t
Ocrevus. See Ocrelizumab
Oculocephalic maneuver (doll’s eye test), 36
Oculomotor apraxia, 39
Olfaction, 3
Oligodendroglioma, 159
One-and-a-half syndrome, 30f
Onfi. See Clobazam
Optic disc, 34–35
Optic nerve function, 3
Orientation, 2
Orthostatic hypotension, 63
Orthostatic intolerance, 64
OSA (obstructive sleep apnea), 109
Otoliths, 36, 56–57
Overflow incontinence, 74
Oxcarbazepine (Trileptal), 128t

P
Palate elevation, 5
Papilledema, 34
Papillitis, 35
Paramedian pontine reticular formation (PPRF), 29
Paraneoplastic antibodies, 152t
Paraneoplastic cerebellar degeneration (PCD), 67
Paraneoplastic phenomena, 152
Parasitic infections of nervous system
neurocysticercosis, 184, 185t
toxoplasmosis, 183–184, 184f
Parasympathetic fibers, 28
Parasympathetic pathway, 31f
Paresthesias, 51
Parinaud syndrome, 38
Parkinson disease (PD), 8, 103
clinical manifestations, 133–134
epidemiology, 133
pathology, 133
pharmacologic treatment of, 135t
treatment, 134–135
Parkinsonian syndromes, 133t
Parkinsonism, 135
Paroxysmal dyskinesias, 140
Paroxysmal kinesigenic dyskinesia, 140
Paroxysmal nonkinesigenic dyskinesias, 140
Parsonage-Turner syndrome, 199
PCD (paraneoplastic cerebellar degeneration), 67
PCNSL (primary CNS lymphoma), 161
PD. See Parkinson disease
Pediatric autoimmune neuropsychiatric disorders, 139
Pediatric neurology
attention deficit-hyperactivity disorder, 224
autistic spectrum disorders. See Autistic spectrum disorders
cerebral palsy. See Cerebral palsy
chromosomal abnormalities, 220t
developmental delay, 219
developmental regression, 221
development and maturation, 217, 218t
hypotonia, 223–224
inherited neurodegenerative disorders, 222t
intellectual disability, 219
lysosomal disorders, 221–222
neurocutaneous disorders, 223
neurocutaneous syndromes, 223t
peroxisomal disorders, 222
Peripheral nerve diseases, 76
Peripheral nerve disorders
associated signs and symptoms, 43
commonly tested movements, 43t
differential diagnosis, 43
laboratory studies, 43
pattern of weakness, 43
Peripheral nerves and mono and polyneuropathies
anatomy and terminology, 201
diagnosis, 203–204
pathophysiology, 201
symptoms and signs, 201–202
Peripheral nerve ultrasound, 15
Peripheral nervous system (PNS), 1
Peripheral neuropathy, classification of, 201
Peripheral nystagmus, 39t
Peripheral vertigo, 56–57
acoustic neuroma, 59–60
medications, 60
Ménière disease, 58–59
vestibular neuritis and labyrinthitis, 58
Persistent vegetative state, 24
Phenobarbital, 128t
Phenytoin (Dilantin), 128t
Physiologic myoclonus, 138
Plexus and plexopathies
anatomy, 198–199, 199f, 200f
diagnosis, 200
pathophysiology, 199
 symptoms and signs, 200
Plexus disorders
associated signs and symptoms, 45
differential diagnosis, 45
laboratory studies, 45
pattern of weakness, 44–45
PMC (pontine micturition center), 72
PML (progressive multifocal leukoencephalopathy), 185–186
PNS (peripheral nervous system), 1
Polyneuropathy, 10
Polyradiculoneuropathy, 205t
Polyradiculopathy, 44
Polysomnography (PSG), 107–108
Pontine micturition center (PMC), 72
Postcentral cortex, 49
Postconcussion syndrome, 143–144
Posterior circulation, 115
Posterior cord (dorsal column) lesions, 193
Posterior reversible encephalopathy syndrome (PRES), 171
“Postganglionic” sympathetic fibers, 37f
Postinfectious cerebellitis, 67
Posttraumatic seizures and epilepsy, 144
Postural instability, 134
Postural tachycardia syndrome (POTS), 63–64
Posturing, 8, 21f
POTS (postural tachycardia syndrome), 63–64
Pott’s disease, 179
Power testing of individual movements, 6f
PPRF (paramedian pontine reticular formation), 29
Pregabalin (Lyrica), 128t
“Preganglionic” sympathetic fibers, 37f
PRES (posterior reversible encephalopathy syndrome), 171
Primary brain tumors
ependymoma, 160
ganglioglioma, 161
glioblastoma multiforme, 157–158
gliomas, 157
hemangioblastoma, 161
low-grade gliomas, 158–159
medulloblastoma, 160–161
meningioma, 159–160
oligodendroglioma, 159
primary CNS lymphoma, 161
schwannoma, 161
sellar and suprasellar tumors, 162
Primary CNS angiitis, 87
Primary CNS lymphoma (PCNSL), 161
Primary headache disorders, location of pain, 80f
Primary muscle disorders, 42
Primitive reflexes, 3
Prion-related diseases, 103–104
Progressive multifocal leukoencephalopathy (PML), 185–186, 186f
Progressive supranuclear palsy (PSP), 103
Prophylaxis, 101
Proprioception, 8
Prosopagnosia, 94
Pseudoathetosis, 66
PSG (polysomnography), 107–108
PSP (progressive supranuclear palsy), 103
Psychogenic gait, 69–70
Psychogenic nonepileptic seizures, 131
Ptosis, 33
Pupillary dilation, 37f
Pupillary dysfunction, 28
Pure motor lacune, 115
Pure sensory lacune, 116

