Oxford Textbook of Sleep Disorders.2017

Oxford Textbook of
Sleep Disorders

Oxford Textbooks in Clinical Neurology
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Oxford Textbook of
Sleep Disorders
Edited by
Sudhansu Chokroverty
Professor and Director of Sleep Research, Co-Chair Emeritus of Neurology,
JFK Neuroscience Institute, Edison, NJ, USA; Professor of Neuroscience,
Seton Hall University, South Orange, NJ, USA; Clinical Professor of Neurology,
Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Luigi Ferini-Strambi
Professor of Neurology, Vita-Salute San Raffaele University; Director of Sleep Disorder
Center, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
Series Editor
Christopher Kennard
1

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Preface
There have been rapid advances recently in basic science, technical, balanced, and easily readable book emphasizing sleep neurology as
clinical, and therapeutic aspects of sleep medicine that have capti- part of the Oxford Textbooks in Clinical Neurology (OTCN) series
vated sleep scientists and clinicians. Concomitantly, there has been a in conformity with the wishes of Professor Chris Kennard, editor of
rapid increase in the number of individuals involved in clinical sleep the new OTCN series.
medicine and sleep research, in addition to an explosive growth in the Most of the recent advances in sleep medicine have been cap-
number of sleep centers, laboratories, and programs and an increas- tured in this monograph, with special emphasis on sleep neurology.
ing number of sleep societies (national and international) and sleep The volume is essentially a clinical compendium, but also provides
medicine journals worldwide. There is an eagerness and increasing a background to the underlying basic science and techniques. The
desire to absorb this evolving knowledge about sleep and its disor- book is divided into 12 sections and several subsections: (1) Basic
ders. Therefore, there is a need for new books encompassing all this science; (2) Laboratory evaluation; (3) Clinical science: general
new knowledge. Despite the publication of a number of sleep-related introduction; (4) Hypersomnias; (5) Insomnias; (6) Circadian
books in the last few years, gaps remain in many areas. It is obvious rhythm disorders; (7) Sleep neurology; (8) Parasomnias; (9) Sleep
that there is a distinct lack of adequate knowledge and awareness of and medical disorders; (10) Sleep and psychiatric disorders; (11)
sleep disorders within the neurological community, and thus sleep Sleep in children, older adults, and women; (12) Miscellaneous
disorders are not dealt with adequately by most practicing neurolo- sleep-related topics.
gists. There are a few neurologically oriented short books available, This book is directed primarily at neurologists and senior train-
but these do not give in-depth coverage of the topic. It is therefore ees, as well as internists (especially those specializing in pulmonary,
an opportune moment to produce a volume in a succinct and lucid cardiovascular, gastrointestinal, renal, and endocrine medicine),
manner, covering the topic in a logical and orderly way and empha- general practitioners/family physicians, psychiatrists, psycholo-
sizing the practical aspects with an underlying basic science compo- gists, pediatricians, otolaryngologists, dentists, neurosurgeons,
nent. Peter Stevenson, Senior Commissioning Editor of Medicine, and neuroscientists, and others interested in understanding sleep
Neurology, Neurosurgery, Psychiatry, and Oxford Medical Libraries (eg, technologists, nurses, and other healthcare professionals). The
at Oxford University Press (OUP), Oxford, United Kingdom con- book should be useful to both beginners and those advanced in
tacted the Senior Editor (SC) to consider compiling such a book to the field.
fill these gaps, in collaboration with a co-editor from the European
continent. Professor Luigi Ferini-Strambi from Milan, Italy agreed
to be co-editor. We then proceeded to produce a comprehensive,

Acknowledgements
We must first thank all the contributors for their scholarly writings contents, making corrections, typing, and editing, in addition to
and their patience in waiting to see the volume finally in production her main function as editorial assistant to the journal. Since Ms.
after a long and protracted period (beyond our control). We also Bacala left, Ms. Jamie Winder, the current editorial assistant took
wish to thank all the authors, editors, and publishers for granting care of these functions. Last but not least, the senior editor must
us permission to reproduce illustrations, boxes, and tables that have express his love and gratitude to his wife, Manisha Chokroverty,
previously been published in other books and journals. We must MD for her unfailing and continued support, love, patience and
thank Peter Stevenson, the Senior Commissioning Editor of the tolerance throughout the long period of editing, writing, and proof-
Oxford Textbooks in Clinical Neurology series for his dedication, reading during the book’s production.
patience, and professionalism, and the editorial and production
staff at the Oxford University Press. The Senior Editor (SC) wishes
to thank Toni Bacala, the editorial assistant to the Sleep Medicine
journal, for her tremendous support in organizing the table of

Contents
Abbreviations xiii 9
Other sleep laboratory procedures
Contributors xix (MSLT, MWT, actigraphy) 81
Fabio Pizza and Carlo Cipolli
SECTION 1 10
Scoring guidelines for sleep-related
movements 89
Basic science Michela Figorilli, Monica Puligheddu,
1
Introduction to basic science 3 and Raffaele Ferri
James T. McKenna and Robert W. McCarley 11
Neuroimaging in normal sleep
2
An overview of sleep medicine: history, and sleep disorders 97
definition, sleep patterns, and architecture 7 Pierre Maquet and Julien Fanielle
Sudhansu Chokroverty and Sushanth Bhat
3
Neurobiology of REM sleep 15 SECTION 3
Pierre-Hervé Luppi, Olivier Clément, Clinical science: general
Christelle Peyron, and Patrice Fort introduction
4
Neuroanatomical, neurochemical, 12
Clinical sleep medicine: an introduction 107
and neurophysiological bases of Jennifer A. Liebenthal and
waking and sleeping 23 Christian Guilleminault
Barbara E. Jones
13
Classification of sleep disorders 109
5
The genetics of sleep 33 Michael Thorpy
Alexandra Sousek and Mehdi Tafti
6
Physiological changes in sleep 43 SECTION 4
Hypersomnias
14
Narcolepsy with cataplexy 119
SECTION 2 Gert Jan Lammers
Laboratory evaluation
15
Idiopathic hypersomnia, Kleine–Levin
7
Polysomnography: technique syndrome, and symptomatic
and indications 55 hypersomnias 131
Nic Butkov Michel Billiard and Yves Dauvilliers
8
Scoring of sleep stages, breathing, 16
Obstructive sleep apnea and upper
and arousals 71 airway resistance syndrome 145
Marco De Los Santos and Max Hirshkowitz Cristina Embid and Josep M. Montserrat

x contents
17
Positive airway pressure therapy 159 28
Sleep and epilepsy 279
Dirk Pevernagie Lino Nobili, Paola Proserpio, Steve Gibbs,
and Giuseppe Plazzi
18
Central sleep apnea and
hypoventilation syndromes 167 29
Autonomic dysfunction and
Mithri R. Junna, Bernardo J. Selim, sleep disorders 291
and Timothy I. Morgenthaler Giovanna Calandra-Buonaura and Pietro Cortelli
30
Neuromuscular disorders and sleep 301
SECTION 5 Katerina Sajgalikova, Erik K. St. Louis,
Insomnias and Peter Gay
19
Insomnias: classification, evaluation, 31
Sleep in other neurological
and pathophysiology 177 disorders—headache 313
Pradeep Sahota and Niranjan N. Singh
Simon D. Kyle and Colin A. Espie
32
Sleep after traumatic brain injury 325
20
Pharmacological and non-pharmacological
Christian R. Baumann
treatments of insomnia 189
Elisabeth Hertenstein, Christoph Nissen, 33
Sleep disorders in multiple sclerosis 327
and Dieter Riemann Luigi Ferini-Strambi and Sara Marelli
34
Sleep and dreams: a clinical
SECTION 6 neurological perspective 333
Circadian rhythm disorders Mark Solms
21
Shift work sleep disorder and jet lag 203 35
Neurological diseases and their effects
Vivek Pillai † and Christopher L. Drake on the sleep–wake cycle 345
Paul J. Reading
22
Advanced, delayed, free-running,
and irregular sleep–wake rhythm 36
Clinical and neurophysiological
disorders 215 aspects of fatigue 355
Guy Warman and Josephine Arendt Sushanth Bhat and Sudhansu Chokroverty
37
Role of positive pressure therapy
SECTION 7 on sleep disordered breathing and
cognition in the elderly 367
Sleep neurology Molly E. Zimmerman and Mark S. Aloia
23
Sleep-related movement disorders 227
Alessandro Gradassi and Federica Provini SECTION 8
24
Restless legs syndrome/Willis– Parasomnias
Ekbom disease 237
Luigi Ferini-Strambi and Sara Marelli 38
REM sleep behavior disorder 375
Ronald B. Postuma
25
An overview of sleep dysfunction
in Parkinson disease 245 39
NREM and other parasomnias 383
Elisaveta Sokolov and K. Ray Chaudhuri Caterina Ferri, Maria Turchese Caletti,
and Federica Provini
26
Sleep disorders in neurodegenerative
diseases other than Parkinson disease
and multiple system atrophy 255 SECTION 9
Raffaele Manni and Michele Terzaghi Sleep and medical disorders
27
Sleep and stroke 263 40
Sleep and the heart 395
Mark Eric Dyken, Kyoung Bin Im, Winfried J. Randerath and Shahrokh Javaheri
George B. Richerson, and Deborah C. Lin-Dyken

contents xi
41
Pulmonary disorders and sleep 409 SECTION 11
Sandrine H. Launois and Patrick Lévy Sleep in children, older adults,
42
Gastrointestinal functioning during sleep 415 and women
William C. Orr
49
Childhood sleep–wake disorders 459
43
Sleep in chronic renal insufficiency 419 Suresh Kotagal and Julie M. Baughn
Giorgos K. Sakkas and Christoforos D. Giannaki
50
Sleep in older adults 469
44
Sleep in endocrine disorders 423 Rosalia Silvestri
Axel Steiger
51
Sleep and its disorders in women 475
45
Sleep disturbances in critically Milena Pavlova
ill patients 429
Gerald L. Weinhouse
SECTION 12
46
Sleep and pain: interactions and Miscellaneous sleep-related topics
syndromes 433
Gilles J. Lavigne, Samar Khoury, 52
Violent parasomnias and sleep forensics 485
Caroline Arbour, and Nadia Gosselin Michel A. Cramer Bornemann and Mark R. Pressman
53
Morbidity, mortality, societal impact,
SECTION 10 and accident in sleep disorders 503
Sergio Garbarino
Sleep and psychiatric disorders
54
Sleep at high altitude and
47
Depression and anxiety disorders 443 during space travel 515
Susan Mackie and John W. Winkelman Yvonne Nussbaumer-Ochsner and Konrad E. Bloch
48
Sleep in other psychiatric disorders 451
Sara Dallaspezia and Francesco Benedetti Index 529

Abbreviations
5-HT 5-hydroxytryptamine (serotonin) BIPN bilateral isolated phrenic neuropathy

5-HT1, … serotonin receptors BMI body mass index
5-HTT serotonin transporter BP blood pressure
A adrenaline (epinephrine) BPAP bilevel positive airway pressure
AAP American Academy of Pediatrics BPSD behavioral and psychological signs of dementia
AASM American Academy of Sleep Medicine BRS baroreflex sensitivity
ABG arterial blood gas BSMI benign sleep myoclonus of infancy
ACE angiotensin-converting enzyme BZD benzodiazepine
ACh acetylcholine BZDRA benzodiazepine receptor agonist
AChR acetylcholine receptor CA central apnea
ACTH corticotropin (adrenocorticotropic hormone) CA confusional arousal
AD Alzheimer disease CAF central activation failure
ADA adenosine deaminase CAP cyclical alternating pattern
ADCADN autosomal dominant cerebellar ataxia, deafness, CBF cerebral blood flow
and narcolepsy CBT cognitive–behavioral therapy
ADH antidiuretic hormone CBTI cognitive–behavioral therapy for insomnia
ADHD attention-deficit hyperactivity disorder CBZ carbamazepine
ADL Activities of Daily Living CCHS congenital central alveolar hypoventilation
ADNFLE autosomal dominant nocturnal frontal syndrome
lobe epilepsy CDR Clinical Dementia Rating
AED antiepileptic drug CFS chronic fatigue syndrome
AHI apnea–hypopnea index CGI clinical global impression
AI apnea index CGRP calcitonin gene-related peptide
AI atonia index CHF chronic heart failure
AIDS acquired immunodeficiency syndrome CHF congestive heart failure
ALMA alternating leg muscle activation CI confidence interval
ALS amyotrophic lateral sclerosis CJD Creutzfeldt–Jakob disease
ALTE apparent life-threatening event CKD chronic kidney disease
AMD acid maltase deficiency CMD congenital muscular dystrophy
AMS acute mountain sickness CMS Centers Medicare and Medicaid Services
ANS autonomic nervous system CMS chronic mountain sickness
APAP autotitrating continuous positive airway pressure CMS congenital myasthenic syndrome
ARAS ascending reticular activating system CMT Charcot–Marie–Tooth disease
ArD arousal disorder CNS central nervous system
ASD autism spectrum disorder CNZ clonazepam
ASPD advanced sleep phase disorder COMT catechol- O-methyltransferase
ASV adaptive servo-ventilation COPD chronic obstructive pulmonary disease
ASV assisted support ventilation CPAP continuous positive airway pressure
ASWPD advanced sleep–wake phase disorder CPG central pattern generator
BALM Basic Language Morningness Scale CRC central respiratory chemoreceptor
BDNF brain-derived neurotrophic factor CRH corticotropin-releasing hormone
BF basal forebrain CRP C-reactive protein
Bic bicuculline CRSD circadian rhythm sleep disorder

xiv abbreviations
CRSWD circadian rhythm sleep–wake disorder FOSQ Functional Outcomes of Sleep Questionnaire
CSB Cheyne–Stokes breathing FOT forced oscillation technique
CSF cerebrospinal fluid FRC functional residual capacity
CSWS electrical status epilepticus during slow-wave FRSD free-running (non-24-hour) sleep disorder
sleep (continuous spike and wave during FSH follicle-stimulating hormone
slow-wave sleep) FSHD facioscapulohumeral muscular dystrophy
CTb cholera toxin b subunit FTD frontotemporal dementia
CV cardiovascular FVC forced vital capacity
CVD cardiovascular disease GABA γ-aminobutyric acid
CWP chronic widespread pain GAD glutamate decarboxylase
D1, … dopamine receptors GBP gabapentin
DA disorder of arousal GBS Guillain–Barré syndrome
DA dopamine GER gastroesophageal reflux
DAT dopamine transporter GERD gastro-esophageal reflux disease
dDpMe dorsal deep mesencephalic reticular nucleus GH growth hormone
DHE dihydroergotamine GHRH growth hormone-releasing hormone
DLB dementia with Lewy bodies GI gastrointestinal
DLCO diffusion capacity of carbon monoxide Gia alpha gigantocellular nucleus
DLMO dim light melatonin onset GiV ventral gigantocellular nucleus
DM dermatomyositis Glu glutamate
DM myotonic dystrophy (dystrophia myotonica) Gly glycine
DMD Duchenne muscular dystrophy GnRH gonadotropin-releasing hormone
DORA dual orexin receptor antagonist GTCS generalized tonic–clonic seizure
DPGi dorsal paragigantocellular nucleus HA histamine
DPS diaphragm pacing stimulation HACE high-altitude cerebral edema
DR dorsal raphe HAPE high-altitude pulmonary edema
DRG dorsal respiratory group HAPH high-altitude pulmonary hypertension
DSM Diagnostic and Statistical Manual of Mental Hcrt, hcrt hypocretin (orexin)
Disorders HCSB Hunter–Cheyne–Stokes breathing
DSPD delayed sleep phase disorder HD hemodialysis
DSPS delayed sleep phase syndrome HD Huntington disease
DSWPD delayed sleep–wake phase disorder HF high-frequency
DU duodenal ulcer HFLM high-frequency leg movements
DZ dizygotic HFpEF heart failure with preserved ejection fraction
EA epileptic activity HFT hypnagogic foot tremor
EAE experimental autoimmune encephalomyelitis HH hypnagogic hallucination
EDS excessive daytime sleepiness HHV human herpesvirus
EDSS Expanded Disability Status Scale HIV human immunodeficiency virus
EEG electroencephalography HLA human leukocyte antigen
EFM excessive fragmentary myoclonus HMSN hereditary motor and sensory neuropathy
EHS exploding head syndrome HPA hypothalamic–pituitary–adrenal
EMG electromyography HPS hypothalamic–pituitary–somatotropic
EOG electrooculography HR hazard ratio
EPAP expiratory positive airway pressure HR heart rate
EPSP excitatory postsynaptic potential HRQoL health-related quality of life
EQS excessive quantity of sleep HRV heart rate variability
ERP event-related potential HUTT head-up tilt test
ESES electrical status epilepticus during sleep HV hippocampal volume
ESRD end-stage renal disease IBS irritable bowel syndrome
ESS Epworth Sleepiness Scale ICD International Classification of Diseases
FAP fixed action pattern ICHD International Classification of Headache Disorders
FASPD familial advanced sleep disorder ICSD International Classification of Sleep Disorders
FASPS familial advanced sleep phase syndrome ICU intensive care unit
FCD focal cortical dysplasia IED interictal epileptiform discharge
FDG [18F]fluorodeoxyglucose IFN interferon
FFI fatal familial insomnia Ig immunoglobulin
FiO2 fraction of inspired oxygen IH idiopathic hypersomnia
FLEPS Frontal Lobe Epilepsy and Parasomnias Scale IL interleukin
fMRI functional magnetic resonance imaging ILD interstitial lung disease

abbreviations xv
IPAP inspiratory positive airway pressure NDRI norepinephrine (noradrenaline)–dopamine

IPN isolated phrenic neuropathy reuptake inhibitor
ipRGC intrinsically photoreceptive ganglion cell NFLE nocturnal frontal lobe epilepsy
IPSP inhibitory postsynaptic potential NIV noninvasive positive pressure ventilation
iRBD idiopathic REM sleep behavior disorder NLP no conscious light perception
IRLSSG International Restless Leg Syndrome Study Group NM nucleus basalis of Meynert
ISI Insomnia Severity Index NMDA N-methyl-D-aspartate
ISWRD irregular sleep–wake rhythm disorder NMO neuromyelitis optica
IVIg intravenous immunoglobulin NMS non-motor symptoms
JLD jet lag disorder NMSQuest Non-Motor Symptoms Questionnaire
JME juvenile myoclonic epilepsy NMSS Non-Motor Symptoms Scale
KLS Kleine–Levin syndrome NO nitric oxide
KSS Karolinska Sleepiness Scale NOA number of awakenings
LC locus coeruleus NOS not otherwise specified
LDT laterodorsal tegmental nucleus NPARM non-polyalanine repeat mutation
LEMS Lambert–Eaton myasthenic syndrome NPs nasal prongs
LES lower esophageal sphincter NREM non-rapid-eye-movement
LEV levetiracetam NRS nonrestorative sleep
LF low-frequency NSAID nonsteroidal anti-inflammatory drug
LGMD limb-girdle muscular dystrophy NTS nucleus tractus solitarius
LH lateral hypothalamus NYHA New York Heart Association
LH luteinizing hormone OA obstructive apnea
LKS Landau–Kleffner syndrome OAHI obstructive apnea–hypopnea index
LTG lamotrigine OCD obsessive–compulsive disorder
LV left-ventricular OCST out-of-center sleep studies
LVEF left-ventricular ejection fraction OHS obesity–hypoventilation syndrome
LVIDd left-ventricular internal diameter in diastole ONS occipital nerve stimulation
MA monoamine OR odds ratio
MAD mandibular advancement device OSA obstructive sleep apnea
MAO monoamine oxidase OSAS obstructive sleep apnea syndrome
MAOI monoamine oxidase inhibitor OXC oxcarbazepine
MCH melanin-concentrating hormone PA paroxysmal arousal
MCI mild cognitive impairment PACO2 alveolar partial pressure of carbon dioxide
MDD major depressive disorder PaCO2 arterial partial pressure of carbon dioxide
MDMA 3,4-methylenedioxymethamphetamine PaO2 arterial partial pressure of oxygen
MEMA middle ear muscle activity PAP positive airway pressure
MEP maximum expiratory pressure PARM polyalanine repeat mutation
MEP motor evoked potential PB phenobarbital
MG myasthenia gravis PCO2 partial pressure of carbon dioxide
MHA morning headache Pcrit critical closing pressure
MIBG meta-iodobenzylguanidine PD Parkinson disease
MIP maximal inspiratory pressure PDSS Parkinson’s Disease Sleep Scale
MMC migrating motor complex PE pulmonary embolism
MMSE Mini Mental State Examination PeF perifornical area
MnPN median preoptic nucleus peri-LCα peri-locus coeruleus alpha nucleus
MRI magnetic resonance imaging PET positron emission tomography
MRS magnetic resonance spectroscopy PFC prefrontal cortex
MS multiple sclerosis PFT pulmonary function tests
MSA multiple system atrophy PGO pontine–geniculate–occipital
MSLT multiple sleep latency test PH posterior hypothalamus
MT1, MT2 melatonin receptors PHT phenytoin
mTBI minor traumatic brain injury PIA pontine inhibitory area
MVC maximum voluntary contraction PIM/AIE psychobiological inhibition/
MWT maintenance of wakefulness test attention–intention–effort
MZ monozygotic PIP periorbital integrated potential
NA noradrenaline (norepinephrine) PLM periodic leg/limb movements
nAChR neuronal nicotinic acetylcholine receptor PLMD periodic limb movement disorder
NAVA neurally adjusted ventilatory assist PLMS periodic leg/limb movements during sleep
NC narcolepsy with cataplexy PLMSI PLMS index

xvi abbreviations
PLMW periodic leg/limb movements during wakefulness SCN suprachiasmatic nucleus