R
Radiculopathy, 44
anatomy, 197
diagnosis, 198
pathophysiology, 197
symptoms and signs, 197–198
Radiofrequency (RF) pulses, 12
Rapid eye movement (REM) sleep, 107, 107f
Red flags, 79
Reflexes, 6
Relative afferent pupillary defect (RAPD), 34
REM (rapid eye movement) sleep, 107, 107f
REM sleep-related parasomnias, 109
Restless legs syndrome (RLS), 108–109
Retinal axons, 28
Rheumatologic diseases, 153
RLS (restless legs syndrome), 108–109
Romberg sign, 8
Root syndromes distribution of abnormalities, 198t

S
SAH (subarachnoid hemorrhage), 118, 118f
Sarcoidosis, 153
Schwannoma, 161
SE (status epilepticus), 129
Secondary angiitis, 87
Secondary (metastatic) brain tumors, 162–163
Secondary headache disorders, 85–86
infectious or inflammatory causes, 88
intracerebral pressure disorders, 88
medication causes, 88
neoplastic causes, 88
traumatic causes, 88
 vascular causes, 86–88
Second-order neurons, 28
Seizures
antiseizure drugs and pregnancy, 131
classification, 122
clinical manifestations
history, 126
physical examination, 126
diagnostic evaluation
brain imaging, 127
electroencephalography, 127–128
laboratory studies, 127
and driving, 131
epidemiology and etiologies, 125–126
epilepsy syndromes, 126t
first aid for, 129–130
focal seizures, 122–123, 123f
with impaired awareness, 123–124
generalized seizures
absence seizures, 124–125
generalized motor seizures, 124
management of status epilepticus, 130t
psychogenic nonepileptic seizures, 131
status epilepticus, 129
sudden unexpected death in epilepsy, 130–131
treatment
antiseizure drugs, 128t
drugs, 128–129
ketogenic diet, 129
surgery, 129
vagus nerve stimulation, 129
types of, 122t, 123f
unclassified, 125
unknown onset, 125
Sellar tumors, 162
Semicircular canals, 36
Sensorimotor abnormalities, localizing patterns of, 1, 2t
Sensorimotor lacune, 116
Sensory ataxia, 69
Sensory cortex, 52f
Sensory dermatomes, 53f
Sensory exam, 7–8
Sensory loss, patterns of, 54, 54t
Sensory system
anatomy of, 49, 50f, 51f, 52f
approach to patient with sensory loss, 52–54, 53f
examination of, 49–52
patterns of sensory loss, 54t
Sensory testing, 21
Sexual dysfunction
 anatomy and physiology, 75–77
causes of, 77
diagnostic evaluation, 77
treatment, 77
Short-lasting unilateral neuralgiform headaches, 84–85
abortive treatment, 85
preventive treatment, 85
Single-photon emission computed tomography (SPECT), 15
Single radiculopathies, 44
Sinusitis, 89
Sleep
apnea, 110
paralysis, 109
stages of, 107, 107f
terrors, 109
Sleep disorders, 107
arousal disorders, 109
circadian rhythms and, 108
physiology of, 107
polysomnography, 107–108
REM sleep-related parasomnias, 109
restless legs syndrome, 108–109
sleep apnea, 110
sleep-wake transition disorders, 109
Sleep-related dissociative disorders, 109
Sleep-wake transition disorders, 109
Somatosensory-evoked potentials (SSEPs), 16
Somnambulism, 109
Spasmodic dysphonia, 138
Spastic gait, 69
Spasticity, 47
Spinal cord
anatomy, 189–191
corticospinal tract from cortex, 190f
diagnostic tests, 195
injury, phases of, 47
posterior view of vertebral bodies, 190f
transverse section of, 190f
Spinal cord diseases, multiple sclerosis, 75
Spinal cord disorders
associated signs and symptoms, 47
differential diagnosis, 47
laboratory studies, 47
pattern of weakness, 45–46, 46f
Spinal cord dysfunction, 191
causes of, 193–195
Spinal cord syndromes, 192
central cord lesions, 192
complete cord transection, 192
conus and cauda equina lesions, 193
 hemicord lesions, 192
posterior cord (dorsal column) lesions, 193
Spinal epidural abscess
clinical findings, 177–178
diagnostic workup, 178
etiology, 178
treatment, 178
Spinothalamic tract (STT), 49
SSEPs (somatosensory-evoked potentials), 16
Status epilepticus (SE), 129
management of, 130t
Status migrainosus, 81
Sternocleidomastoid strength, 5
Stiff-person syndrome, 140
Strength, 5–6
Stress incontinence, 74
STT (spinothalamic tract), 49
Stupor, 18
Subarachnoid hemorrhage (SAH), 118, 118f
Subcortical aphasias, 94
Subdural hematoma, 142–143, 143f
Subfalcine herniation, 145
Sudden unexpected death in epilepsy (SUDEP), 130–131
Suprasellar tumors, 162
Supraspinal diseases
cerebrovascular disease, 74
Parkinson disease, 74–75
Sympathetic fibers, 28
Symptomatic myoclonus, 138
Syringomyelia, 192f
Systemic lupus erythematosus (SLE), 153

T
Tabes dorsalis, 193
Tardive dyskinesia (TD), 136
TCD (transcranial Doppler), 14
TD (tardive dyskinesia), 136
TE (time to echo), 12
Tecfidera. See Dimethyl fumarate
Tegretol. See Carbamazepine
Telangiectasias, 119
Temporomandibular joint disorder (TMD), 89
Tension-type headache
abortive treatments, 83
preventive treatments, 83
Teriflunomide (Aubagio), 169t
Thunderclap headache, 86
TIA (transient ischemic attack), 61
Tiagabine (Gabitril), 128t
Tics, 138–139
Time to echo (TE), 12
Time to repetition (TR), 12
TMD (temporomandibular joint disorder), 89
TME (toxic metabolic encephalopathy), 153–154
Tobacco-alcohol amblyopia, 151
Tone, abnormalities of, 5
Tongue protrusion, 5
Tonic (Adie) pupil, 34
Topiramate (Topamax), 128t
Torticollis, 138
Touch sensation, 49
Toxic metabolic encephalopathy (TME), 153–154
Toxins, 151
Toxoplasmosis, 183–184, 184f
TR (time to repetition), 12
Transcortical motor aphasia, 94
Transcortical sensory aphasia, 94
Transcranial Doppler (TCD), 14
Transient ischemic attack (TIA), 61
Tremor, 6, 136
Trigeminal autonomic cephalalgias (TACs), 83–84
Trileptal. See Oxcarbazepine
Truncal ataxia, 66
Tuberculosis
intracranial tuberculoma, 179
Pott’s disease, 179
tuberculous meningitis, 178–179
Tuberculous meningitis, 178–179
Tuberculous spondylitis, 179f
Tysabri. See Natalizumab