PM polymyositis SD sleep deprivation
PMR progressive muscle relaxation SDB sleep disordered breathing
PMS propriospinal myoclonus SE sleep efficiency
PnC pontis caudalis SEP somatosensory cortical evoked potential
PNE primary nocturnal enuresis Ser serotonin
PnO pontis oralis SF-36 36-Item Short Form Health Survey
PNS peripheral nervous system SFMM sleep-related faciomandibular myoclonus
PO2 partial pressure of oxygen sIBM sporadic inclusion-body myositis
POA preoptic area SIDS sudden infant death syndrome
POAH proptic nucleus of the anterior hypothalamus SLD sublaterodorsal nucleus
PPS postpoliomyelitis syndrome SLE systemic lupus erythematosus
PPT pedunculopontine SMA spinal muscular atrophy
PRM primidone SMR sensorimotor rhythm
PROM proximal myotonic myopathy SN substantia nigra
PrP prion protein SNA sympathetic neural activity
PS paradoxical sleep SNIP supine vital capacity nasal inspiratory pressure
PSG polysomnography SNP single nucleotide polymorphism
PSM propriospinal myoclonus SNRI serotonin and norepinephrine (noradrenaline)
PSP progressive supranuclear palsy reuptake inhibitor
PSQI Pittsburgh Sleep Quality Index SOL sleep onset latency
PST problem-solving therapy SooS sudden onset of sleepiness
PTSD post-traumatic stress disorder SOREMP sleep onset REM period
PTT pulse transit time SOREMS sleep onset REM sleep
PVDF polyvinylidene fluoride SPECT single-photon emission computed tomography
PVR peripheral vascular resistance SRBD sleep-related breathing disorder
PWS Prader–Willi syndrome SRED sleep-related eating disorder
QoL quality of life SRMD sleep-related movement disorder
R&K Rechtschaffen & Kales SSI Standard Shiftwork Index
rACC rostral anterior cingulate cortex SSRI selective serotonin reuptake inhibitor
RAM reward activation model SubC subcoeruleus nucleus
RBD REM sleep behavior disorder SUDEP sudden unexpected death in epilepsy
RBDSS RBD Severity Scale SUNCT short-lasting unilateral neuralgiform headache
rCBF regional cerebral blood flow with conjunctival injection and tearing
RCT randomized controlled trial SW sleepwalking
RDI respiratory disturbance index SWA slow-wave activity
REM rapid eye movement SWD shift work sleep disorder
RERA respiratory-effort-related arousal SWD sleep–wake disorder
RF reticular formation SWS slow-wave sleep
RFM rhythmic foot movement SXB sodium oxybate
RIA radioimmunoassay t-MHA tele-methylhistamine
RIP respiratory inductive plethysmography T&A tonsillectomy/adenoidectomy
RISP recurrent isolated sleep paralysis T2DM type 2 diabetes mellitus
RLP reduced light perception TAC trigeminal autonomic cephalalgia
RLS restless legs syndrome TBI traumatic brain injury
RMD rhythmic movement disorder Th thalamocortical
RMg nucleus raphe magnus TH tyrosine hydroxylase
RMMA rhythmic masticatory muscle activity THC Δ9-tetrahydrocannabinol
RSWA REM sleep without atonia TIA transient ischemic attack
rtPCR real-time polymerase chain reaction TLC total lung capacity
RV residual volume TMD temporomandibular disorder
RWA REM sleep without atonia TMN tuberomammillary nucleus
SAHS sleep apnea–hypopnea syndrome TMS transcranial magnetic stimulation
SaO2 arterial oxygen saturation TNF tumor necrosis factor
SB sleep bruxism TPM topiramate
SBD sleep-related breathing disorder TSH thyroid-stimulating hormone
SCA spinocerebellar ataxia TST total sleep time
SCD sickle cell disease TST total sleep time

abbreviations xvii
TTH tension-type headache VNS vagus nerve stimulation

UA upper airway VNTR variable number tandem repeat
UARS upper airway resistance syndrome VPA valproate
UES upper esophageal sphincter VPSG video-polysomnography
UPPP uvulopalatopharyngoplasty VRG ventral respiratory group
VBM voxel-based morphometry VTA ventral tegmental area
VC vital capacity W wake
vGlut2 vesicular glutamate transporter 2 WASM World Association of Sleep Medicine
vlPAG ventrolateral part of the periaqueductal WASO wake after sleep onset
gray matter WED Willis–Ekbom disease
VLPO ventrolateral preoptic nucleus ZI zona incerta

Contributors
Mark S. Aloia, National Jewish Health, Department of Medicine, Sudhansu Chokroverty, Professor and Director of Sleep Research,
Denver, CO, USA Co-Chair Emeritus of Neurology, JFK Neuroscience Institute,
Edison, NJ, USA; Professor of Neuroscience, Seton Hall
Caroline Arbour, Center for Advanced Research in Sleep University, South Orange, NJ, USA; Clinical Professor of
Medicine and Surgery Department—Trauma, Hospital of the Neurology, Rutgers Robert Wood Johnson Medical School,
Sacred Heart of Montreal, Montreal University, Montreal, New Brunswick, NJ, USA
QC, Canada
Carlo Cipolli, Department of Experimental, Diagnostic and
Josephine Arendt, Professor Emeritus Endocrinology, Faculty of Specialty Medicine (DIMES), University of Bologna,
Health and Medical Sciences, University of Surrey, Guildford, Bologna, Italy
Surrey, UK
Olivier Clément, Centre for Research in Neuroscience Lyon
Julie M. Baughn, Pediatric Pulmonary and Sleep Medicine, (CRNL), Universitè Claude Bernard Lyon 1, RTH Laennec
Department of Pediatrics, Sleep Disorders Center, Mayo Clinic, Faculty of Medicine, Lyon, France
Rochester, MN, USA
Pietro Cortelli, IRCCS, Institute of Neurological Sciences of
Christian R. Baumann, Department of Sleep Medicine, Bologna, Bellaria Hospital, Bologna, Italy; Department of
Department of Neurology, University Hospital Zurich, Biomedical and Neuromotor Sciences (DIBINEM), University
Switzerland of Bologna, Bologna, Italy
Francesco Benedetti, Department of Psychiatry and Clinical Michel A. Cramer Bornemann, Lead Investigator, Sleep
Neurosciences, Scientific Institute Ospedale San Raffaele, Forensics Associates, Minneapolis/Saint Paul, MN, USA; Director,
Milan, Italy Sleep Medicine Services, Olmsted Medical Center, Rochester, MN,
Sushanth Bhat, JFK Neuroscience Institute/Seton Hall University, USA; Visiting Professor, Sleep Medicine Fellowship, Minnesota
Edison, NJ, USA Regional Sleep Disorders Center, Hennepin County Medical
Center, Minneapolis, MN, USA
Michel Billiard, Sleep Disorders Center, Department of Neurology,
Gui de Chauliac Hospital, Montpellier, France Sara Dallaspezia, Department of Psychiatry and Clinical
Neurosciences, Scientific Institute Ospedale San Raffaele,
Konrad E. Bloch, Pulmonary Division and Sleep Disorders Center, Milan, Italy
University Hospital of Zurich, Zurich, Switzerland
Yves Dauvilliers, National Reference Center for Orphan
Nic Butkov, Education Coordinator, Asante Sleep Center, Diseases (Narcolepsy, Idiopathic Hypersomnia, Kleine–Levin
Medford, OR, USA Syndrome), Sleep Disorders Center, Department of Neurology,
Giovanna Calandra-Buonaura, IRCCS, Institute of Neurological Gui de Chauliac Hospital, Montpellier, France
Sciences of Bologna,Bellaria Hospital, Bologna, Italy; Marco De Los Santos, Sleep Medicine Chief Fellow, Baylor College
Department of Biomedical and Neuromotor Sciences of Medicine, Houston, TX, USA
(DIBINEM), University of Bologna, Bologna, Italy
Christopher L. Drake, Sleep Disorders and Research Center, Henry
Maria Turchese Caletti, Department of Biomedical and Ford Health System, Detroit, MI, USA
Neuromotor Sciences, University of Bologna, Bologna, Italy
Mark Eric Dyken, Professor of Neurology, Director, Sleep
K. Ray Chaudhuri, Professor of Movement Disorders, Lead, Disorders Center and Sleep Medicine and Clinical
National Parkinson Foundation Centre of Excellence, Neurophysiology Fellowship Programs, University of Iowa
King’s College London, UK Carver College of Medicine, Iowa City, IA, USA

xx contributors
Cristina Embid, Sleep Unit, Respiratory Department Hospital Shahrokh Javaheri, Sleep Physician, Sleep Center, Bethesda
Clinic, Barcelon, Spain; IDIBAPS. University of Barcelona, North Hospital, Professor Emeritus of Medicine, Pulmonary
CIBERES, Spain Diseases and Sleep, University of Cincinnati, Cincinnati,
Ohio, USA
Colin A. Espie, Sleep and Circadian Neuroscience Institute, Nuffield
Department of Clinical Neurosciences, University of Oxford, UK Barbara E. Jones, Professor, Department of Neurology and
Neurosurgery, Montreal Neurological Institute, McGill
Julien Fanielle, Cyclotron Research Centre and CHU Liège, University, Montreal, QC, Canada
Department of Neurology, University of Liège, Belgium
Mithri R. Junna, Assistant Professor in Neurology, Mayo Clinic
Luigi Ferini-Strambi, Professor of Neurology, Chair, Department Center for Sleep Medicine, Department of Neurology, Mayo
of Neurology OSR-Turro, Director, Sleep Disorders Center, Clinic, Rochester, MN, USA
Università Vita-Salute San Raffaele, Milan, Italy
Samar Khoury, Center for Advanced Research in Sleep
Caterina Ferri, Department of Biomedical and Neuromotor Medicine and Surgery Department—Trauma, Hospital of
Sciences, University of Bologna, Bologna, Italy the Sacred Heart of Montreal, Montreal University, Montreal,
Raffaele Ferri, President, Italian Association of Sleep Medicine, QC, Canada
Department of Neurology IC, Oasi Institute for Research on Suresh Kotagal, Division of Child and Adolescent Neurology,
Mental Retardation and Brain Aging (IRCCS), Troina, Italy Sleep Disorders Center, Mayo Clinic, Rochester, MN, USA
Michela Figorilli, Sleep Disorder Center, Department of Medical Simon D. Kyle, Sleep and Circadian Neuroscience Institute,
Sciences and Public Health, University of Cagliari, Monserrato Nuffield Department of Clinical Neurosciences, University of
(CA), Italy Oxford, UK
Patrice Fort, Centre for Research in Neuroscience Lyon (CRNL), Gert Jan Lammers, Neurologist and Clinical Neurophysiologist,
Universitè Claude Bernard Lyon 1, RTH Laennec Faculty of Somnologist, Department of Neurology, Leiden University
Medicine, Lyon, France Medical Center, Leiden, The Netherlands; Sleep Wake
Sergio Garbarino, Centre of Sleep Medicine, Department of Center SEIN, Stichting Epilepsie Instellingen Nederland,
Neuroscience, Rehabilitation, Ophthalmology, Genetics, The Netherlands
Maternal and Child Health, University of Genoa, Genoa, Italy Sandrine H. Launois, Somnology and Pulmonary Function Unit,
Peter Gay, Mayo Center for Sleep Medicine, Department of University Hospital Saint-Antoine, Paris, France
Medicine, Mayo Clinic and Foundation, Rochester, MN, USA Gilles J. Lavigne, Center for Advance Research in Sleep
Christoforos D. Giannaki, Department of Life and Health Sciences, Medicine and Surgery Department—Trauma, Hospital of the
University of Nicosia, Cyprus Sacred Heart of Montreal, Montreal University, Montreal,
QC, Canada
Steve Gibbs, C. Munari Center of Epilepsy Surgery, Centre of Sleep
Medicine, Department of Neuroscience, Niguarda Hospital, Patrick Lévy, Grenoble Alpes University, Grenoble, France;
Milan, Italy Grenoble Alpes University Hospital, Department of Physiology
and Sleep, Grenoble, France
Nadia Gosselin, Center for Advanced Research in Sleep Medicine
and Surgery Department—Trauma, Hospital of the Sacred Jennifer A. Liebenthal, Stanford University Sleep Medicine
Heart of Montreal, Montreal University, Montreal, QC, Canada Division, Stanford, CA, USA
Alessandro Gradassi, Department of Biomedical and Neuromotor Deborah C. Lin-Dyken, Clinical Associate Professor of Pediatrics,
Sciences, University of Bologna, Bologna, Italy Stead Family Department of Pediatrics, University of Iowa Roy J.
and Lucille A. Carver College of Medicine, Iowa City, IA, USA
Christian Guilleminault, Stanford University Sleep Medicine
Division, Stanford, CA, USA Pierre-Hervé Luppi, Centre for Research in Neuroscience Lyon
(CRNL), Universitè Claude Bernard Lyon 1, RTH Laennec
Elisabeth Hertenstein, Department of Clinical Psychology and Faculty of Medicine, Lyon, France
Psychophysiology, Center for Mental Disorders, Freiburg
University Medical Center, Germany Susan Mackie, Department of Internal Medicine, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA, USA;
Max Hirshkowitz, Professor (emeritus), Department of Medicine, Massachusetts General Hospital, Department of Psychiatry,
Baylor College of Medicine, Houston, TX, USA; Consulting Boston, MA, USA; Instructor in Medicine, Harvard Medical
Professor, Stanford University, School of Medicine, Division of School, Boston, MA, USA
Public Mental Health and Population Sciences, Stanford, CA
Raffaele Manni, Unit of Sleep Medicine and Epilepsy, C. Mondino,
Kyoung Bin Im, Assistant Professor of Neurology in the National Neurological Institute, Pavia, Italy
Department of Neurology Sleep Disorders Center, University
of Iowa Roy J. and Lucille A. Carver College of Medicine, Pierre Maquet, Cyclotron Research Centre and CHU Liège,
Iowa City, IA, USA Department of Neurology, University of Liège, Belgium

contributors xxi
Sara Marelli, Department of Neurology OSR-Turro, Sleep Disorders Mark R. Pressman, Sleep Medicine Services, Clinical Professor,
Center, Università Vita-Salute San Raffaele, Milan, Italy Lankenau Institute for Medical Research, Wynnewood, PA,
USA; Clinical Professor of Medicine, Jefferson Medical College,
Robert W. McCarley, Veterans Affairs Boston Healthcare Philadelphia, PA, USA; Adjunct Professor of Law, Villanova
System/Harvard Medical School, Department of Psychiatry, University, Philadelphia, PA, USA
Brockton, MA, USA
Paola Proserpio, C. Munari Center of Epilepsy Surgery, Centre
James T. McKenna, Veterans Affairs Boston Healthcare of Sleep Medicine, Department of Neuroscience, Niguarda
System/Harvard Medical School, Department of Psychiatry, Hospital, Milan, Italy
West Roxbury, MA, USA
Federica Provini, Department of Biomedical and
Josep M. Montserrat, Sleep Unit, Respiratory Department, Neuromotor Sciences, University of Bologna, Bologna, Italy;
Hospital Clinic, Barcelona, Spain; IDIBAPS, University of IRCCS, Institute of Neurological Sciences, Bellaria Hospital,
Barcelona, Spain; CIBERES, Spain Bologna, Italy
Timothy I. Morgenthaler, Chief Patient Safety Officer, Professor Monica Puligheddu, Sleep Disorder Center, Department of
of Medicine, Co-Director of the Mayo Clinic Center for Sleep Medical Sciences and Public Health, University of Cagliari,
Medicine, Division of Pulmonary and Critical Care Medicine, Monserrato (CA), Italy
Mayo Clinic, Rochester, MN, USA
Winfried J. Randerath, Professor of Medicine, University of
Christoph Nissen, Department of Clinical Psychology and Cologne, Clinic of Pneumology and Allergology, Center for
Psychophysiology, Center for Mental Disorders, Freiburg Sleep Medicine and Respiratory Care, Bethanien Hospital,
University Medical Center, Germany Solingen, Germany
Lino Nobili, C. Munari Center of Epilepsy Surgery, Centre of Sleep Paul J. Reading, Consultant Neurologist, Department of
Medicine, Department of Neuroscience, Niguarda Hospital, Sleep Medicine, The James Cook University Hospital,
Milan, Italy Middlesbrough, UK
Yvonne Nussbaumer-Ochsner, Pulmonary Division and Sleep George B. Richerson, Professor and Chairman, Neurology;
Disorders Center, University Hospital of Zurich, Zurich, Switzerland Professor, Molecular Physiology and Biophysics, The Roy J.
William C. Orr, President Emeritus, Lynn Health Science Institute, Carver Chair in Neuroscience, University of Iowa Roy J. and
Clinical Professor of Medicine, University of Oklahoma Health Lucille A. Carver College of Medicine, Iowa City, IA, USA
Sciences Center, Oklahoma City, OK, USA Dieter Riemann, Department of Clinical Psychology and
Milena Pavlova, Assistant Professor of Neurology, Harvard Medical Psychophysiology, Center for Mental Disorders, Freiburg
School Medical Director, BWFH Sleep and EEG Testing Center, University Medical Center, Germany
Department of Neurology, Brigham Health, Boston, MA, USA Pradeep Sahota, Professor and Chairman, Department of
Dirk Pevernagie, Sleep Medicine Centre, Kempenhaeghe Neurology, Director, Sleep Disorders Center, University of
Foundation, Heeze, the Netherlands; Department of Internal Missouri—School of Medicine, University of Missouri Health
Medicine, Faculty of Medicine and Health Sciences, University Care, Columbia, MO, USA
of Ghent, Ghent, Belgium Katerina Sajgalikova, Sleeping Laboratory, International Clinical
Christelle Peyron, Centre for Research in Neuroscience Lyon Research Center of St Anne’s University Hospital Brno
(CRNL), Universitè Claude Bernard Lyon 1, RTH Laennec (FNUSA-ICRC), Czech Republic
Faculty of Medicine, Lyon, France Giorgos K. Sakkas, Faculty of Sports and Health Sciences,
Vivek Pillai †,Sleep Disorders & Research Center, Henry Ford University of St Mark and St John, Plymouth, UK
Health System, Detroit, MI, USA Bernardo J. Selim, Assistant Professor in Medicine, Mayo Clinic
Fabio Pizza, Department of Biomedical and Neuromotor Sciences Center for Sleep Medicine, Division of Pulmonary and Critical
(DIBINEM), University of Bologna, Bologna, Italy; IRCCS Care Medicine, Mayo Clinic, Rochester, MN, USA
Istituto delle Scienze Neurologiche di Bologna, ASL di Bologna, Rosalia Silvestri, Associate Professor of Neurology, Sleep Medicine
Bologna, Italy Center, Department of Clinical and Experimental Medicine,
Giuseppe Plazzi, DIBINEM, Alma Mater Studiorum University Messina University, Italy
of Bologna, Bologna, Italy; IRCCS, Istituto delle Scienze Niranjan N. Singh, Associate Professor of Clinical Neurology,
Neurologiche, Bologna, Italy University of Missouri—School of Medicine, Columbia,
Ronald B. Postuma, Associate Professor, Department of MO, USA
Neurology, McGill University, Montreal General Hospital, Elisaveta Sokolov, Specialist doctor of neurophysiology,
Montreal, QC, Canada Kings College Hospital, London
† It is with regret that we report the death of Vivek Pillai during the Mark Solms, Department of Psychology, University of Cape Town,
preparation of this edition of the textbook Rondebosch, South Africa

xxii contributors
Alexandra Sousek, Department of Physiology, Faculty of Biology Guy Warman, Associate Professor, Department of Anaesthesiology,
and Medicine, University of Lausanne, Lausanne, Switzerland School of Medicine, Faculty of Medical and Health Sciences,
University of Auckland, Auckland, New Zealand
Erik K. St. Louis, Mayo Center for Sleep Medicine, Departments
of Medicine and Neurology, Mayo Clinic and Foundation, Gerald L. Weinhouse, The Division of Pulmonary and Critical
Rochester, MN, USA Care Medicine, Brigham and Women’s Hospital, Boston,
MA, USA
Axel Steiger, Max Planck Institute of Psychiatry, Munich, Germany
Mehdi Tafti, Department of Physiology, Faculty of Biology and John W. Winkelman, Massachusetts General Hospital,
Medicine, University of Lausanne, Lausanne, Switzerland Department of Psychiatry, Boston, MA, USA; Associate
Professor of Psychiatry, Harvard Medical School, Boston,
Michele Terzaghi, Unit of Sleep Medicine and Epilepsy, MA, USA
C. Mondino, National Neurological Institute, Pavia, Italy
Molly E. Zimmerman, Fordham University, Department of
Michael Thorpy, Director, Sleep–Wake Disorders Center, Psychology, Bronx, NY, USA
Montefiore Medical Center, and Professor of Neurology, Albert
Einstein College of Medicine, Bronx, NY, USA