U
UMN (upper motor neuron), 46f
Uncal herniation, 145
Unclassified seizures, 125
Unilateral optic disc swelling, 35
Unknown onset seizures, 125
Upper motor neuron (UMN), 46f
Upside-down ptosis, 33
Urge incontinence, 74
Urinalysis, 25–26
Urinary dysfunction
bladder continence
anatomy and physiology, 72
classification, 74
control of bladder function, 73f
diagnostic evaluation, 72–73
neurogenic bladder, 74t
treatment, 75
Urinary incontinence, treatment of, 76t
V
Vacuolar myelopathy, 185
VA dissection, 116
Vagus nerve stimulation, 129
Valproate, 138
Valproic acid (Depakote), 128t
Vascular anatomy, 112, 113f
anterior circulation, 112
Vascular dementia, 101
Vascular disease
brain ischemia. See Brain ischemia
common ischemic stroke syndromes. See Common ischemic stroke syndromes
diagnostic evaluation, 116–117, 116f–117f
intracranial hemorrhage
intracerebral hemorrhage, 119
subarachnoid hemorrhage, 118, 118f
posterior circulation, 113, 114f
transient ischemic attack, 118
treatment, 117–118
vascular anatomy, 112, 113f
anterior circulation, 112
vascular malformations, 119
Vascular imaging studies, 14–15
Vascular malformations, 119
Vascular territories of brain, 113f
Vasovagal syncope, 63
Vertigo, 56
central vertigo. See Central vertigo
characteristics of causes of, 62t
peripheral vertigo. See Peripheral vertigo
Vestibular function, 3
Vestibular migraine, 61
Vestibular neuritis, 58
Vestibular schwannoma, 59–60, 60f
Vestibulo-ocular reflex (VOR), 36
Vibration, 8
Vimpat. See Lacosamide
Viral infections
encephalitis, 181–182
viral meningitis, 181
Zika virus, 182
Vision, 35
loss, 35
Visual acuity, 3
Visual fields, 3
Visual loss, causes of, 36, 36t
Visual pathways, 29f
Visual phenomena, positive and negative, 32–33
Visuospatial function, 3, 3f
Voluntary micturition, 72
VOR (vestibulo-ocular reflex), 36

W
Waddling gait, 69
Wallenberg (or lateral medullary) syndrome, 61
WD (Wilson disease), 139
Weakness, approach to
cerebral hemispheres and brainstem disorders. See Cerebral hemispheres and brainstem
disorders
differential diagnosis, 42
nerve root disorders. See Nerve root disorders
neuromuscular junction problems. See neuromuscular junction
peripheral nerve disorders. See Peripheral nerve disorders
plexus disorders. See Plexus disorders
primary muscle disorders. See Primary muscle disorders
principles, 40–41
spinal cord disorders. See Spinal cord disorders
Wernicke aphasia, 93
Wernicke encephalopathy, 151
Wilson disease (WD), 139
Writer’s cramp, 138

X
Xanthochromia, 10
Z
Zarontin. See Ethosuximide
Zonegran. See Zonisamide
Zonisamide (Zonegran), 128t