SECTION 1
Basic science

CHAPTER 1
Introduction to basic science

James T. McKenna and Robert W. McCarley
Sleep disorders are increasingly recognized as a major public health NREM sleep electrographic characteristics are strikingly differ-
issue [1,2]. Sleep disorders of primary etiology include narcolepsy, ent than those of wake, since the cortical EEG slows in frequency (to
insomnia, sleep apnea, and restless leg syndrome. Recent clinical predominantly delta) as the overall amplitude increases. Although
attention has focused on sleep disturbance concomitant to psy- early studies assumed that sleep states were simply due to cessation
chiatric and neurological disease [3,4]. Furthermore, sleep loss of activity in arousal systems, more recent findings now indicate
due to vocational demands may attenuate attentional and cogni- that there are specific sleep-â•‰active brain regions. For example, the
tive processing, as well as producing dysfunctional physiologi- reticular nucleus of the thalamus is active during NREM sleep,
cal sequelae. Correspondingly, understanding of neural vigilance exhibiting phasic spindle activity (8–â•‰14 Hz) [13]. Also, select
state regulation—â•‰wake, rapid eye movement (REM) sleep, and GABAergic hypothalamic preoptic nuclei inhibit components
non-â•‰REM (NREM) sleep—â•‰has increased tremendously in the last of the ARAS, allowing transitions into NREM sleep [14,15] In
half-â•‰century owing to advances in basic research employing lesion- the “flip-â•‰flop switch” model of sleep–â•‰wake systems (see Fig. 1.2)
ing, pharmacological, electrophysiological, molecular, optogenetic, [14], histaminergic tuberomammillary nucleus (TMN), seroton-
chemogenetic, and calcium imaging techniques. The practitioner ergic dorsal raphe (DR), and noradrenergic locus coeruleus (LC)
should have a sound understanding of the neurobiology involved neurons are wake-â•‰active, and inhibit sleep-â•‰active ventrolateral
in sleep–â•‰wake regulation in order to effectively treat sleep-â•‰related preoptic (VLPO) GABAergic/â•‰galaninergic neurons during wake.
disorders. For example, understanding of the mechanism of action During sleep, VLPO neurons are active, inhibiting TMN, DR,
of the recently introduced hypnotic suvorexant depends on a and LC neurons. Furthermore, lateral hypothalamic orexinergic
knowledge of the orexin system and its projections and receptors. neurons stabilize the wake state by excitatory projections to the
This section of this volume, on basic science, therefore provides an TMN, DR and LC, and during sleep they are inhibited by VLPO
overview of the neurocircuitry and physiology involved and cites neurons.
key references. For a comprehensive review, see Brown et al. [5]â•„. REM sleep is also termed paradoxical sleep, since the cortical
As first described in the 1930s, vigilance states are defined by EEG exhibits low-â•‰amplitude, high-â•‰frequency activity similar to
the neuronal field activity recorded in the cortex by means of elec- that of wake. Unlike wake, though, little muscle tone or move-
troencephalography (EEG). [6–â•‰8]. In animal research, invasive ment occurs during this state. Other defining REM sleep char-
cortical and subcortical electrophysiological recordings may also acteristics beyond the EEG profile include brainstem neuronal
be utilized, such as single-â•‰unit and local field potential electrode spiking activity, muscle atonia, pontine–â•‰geniculate–â•‰occipital
recordings. During wake, the cortical EEG exhibits low-â•‰amplitude (PGO) waves, hippocampal theta-â•‰wave oscillations, and REMs.
activity with a prevalence of high frequency (theta, alpha, and McCarley and colleagues initially proposed the “reciprocal
gamma/â•‰beta). This electrical activity, indicative of arousal, is pro- interaction” model of the brain circuitry and neurotransmitters
duced by the various components of the ascending reticular acti- involved in the transition to and maintenance of the REM sleep
vating system (ARAS), as neural activity initiated in the brainstem state [16]. This model includes reactivation of cholinergic neu-
traverses the thalamus (dorsal node) and basal forebrain (ventral rons that are largely silent during NREM sleep, although sero-
node) to eventually promote cortical activation [9]â•„. These sub- tonergic and noradrenergic populations remain inactive. More
cortical ARAS nodes are largely responsible for the phasic oscil- recent investigations have defined specific REM sleep-â•‰active brain
latory activity evident during wake; for example, basal forebrain regions, including GABAergic neurons of the extended region
GABAergic parvalbumin neurons play a major role in promot- of the ventrolateral preoptic nuclei [17], GABAergic and gluta-
ing cortical gamma-â•‰band oscillatory activity important in cog- matergic neurons of the subcoeruleus (also termed the sublat-
nition and memory [10]. Numerous brain regions are involved erodorsal nucleus) and nucleus pontine oralis [18–â•‰20], as well as
in the ARAS, utilizing a number of neurotransmitters, including neurons containing melanin-â•‰concentrating hormone (MCH) that
acetylcholine, serotonin, norepinephrine (noradrenaline), hista- reside in the lateral hypothalamus [21]. Narcolepsy is a unique
mine, γ-â•‰aminobutyric acid (GABA), and glutamate (see Fig. 1.1) sleep disorder in which orexinergic neuronal dysfunction leads
[5,11,12]. In addition, neurons containing the neuropeptide orexin to symptoms including cataplexy, excessive daytime sleepiness,
(also known as hypocretin) and residing in the lateral hypothala- sleep paralysis, and sleep-â•‰onset REM periods [22]. Investigations
mus are anatomically connected to both wake-â•‰and sleep-â•‰active have concluded that disruption of orexinergic systems produces
neurons, and play a central role in the maintenance of wakefulness abnormal transitions between vigilance states, particularly from
(reviewed below). wake to REM sleep.

4 Section 1 basic science
Cortex
DR
Thalamus LDT
PPT LC
Basal Re
tic
ula
forebrain LH r for
ma
tio
n
TMN
Fig. 1.1 The ascending reticular activating system (ARAS) is responsible for the cortical activation indicative of wake. In the dorsal pathway (black), brainstem
glutamatergic reticular formation neurons, as well as serotonergic dorsal raphe (DR), noradrenergic locus coeruleus (LC), and cholinergic laterodorsal tegmental (LDT) and
pedunculopontine tegmental (PPT) neurons, project to the thalamus, which in turn innervates the cortex. In the ventral pathway (gray), these same brainstem regions
innervate the basal forebrain directly, or indirectly by means of projections to the GABAergic/histaminergic tuberomammillary nucleus (TMN) or orexinergic lateral
hypothalamus (LH). The basal forebrain in turn innervates widespread cortical regions. For a comprehensive review, see Brown et al. [5]‌.
Reproduced from Physiol Rev, 92(3), Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW, Control of sleep and wakefulness, pp. 1087–187, Copyright (2012), with permission from
The American Physiological Society.
As described by Borbély, sleep is modeled by the homeostatic

LH Orex
Wake in (+
) (process S) and circadian (process C) drives to sleep [23]. Process
S can be understood as the drive to sleep that is produced by the
tamine (–) TMN amount of time spent awake; that is, the more an organism stays
GABA/his
Serotonin (–) awake, the more it needs to sleep. Process C, the circadian drive,
VLPO DR consists of rhythms of behavior and physiology of an approxi-
Norepinephr
ine (–)
mately 24-hour periodicity. Circadian rhythms are controlled by
LC
environmental cues (zeitgebers), as well as endogenous neural
oscillators including the suprachiasmatic nucleus (SCN) of the
Sleep Wake hypothalamus. Melanopsin is a photosensitive molecule found
in retinal ganglion cells that project to the SCN, allowing direct
input from zeitgebers (eg, light) to endogenous oscillatory sys-
LH tems [24]. The SCN exhibits rhythmicity, driven by autoregula-
Sleep
tory loops involving period gene products (PER1 and PER2),
cryptochrome gene products (CRY1 and CRY2), and transcrip-
(–)
TMN
tion factors (CLOCK and BMAL1) [25,26]. Furthermore, the cir-
in
)
an
(–
anin
gal
gal DR cadian oscillation of BMAL1 is regulated by the orphan nuclear

BA/
/
BA
–)
GA nin ( receptors Rev-Erbα and the retinoid-related orphan receptor α
GA
BA /gala
GA (–) LC (Rora). Mutations in clock-related genes may contribute to cir-
alanin
GABA/g cadian rhythm sleep disorders (eg, advanced-and delayed-phase
VLPO disorders) [27–28].
Basic research studies have begun to describe the possible func-
Sleep Wake tions of sleep, including consolidation of learning and memory.
Consequences of sleep loss include attenuated attention, as well
Fig. 1.2 In the “flip-flop switch” model of sleep–wake transitions [14], as dysfunctions in mood, memory formation, and executive func-
GABAergic/histaminergic tuberomammillary (TMN), serotonergic dorsal raphe tion [29]. Some investigators have suggested that a function of sleep
(DR), and noradrenergic locus coeruleus (LC) neurons are wake-active, and inhibit is to allow a reversal of learning-related synaptic potentiation that
sleep-active ventrolateral preoptic (VLPO) neurons. VLPO neurons are active occurs during wake [30]. Others, though, argue that memory con-
during sleep, and inhibit TMN, DR, and LC neurons by means of GABAergic/ solidation occurs during both NREM and REM sleep by means of
galaninergic inhibitory projections. Orexinergic lateral hypothalamic neurons (LH)
synaptic potentiation that accompanies fast oscillatory wave activ-
provide stabilization of wake by means of projections to the TMN, DR, and LC,
and are inhibited by VLPO neurons during sleep. ity. For example, hippocampal theta activity during REM sleep may
Reproduced from Trends Neurosci., 24(12), Saper CB, Chou TC, Scammell TE, The sleep switch: promote synaptic potentiation integral for memory formation [31].
hypothalamic control of sleep and wakefulness, pp. 726–31, Copyright (2001), with permission Also, hippocampal slow-wave/spindle/ripple coupling during
from Elsevier. NREM sleep may allow consolidation of memory and promote

Chapter 1 introduction to basic science 5
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CHAPTER 2
An overview of sleep medicine

History, definition, sleep
patterns, and architecture
A brief history of sleep medicine phenotype could be created by mutation of hypocretin 2 recep-
tors (HCTR2) [11] and that a similar phenotype could be created
The importance of sleep is well recognized today, among both the in prepro-â•‰hypocretin knockout and transgenic mice [12,13]. The
academic and clinical communities. Advancements and refine- documentation of decreased hypocretin 1 in cerebrospinal fluid
ment of functional neuroimaging have led to the ability to map in humans [14] and of decreased hypocretin neurons in the lateral
various areas of the brain in different stages of sleep, and neu- hypothalamus at autopsy [15–â•‰17] in human narcolepsy patients
rophysiological techniques have allowed researchers to study added clinical significance to previous research.
changes at the cellular level. However, the history of research into
the mechanisms of sleep is one of fits and starts. The dawn of mod-
ern sleep medicine can be traced back to the identification of the Definition of sleep
different electroencephalography (EEG) stages of sleep by Loomis Research has led to the realization that sleep is not simply an
and colleagues in 1937 [1]â•„. Rapid eye movement (REM) sleep was absence of wakefulness and perception, nor is it just a suspension
described in 1953 by Aserinsky and Kleitman [2], and the first of sensorial processes, but is a result of a combination of a passive
identification of loss of muscle tone in REM sleep, or REM ato- withdrawal of afferent stimuli to the brain and functional activation
nia, soon followed [3]. The standardization of what would become of certain neurons in selective brain areas.
the science of polysomnography (PSG) began when Rechtschaffen Distinguishing normal physiological sleep from pathological
and Kales (4) produced the standard sleep scoring technique states of decreased or absent consciousness, such as coma, mini-
monograph in 1968 (the R-â•‰K scoring technique), which for sev- mally conscious state, and persistent vegetative state (unresponsive
eral decades remained the gold standard. Today, the scoring rules wakefulness syndrome), is instructive in determining the under-
published in the American Academy of Sleep Medicine (AASM) lying mechanisms of sleep. Pathological states of decreased con-
Manual for the Scoring of Sleep and Associated Events [5] are uni- sciousness all differ significantly from sleep in a number of ways.
versally accepted in clinical sleep medicine and in sleep research Consciousness requires two components: awareness (a function of
(see Chapter 11). The clinical community began to take notice of the cerebral cortex) and arousal (a function of the ascending reticu-
sleep medicine when obstructive sleep apnea (OSA) was found to lar activating system). Sleep is always reversible, whereas, depend-
be a common cause of cardiovascular morbidity and mortality, as ing on the underlying cause, this is not the case with pathological
well as a significant cause of impairment of quality of life [6,7]. states of decreased consciousness. Brain metabolism and circula-
The identification of continuous positive airway pressure (CPAP) tion, which show marked depression and impairment in pathologi-
devices as safe, effective, noninvasive means to dramatically relieve cal states of decreased consciousness, show only slight alterations
OSA-â•‰related symptoms [8] jump-â•‰started modern sleep medicine in sleep. Indeed, in some stages of sleep, particularly REM sleep,
practice and led to the proliferation of sleep laboratories through- the brain is as metabolically active as it is in wakefulness, which is
out the world. Since then, several new intervention techniques, not so in pathological states of decreased consciousness. The EEG
including dental appliances, tongue-â•‰retaining devices, surgical in sleep shows an orderly progression from wakefulness to light
procedures, nasal end-â•‰expiratory devices, and hypoglossal nerve sleep, deep sleep, and REM sleep, cycling throughout the night,
stimulators have become available as alternatives to CPAP treat- whereas patients in pathological states of decreased consciousness
ment in selected populations, making the field of sleep medicine almost always have slow disorganized abnormal backgrounds with
truly multidisciplinary. Another seminal moment in the history lack of well-â•‰organized sleep architecture or progression of stages.
of sleep medicine occurred when two independent groups of Ultimately, the distinction between sleep and pathological states of
researchers contemporaneously identified a pair of neuropeptides, decreased consciousness is made on both neurophysiological (i.e,
hypocretin 1 and 2 (orexin A and B) in the lateral hypothalamus EEG, electrooculography (EOG), and electromyography (EMG})
and perifornical regions [9,10]. In the years that followed, the and clinical (i.e, behavioral) grounds. Table 2.1 and Table 2.2 list
mechanisms underlying narcolepsy were better defined by pivotal the behavioral and physiological criteria for wakefulness and vari-
research that showed that a canine model of the human narcolepsy ous stages of sleep.

Table 2.1 Behavioral criteria for wakefulness and sleep is essential for optimal cognitive functioning, research data have
provided discordant findings. Memory reinforcement with consoli-
Criterion Awake NREM sleep REM sleep dation has been demonstrated to take place during REM sleep [23],
and hippocampus-dependent memories (declarative memories)
Posture Erect, sitting, Recumbent Recumbent
benefit primarily from slow-wave sleep [24]. Sleep spindle activ-
or recumbent
ity has been demonstrated to correlate with cognitive abilities and
Mobility Normal Slightly reduced Moderately reduced learning [25]. Yet, some studies have shown that individuals with
or immobile; or immobile; brainstem lesions with elimination of REM sleep or those on anti-
postural shifts myoclonic jerks
depressant medications suppressing REM sleep exhibit no apparent
Response to Normal Mildly to Moderately reduced cognitive deficits [26,27].
stimulation moderately to no response Thermoregulation also appears to be an important function of
reduced sleep; thermoregulatory homeostasis is maintained during sleep,
Level of Alert Unconscious but Unconscious but whereas severe thermoregulatory abnormalities follow total sleep
alertness reversible reversible deprivation [28]. The preoptic anterior hypothalamic neurons par-
Eyelids Open Closed Closed ticipate in thermoregulation and NREM sleep. These two processes
are closely linked by preoptic anterior hypothalamic neurons, but
Eye Waking eye Slow rolling eye Rapid eye
are clearly separate. Thermoregulation is maintained during NREM
movements movements movements movements
sleep but suspended during REM sleep, when, owing to a loss of
thermosensitivity in the preoptic anterior hypothalamic neurons,
thermoregulatory responses such as shivering, piloerection, pant-
Theories of the function of sleep ing, and sweating are impaired.
Sleep is an essential biological function, but its exact function
remains unclear. Despite great strides in research into sleep, the The glymphatic system
answers to fundamental questions such as what sleep is and why it A recent discovery in the CNS of mice of a new metabolic waste-
occurs remain tantalizingly elusive. Sleep deprivation is clearly det- clearing pathway (equivalent to the lymphatic system in the body),
rimental; it has been experimentally demonstrated that sleep depri- termed the “glymphatic system” because of its dependence on
vation causes daytime sleepiness and impairment of performance, glial cells (astrocytes) performing a “lymphatic”-like cleansing of
vigilance, attention, mood, concentration, and memory [18], as the brain interstitial fluid in the perivascular space between the
well as metabolic, hormonal, and immunological effects, as dis- brain blood vessels and leptomeningeal sheathes surrounding
cussed in later sections of this chapter. these vessels. In sleep, the glial cells shrink and the extracellular
Sleep appears to engender an anabolic state; there is increased pace expands, promoting clearance of interstitial waste products
secretion of anabolic hormones (eg, growth hormone, prolactin, (Fig. 2.1). Furthermore, it appears that the ability of this system to
testosterone, and luteinizing hormone) and decreased levels of cat- remove misfolded or aggregated proteins (demonstrated experi-
abolic hormones (eg, cortisol) during sleep. Cerebral protein and mentally by injection of labeled β-amyloid proteins into the brains
nucleic acid synthesis is enhanced by sleep [19]. During non-REM
(NREM) sleep, brain metabolism and cerebral blood flow decrease,
whereas during REM sleep, the level of metabolism is similar to that
of wakefulness and the cerebral blood flow increases. Nevertheless,
sleep may represent an energy-saving process; overall reductions
in general metabolism, including metabolic heat production, low-
ering of core body temperature, and certain behavioral signs (eg,
immobile posture minimizing heat exchange), conserve energy.
Some researchers have suggested that a primary function of sleep
is the maintenance of synaptic and neuronal network integrity and
synaptic reorganization [20–22]. While it is generally held that sleep
Table 2.2 Physiological criteria for wakefulness and sleep
Criterion Awake NREM sleep REM sleep

Electroence Alpha waves; Synchronized Theta or
phalography desynchronized sawtooth waves; Fig. 2.1 An illustration of the glymphatic system, depicting the physiological
desynchronized differences in cerebrospinal fluid (CSF) flow between the awake and the sleeping
brain of mice. The tissue perfused by CSF is correlated with CSF influx. and blood
Electromyography Normal Mildly reduced Moderately to
vessels are indicated in shaded (arteries) and white (veins). The extracellular
(muscle tone) severely reduced (interstitial) space in the cortex of the mouse brain, through which CSF moves,
or absent increases from 14% in the awake animal to 23% in the sleeping animal, an increase
Electro- Waking eye Slow rolling eye Rapid eye that allows the faster clearance of metabolic waste products.
oculography movements movements movements Reproduced from Science, 342(6156), Herculano-Houzel, S., Sleep It Out, pp. 316–317,
Copyright (2013), with permission from AAAS.

Chapter 2 an overview of sleep medicine: history, definition, sleep patterns, and architecture 9
Table 2.3 Summary of NREM and REM sleep states REM sleep. It is important to be aware of these facts because certain
abnormal motor activities (NREM parasomnias like sleepwalking,
Sleep state % sleep time night terrors, and confusional arousals) are characteristically asso-
ciated with SWS and therefore occur in the first third of the night,
NREM sleep 75–80
and others (REM parasomnias like REM behavior disorder) occur
N1 3–8 in the last third of the night, i.e, early morning.
N2 45–55 A hypnogram (Fig. 2.2) is a graphical representation of the events
that occur during a sleep session as recorded during PSG. In addi-
N3 15–23
tion to sleep stages, it typically depicts respiratory events, motor
REM sleep 20–25 events, arousals, and position, and allows for a quick screening for
Tonic stage — abnormalities.
Phasic stage — Sleep stages
The scoring criteria for wakefulness and various stages of sleep
depend on EEG, EMG, and EOG recordings, and are described in
of sleeping and awake mice) is hampered. Although these findings detail in Chapter 10. The following subsections provide only a brief
have yet to be replicated in humans, they may play a role in drug overview of normal sleep architecture.
development to prevent or halt the progression of these neurode-
generative diseases such as Alzheimer disease, Parkinson disease, NREM sleep
and others [29–33]. NREM sleep accounts for 75–80% of sleep time in an adult human.
According to the AASM Scoring Manual [5]‌, NREM sleep is fur-
ther subdivided into three stages (N1, N2, and N3), primarily on
Normal sleep architecture the basis of EEG criteria. Stages N1 and N2 are generally referred
Sleep is divided into NREM and REM sleep (Table 2.3). During a to as “light sleep,” and stage N3 as “deep sleep” or slow-wave
night of normal sleep, NREM and REM sleep alternate in a cyclic sleep (SWS). Stage N1 sleep occupies 3–8% of total sleep time, N2
manner, with 4–6 cycles occurring per night, each cycle lasting on 45–55%, and N3 15–23%. As a subject passes from wakefulness
an average from 90–110 minutes. The first two cycles are dominated to stage N1, which is essentially a transitory phase into deeper
by slow-wave sleep (SWS) (stage N3 sleep, see below); subsequent stages of sleep, the posterior dominant rhythm (usually in the
cycles contain less or no SWS. In contrast, REM increases as the alpha range of 8–13 Hz) slows, becomes less well defined, and ulti-
night progresses, with each REM sleep episode becoming longer mately disappears to be replaced by poorly organized low-voltage
than the one preceding it; the longest REM sleep episode toward mixed frequencies, predominantly theta rhythms (4–7 Hz) and
the end of the night may last for an hour. Thus, in normal human beta waves. EMG activity decreases slightly, slow lateral eye move-
adult sleep, the first third is dominated by SWS and the last third by ments (SLEMs) appear, and vertex sharp waves are noted. Stage
Fig. 2.2 Hypnogram from the polysomnogram of a 35-year-old male patient referred to the sleep laboratory for possible sleep apnea. The hypnogram is a graphical
representation of the night’s events. From top to bottom, this hypnogram represents sleep stages, arousals, leg movements, respiratory events, pulse oximetry, heart rate,
and oxygen desaturations over time. Hypnograms provide quick, informative snapshots of the entire sleep study that aid in clinical decision making.

N2 begins approximately 10–12 minutes after stage N1. Sleep spin- sleep, and scattered apneas and hypopneas are not uncommon.
dles and K-complexes herald the onset of stage N2 sleep. Towards Sawtooth waves are EEG trains of sharply contoured, often ser-
the end of each cycle of stage N2 sleep, the EEG may show theta rated, 2–6 Hz waves, usually with rapid ascent and slow descent,
waves and slow waves (0.5–2 Hz) that occupy less than 20% of the seen maximally over the central regions, and are thought to be
epoch. Stage N3 sleep begins about 30–60 minutes after the onset the gateway to REM sleep, often preceding a burst of REMs. PIPs
of stage N2. Slow waves comprise 20–100% of each epoch of stage are seen during REMs (Fig. 2.4), but not all REMs are accompa-
N3. Both eye and body movements normally decrease and nearly nied by PIPs.
disappear as a subject progresses from light sleep to deep sleep. Sleep macrostructure (eg, sleep states and stages, sleep cycles,
However, with the use of certain antidepressant medications (tri- sleep latency and efficiency, and wakefulness after sleep onset) may
cyclic antidepressants, selective serotonin reuptake inhibitors, and be modified by a number of endogenous and exogenous factors
monoamine oxidase inhibitors), mixtures of slow lateral eye move- (Box 2.1).
ments and rapid eye movements may occur late into stage N2 and
sometimes N3 sleep; these are colloquially known as “Prozac eyes”
(Fig. 2.3). Cyclical alternating pattern
The cyclical alternating pattern (CAP) (Fig. 2.5) is an EEG pattern
REM sleep seen in NREM sleep that indicates sleep instability [36]. A CAP
REM sleep accounts for 20–25% of total sleep time. The EEG cycle [37] consists of an unstable phase (phase A) and a relatively
in REM sleep is desynchronized and consists of low-voltage, stable phase (phase B), each lasting between 2 and 60 s. Phase A of
mixed-frequency activity similar to that seen in stage N1 sleep. CAP is marked by an increase in EEG potentials, with contribu-
The EMG channels show hypotonia or atonia of antigravity mus- tions from both synchronous high-amplitude slow activity and
cles, with the exception of the diaphragm and the oculomotor desynchronized fast rhythms in the EEG recording, standing out
muscles. While this “tonic” stage persists throughout REM sleep, from a relatively low-amplitude slow background. The A phase is
there is a superimposed intermittent “phasic” stage character- associated with increases in heart rate, respiration, blood pressure,
ized by bursts of REMs in all directions, in singlets or clusters and muscle tone. CAP rate (total CAP time during NREM sleep)
(noted on EOG channels). Phasic swings in blood pressure and and arousals both increase in older individuals and in a variety of
heart rate, irregular respiration, spontaneous middle ear muscle sleep disorders, including both diurnal and nocturnal movement
activity (MEMA), periorbital integrated potentials (PIPs) [34], disorders. Non-CAP (sleep periods without CAP for at least 60 s) is
myoclonic twitching of the facial and limb muscles, and tongue thought to indicate a state of sustained stability. CAP is considered
movements [35] are all characteristics of phasic REM sleep. part of the sleep microstructure, which also includes sleep spindles,
Breathing tends to become irregular, especially in phasic REM K-complexes, and arousals.
Fig. 2.3 A 60-second epoch from the overnight polysomnogram of a 35-year-old man complaining of excessive daytime sleepiness and with a prior diagnosis of
obstructive sleep apnea. He also has a history of depression and is on citalopram, a selective serotonin reuptake inhibitor (SSRI). This epoch represents stage N2 sleep,
as evidenced by the presence of K-complexes and sleep spindles. Note the presence of excessive eye movements, representing a combination of slow and rapid eye
movements. Eye movements generally do not persist into stage N2 and beyond, but are often seen in patients on SSRIs (colloquially referred to as “Prozac eyes”). Top
eight channels: EEG recording with electrodes placed according to the 10-20 international electrode placement system; Chin1-Chin2: submental electromyogram (EMG);
EKG: electrocardiogram; HR: heart rate; LTIB, RTIB: left and right tibialis anterior EMG; LGAST, RGAST: left and right gastrocnemius EMG; OroNs1-OroNS2: oronasal
airflow; Pflw1-Pflw2: nasal pressure transducer recording; Chest and ABD: effort belts; SaO2: arterial oxygen saturation by finger oximetry. Also included is a snore channel.
Reproduced from S. Chokroverty & R. Thomas [eds.], Atlas of Sleep medicine [2nd ed.], Copyright (2014), with permission from Elsevier.

Fig. 2.4 A 20-second epoch of rapid eye movement (REM) from the overnight polysomnogram of a 54-year-old woman referred to the sleep laboratory with possible
sleep apnea. Note the sharp periorbital integrated potentials (PIPs) in the left orbicularis oculi muscle channel (Lt O Oculi), co-occurring with rapid eye movements,
as noted in the electrooculography channels (E1-M2, E2-M2). Top eight channels: EEG recording with electrodes placed according to the 10-20 international electrode
placement system; Chin1-Chin2: submental electromyogram (EMG); EKG: electrocardiogram; HR: heart rate; LTIB, RTIB: left and right tibialis anterior EMG; LGAST,
RGAST: left and right gastrocnemius EMG; OroNs1-OroNS2: oronasal airflow; Pflw1-Pflw2: nasal pressure transducer recording; Chest and ABD: effort belts; SaO2: arterial
oxygen saturation by finger oximetry. Also included is a snore channel.
there is usually nocturnal sleep consolidation by the age of 1 year.

Box 2.1 Factors modifying sleep macrostructure By age 4–6 years, most children stop daytime napping; at this age,
total sleep decreases to about 10 hours [39]. Sleep duration falls
u Exogenous
precipitously from childhood to adolescence; one recent large study
• Noise showed decreases across the adolescent period from 8.5 hours per
• Exercise night at age 13 years to 7.3 hours at age 18 years [40], and there
seems to have been a historical trend of a fall in adolescent sleep
• Ambient temperature over the past few decades [41]. Several factors seem to be responsi-
• Drugs and alcohol ble for this, including a combination of natural phase delay at this
age (see below), early school start times [42] and the impact of bed-
u Endogenous
time use of electronic media [43].
• Age NREM–REM cycles also evolve with age. Newborn babies may
• Prior sleep-wakefulness enter sleep directly through REM sleep, or active sleep, almost half
the time, which is accompanied by twitching of the limbs and face,
• Circadian phase irregular breathing, and brief central apneas. By 3 months of age,
• Sleep pathologies the NREM–REM cyclic pattern of adult sleep is better established,
but is shorter in infants, lasting for approximately 45–50 minutes
and increasing to 60–70 minutes between 5 and 10 years and reach-
Evolution of sleep with age ing the normal adult cyclic pattern of 90–100 minutes by 10 years.
REM sleep progressively declines with age, occupying 50% of total
Sleep from birth through adolescence sleep time in newborns, about 30–35% by the end of the first year,
Sleep patterns, sleep architectures, sleep habits, and sleep require- and decreasing to adult levels of 20–25% by 5–6 years. A weak cir-
ments evolve throughout the lifetime of an individual. Newborns cadian rhythm is probably present at birth, but by 6–8 weeks it is
sleep up to 16 hours in a 24-hour cycle, and their sleep occurs in established.
the form of short scattered naps throughout the day, not consoli- Sleep spindles appear from 6–8 weeks and are well formed by
dating into longer sleep periods until about 6 months of age [38]. 3 months (they may be asynchronous during the first year, but by
The napping frequency continues to decline after 1.5 months, and age 2 are synchronous). K-complexes are seen at 6 months, but

Phase A Phase B
C4–A1
100 1 Sec
µV
CAP Cycle
Fig. 2.5 A cyclical alternating pattern (CAP) sequence in stage N2 sleep with a highlighted CAP cycle (black box). The CAP cycle is defined by a phase A (aggregate of
phasic events) and phase B (interval between two successive A phases). EEG recording with electrodes placed according to the 10-20 international electrode placement
system.
Reproduced from S. Chokroverty & R. Thomas [eds.], Atlas of Sleep medicine [2nd ed.], Copyright (2014), with permission from Elsevier.
begin to appear at ages over 4 months. Hypnogogic hypersyn- in normal elderly individuals remains relatively constant and the
chrony characterized by transient bursts of high-amplitude waves total duration of sleep time within 24 hours is also no different
in the slower frequencies appears at 5–6 months and is prominent from that of young adults; however, elderly individuals often nap
at 1 year. Pre-adolescents are highly alert during the day, with the during the daytime compensating for lost sleep during the night.
multiple sleep latency test (MSLT) showing a mean sleep latency of Patients with neurodegenerative conditions such as Alzheimer dis-
17–18 minutes. ease, however, may experience sleep fragmentation due to lesions
of the suprachiasmatic nucleus, resulting in irregular sleep–wake
Sleep in adults cycles [55].
Adults sleep an average duration of 7.5–8 hours per night, Figure 2.6 schematically represents the evolution of sleep step
although this may be more a reflection of the exigencies of day- distribution in newborns, infants, children, adults, and elderly
to-day living than of actual sleep requirements. Indeed, it has gen- adults. Night sleep histograms of children, young adults, and of
erally been held that we are chronically sleep-deprived in modern elderly adults are shown in Fig. 2.7.
society [44]. However, the question of the “normal” amount of
sleep that an adult needs is far from a settled issue. Chronic short
sleep duration has been linked to a variety of health concerns,
such as hypertension, obesity, insulin resistance and diabetes, and 100
REM sleep
overall increased mortality [45,46], as well as cognitive issues and 90
NREM sleep
poor daytime functioning [47]. On the other hand, long sleep 80
duration has also been associated with increased cardiovascular 70
mortality [48,49]. Clinicians recognize the existence of short-
60
sleepers (who sleep less than 6 hours a day) and long-sleepers
(who sleep more than 10 hours a day) [50], suggesting that the 50
need for sleep may vary considerably among normal individuals 40
and may be genetically determined. Multiple studies evaluating 30
differences between short-and long-sleepers in various physio- 20
logical, psychological, and health-related spheres have not found
10
consistent differences [51–53].
As adults age, sleep quality is generally thought to deteriorate. 0
Newborn 2wks 6 mos 6 yrs 12 yrs 20– 31– 51–
PSG analysis shows that older subjects spend more time awake and 30 yrs 50 yrs 90 yrs
have repeated awakenings, resulting in low sleep efficiency and
sleep maintenance. There is also an advancement of sleep phase Fig. 2.6 Graphic representation of percentages of REM and NREM sleep at
different ages. Note the dramatic changes in REM sleep in the early years.
(see the next section), resulting in early morning awakenings that
Reproduced from Chokroverty S [ed], Sleep Disorders Medicine: Basic Science, Technical
prematurely terminate the night sleep. A marked reduction in the Considerations, and Clinical Aspects [3rd ed], Copyright (2009), with permission from Elsevier;
amplitude of the slow waves occurs, resulting in a decreased per- Source data from Science, 152(3722), Roffwarg HP, Muzzio JN, Dement WC, Ontogenic
centage of SWS in this age group [54]. The percentage of REM sleep development of the human sleep-dream cycle, pp. 604–619, Copyright (1966), AAAS.

CHILDREN kinase 1 epsilon and casein kinase 2 delta), but this field of research
Awake
REM
is in its embryonic stage and much work remains to be done [57].
The circadian rhythm, which regulates sleep–wake cycles, also
Sleep stages
1
2 coordinates with several other independent but synchronized
3 biological rhythms, including those of body temperature and
4 neuroendocrine secretion (see Chapter 6). Sleep decreases body
1 2 3 4 5 6 7
temperature, whereas activity and wakefulness increase it. Body
temperature rhythm is sinusoidal, and cortisol and growth hor-
YOUNG ADULTS mone secretion rhythms are pulsatile. Cortisol has its own cir-
Awake
REM cadian rhythm, independent of sleep, whereas growth hormone
Sleep stages
1 secretion is coupled to SWS. It is also well known that plasma levels

2 of prolactin and testosterone are all increased during sleep at night.
3 The secretion of melatonin, the hormone synthesized by the pineal
4
gland, has its own circadian rhythm, but is suppressed by light and
1 2 3 4 5 6 7 thus may be an important modulator of human circadian rhythm
entrainment by the light–dark cycle.
ELDERLY
Awake From a clinical perspective, circadian rhythm disorders are impor-
REM tant when they affect the day-to-day functioning of patients. For
Sleep stages
1 example, there is a natural tendency toward a delayed sleep phase

2
(going to bed late, usually after 3 AM and awakening well after noon)
3
4 in adolescents and young adults; similarly, in older adults, there is a
shift in circadian rhythms in the opposite direction (advanced sleep
1 2 3 4 5 6 7 phase), with a tendency toward earlier bedtimes and early morning
Hours of sleep awakenings. While not pathological in themselves, they are labeled
as “delayed sleep phase syndrome” and “advanced sleep phase syn-
Fig. 2.7 Night sleep histograms from children, young adults, and elderly persons.
drome,” respectively, when they affect quality of life, such as school,
Note the significant reduction of stage 4 NREM sleep with age.
Reproduced from Chokroverty S [ed], Sleep Disorders Medicine: Basic Science, Technical
work, or time with family. Additionally, there are environmentally
Considerations, and Clinical Aspects [3rd ed], Copyright (2009), with permission from Elsevier; induced circadian rhythm disorders, such as jet lag and shiftwork
Source data from N Engl J Med, 290, Kales A, Kales JD, Sleep disorders: recent findings in the disorder, and those caused by underlying neurological disorders,
diagnosis and treatment of disturbed sleep, pp. 487–99, Copyright (1974), Massachusetts such as non-24-hour rhythms (irregular rhythm and free-running
Medical Society. rhythm). Treatment of these conditions involves various combina-
tions of timed light exposure and avoidance (phototherapy), alerting
and sedating medications (pharmacotherapy), and changes in sleep
Circadian sleep–wake rhythm hours (chronotherapy) as appropriate for any given disorder. These
are discussed in more detail in Chapters 21 and 22.
Circadian rhythm disorders are discussed in detail in Chapters 21
and 22. This section provides a brief introduction to the underlying
concepts. References
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CHAPTER 3
Neurobiology of REM sleep
Pierre-â•‰Hervé Luppi, Olivier Clément,
Christelle Peyron, and Patrice Fort
Network generating paradoxical (REM) GABA) in the SLD did not increase in rats displaying an REM sleep
rebound compared with control or REM â•‰sleep-â•‰deprived animals
sleep [12]. In contrast, our results have shown that most of the c-â•‰Fos-â•‰
Glutamatergic neurons located in the SLD trigger labeled neurons localized in the SLD after REM sleep hypersomnia
REM sleep express a specific marker of glutamatergic neurons (vesicular glu-
tamate transporter 2, vGlut2) [13] and are therefore glutamatergic.
REM sleep characterized by EEG activation and rapid eye move-
Further, a large number of the REM sleep-â•‰on neurons recorded in
ments (REMs) was discovered in 1953 by Aserinsky and Kleitman.
the SLD have been found to be glutamatergic [10].
It was shown to correlate in humans with dream activity [1,2].
A number of results further indicate that SLD REM sleep-â•‰on
In 1959, Jouvet and Michel discovered in cats that REM sleep is
glutamatergic neurons generate muscle atonia via descending
also characterized by a complete disappearance of muscle tone,
medullary projections to GABA/â•‰glycinergic neurons. Indeed, it
paradoxically associated with a cortical activation and REMs, and
has been shown that the SLD sends direct efferent projections to
named this state paradoxical sleep (PS) [3,4]. Soon after, they dem-
glycinergic neurons in the ventral (GiV) and alpha (Gia) giganto-
onstrated that the brainstem is necessary and sufficient to trigger
cellular nuclei (corresponding to the cat magnocellular reticular
and maintain REM sleep in cats. Using electrolytic and chemical
nucleus, Mc) and the nucleus raphe magnus (RMg). In addition,
lesions, it was then shown that the dorsal part of the pontis oralis
glycinergic neurons of the Gia, GiV and RMg express c-â•‰Fos after
(PnO) and caudalis (PnC) nuclei contain the neurons responsi-
induction of REM sleep by bicuculline (Bic, a GABAA antagonist)
ble for REM sleep onset [5]â•„. Furthermore, bilateral injections of a
injection in the SLD [7]â•„. Further, glycinergic neurons of these
cholinergic agonist, carbachol, into these structures promote REM
structures project monosynaptically to lumbar spinal motoneu-
sleep in cats. The dorsal part, where carbachol injection induces
rons [14]. These results suggest that Gia, GiV, and RMg glycinergic
REM sleep with the shortest latency, was termed the peri-â•‰locus
neurons hyperpolarize motoneurons. It is likely that these neurons
coeruleus alpha nucleus (peri-â•‰LCα), the pontine inhibitory area
are also GABAergic, since a large majority of the c-â•‰Fos-â•‰labeled
(PIA), or the subcoeruleus nucleus (SubC) [6]. In contrast to the
neurons localized in these nuclei after 3 hours of REM sleep recov-
data from cats, carbachol iontophoresis into the rat sublaterodor-
ery following 72 hours of REM sleep deprivation express GAD
sal tegmental nucleus (SLD), the equivalent of the cat peri-â•‰LCα,
[12]. Further, it has been shown that combined microdialysis of
induces waking (W) with increased muscle activity [7]. Further,
bicuculline, strychnine and phaclofen (a GABAB antagonist) in
in rats, only a few of the numerous c-â•‰Fos-â•‰labeled cells located in
the trigeminal nucleus restored muscle tone during REM sleep
the laterodorsal tegmental nucleus (Ldt) and SLD after REM sleep
[15,16]. Altogether, these results indicate that the premotoneurons
hypersomnia were cholinergic [8]. Moreover, it has been shown that
responsible for muscle atonia of REM sleep are localized in the
injection of scopolamine, a cholinergic muscarinic antagonist, into
GiV and co-â•‰release GABA and glycine.
the SLD has nearly no effect on REM sleep [9]. In addition, it has
been shown that cholinergic neurons of the Ldt and SLD are active
during both W and REM sleep and therefore should play a role SLD glutamatergic neurons are inhibited
in cortical activation during both W and REM sleep rather than a by GABAergic neurons during wake and SWS
specific role in REM sleep genesis [10]. However, it has also been A long-â•‰lasting REM sleep-â•‰like episode can be pharmacologically
shown that optogenetic activation of Ldt and pedunculopontine induced with a short latency in head-â•‰restrained unanesthetized
(PPTg) cholinergic neurons increases the probability of REM sleep rats by iontophoretic applications of bicuculline or gabazine, two
occurrence [11]. Altogether, these results strongly suggest that the GABAA receptor antagonists, specifically to the SLD. Further, neu-
pontine cholinergic neurons play a modulatory role in REM sleep rons within the SLD specifically active during REM sleep are acti-
genesis and a more central role in cortical activation during both vated following bicuculline or gabazine iontophoresis [7]â•„. Taken
W and REM sleep. together, these data indicate that the onset of SLD REM sleep-â•‰on
In addition, we have shown that SLD REM sleep-â•‰on neurons are neurons is mainly due to the removal during REM sleep of a tonic
not GABAergic. Indeed, the small number of c-â•‰Fos-â•‰positive neu- GABAergic tone present during W and slow-â•‰wave sleep (SWS). It
rons expressing a specific marker of GABAergic neurons (gluta- is likely that such a strong tonic GABAergic inhibition is necessary
mate decarboxylase, GAD, the enzyme responsible for synthesis of to preclude in healthy subjects the occurrence of sleep onset REM

sleep (SOREMS) and cataplexy. Combining retrograde tracing to the LC and DRN that is active during sleep and strongly suggest
with cholera toxin b subunit (CTb) injected in the SLD and GAD that an increased GABA release is responsible for the REM sleep-
immunostaining, we then identified neurons at the origin of the selective inactivation of monoaminergic neurons. By combining
GABAergic innervation. These neurons were localized within the retrograde tracing with CTb and GAD immunohistochemistry
pontine (including the SLD itself) and the dorsal deep mesence- in rats, we found that the LC and DRN receive GABAergic inputs
phalic reticular nuclei (dDpMe) [17]. Further, the ventrolateral part from neurons located in a large number of distant regions from the
of the periaqueductal gray (vlPAG) and the dDpMe are the only forebrain to medulla [24]. Two brainstem areas contained numer-
pontomedullary structures containing a large number of c-Fos- ous GABAergic neurons projecting both to the DRN and LC, and
positive neurons expressing GAD67mRNA after 72 hours of REM were thus candidates for mediating the REM sleep-related inhibi-
sleep deprivation [12]. In addition, injection of muscimol in the tion of monoaminergic neurons: the vlPAG and the dorsal paragi-
vlPAG and/or the dDpMe induces a strong increase in REM sleep gantocellular nucleus (DPGi) [24]. We then demonstrated by using
quantities [12]. These congruent experimental data lead us to pro- c-Fos that both nuclei contain numerous LC-projecting neurons
pose that GABAergic neurons within the vlPAG and the dDpMe selectively activated during REM sleep rebound following REM
are gating REM sleep during W and SWS by tonically inhibiting sleep deprivation [25]. Since the DPGi has not previously been
REM sleep-on neurons from the SLD. considered in sleep mechanisms, we studied the firing activity of
the DPGi neurons across the sleep–wake cycle in head-restrained
Role of monoaminergic neurons in the control rats [26]. In full agreement with our functional data using c-Fos,
of REM sleep we found that the DPGi contains numerous REM sleep-on neurons
A major achievement in the identification of the mechanisms con- that are silent during W and SWS and fire tonically during REM
trolling REM sleep was the finding that serotonergic neurons from sleep. The REM sleep-on neurons start discharging approximately
the raphe nuclei and noradrenergic neurons from the LC cease fir- 15 s before REM sleep onset and become silent around 10 s before
ing specifically during REM sleep, i.e, show a REM sleep-off firing EEG signs of arousal. Taken together, these data highly suggest that
activity, reciprocal to that of REM sleep-on neurons [18]. Later, it the DPGi contains the neurons responsible for the inactivation of
was shown that histaminergic neurons from the tuberomammillary LC noradrenergic neurons during REM sleep [26]. A contribution
nucleus and hypocretinergic neurons from the perifornical hypo- from the vlPAG to this inhibitory mechanism is also likely. Indeed,
thalamic area also exhibit REM sleep-off firing activity [19]. These an increase in c-Fos/GAD immunoreactive neurons has been
electrophysiological data were the basis for a well-accepted hypoth- reported in the vlPAG after a REM sleep rebound induced by dep-
esis suggesting that REM sleep onset is gated by reciprocal inhibitory rivation in rats [12]. In summary, a large body of data indicates that
interactions between REM sleep-on and REM sleep-off monoamin- GABAergic REM sleep-on neurons localized in the vlPAG and the
ergic neurons [18]. Supporting this neuronal model, drugs enhanc- DPGi hyperpolarize monoaminergic neurons during REM sleep.
ing serotonergic and noradrenergic transmission—monoamine
oxidase inhibitors (MAOs) and serotonin and norepinephrine Role of the hypothalamus in REM sleep control
(noradrenaline) reuptake inhibitors (SNRIs)—specifically suppress Surprisingly, a very large number of c-Fos-positive cells were
REM sleep [20]. Further, applications of norepinephrine, epineph- observed in the posterior hypothalamus (PH), including the zona
rine (adrenaline), or benoxathian (an α2 adrenergic agonist) to the incerta (ZI), the perifornical area (PeF), and the lateral hypotha-
peri-LCα inhibit REM sleep, but application of serotonin has no lamic area (LH), after REM sleep hypersomnia [27]. By using
effect [21]. It is of note that our data combining a marker of noradr- double-immunostaining, it has been further shown that around 75%
energic neurons (tyrosine hydroxylase, TH) and c-Fos staining after of PH cells labeled for c-Fos after REM sleep rebound express
REM sleep deprivation and recovery suggest that it is unlikely that GAD67mRNA and are therefore GABAergic [28]. One-third of
the LC noradrenergic neurons are involved in the inhibition of REM these GABAergic neurons were also immunoreactive for two neu-
sleep, particularly during its deprivation. Indeed, the LC noradrener- ropeptides, melanin-concentrating hormone (MCH) [27] and
gic neurons do not display c-Fos after 72 hours of REM sleep depri- nesfatin [29]. In support of these data, it has been shown in head-
vation. Furthermore, no projection has been observed from the LC restrained rats that MCH neurons fire exclusively during REM sleep
to the SLD [17]. Nevertheless, a substantial number of noradrenergic [30]. Rats receiving intracerebroventricular (icv) administration of
neurons from A1 and A2 cell groups display c-Fos after REM sleep MCH showed a strong dose-dependent increase in quantities of
deprivation, indicating that noradrenergic neurons from these med- REM sleep and, to a minor extent, SWS [27]. Such a sleep increase
ullary cell groups might contribute to REM sleep inhibition [22]. In has been obtained using chronic (24-hour) optogenetic activation
summary, it is clear that norepinephrine and serotonin inhibit REM of MCH neurons [31]. Finally, it was shown that optogenetic acti-
sleep, but the targeted neurons remain to be identified. We propose vation of MCH neurons specifically at the onset of SWS epoch did
that rather than inhibiting SLD REM sleep-on neurons, norepineph- not increase SWS duration but increased the probability of SWS-
rine and serotonin might inhibit REM sleep by means of a tonic exci- to-REM sleep transition. More important, optogenetic stimulation
tation of the dDpMe and vlPAG REM sleep-off GABAergic neurons. of MCH neurons at the REM sleep onset significantly prolonged
the duration of REM sleep episodes [32]. In agreement with our
GABAergic neurons are responsible for the results showing that MCH neurons constitute only one-third of the
inactivation of monoaminergic neurons GABAergic neurons activated during REM sleep hypersomnia, it
during REM sleep has been shown that a large population of GABAergic neurons not
The application of bicuculline to monoaminergic neurons during expressing MCH localized in the LH area also discharge maximally
SWS or REM sleep induces a tonic firing in both types of neurons during REM sleep [33]. Since these neurons anticipate REM sleep
[23,24]. These results indicate the existence of a tonic GABA input onset, they could play a role in triggering REM sleep.

Chapter 3 neurobiology of rem sleep 17
To determine the function of the LH MCH+/GABA+ and MCH−/ induced by REM sleep deprivation and REM sleep hypersomnia. In
GABA+ neurons in REM sleep control, either all LH neurons were the future, it will be important to employ additional experimental
inactivated with muscimol (a GABAA agonist) or only those bear- approaches to fully determine the role of these neurons, including
ing α2-adrenergic receptors were inactivated using clonidine. It was tract-tracing, single-unit recordings, and inactivations and acti-
found that muscimol and to a lesser degree, clonidine after bilat- vations by genetic or pharmacological tools. Furthermore, sev-
eral injections in the LH induced an inhibition of REM sleep with eral regions that contain a large number of c-Fos-labeled neurons
or without an increase in SWS quantities, respectively. It has been require additional studies, including the lateral paragigantocellular
further shown that after muscimol injection in the LH, the vlPAG/ nucleus, the lateral parabrachial nucleus, the nucleus raphe obscu-
dDpMe region contains a large number of c-Fos/GAD67+ and of rus, and the dorsal PAG [8]‌.
c-Fos/CTb+ neurons in animals with a CTb injection in the SLD. The observation that REM sleep episodes in the rat start from
Our results indicate that the activation of REM sleep-on MCH/ SWS after a relatively long intermediate state during which the EEG
GABAergic neurons localized in the LH is a necessary step for REM displays a mix of spindles and theta activity, and then terminate
sleep to occur. They further suggest that MCH/GABAergic REM abruptly by a short microarousal, deserves further attention. These
sleep-on neurons localized in the LH control REM sleep onset and findings suggest that different mechanisms are responsible for the
maintenance by means of a direct inhibitory projection to vlPAG/ entrance to and exit from REM sleep. Altogether, these character-
dDpMe REM sleep-off GABAergic neurons. On the basis of our istics, as well as our current knowledge of the neuronal network,
results, it can be proposed that MCH/GABAergic neurons of the lead us to propose an updated model of the mechanisms control-
LH constitute a “master” generator of REM sleep that controls a ling REM sleep onset and maintenance.
“slave” generator located in the brainstem. To reconcile the Jouvet REM sleep onset would be due to the activation of glutamatergic
hypothesis (i.e, that the brainstem is necessary and sufficient to REM sleep-on neurons in the SLD (Fig. 3.1). During W and SWS,
generate a state characterized by muscle atonia and REM [5]‌) with the activity of these REM sleep-on neurons would be suppressed by
our results, it can therefore be proposed that after removal of the a tonic inhibitory GABAergic tone originating from REM sleep-off
forebrain, the brainstem generator is sufficient to induce a state neurons localized in the vlPAG and the dDpMe (Fig. 3.2). These
with muscle atonia and REM by means of a reorganization of the REM sleep-off neurons would be activated during W by the Hcrt
brainstem systems generating REM sleep. However, the brainstem and the aminergic neurons. The onset of REM sleep would be due
generator would be under control of the LH generator in intact to the activation by intrinsic “clock-like” mechanisms of REM
animals. sleep-on MCH/GABAergic hypothalamic neurons and REM sleep-
In addition to the descending pathway to the REM sleep-off on GABAergic neurons localized in the DPGi and vlPAG. These
GABAergic neurons, the MCH/GABAergic REM sleep-on neurons neurons would inactivate the REM sleep-off GABAergic neurons
might also promote REM sleep by means of other pathways to the his- and the aminergic and Hcrt waking neurons. The disinhibited
taminergic neurons, the monoaminergic REM sleep-off neurons and ascending SLD REM sleep-on neurons would in turn induce corti-
the hypocretinergic neurons [7,32]. Indeed, Jego et al [32] have shown cal activation via their projections to intralaminar thalamic relay
that optogenetic activation of MCH neurons inhibit other postsynaptic neurons in collaboration with W/REM sleep-on cholinergic and
targets, such as histaminergic cells in the TMN and neurons of the glutamatergic neurons from the laterodorsal (Ldt) and peduncu-
medial septum, through activation of the GABAA receptor. lopontine (PPT), mesencephalic, and pontine reticular nuclei and
The mechanisms at the origin of the activation of the MCH/ the basal forebrain. Descending REM sleep-on SLD neurons would
GABAergic neurons of the LH at the entrance to REM sleep remain induce muscle atonia via their excitatory projections to glyciner-
to be identified. A large number of studies indicate that MCH neu- gic neurons localized in the Gia and GiV reticular nuclei and the
rons also play a key role in metabolic control [34]. Therefore, the nucleus raphe magnus (RMg) (Fig. 3.2). The exit from REM sleep
activation of these neurons at the onset of and during REM sleep would be due to the activation of waking systems. The waking sys-
could be influenced by the metabolic state. In addition, it is likely tems would inhibit the hypothalamic MCH/GABAergic and the
that yet undiscovered endogenous cellular or molecular clock-like brainstem GABAergic REM sleep-on neurons.
mechanisms may play a role in their activation.
The cessation of activity of the MCH/GABAergic REM sleep-on Dysfunctions of the network that are responsible
neurons and, more widely, of all the REM sleep-on neurons at the for REM sleep behavior disorder
end of REM sleep episodes may be due to a different mechanism REM sleep behavior disorder (RBD) is characterized by the acting
than the entrance into the state, possibly the reactivation of the out of dreams that are vivid, intense, and violent. Dream-enacting
arousal circuits, which are known to silence MCH neurons in vitro behaviors include talking, yelling, punching, kicking, sitting, jump-
[35]. Indeed, animals enter REM sleep slowly from SWS, whereas ing from bed, arm flailing, and grabbing. The person may be awak-
they exit it abruptly by a microarousal. This indicates that the end ened or may wake up spontaneously during the acting and vividly
of REM sleep episodes is induced by the activation of the wake sys- recall the dream that corresponds to the physical activity. RBD
tems like the monoaminergic, hypocretinergic, or histaminergic is usually seen in middle-aged to elderly men. The disorder may
neurons. However, the precise mechanisms responsible for their occur in association with various degenerative neurological con-
activation remain to be identified. ditions such as Parkinson disease (PD), multiple system atrophy
(MSA), and dementia with Lewy bodies (DLB) [36].
A network model for REM sleep onset Several studies indicate that it is unlikely that RBD is due to a dys-
and maintenance function of the dopaminergic nigrostriatal system. The strongest
As described above, most of the populations of neurons responsible arguments are that RBD does not occur in about half of PD patients
for REM sleep control were identified by means of c-Fos labeling and that the use of dopaminergic agents usually does not improve

Waking CORTICAL
ACTIVATION
Thalamus vlPAG
dDPMe
DRN
LC
PH DPGi
BF SCN SLD
VLPO
TMN
GiV
W/PS-on neurons W-on neurons PS-on neurons Inhibitory pathways
SWS-on neurons PS-off neurons Excitatory pathways
Fig. 3.1 State of the network responsible for REM sleep during wake and at the end of a REM sleep episode. During wake, REM sleep-off GABAergic neurons located
in the vlPAG and dDpMe tonically inhibit SLD glutamatergic neurons. These REM sleep-off GABAergic neurons are excited by monoaminergic and hypocretin inputs.
Wake-on neurons activate the cortex either directly or by means of a relay in the intralaminar thalamic nuclei. Direct pathways from the noradrenergic and serotonergic
neurons to the cortex contributing to wake are not shown here for clarity. 5HT: serotonin; Ach: acetylcholine; BF: basal forebrain, DPGi: dorsal paragigantocellular reticular
nucleus; dDpMe: dorsal deep mesencephalic reticular nucleus; DRN: dorsal raphe nucleus; GiV: ventral gigantocellular reticular nucleus; Glu: glutamate; Gly: glycine;
Hcrt: hypocretin (orexin)-containing neurons; His: histamine; LC: locus coeruleus; Ldt: laterodorsal tegmental nucleus; LPGi: lateral paragigantocellular reticular nucleus;
MCH: melanin-concentrating hormone; PH: posterior hypothalamus; PPT: pedunculopontine nucleus; vlPAG: ventrolateral periaqueductal gray; VLPO: ventrolateral
preoptic nucleus; SCN: suprachiasmatic nucleus; SLD: sublaterodorsal nucleus.
RBD. In neurodegenerative diseases, where RBD is frequent, during REM sleep. The phasic events include large limb twitches,
neuronal cell loss has been observed in the brainstem structures locomotion, fear, and attack and defensive behaviors [37]. Notably,
modulating REM sleep, such as the locus subcoeruleus, the pedun- larger lesions induce a decrease in the total quantities of REM
culopontine nucleus, and the gigantocellular reticular nucleus, and sleep [5]‌, whereas RBD patients display normal quantities of REM
also in their rostral afferents, especially the amygdala [36]. In cats sleep. Selective experimental lesions in the ventromedial medul-
and rats, electrolytic and neurochemical lesions limited to the SLD lary reticular nuclei have been also reported to induce a decrease
eliminate the tonic muscle atonia and induce phasic muscle activity of atonia during REM sleep with an increase of phasic events [38].
Paradoxical (REM) sleep

CORTICAL
ACTIVATION
Thalamus vlPAG
dDPMe
Ldt
DRN LC
PPT
PH DPGi
SCN SLD
BF VLPO
TMN
GiV
Spinal
W/PS-on neurons motoneurons
W-on neurons PS-on neurons Inhibitory pathways
SWS-on neurons PS-off neurons Excitatory pathways

MUSCLE
ATONIA
Fig. 3.2 State of the REM sleep-generating network during a REM sleep episode. The onset and maintenance of REM sleep is due to the intrinsic “clock-like” activation
of GABAergic neurons localized in the posterior hypothalamus (some of them also containing MCH), the vlPAG/dDpMe, and the DPGi. These neurons inhibit all
W neurons and the REM sleep-off GABAergic neurons of the vlPAG and dDpMe. SLD glutamatergic neurons are disinhibited and start to generate muscle atonia
and cortical activation by means of their descending and ascending projections, respectively. They excite glycinergic/GABAergic neurons of the GiV, which in turn
hyperpolarize spinal and cranial motoneurons.

Idiopathic RBD CORTICAL

ACTIVATION
Motor
cortex
Thalamus vlPAG
dDPMe
DRN Ldt
LC
PPT
PH
DPGi
BF SLD
TMN GiV
Spinal
motoneurons
Degenerating neurons W-on neurons PS-on neurons Inhibitory pathways

Movements
W/PS-on neurons PS-off neurons Excitatory pathways
Fig. 3.3 State of the network responsible for REM sleep during idiopathic RBD. In idiopathic RBD patients, the descending but not the ascending SLD glutamatergic
neurons have degenerated. Another possibility is that only the GiV glycinergic/GABAergic neurons have degenerated. Movements are induced during REM sleep by
direct or indirect glutamatergic projections from the motor cortex to spinal and cranial motoneurons.
On the basis of these and our own experimental data, we propose EDS occurs daily and is characterized by sleep episodes with a
that RBD in patients without atonia during REM sleep could be premature onset of REM sleep. A sudden decrease in muscle tone
due to a lesion of a subpopulation of REM sleep-on glutamater- triggered by emotional factors, most often positive, characterizes
gic neurons of the SLD responsible for inducing muscle atonia via cataplexy. It can affect all striated muscles or can be limited to facial
their descending projections to the premotor GABA/glycinergic muscles or to the upper or lower limbs. The monosynaptic H-reflex
neurons of the GiV. This implies that REM sleep-on neurons of the is suppressed, as during REM sleep. Patients remain fully conscious
SLD are divided into at least two subpopulations: one descending during cataplexy [40]. All these symptoms suggest that REM sleep
and responsible for muscle atonia, and the other inducing the state is disinhibited in narcoleptic patients. It has been shown that dis-
of REM sleep itself and EEG activation (Fig. 3.3). Data obtained in ruption of the type 2 hypocretin receptor induces narcolepsy in
cats supports the existence of these two populations of SLD REM dogs and mice [41,42]. No mutation has been found in human
sleep-on cells (see above), but they have not been identified in rats. narcoleptics [43]. Instead, a marked reduction in the quantities
If these two populations exist, it remains to be discovered why only of the peptide Hcrt 1 was found in their cerebrospinal fluid and a
the descending SLD neurons would be destroyed in RBD patients. disappearance of Hcrt staining was observed in the hypothalamus
In any case, RBD patients should not have a large lesion of the SLD of post-mortem brain tissues [43]. It is notable that Hcrt neurons
and surrounding nuclei, since they do not display a decrease in are specifically active during W and increase their activity during
REM sleep amount. Another possibility is that SLD neurons are muscle activation [19]. They are silent during SWS or REM sleep,
intact and the premotor GABA/glycinergic neurons of the GiV are except during phasic twitches, when they can fire in bursts. It is of
damaged. This better fits with the fact that only the atonia is lost in interest that they start to fire several seconds before the onset of W
RBD, and not the state of REM sleep per se (Fig. 3.3). at the end of REM sleep episodes [33]. Hcrt neurons, like aminergic
The RBD reported in narcoleptic patients is likely due to the neurons, send projections throughout the brain, from the olfactory
absence of hypocretin, although it cannot be completely ruled out bulb, cerebral cortex, and thalamus to the brainstem and the spinal
that the SLD–GiV atonia pathway is lesioned in these patients. One cord [44]. It is therefore difficult to determine, solely on the basis
possibility is that, under normal conditions, Hcrt neurons excite the of the projections of the Hcrt neurons, which missing pathway(s)
SLD–GiV atonia pathway during REM sleep, in particular during are responsible for the four symptoms of narcolepsy. It has been
the muscle twitches induced by a phasic glutamatergic excitation proposed that the absence of dense Hcrt projections to the hista-
of the motoneurons (Fig. 3.4). Two results support this hypothesis. minergic and noradrenergic LC neurons might be responsible for
First, although Hcrt neurons are mainly active during active wak- narcolepsy symptoms. Indeed, icv administration or local injection
ing, they display bursts of activity during the twitches of REM sleep of Hcrt in the noradrenergic LC or the histaminergic TMN neurons
[19]. Second, application of hypocretin in the SLD region induces induces W and inhibits REM sleep [45,46]. Further, administration
REM sleep with atonia [39]. of selective norepinephrine reuptake inhibitors and α1-adrenergic
agonists specifically suppress cataplexy [40]. Besides, the absence
Dysfunctions of the network that are responsible of the hypocretin input on serotonin neurons could also play a role,
for cataplexy in narcoleptic patients since serotonin reuptake inhibitors are effective in treating cata-
Narcolepsy–cataplexy is characterized by two major symptoms, plexy, at least in humans [40]. Strongly supporting this hypothesis, it
excessive daytime sleepiness (EDS) and cataplexy, and two aux- has been shown that targeted restoration of orexin receptor expres-
iliary symptoms, hypnagogic hallucinations and sleep paralysis. sion in the dorsal raphe (DR) and in the locus coeruleus (LC) of

RBD in narcoleptics
CORTICAL
ACTIVATION
Motor
cortex
Thalamus vlPAG
dDPMe
DRN Ldt
Hcrt LC
PPT
PH
DPGi
SLD
BF VLPO SCN
TMN GiV
Spinal
motoneurons
W/PS-on neurons W-on neurons PS-on neurons Inhibitory pathways

Movements
Degenerated neurons SWS-on neurons PS-off neurons Excitatory pathways
missing pathway
Fig. 3.4 State of the network responsible for REM sleep during RBD in narcoleptic patients. In narcolepsy, the network responsible for muscle atonia is intact. Phasic
movements during REM sleep are induced by a phasic activation of motoneurons due to the absence of an excitatory projection of the Hcrt neurons specifically to the
descending SLD REM sleep-on neurons.
mice lacking orexin receptors inhibited cataplexy-like episodes and in SOREMS [12]. It thus can be hypothesized that during emotions
pathological fragmentation of wakefulness (i.e, sleepiness), respec- in healthy subjects, there is a phasic increase in hypocretin release
tively [47]. Finally, a missing hypocretin projection to GABAergic on GABAergic REM sleep-off neurons. Since the hypocretiner-
REM sleep-off neurons might be implicated, since the most recent gic neurons also project to aminergic neurons, they would excite
treatment for cataplexy, namely γ-hydroxybutyrate (GHB), may act these neurons, which in turn would reinforce the activation of the
through increased GABAB transmission [48]. This is an attractive GABAergic REM sleep-off neurons via direct projections (Fig. 3.1).
hypothesis in view of our finding that GABAergic REM sleep-off The phasic increase in inhibition by GABAergic REM sleep-off neu-
neurons localized in the vlPAG/dDpMe region gate the onset of rons would counterbalance an increased glutamatergic excitation
REM sleep by means of their tonic inhibition of the SLD neurons of SLD neurons arising in the central amygdala (Fig. 3.5). We have
during W and SWS. Further, we have found that inactivating neu- indeed demonstrated that non-GABAergic neurons of the central
rons in the vlPAG/dDpMe region by means of muscimol induces amygdala project to the SLD [17]. Further, neurons increasing
not only an increase in REM sleep quantities but also an increase their activity during W and/or REM sleep or prior to and during
Cataplexy CORTICAL
ACTIVATION
Thalamus vlPAG
dDPMe
DRN
LC
PH DPGi
BF SLD
ACE
TMN
GiV
Spinal
motoneurons
Degenerated neurons W-on neurons PS-on neurons Inhibitory pathways
W/PS-on neurons PS-off neurons Excitatory pathways

MUSCLE
ATONIA
Fig. 3.5 State of the network responsible for REM sleep during cataplexy. Cataplexy is induced by activation of a glutamatergic pathway from the emotionally driven central
amygdala (ACE) to the descending SLD glutamatergic neurons. In healthy subjects, the hypocretin neurons would be excited. They would excite GABAergic REM sleep-off
neurons located in the vlPAG/dDpMe and thereby increase the inhibition of SLD glutamatergic neurons and counteract the excitation coming from the central amygdala.

cataplexy were recorded in the central amygdala [49]. In addition, glutamatergic neurons in the pontomesencephalic tegmentum of the
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CHAPTER 4
Neuroanatomical,
neurochemical, and
neurophysiological bases
of waking and sleeping
Barbara E. Jones
Introduction basal forebrain, where neurons of the basalocortical system also pro-
ject in turn in a widespread manner to the cerebral cortex to stimulate
Over the past century, studying the basic mechanisms of sleep–â•‰wake cortical activation. Some neurons in the medullary RF also give rise
states has evolved from dissecting the principal neuroanatomical to ascending projections by which they can influence other neurons
structures to identifying the important chemical neurotransmitters in the rostral brainstem. By certain of these, SWS can be promoted.
and revealing the precise physiological discharge by which specific But the medullary RF neurons are most prominently involved in the
neural systems influence the brain and body for execution of wak- modulation of movement and muscle tone, some enhancing during
ing or sleeping (Fig. 4.1). waking, others inhibiting muscle tone to induce muscle atonia of
In both animals and humans, the sleep–â•‰wake cycle is actually REM sleep via descending projections to the spinal cord.
composed of three distinct states: waking (W); non-â•‰REM (NREM) Also in early work, von Economo [4]â•„revealed the important role
sleep, including slow-â•‰wave sleep (SWS); and REM sleep. W is char- of the hypothalamus in controlling sleep–â•‰wake states (Fig. 4.1). From
acterized by prominent fast activity recorded on the cerebral cortex neuropathological analysis of brains from patients with encephalitis
(EEG, upper left in Fig. 4.1), particularly in a gamma frequency lethargica, he associated symptoms of insomnia with lesions of the
range (30–â•‰60 Hz and up to 120 Hz), together with continuous pos- anterior hypothalamus and those of coma with lesions of the pos-
tural muscle tone (on the EMG, lower right in Fig. 4.1). SWS is terior hypothalamus (PH) and thus proposed the existence in the
characterized by attenuated fast activity and prominent slow activ- hypothalamus of opponent sleep and wake centers, a notion later
ity, particularly in a delta frequency range (0.5–â•‰<4 Hz), together confirmed experimentally in animals by Nauta [5]. Later work indi-
with a decrease in postural muscle tone. REM sleep is character- cated the additional importance of the more anterior preoptic area
ized by moderate fast EEG activity, paradoxically occurring dur- (POA), including the ventrolateral preoptic nucleus (VLPO), in the
ing behavioral sleep with the total absence of postural muscle tone promotion of sleep (Fig. 4.1) [6,7].
on the EMG, or muscle atonia, which was originally discovered by These early studies and their later pursuit have revealed a con-
Jouvet [1]â•„, who thus called this state paradoxical sleep (PS, a name tinuous reticular core through the brainstem, diencephalon, and
still used today) in animals. basal telencephalon where neurons promoting cortical activation
and/â•‰or behavioral arousal with waking appear to be concentrated
Neuroanatomical substrates at certain levels and those promoting cortical deactivation and/â•‰or
of sleep–â•‰wake state systems behavioral quiescence at other levels. These different neuronal clus-
ters could effect their state alterations through local projections to
Since the early work of Moruzzi and Magoun [2,3], it has been known other levels of the reticular core and long projections ascending to
that the neurons distributed through the core of the brainstem in the the cerebral cortex or descending to the spinal cord (Fig. 4.1).
mesencephalic, pontine, and medullary reticular formation (RF) are
essential for maintaining a waking state with cortical activation and
postural muscle tone along with behavioral arousal and responsive- Neurochemical identity and
ness (Fig. 4.1). Within this core, the neurons in the oral pontine and neurophysiological properties
mesencephalic RF are most important for cortical activation and form
the ascending reticular activating system. They project rostrally along of sleep–â•‰wake neural systems
a dorsal course to the thalamus, where neurons of the nonspecific First through pharmacological evidence, then through histochemi-
thalamocortical projection system project in turn in a widespread cal studies, the important roles of particular chemical neurotrans-
manner to the cerebral cortex to stimulate cortical activation. They mitters and their neurons in sleep–â•‰wake state control became
also project ventrally into and through the hypothalamus up to the evident, pioneered in large part by Jouvet [8]â•„.

Fast EEG (W & REM):
Slow EEG (SWS):
Cx
Th
BF
PH
DR
POA Mes Ω
TM VTA RF LDT
LC
Cortical activation (W/REM): Glu CB

Pons
GABA
ACh
Cortical deactivation (SWS): Glu
GABA
Behavioral arousal (W): Glu
NA/DA
Ω Ser RF
Medulla
HA
Orx
Behavioral quiescence (SWS/REM): Glu
GABA/Gly
MCH W EMG:
SWS EMG:
SC REM EMG:
Fig. 4.1 (See colour plate section) Sleep–wake state substrates. Sagittal schematic view of the human brain depicting neurons with their chemical neurotransmitters
and pathways by which they influence cortical activity or behavior across the sleep-wake cycle. Neurons that are active during waking (red symbols) include cells with
ascending projections toward the cortex, which stimulate cortical activation, and cells with descending projections toward the spinal cord, which stimulate behavioral
arousal with postural muscle tone. Those with predominantly ascending projections discharge in association with fast, gamma EEG activity and cease firing with slow,
delta activity to be active during both W and REM sleep (W/REM or W/PS, filled red symbols); they include neurons that release glutamate (Glu, diamonds), GABA
(triangles) or acetylcholine (ACh, circles) (W/PS-max active, Fig. 4.2). Those with more diffuse or descending projections discharge in association with behavioral arousal
and EMG activity and cease firing with muscle atonia to be active during W and silent during REM (W, empty red symbols); they include neurons that release glutamate
(Glu, diamonds), noradrenaline (NA, square), serotonin (Ser, omega), histamine (HA, cross) or orexin (Orx, asterisk) (W-max active, Figs. 4.4 and 4.7). Neurons that are
active during sleep (blue or aqua symbols) include cells with ascending projections toward the cortex, which dampen fast cortical activity, and those with descending
projections toward the hypothalamus, brainstem or spinal cord, which diminish behavioral arousal and muscle tone. Those sleep-active neurons with ascending
projections to the cortex or local relay neurons discharge in association with slow EEG activity during SWS (SWS, blue triangle; SWS-max active, Fig. 4.3). They include
GABAergic neurons that can inhibit other W/REM cortical or subcortical neurons. Those sleep-active neurons with descending projections to the spinal cord or local
relay neurons discharge in association with decreasing muscle tone and EMG (SWS/REM, aqua diamonds and triangles; PS-max active see Figs. 4.5 and 4.6). They include
GABAergic neurons in the basal forebrain, preoptic area, hypothalamus and brainstem that can inhibit other W neurons, including Glu, MA or Orx neurons. They also
include MCH neurons (aqua star, PS-max active, Fig. 4.7), which have more diffuse projections but can exert an inhibitory influence upon other neurons of the arousal
systems including the MA, HA and Orx neurons. SWS/REM GABAergic neurons, which can also contain glycine (GABA/Gly), in the ventral medullary RF can inhibit
motor neurons in the brainstem and spinal cord, particularly during REM sleep. BF, basal forebrain; CB, cerebellum; Cx, cortex; DR, dorsal raphe; LC, locus coeruleus
nucleus; LDT, laterodorsal tegmental nucleus; Mes, mesencephalon; PH, posterior hypothalamus; POA, preoptic area; RF, reticular formation; SC, spinal cord; Th, thalamus;
TM, tuberomammillary nucleus; VTA, ventral tegmental area.
Adapted from Jones BE, “Neurobiology of waking and sleeping” from Vinken PJ and Bruyn GW (eds), Handbook of clinical neurology, pp. 131–49, Copyright (2011), with permission from Elsevier.
Catecholamine systems A-containing neurons are located within the medulla, concentrated
Through the actions of drugs associated with enhanced synaptic in regions associated with cardiorespiratory regulation (not shown);
levels of catecholamines, such as amphetamine, it is clear that dopa- NA-containing neurons are predominantly located within the pon-
mine (DA), noradrenaline (norepinephrine) (NA) and adrenaline tine tegmentum and concentrated within the locus coeruleus (LC);
(epinephrine) (A) have the capacity to promote both cortical activa- and DA-containing neurons are located in the mesencephalic teg-
tion and behavioral arousal. Containing different synthetic enzymes, mentum in the substantia nigra (SN) and ventral tegmental area

Chapter 4 neuroanatomical, neurochemical, and neurophysiological bases of waking and sleeping 25
(VTA) (Fig. 4.1). In early studies involving lesions of these neurons, it Acetylcholine neurons
appeared that NA neurons are important for promoting cortical acti-
Neurons utilizing acetylcholine (ACh) have long been known to
vation of W and DA neurons for behavioral arousal and movement
play an important role in stimulating cortical activation [22].
during W [8,9]. The NA LC neurons give rise to diffuse projections
Indeed, the ascending reticular activating system was once consid-
locally into the RF and distally to the thalamus, hypothalamus, and
ered to be the cholinergic reticular activating system based upon
basal forebrain, where they relay onto cortically projecting neurons,
early histochemical and pharmacological studies. With immuno-
while also continuing directly to the cerebral cortex [10]. They also
histochemical studies, it became evident that ACh-containing neu-
project to the spinal cord. Thus, through varicose fibers and extensive
rons were distributed in clusters through the reticular core, in the
collateralization similar to peripheral sympathetic nerves, single NA
medullary RF (not shown), in the pontomesencephalic tegmentum
LC neurons can simultaneously influence the entire brain and spinal
within the laterodorsal tegmental nucleus (LDT) and adjoining the
cord. LC neurons discharge selectively during W and become silent
SubLDT and pedunculopontine tegmental nuclei (SubLDT and
during REM(PS) [11,12]. Through their actions upon different adr-
PPT, not shown), and in the basal forebrain (BF) (Fig. 4.1). The
energic receptors, they would accordingly have the capacity to simul-
ACh neurons in the medulla project locally into the RF and also
taneously stimulate cortical activation and behavioral arousal with
to the spinal cord. Those in the LDT, SubLDT, and PPT project in
postural muscle tone. The role of DA SN and VTA neurons is more
parallel with other neurons of the RF, first locally into the brainstem
ambiguous, since they continue to discharge through the sleep–wake
RF and most prominently into the forebrain and distally into the
cycle, including REM(PS) sleep, when they may burst as during wak-
thalamus onto the nonspecific thalamocortical projection system.
ing in association with emotive situations [13]. Their role in stimu-
They also send some fibers into the hypothalamus and BF and a
lating movement during waking, as evidenced in their absence in
few directly up to the prefrontal cortex. The ACh neurons in the
patients with Parkinson disease, is thus less direct than that of LC NA
BF project in a widespread, though also topographical, manner to
neurons and may be overridden by other inhibitory mechanisms dur-
the cerebral cortex, where, through muscarinic and nicotinic recep-
ing REM(PS) sleep. On the other hand, their role in emotive behavior
tors on different target neurons, they promote cortical activation
may contribute during REM(PS) to the emotive content of dreams.
[23]. However, in contrast to the MA neurons, which can also pro-
Serotonin neurons mote cortical activation, ACh neurons do not appear to promote
behavioral arousal with muscle tone. On the contrary, they appear
Also located in the brainstem, serotonin (Ser)-containing neurons
to promote cortical activation with loss of muscle tone, as occurs
are situated in midline, raphe nuclei through the medulla, pons,
during natural REM(PS) sleep and narcolepsy with cataplexy [24].
and mesencephalon. These neurons give rise to different projec-
Indeed, it was established by unit recording studies that, in contrast
tions, such that those in the medulla project predominantly to the
to the MA neurons, ACh neurons in the BF and LDT/SubLDT/PPT
brainstem and spinal cord, whereas those in the pons and mesen-
discharge in association with cortical activation (with high gamma
cephalon, such as in the dorsal raphe (DR), give rise to ascending
EEG activity) during both W and PS (Fig. 4.2) [25–27]. They are
projections to provide the major Ser innervation to the forebrain,
silent during SWS. Their discharge is thus positively correlated with
including the cerebral cortex (Fig. 4.1). The latter projections are
gamma EEG activity and not correlated with EMG activity across
widespread, yet not diffuse like the NA ones. Ser neurons were once
the sleep–wake cycle. Likely dependent upon the simultaneous
thought to play an important role in promoting sleep, since lesions
activity or inactivity of other arousal systems, such as the NA LC
of the raphe nuclei resulted in insomnia [8]‌. However, the presumed
neurons (or Orx neurons, discussed later in this section), ACh can
Ser raphe neurons were found to discharge during waking and actu-
induce cortical activation with either behavioral arousal or muscle
ally be silent, like the NA neurons, during SWS and REM(PS) sleep
atonia and PS. This conditional role of ACh neurons is evident from
(14). Ser also appears to have a facilitatory role in motor activity
the induction of REM(PS) pharmacologically with systemic or
and muscle tone. However, there is evidence that Ser can dampen
local enhancement of synaptic ACh (by, for example, cholinester-
cortical activation through its actions upon other relay neurons [15].
ase inhibitors) or activation of ACh receptors (by, for example, car-
Single-unit recording studies have indicated that Ser neurons may
bachol) under conditions of MA depletion or loss of other arousal
facilitate rhythmic motor activity, such as grooming [16], which
systems [22,28]. The importance of the ACh LDT/SubLDT/PPT
could be associated with a more quiet behavioral waking stage.
neurons in the promotion of PS with muscle atonia was indicated
Clustered in the PH within the tuberomammillary nucleus (TM),
by the loss of PS following their destruction [29]. However, these
histamine (HA)-containing neurons also play a role in promoting
neurotoxic lesions also destroyed other non-ACh neurons situated
waking. Like the NA LC neurons, HA neurons give rise to diffuse
in the same region.
projections through the forebrain and brainstem. Their role in pro-
moting waking is particularly known through the pharmacological
effects of antihistamine drugs that produce sleepiness. From ani- GABA and glutamate neurons
mal experimental work, HA appears to be particularly important Like other neurons through the reticular core, the ACh neurons
for attentive waking [17]. Like other monoamine (MA) neurons, lie intermingled with many other noncholinergic neurons. These
the HA TM neurons discharge selectively during waking, particu- include large populations of GABA-containing and Glutamate
larly vigilant waking, and are silent during SWS and REM(PS) sleep (Glu)-containing neurons (Fig. 4.1). Unlike the ACh and MA neu-
[18]. Their role appears to be more prominent in stimulating corti- rons, these cell populations are functionally heterogeneous. In each
cal activation than in affecting muscle tone [19]. region, they include different functional subtypes and as such can
These neuromodulatory MA systems function together in par- modulate different parameters of waking or sleeping.
tially redundant arousal systems, since no one system has proven First of all, intermingled with the ACh neurons in both the BF
to be essential for the maintenance of waking [20,21]. They also and LDT/SubLDT/PPT, are both GABA and Glu neurons, which
appear to play slightly different roles in waking behaviors. discharge in parallel with the ACh neurons during both W and

W/PS-max: Nb+/VAChT+neuron (LDT) PS and in association with cortical activation (Figs. 4.1 and 4.2)
(a)
[26,27]. Such neurons are likely distributed through the RF in what
SWS aW is the large population of neurons contributing to the ascending
EEG reticular activating system (RF) and its relays in the nonspecific
1 EMG
thalamocortical (Th) and basalocortical (BF) projection systems.
Precisely why there are both GABA and Glu neurons with such
Unit an activity profile and projections remains to be understood, since
GABA is the major inhibitory neurotransmitter and Glu the major
aW
EEG
excitatory neurotransmitter in the brain. Depending upon the tar-
2 EMG
get neurons in the cortex, however, as interneurons or projection
neurons, both GABA and Glu neurons could produce increased
Unit excitability and activity of pyramidal neurons. In addition, GABA
neurons, which are generally fast-spiking neurons, can also serve to
SWS
pace activity in certain target neurons.
EEG Second, there are GABA and Glu neurons that discharge in a
3 EMG reciprocal manner to the ACh neurons, being maximally active
Unit during SWS (Figs. 4.1 and 4.3). Though not very numerous, these
SWS-max active neurons have been found in the BF and hypothala-
tPS PS mus [26,30]. Chemically unidentified neurons with this discharge
EEG profile have also been identified in the preoptic area (POA) [31],
4 EMG
including the ventrolateral preoptic area (VLPO) [32], where, as in
the BF, GABA neurons that are active during sleep and inhibited
Unit by NA have been identified [33,34]. Here again, the fact that there
are both GABA and Glu neurons with a sleep-active profile of dis-
PS charge suggests that inhibition of one population of cells during
EEG
excitation of another is integral to the sleep–wake cycle.
5 EMG
Third, there are Glu neurons that discharge during W and pro-
Unit gressively decrease their discharge during sleep to become silent
EEG/EMG: 1 mV
during PS with muscle atonia (Figs. 4.1 and 4.4). These W-max
Unit: 2 mV
1s
active Glu neurons have been recorded in the BF and LDT/SubLDT/
PPT [26,27], though they are presumed to be present more widely
(b) through the RF. (Only two W-max active GABA neurons have yet
10 to be identified, one in BF and one in LH (Hassani, Boucetta, and
Jones, unpublished data).) The discharge of the W-max active Glu
Unit spike rate (Hz)
8 neurons is positively correlated with EMG activity. They are thus

6 presumed to give rise to local and descending projections by which
they may stimulate muscle tone and behavioral arousal.
4
Fourth, there are Glu and GABA neurons that discharge mini-
2 mally during W and maximally during PS (Figs. 4.1, 4.5, and 4.6).
0
Such identified Glu and GABA PS-max active neurons have been
aW qW tSWS SWS tPS PS recorded in the BF, hypothalamus, and LDT/SubLDT/PPT, but
are presumed to be distributed more widely through the reticular
Fig. 4.2 (See colour plate section) Discharge of cholinergic W/PS-max active unit
core [26,27,30]. Glu PS-max active neurons have been recorded
across sleep–wake states in rat. Data from a recorded, Neurobiotin (Nb)-labeled cell
(#CBS28U03) that was identified as immunopositive for vesicular ACh transporter in the BF and LDT/SubLDT/PPT regions, including the SubLDT
(VAChT) and located in the LDT. (a) Polygraphic records from 10 s epochs or periods (ventral to the LDT), a region that, together with the more caudal
of the unit together with EEG (from retrosplenial cortex) and EMG activity during a subcoeruleus (ventral to the LC), corresponds to an area where
transition from SWS to aW (1), aW (2), SWS (3), a transition from tPS to PS (4), and lesions produce a marked loss of PS and muscle atonia [35–37].
PS (5). (b) Bar graph showing mean spike rate of the unit across sleep–wake stages. These Glu PS-max active neurons could exert an excitatory action
Note that during W (2), the unit discharged tonically at a slow rate (1.91 Hz) with upon other GABA or GABA/glycine (Gly) PS-max active neurons.
prominence of fast EEG activity, ceased firing during SWS (3) (0.06 Hz) in association
The GABA PS-max active neurons likely correspond to those iden-
with slow EEG activity (~1–4 Hz), and discharged maximally and tonically to reach
its highest rates during PS (5) (9.70 Hz) in association with prominent rhythmic theta tified by c-Fos, an indicator of enhanced neural activity, in studies
(~6–8 Hz) along with fast EEG activity. It changed its rate of discharge prior to cortical of PS rebound following deprivation [38–41]. They likely comprise
activation in the transition from SWS to aW (1) and prior to PS during tPS (4) as EEG GABAergic neurons in various regions that have the capacity to
activity progresses to theta. The unit discharge was significantly positively correlated inhibit other W-active neurons, including the W-max active Glu
with EEG gamma (r = 0.37) along with theta activity (r = 0.93). aW: active wake; qW: neurons in BF, PH, and LDT/SubLDT/PPT or RF, the NA and
quiet wake; tSWS: transition to slow-wave sleep; SWS: slow-wave sleep; tPS: transition Ser neurons in the brainstem, the HA neurons (and Orx neu-
to paradoxical sleep; PS: paradoxical sleep.
rons, discussed later in this section) in the PH. They would also
Reproduced from J Neurosci, 34(13), Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE,
Discharge Profiles across the Sleep–Waking Cycle of Identified Cholinergic, GABAergic, and
likely comprise the GABA/Gly neurons in the medulla, which can
Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat, pp. 4708–27, inhibit motor neurons in the brainstem or spinal cord during PS
Copyright (2014), with permission from Society for Neuroscience. (Fig. 4.1) [42,43].

SWS-max: Nb+/GAD+ neuron (BF) W-max: Nb+/VGluT2+ neuron (SubLDT)
(a)
(a) aW
aW OB
OB
PF
PF
1 RS
1 RS
EMG
EMG
Unit
Unit
EEG/EMG: 1 mV
Unit: 2 mV
1s
SWS SWS
OB
OB
PF PF
2
RS RS
2
EMG EMG
Unit
Unit
PS
PS OB
OB PF
3
PF RS
3 RS EMG
EMG Unit
Unit
(b)
20
18
16
14
(b) 12
5
10
4 8
6
3 4
2
2 0
aW qW tSWS SWS tPS PS
1
Fig. 4.4 (See colour plate section) Discharge of glutamatergic W-max active unit
0
aW qW tSWS SWS tPS PS across sleep–wake states in rat. Data from a recorded, Nb-labeled cell (#CBS47U02)
that was identified by in situ hybridization as expressing the vesicular Glu
Fig. 4.3 (See colour plate section) Discharge of GABAergic SWS-max active unit transporter (VGluT2) and was located in the SubLDT. (a, b) Note that this VGluT2+
across sleep–wake states in rat. Data from a recorded, Nb-labeled cell (c120u04) that cell discharged maximally and tonically during aW (1) (17.40 Hz) with fast EEG
was identified as immunopositive for glutamic acid decarboxylase (GAD) and located activity and high neck muscle tone, decreased its firing during SWS (2) (6.83 Hz) in
in the BF. (a) Polygraphic records from 10 s epochs of the unit spiking together with association with slow EEG activity and low muscle tone, and ceased firing during
EEG and EMG activity during aW (1), SWS (2), and PS (3). (b) Bar graph showing PS (3) (0.78 Hz) in association with theta EEG activity and muscle atonia. The unit
mean spike rate of the unit across sleep–wake stages. Note that the unit was virtually discharge was positively correlated with EMG activity (r = 0.69).
silent during aW (0.1 Hz), increased slightly during qW, then increased substantially Reproduced from J Neurosci, 34(13), Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE,
with tSWS to reach the highest rates during SWS (4.74 Hz), decrease slightly during Discharge Profiles across the Sleep–Waking Cycle of Identified Cholinergic, GABAergic, and
tPS, and decrease substantially during PS (0.4 Hz). Across sleep–wake stages, the unit’s Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat, pp. 4708–27,
discharge rate was significantly, positively correlated with delta EEG amplitude (r = Copyright (2014), with permission from Society for Neuroscience.
0.60). Calibrations: horizontal, 1 s; vertical, 1 mV (EEG, EMG), 2 mV (unit). OB: olfactory
bulb; PF: prefrontal cortex; RS: retrosplenial cortex.
According to these neurochemical and neurophysiological find-
Reproduced from J Neurosci., 29(38), Hassani OK, Lee MG, Henny P, Jones BE, Discharge
profiles of identified GABAergic in comparison to cholinergic and putative glutamatergic
ings, it appears that the major effector neurons of waking and sleep-
basal forebrain neurons across the sleep–wake cycle, pp. 11828–40, Copyright (2009), with ing and their cortical and peripheral variables are Glu and GABA
permission from Society for Neuroscience. neurons distributed through the reticular core of the brainstem

PS-max: Nb+/VGluT2+ neuron (LDT) PS-max: Nb+/GAD+ neuron (SubLDT)
(a) (a)
aW aW
OB OB
PF
PF
1 1 RS
RS
EMG
EMG
Unit
Unit EEG/EMG: 1 mV
Unit: 2 mV
EEG/EMG: 1 mV 1s
Unit: 2 mV
1s SWS
SWS
OB
OB
PF
PF
2 RS
2 RS
EMG
EMG
Unit
Unit
PS
PS OB
OB
PF
PF
3 RS
3 RS
EMG
EMG Unit
Unit
(b)
25
(b)
10 20
8 15
6 10
4
5
2
0
0 aW qW tSWS SWS tPS PS
aW qW tSWS SWS tPS PS
Fig. 4.6 (See colour plate section) Discharge of GABAergic PS-max active unit
Fig. 4.5 (See colour plate section) Discharge of glutamatergic PS-max active across sleep–wake states in rat. Data from recorded, Nb-labeled cell (#CBS28U04)
unit across sleep–wake states in rat. Data from a recorded, Nb-labeled cell that was immunopositive for GAD and located in the SubLDT. (a, b) Note that
(#CBS46U02) that that was identified by in situ hybridization as expressing this GAD+ cell discharged at relatively low rates during aW (1) (3.90 Hz) with fast
VGluT2 and was located in the LDT. (a, b) Note that this VGluT2+ cell discharged EEG activity and high EMG amplitude, increased firing during SWS (2) (6.05 Hz)
at its lowest rates during aW (1) (0.13 Hz) with fast EEG activity and high neck in association with slow delta EEG activity and low muscle EMG, and discharged
muscle tone, increased its firing during SWS (2) (1.77 Hz) in association with slow maximally during PS (3) (20.98 Hz) with theta and fast EEG activity accompanied
EEG activity and low muscle tone, and discharged maximally to reach its highest by muscle atonia. It increased its discharge most markedly immediately preceding
rate during PS (3) (9.42 Hz) in association with theta EEG activity and muscle PS during tPS. The unit discharge was positively correlated with EEG theta activity
atonia. It increased its rate most markedly immediately preceding PS during tPS. (r = 0.53) and negatively correlated with EMG amplitude (r = −0.45).
Reproduced from J Neurosci, 34(13), Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE, Reproduced from J Neurosci, 34(13), Boucetta S, Cisse Y, Mainville L, Morales M, Jones BE,
Discharge Profiles across the Sleep-Waking Cycle of Identified Cholinergic, GABAergic, and Discharge Profiles across the Sleep-Waking Cycle of Identified Cholinergic, GABAergic, and
Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat, pp. 4708–27, Glutamatergic Neurons in the Pontomesencephalic Tegmentum of the Rat, pp. 4708–27,
Copyright (2014), with permission from Society for Neuroscience. Copyright (2014), with permission from Society for Neuroscience.

and subcortical forebrain. The alternating activity of different Orexin neurons

W/PS-max active versus SWS-max active and W-max active versus With the discovery that mice lacking orexin (Orx, also called hypo-
PS-max active neurons would determine the cyclic changes in EEG cretin) and dogs lacking the receptor for Orx were afflicted with
activity from fast to slow and EMG activity from tonic to atonic, narcolepsy with cataplexy [44,45], it became evident that the Orx
corresponding to cortical activation to deactivation and behavio- neuropeptide was essential for the maintenance of waking with
ral arousal to quiescence (Fig. 4.1). Owing to oscillations in these muscle tone (Fig. 4.1). Orx-containing neurons are located in the
reciprocally active and interacting cell groups, a sleep–wake cycle PH in that region originally found to be important for the main-
with three states can emerge. These oscillations and resulting states tenance of waking. Like NA LC neurons, they give rise to highly
are modulated by MA and ACh, which act through their diverse diffuse projections through the entire brain and spinal cord, with
receptors differentially upon the executive Glu and GABA neurons. one neuron able to reach the cortex and spinal cord [46,47]. Under
Other important modulators of these systems are the neuropep- normal conditions, they are excited by all other arousal systems
tides, which have yet slower actions than the MA and ACh. and excite in turn all other arousal systems, including the NA, DA,
W-max: Orexin neuron (PH) PS-max: MCH neuron (PH)
(a) (c)
aW aW
EMG EMG
RS RS
Unit Unit
SWS SWS
EMG EMG
RS RS
Unit Unit
PS PS
EMG EMG
RS RS
Unit Unit
(b) (d)
1.2
5.0
1.0
4.0
0.8
3.0
0.6
2.0
0.4
1.0 0.2
0 0
aW qW tSWS SWS tPS PS aW qW tSWS SWS tPS PS
Fig. 4.7 (See colour plate section) Reciprocal discharge profile of Orx and MCH neurons across sleep-wake states in rat. (a, b) The mean spike rate per stage of Nb+/Orx+
units (n = 6; from [53]) varies in a reciprocal manner to that of Nb+/MCH+ units (c, d). The reciprocal firing profiles were not correlated with EEG gamma or delta activity,
but were correlated in an inverse manner with EMG amplitude, positively for the wake-active Orx neurons and negatively for the MCH sleep-active neurons.
Reproduced from Proc Natl Acad Sci U S A, 106(7), Hassani OK, Lee MG, Jones BE, Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep–
wake cycle, pp. 2418–22, Copyright (2009), with permission from National Academy of Sciences.

Ser, HA, ACh basalocortical, and Glu thalamocortical systems [48]. Acknowledgements
They can also directly excite neurons in the cerebral cortex [49] and
motor neurons in the spinal cord [50]. Moreover, they release Glu I thank my colleagues and members of my laboratory, particularly
in addition to Orx from certain terminals [51,52]. In unit record- Soufiane Boucetta, Oum Hassani and Maan Gee Lee, whose work
ing studies, it was found that Orx neurons discharge during waking (as cited) contributed greatly to the content of this chapter, and my
and become silent during sleep, as W-max active neurons (Fig. 4.7) sources of funding (the Canadian Institutes of Health Research
[53,54]. When specifically activated by optogenetic stimulation (CIHR MOP-13458 and 82762) and the United States National
during sleep, they promote awakening [55]. They can thus play a Institutes of Health (NIH R01 MH-60119-01A)).
central role in stimulating and maintaining waking and do so by
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CHAPTER 5
The genetics of sleep

Alexandra Sousek and Mehdi Tafti
Why hunt for genes involved in sleep? that processes of sleep homeostasis are under strong genetic control
[14]. Supporting Van Dongen’s claim that human neurobehavioral
The obvious variation of sleep phenotypes within the human popu- response toward sleep loss was an inter-â•‰individual trait-â•‰like charac-
lation and their intra-â•‰individual stability, as well as familial aggre- teristic, the neurobehavioral reaction toward sleep deprivation was
gation of certain sleep-â•‰related disorders, led to the hypothesis that determined as a highly heritable trait, in that decline in vigilance is
sleep might be influenced by genetic background. A multitude of significantly more similar in MZ than in DZ twins [13,20]. Since
twin studies and familial analyses on the prevalence and trans- increases in slow-â•‰wave activity (SWA) and delta power during
mission of sleep traits suggested a genetic contribution to various NREM sleep of recovery after sleep loss are well-â•‰established mark-
aspects of sleep and its disturbances. In particular, the human sleep ers for sleep homeostasis in humans, twin studies recording EEGs
EEG was found to be strongly influenced by genetic factors, which during and after sleep deprivation could further elucidate the herit-
is consistent with the finding that the human EEG in general is a ability of these homeostatic processes [21].
highly heritable trait [1,2]. However, modulations by age, gender, Another important aspect of sleep that has been intensively inves-
and environmental factors remain to be fully determined. For a tigated is subjective sleep quality, mainly assessed by the Pittsburgh
summary of twin studies, see Table 5.1, and for findings drawn Sleep Quality Index (PSQI). Substantial heritability of up to 44%
from familial studies, see Table 5.2.
Twin studies
Early twin studies already found a higher concordance of sleep Table 5.1â•‡ Genetic contribution to sleep phenotypes
habits, such as sleep duration and quality, in monozygotic (MZ)
than in dizygotic (DZ) twins, even when they were living apart and Sleep trait Estimated heritability References
thus exposed to different environments [3–â•‰5]. The first polysomno- Sleep duration 30–â•‰44% [3–â•‰5]
graphic recordings revealed concordant temporal sleep patterns in
Sleep quality 44–â•‰46% [5,22,25]
terms of sleep stages in MZ [6]â•„. Since then, many twin studies have
been performed to untangle the impact of dominant or additive Sleep efficiency and wake 50% and 42%, in males [10,13,33]
genetic influences and shared or nonshared environmental factors after sleep onset only
on the various aspects of sleep. Genetic background was proposed Sleep onset latency High sign correlation [10]
to contribute substantially to sleep duration, quality, onset latency in MZ only
and efficiency, diurnal preference, sleep structure, and characteris- Sleep architecture, stage Higher concordance [6,10,17,19]
tics of NREM sleep such as amount of sleep stages 2 and 4, delta/â•‰ changes, frequency profiles in MZ than DZ, sign
slow-â•‰wave sleep (SWS), and spindle density, as well as REM sleep correlation in MZ
and wake after sleep onset (see Table 5.1) [6–â•‰13]. While findings on 96%
REM sleep remain controversial, NREM sleep is found consistently
NREM sleep characteristics 50–â•‰96% [7,9,11,13,17,19]
to be under strong genetic control in humans and mice [1,8,14,15].
REM sleep amount was found to be significantly correlated in MZ (frequency profile, stage 2
amount, stage 3/â•‰4 amount
twins, and REM density was estimated to be up to 95% heritable
(SWS), spindle density)
in some studies, although others found no such relation [6,8–â•‰11].
Genetic influence on NREM sleep is well established. Even a geneti- REM sleep characteristics 50–â•‰95% [6,7,10,11,13]
cally determined “individual fingerprint” of NREM sleep structure (patterns, amount, density)
has been proposed, according to which an individual can be reli- Diurnal preference 45–â•‰52% [22,34,35]
ably distinguished from others, irrespective of sleep pressure as
Neurobehavioral reaction 83% [13]
assessed by sleep deprivation studies [16–â•‰18]. Further, theta, delta,
to sleep loss
alpha, and sigma frequency bands of the wake and NREM sleep
EEG were more significantly correlated in MZ than DZ twins [19]. Insomnia 43–â•‰57% [24–â•‰26]
Different aspects of sleep homeostasis, as assessed by effects of RLS and related symptoms 48–â•‰69% [28,36]
sleep deprivation, were found to be under genetic control in humans
Sleep-â•‰talking, bruxism, 54–â•‰70% in children [29–â•‰31]
and mice. Franken et al. were able to show in various inbred mouse enuresis 48–â•‰53% in adults
stains that delta activity rebound after sleep deprivation, and thus

Table 5.2 Familial and linkage studies can contribute to the development of appropriate treatments, risk
assessment, and prevention. In the following, the potential of such
Disease Mode of Involved molecules References studies will be demonstrated on the examples of familial advanced
inheritance or loci sleep phase syndrome, restless legs syndrome, and primary noctur-
nal enuresis.
Familial advanced Autosomal hPer2, CK1ɛ, and [37,38]
sleep phase dominant CK1δ Familial advanced sleep phase syndrome
syndrome (FASPS) Familial advanced sleep phase syndrome (FASPS) shows an auto-
Restless legs Autosomal 12q: RLS1 [43–49,54,59] somal dominant pattern of inheritance with high penetrance. Since
syndrome (RLS) dominant 14q: RLS2 this disease is characterized by early bedtime and early morn-
9q: RLS3 and RLS3* ing awakening, it is not surprising that links to genes underly-
2q: RLS4 ing circadian rhythmicity have been found. In a linkage analysis,
20p: RLS5
a specific haplotype of the human period (PER2) gene was found
co-segregating with FASPS [37]. Within this haplotype, an A-to-
19p
G transition leads to substitution of a conserved serine by glycine.
RLS Autosomal 12q: RLS1 [50] This missense mutation alters binding of casein kinase 1ε (CK1ε) to
recessive the Per2 protein and thus its phosphorylation. Further, a mutation
RLS Unclear 12q: RLS2 [52,55–58] in the gene encoding CK1δ (CSNK1D) itself can be causal for the
14q: RLS2 disease. Screening an FASPS kindred for mutations, a T-to-A trans-
MEIS1, BTBD9, version in a highly conserved sequence of CSNK1D was detected,
MAP2K5, LBOXCOR1, which co-segregates with the disease [38]. This missense mutation
DMT1 entails a threonine-to-alanine substitution leading to a decrease
Primary nocturnal Autosomal 4q [60,62–65]
in enzymatic activity and phosphorylation. Accordingly, animal
enuresis (PNE) dominant models carrying this mutation showed similar affected circadian
12q
phenotypes.
13q: ENUR1
22q: ENUR3 Restless legs syndrome
Restless legs syndrome (RLS) is suggested to be a polygenetic dis-
ease, with high familial vulnerability and an estimated heritabil-
ity of 50%, whereas the involved genetic regions and their mode
was estimated in several studies [5,22]. Further, with 94% asso- of inheritance remain controversial, indicating high heterogene-
ciation, a strong overlap of genetic influence on sleep quality and ity and complexity [39–41]. Linkage studies of affected families
diurnal preference was determined, suggesting common underly- revealed six associated loci on chromosomes 12q, 14q, 9p, 2q,
ing mechanisms [22]. 20p, and 6p termed RLS1–6, but without characterization of the
In dyssomnias and parasomnias, higher concordance and thus responsible genes [40,42–49]. Autosomal dominant transmission
estimated heritability rates were found in MZ compared with DZ was mainly suggested for RLS2 and RLS3, and in families with early
twins (see Table 5.1). Parasomnias comprise atypical behavior or onset of the disease, while RLS1 was repeatedly found to be reces-
physiological events occurring during specific sleep periods, such sive [40,42,44,50,51].
as sleepwalking or enuresis, while dyssomnias are characterized by Loci on chromosome 9 (RLS3 and possibly RLS3*) were con-
unusual amount, quality, or timing of sleep. A study on 100 MZ sistently found important [8, 43–45], while for other loci findings
and 199 DZ 8-year-old twin pairs estimated 71% of genetic con- remained more controversial. Bonati et al. reported linkage to a
tribution to variability for dyssomnias and 50% for parasomnias locus on 14q (RLS2) and co-segregation in an autosomal dominant
[23]. Studies on insomnia revealed up to 57% estimated heritabil- manner, while others could not confirm this in several French-
ity, whereas distinctive symptoms such as “trouble staying asleep” Canadian families [48,52]. Desautels et al. were able to define a
were found to be differentially modulated by genetic background 14.71 cM region on chromosome 12q (RLS1) conferring suscepti-
or gender [24–26]. Likewise, in sleepwalking, genetic effects were bility to the disease in an autosomal recessive way in a large French-
estimated to account for 80% of variability in males and 36% in Canadian family. This is especially interesting, since neurotensin
females [27]. Sleep-related breathing disorders and their associ- (NTS) is encoded in that region and acts as neuromodulator of
ated disabling symptoms such as excessive daytime sleepiness were dopaminergic transmission, which has repeatedly been associated
found to be heritable in up to 52% of cases [28]. Other conditions with RLS [49]. This putative connection is strongly supported by
with substantial genetic contribution are enuresis, bruxism, sleep- the observed relief of symptoms upon treatment with dopamine
talking, and restless legs syndrome [28–32]. agonists [42]. However, sequencing of this gene in four affected
families revealed two polymorphisms in the intronic region and
Familial studies and linkage analysis one in the 5′ UTR, but no co-segregation with the disease [53]. In
Certain sleep-related diseases show high familial risk and spe- contrast to the findings by Desautels et al. Kock et al. determined
cific modes of transmission (see Table 5.2). Linkage studies using autosomal dominant transmission concerning the 12q locus in two
microsatellite markers and phenotypes, testing for co-segregation South Tyrolean families [54]. Further analyses in 19 affected fami-
and inheritance patterns, aim to define chromosomal regions lies confirmed autosomal recessive transmission in some, and thus
conferring risk and susceptibility to the development of a disease, the involvement of another crucial locus was suggested [50]. The
and thus provide help to find the underlying genetic factors. This complexity and heterogeneity of the etiology of this disease are also

Chapter 5 the genetics of sleep 35
supported by findings of a study assessing linkage of RLS1, RLS2, analysis including affected families from eight European countries,
and RLS3 in 12 Bavarian families, where neither clear proof nor a novel region significantly linked to RLS in an autosomal domi-
disproof of linkage could be determined using parametric linkage nant manner was detected [59]. However, mutations in the genes of
analysis [55]. interest located in that area could not be found.
Xiong in 2007 investigated the possible influence of divalent Primary nocturnal enuresis
metal transporter 1 (DMT1), which is a good candidate, given
Linkage analyses concerning primary nocturnal enuresis (PNE)
the reduced iron levels in the brains of affected individuals, the
have revealed involvement of regions on chromosomes 12q, 13q
association with anemia, and the location of the gene on chromo-
(ENUR1), and 22q (ENUR3) [60–63]. Intriguingly, within the con-
some 12q, close to the RLS1 locus. Cell culture techniques showed
fined region on chromosome 12q, the aquaporin-2 water channel is
no difference in protein levels in blood cells of patients and con-
encoded, but the transitions found did not lead to functional altera-
trols. Neither a linkage between the DMT1 gene region and RLS
tion of the protein [62]. More recently, a new locus on chromo-
nor any underlying mutations within the gene region were found.
some 4 has been found to segregate with nocturnal enuresis and
However, two single nucleotide polymorphisms (SNPs) in the
incontinence with high penetrance. This region on 4p16 contains
intronic region were associated with the disease in patients with
the dopamine receptor genes DRD5 and D1B, which might be good
anemia [56].
candidates [64].
More recently, further regions conferring susceptibility have
been identified by applying genome-wide association analysis
(GWAS). Winkelmann et al. determined highly significant associa- Effects of genetic variation on sleep
tions between the disease and intronic variants of MEIS1 (home- To understand the contribution of genetic variation and involved
obox) on 2p, BTBD9 (POZ domain) on 6p, and a locus containing molecular pathways to sleep phenotypes and the development of
the MAP2K5 (kinase) and LBOXCOR1 (transcription factor) genes disease, association to, and thus assumed influence of, naturally
on chromosome 15q [57]. Accordingly, Stefansson found a com- occurring SNPs and variable number of tandem repeats (VNTRs)
mon intronic variant of the BTBD9 gene significantly associated have been extensively studied. This has indeed led to a considerable
with the disease and responsible for 50% of risk in this population amount of knowledge being obtained about the factors involved,
[58]. Intriguingly, this was accompanied by decreased serum fer- but the picture is not complete, and the interaction and mutual
ritin levels, since RLS is considered to be associated with disturbed influence of involved pathways remain unclear and require further
brain iron metabolism [42,58]. This region on chromosome 6p21 is study. For an overview of genetic variations affecting sleep pheno-
also referred to as RLS6 [40]. Recently, in a genome-wide linkage types, see Table 5.3.
Table 5.3 Genetic variations affecting sleep phenotypes
Gene Modification Affected phenotype/trait References

ADA SNP, missense mutation Sleep architecture, SWS and delta power, reaction to sleep deprivation [67,68]
ADORA SNPs EEG frequencies in sleep and wake, sensitivity to caffeine, vigilance, [69,70]
reaction to sleep deprivation
MAOA VNTR Sleep quality, depression, RLS, narcolepsy controversial [71–74]
COMT Missense mutation SWS, reaction to sleep deprivation, sensitivity to modafinil, narcolepsy [74,78–80]
symptoms
SLC6A3 (DAT) VNTR Reaction to sleep deprivation, sensitivity to caffeine [83]
HTR2A (5-HT2A SNP Risk for OSA [90,91]
receptor)
SLC6A4 (5-HTT) Insertion/deletion variant Risk for primary insomnia and sleep quality [92–95]
GABRA (GABAA Missense mutation Primary insomnia [99]
receptors)
BDNF Missense mutation NREM frequencies, SWS, reaction to sleep deprivation, working memory [101]
TNFA SNPs in promoter and coding region Association with narcolepsy, partly dependent on HLA type [107,112]
TNFR2 Missense mutation Association with narcolepsy [113]
PRNP Missense mutations Trigger of FFI/CJD and modulation of phenotype [114,116]
HCRT Missense mutation in signal peptide Severe early onset narcolepsy with cataplexy [119]
PER3 VNTR, SNPs in promoter region, Diurnal preference, sleep latency, DSPS, reaction to sleep deprivation [135,136,138–142]
PER2 and CSNK1 Missense mutations DSPS [37,38]
CLOCK SNP in 5′ UTR Diurnal preference [143,144]

Adenosinergic neurotransmission Dopaminergic neurotransmission

Adenosinergic neurotransmission is suspected to play a major role A G-to-A transition in catechol-O-methyltransferase (COMT)
in the regulation of sleep and wakefulness and their homeostasis entails a functional polymorphism resulting in a valine–methionine
in mice and humans [14,66]. Common genetic variants affecting exchange. This leads to reduced activity of the dopamine-
different aspects of sleep homeostasis in healthy humans support metabolizing enzyme and thus higher dopaminergic transmis-
this hypothesis. A functional SNP on the human chromosome sion. Indeed, Val/Val homozygous subjects show less dopaminergic
20q13.11 changes a guanine (G) to adenine (A) in the adenosine signaling in their prefrontal cortex (PFC) than those carrying Met/
deaminase (ADA) enzyme. Asparagine (in the ADA*1 variant) is Met [77]. Bodenmann et al. found no effects of this polymor-
changed into aspartic acid (in the ADA*2 variant), which results phism on baseline sleep, while Goel observed differences in SWS
in lower enzymatic activity and thus less adenosine degradation decline [78,79]. In chronic partial sleep deprivation of five consec-
in heterozygous G/A (ADA*1–2) carriers compared with G/G utive nights with 4 hours sleep, Val homozygotes showed smaller
(ADA*1). Concerning sleep, Retey et al. found an increase in slow- increase in SWS, while Met homozygotes had steeper SWS decline.
wave sleep (SWS) during an undisturbed night in ADA*1–2 carri- This was accompanied by shorter REM sleep latency in Val/Val
ers resembling the effects of one night of sleep deprivation. This was subjects [79]. Further, the commonly used stimulant modafinil,
further accompanied by higher delta power in NREM sleep, which which promotes dopaminergic neurotransmission, was shown
is a marker of sleep need [67,68]. Also, the response to sleep depri- to be effective in terms of counteracting total sleep deprivation-
vation was found to be modulated by this genotype, with elevated induced impairments of attention and other cognitive functions in
SWS and delta activity in NREM sleep of recovery nights after 40 Val homozygotes only [80]. Val genotype enhanced certain NREM
hours of prolonged wakefulness in ADA*1–2 subjects [67]. Thus, it frequency bands during recovery sleep, but without changing slow-
is assumed that reduced enzymatic activity due to genetic variabil- wave activity [78]. Thus, homeostatic processes as well as stimulant
ity leads to enhanced build-up of sleep pressure. efficiency seem to be modulated by dopaminergic signaling, and
Among adenosine receptors, it is mainly subtypes A1 and A2A that this polymorphism might be of interest in stimulant treatments.
are considered important in sleep regulation [66]. The thymine (T)- Dauvilliers et al. found no association between COMT genotype
to-cytosine (C) transition in the coding region of the A2A receptor and narcolepsy, but an interaction of gender and genotype as well as
gene (ADORA2A) on chromosome 22q11.2 not only affects EEG a strong influence on severity of the disease independent of gender
activity, generally irrespective of sleep and wake, but also modu- was observed [74]. Females homozygous for the less active allele
lates the effects of its antagonist caffeine on sleep and sleep depri- as well as heterozygotes exhibit higher sleep latency than those
vation. Only C/C carriers show increases in high-frequency EEG homozygous for the highly active variant. The opposite effect was
after sleep deprivation. Further, the C-allele was found to confer observed in males. Irrespective of gender, more sleep paralysis but
sensitivity to caffeine-induced sleep disturbances [69]. Analysis of less sleep onset REM periods were observed in heterozygous nar-
the effects of combinations of eight SNPs of the ADORA2A gene coleptic patients. HLA type was found not to interact with COMT
revealed that one haplotype (HT4) was associated with enhanced genotype.
vigilance at the baseline, but resistance to caffeine-induced rescue A crucial player in dopaminergic signaling is the dopamine
of vigilance decline after sleep loss was observed in non-HT4 car- transporter (DAT), whose blockage by modafinil results in ele-
riers. Likewise, caffeine had differential effects on SWS in recovery vated dopamine levels in the extracellular space. DAT knockout
sleep that were dependent on genotype. While non-HT4 carriers mice are insensitive to modafinil, but show increased consolidated
showed reduced SWS upon caffeine administration, this effect was wakefulness, less REM sleep, and hypersensitivity to caffeine [81].
missing in HT4 individuals. The build-up of sleep pressure assessed In humans, a VNTR polymorphism in the 3′ UTR of the DAT-
by EEG and increase in subjective sleepiness were not affected [70]. encoding gene SLC6A3 leads to less DAT in the striatum in indi-
viduals homozygous for the long 10-repeat allele as compared with
Monoamine oxidase carriers of the 9-repeat allele [82]. According to the animal data,
10/10 carriers are more sensitive to caffeine generally, as well as to
Monoamine oxidase (MAO) A and B are encoded on the
its effect on reducing SWS rebound after sleep deprivation, which
X-chromosome and catalyze the degradation of monoamines:
was found more pronounced in 10-repeat homozygotes [83].
the catecholamines dopamine, noradrenaline (norepinephrine),
and adrenaline (epinephrine) and the tryptamines serotonin and
melatonin. Thus, it is an important enzyme for the regulation of Serotonergic neurotransmission
major neurotransmitters implicated in sleep. Females carrying an It is well established that serotonergic or 5-hydroxytryptamine
allele conferring higher activity due to a variable number tandem (5-HT) activity promotes wakefulness and inhibits REM sleep.
repeat (VNTR) polymorphism in the MAO-A promoter region are The serotonergic receptors 5-HT1–7 exert different functions
at higher risk of developing RLS [71]. Further, the less active allele according to their associated second messengers. Thus, postsyn-
seems to confer susceptibility to depression and poor sleep quality aptic cells can either be inhibited (5-HT1A and 5-HT1B) or depo-
[72]. Koch et al. proposed an association of a VNTR in intron 1 of larized (5-HT2A/2C, 5-HT3, and 5-HT7) upon receptor activation.
the MAOA gene and a dinucleotide repeat in intron 2 of the MAOB Further, the outcome of their activation depends on their locali-
gene with the occurrence of narcolepsy with cataplexy [73]. This zation. Activation of 5-HT1A and 5-HT1B receptors expressed by
could not be confirmed by others, suggesting HLA type and gen- GABAergic and of 5-HT3 receptors expressed by glutamatergic
der as underlying causes for the difference [74]. However, MAO-A interneurons lead to disinhibtion and stimulation, respectively.
and -B inhibitors are capable of reducing symptoms of narcolepsy On the other hand, activation of 5-HT2A/2C or 5-HT7 expressed by
such as cataplexy and abnormal REM sleep [75,76]. GABAergic interneurons leads to inhibition, and the activation of

all receptor types leads to inhibition of cholinergic neurons. Within leads to amino acid substitution from valine to methionine and
this complex system, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3, thus impaired activity-dependent secretion of the protein, which
and 5-HT7 receptors have been shown to be involved in the regu- is implicated in synaptic plasticity and associated with cognitive
lation of wakefulness and REM sleep [84]. Mice lacking 5-HT1A performance [1]‌. Heterozygous carriers of the Met allele show
or 5-HT1B receptors have more REM sleep than wild types, but decreased slow wave sleep and delta and theta power in NREM
unchanged wake and SWS [85,86]. 5-HT7 knockouts show lower sleep during undisturbed nights, as well as after one night of sleep
amounts and fewer episodes of REM sleep [87]. 5-HT2 subunits deprivation [101]. Likewise, in previous studies, impacts on cogni-
were suspected to be implicated in NREM sleep regulation, and tive function, i.e. working memory, were observed [101,102]. Thus,
knockout of 5-HT2A or 5-HT2C leads to more wake, reduced NREM implication of this polymorphism in plasticity and regulation of
sleep, and abnormalities in REM sleep in mice [88,89]. sleep homeostasis is assumed.
In humans, polymorphisms in the gene HTR2A encoding the
5-HT2A receptor have been suspected to confer risk of obstruc- Tumor necrosis factor
tive sleep apnea (OSA), and functional binding of serotonin to Tumor necrosis factor (TNF) α is a pro-inflammatory cytokine
5-HT2A expressed on motor neurons of the upper airways is crucial involved in many processes and also proposed to be involved in
to ensure proper respiration during sleep. Recent meta-analyses of sleep regulation. Evidence comes from observations that injection
studies investigating associations of a −1438G/A polymorphism of TNF-α in rodents dose-dependently increases NREM sleep and
in the promoter region of HTR2A and/or silent T102C polymor- suppresses REM sleep [103–105]. Accordingly, disruption of its
phisms with the risk of OSA found a significant association for the functionality by administration of anti-TNF-antibodies or creation
first only in that homozygosity for the A variant confers risk, espe- of TNF receptor knockout mice lead to blockage of NREM sleep
cially in males [90,91]. and sleep disturbances [105,106]. Since in humans several poly-
Also, the serotonin transporter (5-HTT), which determines morphisms in the promoter region of the TNFA gene are known
the amount of serotonin in the synaptic cleft, might be involved. and linked to neurological and inflammatory diseases and the gene
A common 44 base-pair insertion/deletion variant in the regula- lies within the HLA class II cluster, it has become a target of inter-
tory 5′ region of the serotonin transporter gene SLC6A4 affects its est in the pathophysiology of narcolepsy [107]. Indeed, narcoleptic
expression and thus the abundance of 5-HTT at the synapse. An patients show elevated plasma levels of TNF-α and soluble TNF-
association study revealed that the short variant of this polymor- α receptor but no mutation either in TNFA or in TNF-α receptor
phism is significantly more common in patients suffering from genes was detected [108–111]. Results for the numerous SNPs are
insomnia than in healthy controls [92]. Further, this polymorphism inconsistent, partly owing to HLA type or ethnicity. In association
was proposed to mediate environmental effects such as chronic studies, Hohjoh et al. found a SNP in the promoter region of TNFA
stress and stressful life events on sleep quality and length, respec- significantly associated with narcolepsy independent of HLA
tively [93,94]. Nevertheless, another study found homozygosity for haplotype DRB1*15:01 as well as an association of disease with a
the long allele to be associated with poor sleep [95]. polymorphism in the TNF receptor 2 gene (TNFR2) that leads to
exchange of a methionine with an arginine [112,113]. Wieczorek
GABAergic neurotransmission et al. found a C857T polymorphism in TNFA associated with nar-
Several lines of evidence point to involvement of the main inhibi- colepsy, but only in DRB1*15/16-negative German patients, while
tory neurotransmitter γ-aminobutyric acid (GABA) in the initia- no such link was detected in a Taiwanese study [107,108]. The SNPs
tion of sleep, as well as in the etiology and maintenance of primary C863A and G308A of TNFA and a microsatellite adjacent to the
insomnia. Studies applying magnetic resonance spectroscopy gene were not found to be linked to narcolepsy independent of
found reduced GABA levels globally or in the occipital cortex and HLA in a German sample [107]. Likewise T-1031C, C-863A, and
anterior cingulate cortex but not the thalamus of patients with pri- a SNP leading to a missense mutation in TNFR2 were found not to
mary insomnia [96,97]. Others detected elevated occipital corti- be associated in the Taiwanese population [108].
cal GABA levels and proposed that this was a countermeasure to
hyperarousal [98]. Consistently, they found levels of GABA to be Prion protein
negatively correlated with the amount of wake after sleep onset Fatal familial insomnia (FFI) is a highly penetrant hereditary dis-
[96,98]. Screening for mutations in ligand-binding domains of the ease transmitted in an autosomal dominant manner. FFI is char-
α1, β3, and γ2 genes of the GABAA receptor revealed a heterozy- acterized by disrupted sleep, i.e., loss of sleep spindles and SWS,
gous missense mutation in one patient with chronic insomnia. The and impaired sleep stage organization, as well as progressive reduc-
substitution of arginine for histidine presumably entails reduced tion of sleep time. This goes along with reduced metabolism in
GABAergic inhibition [99]. thalamic and limbic regions and degeneration of thalamic nuclei.
Investigation of two Italian affected kindred revealed an underlying
Brain-derived neurotrophic factor point mutation in the prion protein (PrP) gene (PRNP) on chro-
Evidence for the involvement of brain-derived neurotrophic fac- mosome 20. A missense mutation, a G-to-A transition at codon
tor (BDNF) in sleep–wake regulation was found in animal stud- 178, leads to substitution of aspartate for asparagine [114,115].
ies [14,100]. In a sleep deprivation study on six inbred mouse Creutzfeldt–Jakob disease (CJD) is characterized by the same muta-
strains, a chromosomal region containing the gene encoding the tion and accumulation of protease-resistant prion protein plaques,
BDNF receptor tyrosine kinase B (TrkB) determined 49% of vari- but differs from FFI regarding a polymorphism at codon 129,
ance in the build-up of sleep pressure [14]. In rats, BDNF secre- which is common and leads to either incorporation of a methio-
tion was suggested to be a mediator of sleep homeostasis [100]. In nine or valine, and further to protein isoforms differing in size and
humans, a common functional polymorphism, a G-to-A transition, glycosylation pattern [116]. While in FFI-affected individuals the

mutated allele encodes for methionine, those with CJD express the basic helix–loop–helix PAS transcription factors CLOCK and
valine on the mutated PRNP allele [117]. Studies on further kin- BMAL1 form the heterodimer BMAL1/CLOCK (alternatively
dred confirmed the influence of the 129 polymorphism on the BMAL1/NPAS2), which binds to E-Box elements of promoters and
expressed phenotypes of the different prion-related diseases [115]. induces transcription of, among others, the cryptochrome 1 and
2 (CRY1 and CRY2) and period (PER1–3, PER3 only in humans)
Orexin/hypocretin genes and the gene encoding the nuclear receptor Rev-Erbα
Neurons expressing the neuropeptides hypocretin-1 (HCRT-1) (NR1D1). The PER and CRY proteins, in turn, act as negative regu-
and -2 (HCRT-2), also termed orexin A and B, which are pro- lators of CLOCK/BMAL1 activity by forming a repressor complex
cessed from their common precursor prepro-hypocretin (HCRT), with casein kinase (CK) 1ε (encoded by the CSNK1E gene) and
are exclusively found in the lateral hypothalamus. They have CK1δ (CSNK1D). Rev-Erbα represses transcription of CLOCK and
widespread projections throughout the brain, such as the cortex BMAL1 [128–130]. Besides their function in circadian rhythmic-
and pons, and are involved in the arousal system. Two receptors ity, clock genes have also been found to influence sleep variables.
(HCRTR-1 and HCRTR-2) have been defined up to now. Several Supporting evidence comes from animal models showing that
lines of evidence point toward involvement of deficiency in this knockout of BMAL1 and NPAS2 and double knockout of Cry1 and
system in narcolepsy. In humans, reduced levels of HCRT-1 in cer- Cry2 lead to abnormalities in sleep homeostasis in mice [131–134].
ebrospinal fluid (CSF) and several brain regions and deficiency of One of the most intensively studied “clock” genes is the human
prepro-hypocretin mRNA in the hypothalamus, as well as loss of period 3 (PER3) gene on chromosome 1. PER3 polymorphism has
orexin-producing cells, have been documented [118–120]. In dogs, repeatedly been associated with diurnal preference and delayed
an autosomal recessive mutation in the Hcrtr2 gene causes narco- sleep phase syndrome (DSPS) [135–138]. A VNTR in the cod-
lepsy, and mice that lack prepro-hypocretin show symptoms of the ing region leads to either a short or a long allele; PER34 or PER35,
disease [121,122]. Consequently, intensive screening for human respectively. Homozygosity for the longer variant PER35/5 is con-
mutations has been performed. Neither a common C-to-T poly- sistently found to be associated with morningness, and homozygo-
morphism in HCRT nor a previously reported polymorphism in its sity for PER34/4 with eveningness. This variation further influences
5′ UTR were found to be associated with narcolepsy in a study with sleep latency, amount of SWS, and differences in recovery from
105 families [123]. This holds also for 14 defined polymorphisms in sleep deprivation. Individuals homozygous for the long allele
hypocretin receptors, although normal CSF levels of HCRT-1 found (PER35) show more SWS in NREM and more alpha activity in
in some patients point toward receptor defects [119]. Similarly, REM sleep, earlier wake and bed times, and less daytime sleepiness,
there are families lacking HCRT-1 in the CSF without mutations as well as a more intense response to sleep deprivation regarding
in the HCRT gene and delayed onset of disease [119]. To date, only cognitive decline and reduced brain activation when performing
one functional polymorphism is known, found in a patient with executive tasks, especially in the early morning [138–140]. Other
severe cataplexy and unusually early onset of the disease. A G-to-T studies applying chronic partial sleep deprivation found an effect
transversion leads to a change in the signal peptide of HCRT, where of the polymorphism on sleep homeostasis but not on cognitive
a highly charged arginine is introduced in a hydrophobic polyleu- performance [141]. Several further polymorphisms of PER3 were
cine stretch of the peptide, which alters trafficking and impairs defined and associated with DSPS [142]. Four haplotypes consist-
cleavage. The attempt to assign this as a de novo mutation failed ing of five polymorphisms in the coding region were investigated
because DNA was only available from the unaffected mother but and one haplotype was found to be significantly associated with
not the unaffected father [119]. the disease. Functionally, the glycine incorporated into the protein
The strong association of the disease with HLA allelic variants instead of a valine in that haplotype was suggested to alter phospho-
led to the hypothesis of autoimmune destruction of hypothalamic rylation of the PER3 protein by CKIɛ. Further, the majority (75%)
hypocretin neurons [124]. Enriched tribbles homologue 2 (TRIB2), of patients suffering from DSPS were found to carry the PER34/4
which can serve as an autoantigen, in hypocretin-producing neurons variant, which is associated with eveningness [136]. A study inves-
of a transgenic mouse model, as well as elevated levels of TRIB2- tigating the promoter region of PER3 revealed two SNPs that were
specific antibodies in serum of narcoleptic patients corroborate this more prevalent in DSPS patients compared with either morning or
theory [125,126]. However, the exact underlying mechanism of the evening types of the healthy control subjects and thus could con-
destruction of orexin-producing cells remains unknown. tribute to the disease by changing the expression levels [135]. As
A recent study showed that the re-expression of orexin receptors described in the section on FASPS earlier in this chapter, altered
on noradrenergic neurons in the locus coeruleus and on seroton- phosphorylation of PER2 due to a missense mutation of CK1 or its
ergic neurons in the dorsal raphe nuclei of orexin receptor knock- binding site is involved in FASPS [37,38].
out mice could rescue symptoms of narcolepsy [127]. Intriguingly, In 1998 Katzenberg found a T3111C polymorphism in the 3′
the amount of restored orexin signaling on serotonergic neurons UTR of CLOCK associated with diurnal preferences, in that car-
correlated with the observed reduction in cataplexy, and that on riers of the C allele are more often evening-type [143]. Since then,
noradrenergic neurons correlated with reduced fragmentation of controversial replications of that finding have been reported. In
wakefulness [127]. This suggests a crucial interaction of different a Japanese sample, the highest eveningness was likewise found
neurotransmitter systems in the pathophysiology of narcolepsy. in C/C homozygous subjects, together with significantly delayed
sleep onset, shorter sleep duration, and higher daytime sleepiness
Circadian “clock” genes compared with either heterozygous or homozygous T-allele carri-
In mammals, a transcription–translation feedback loop serves as ers. [144]. On the contrary, studies performed in Caucasian and
the basic mechanism for the clock machinery in the suprachias- Brazilian subjects found no association with either diurnal prefer-
matic nucleus (SCN) to control circadian rhythmicity. Briefly, ence or DSPS [145,146].

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CHAPTER 6
Physiological changes in sleep

Sleep is not a passive state where physiological processes are sim- Changes in cerebral blood flow and metabolism during sleep are
ply suspended. Research has shown that several important, well-â•‰ discussed in detail later in the chapter.
defined physiological changes occur during sleep, involving the
central nervous system (CNS) and the autonomic nervous sys- Changes in the autonomic nervous system
tem (ANS), the neuromuscular, respiratory, and cardiovascular
systems, the gastrointestinal tract, the endocrine system, and the The ANS receives input from, and has widespread effects on, several
systems controlling temperature regulation and immune regula- body systems and functions. Peripheral receptors in the cardiovas-
tion. An understanding of these changes is important for the clini- cular and respiratory systems, as well as the gastrointestinal tract,
cal care of patients with sleep disorders and sleep deprivation from relay to the medullary NTS, which, through its diffuse afferent and
a number of causes. This chapter provides a brief overview of the efferent projections, exerts autonomic control on cardiac rhythm
physiological changes associated with sleep in the above systems. and rate, circulation, respiration, and gastrointestinal motility and
secretion. The efferents from the NTS also project to the hypotha-
lamic and limbic regions and to the ventral medulla, which exert
Changes in the central nervous system significant control over cardiovascular regulation. The final com-
The brain is not quiescent during sleep. Various areas of the CNS mon pathways from the NTS are parasympathetic efferents aris-
are highly active during sleep, as demonstrated by electrophysio- ing in the nucleus ambiguus and traveling through the vagus nerve,
logical, immunohistochemical, and functional imaging studies of and sympathetic fibers arising in the hypothalamic paraventricular
the brain, such as positron emission tomography (PET) and func- nucleus to sympathetic preganglionic neurons in the spinal cord.
tional magnetic resonance imaging (fMRI), showing activation Acting together, these autonomic mechanisms maintain internal
and deactivation of specific regions of the brain (see Chapter 11). homeostasis [2–â•‰4].
There is decreased intracortical facilitation in rapid eye movement Changes in the ANS during sleep result in profound alterations
(REM) sleep and increased intracortical inhibition of interneurons in multiple systems [5]â•„. The basic autonomic changes during sleep
in non-â•‰REM (NREM) sleep. During NREM sleep, some regions include increased parasympathetic tone and decreased sympa-
(such as the ventrolateral preoptic and median preoptic neurons thetic activity during NREM sleep, accompanied by a reduction
in the anterior hypothalamic nuclei, and, to a certain extent, also of circulating levels of norepinephrine (noradrenaline) and epi-
the lower brainstem nucleus tractus solitarius (NTS) and the me- nephrine (adrenaline). These changes lead to pupillary constric-
dullary GABAergic parafacial zone) are activated, whereas the tion, a fall in blood pressure and bradycardia. During REM sleep,
activity of other regions (wakefulness-â•‰promoting histaminergic, there is a further increase in parasympathetic tone and a further
aminergic, serotoninergic, and orexinergic neurons, the ascend- decrease in sympathetic activity; however, there is an intermittent
ing reticular activating system, and most of the cerebral cortical increase of sympathetic activity during phasic REM sleep result-
regions) is markedly reduced. During REM sleep, much of the cor- ing in phasic pupillary dilatation and swings in blood pressure and
tical regions are activated, along with the generators of REM sleep heart rate, causing tachy–â•‰brady arrhythmias. Heart rate variabil-
in the pons (the pedunculopontine and laterodorsal tegmental nu- ity (HRV) studies [6] reflect these changes; during NREM sleep,
clei, and the sublaterodorsal (SLD) nucleus in rats, which is equiva- the low-â•‰frequency (LF) component decreases, whereas the high-â•‰
lent to the peri-â•‰locus coeruleus alpha in cats and the subcoeruleus frequency (HF) component increases, reflecting increased vagal
in humans); simultaneously, mechanisms that paralyze the body tone. In contrast, during REM sleep, extreme variation in LF and
are brought into action to ensure REM atonia, preventing dream-â•‰ HF with increased LF and decreased HF components occurs. The
enacting behavior. Both somatosensory cortical (SEP) and motor HF component mainly reflects the respiration–â•‰vagal modulation of
evoked potential (MEP) amplitudes attenuate in sleep. There is sinus rhythm, whereas the nonrespiratory LF component reflects
dampening of spinal and cranial motor reflexes because of motor the sympathetic modulation of the heart in addition to baroreflex
neuron hyperpolarization, presynaptic inhibition, and dysfacilita- responsiveness to beat-â•‰to-â•‰beat variations in blood pressure [7–â•‰10].
tion of brainstem aminergic and lateral hypothalamic orexinergic Power spectral analysis [11] suggests that the wake/â•‰sleep transition
neurons projecting to brainstem motor neurons as well as to ven- period represents a transitional process between two physiologi-
tral horn cells of the spinal cord. The extensor plantar response cally different states, with a decrease in LF power and unchanged
(Babinski’s response), which is absent in wakefulness in normal HF power causing a decrease in the LF/â•‰HF ratio and reflecting a
individuals, may be elicited in sleep [1]â•„. shift toward parasympathetic predominance. Thus, NREM sleep is

a state of relative cardiorespiratory stability, whereas REM sleep is a 0

state of profound instability with intense autonomic and respiratory Awake
Asleep
dysregulation. Reduced HRV may be noted in patients with myo- 4
cardial infarction, cardiac transplantation, or diabetic autonomic
Time (days)
neuropathy. Reduced HRV is a strong and independent predictor 8
of mortality after acute myocardial infarction [12]. Additionally,
lethal arrhythmias are related to either increased sympathetic activ- 12
ity or decreased vagal activity.
16
Sleep disorders can affect the normal changes that occur in the Low point
ANS during sleep. For example, patients with OSA have chronic in body temperature
20
sympathetic hyperactivity, which is thought to predispose to day-
time hypertension, cardiac ischemia, heart failure, and stroke [13]. 0 12 24 12 24 12 24 12 24 12 24
Similarly, patients with sleep terror, REM sleep behavior disorder Time of day (hours)
(RBD), and narcolepsy suffer from episodic disruptions of autonomic
Fig. 6.1 Synchronized (light-entrained) and desynchronized (free-running)
control during sleep, which may have implications for the control of rhythms in a person showing dissociation between body temperature and sleep-
the circulatory, respiratory, gastrointestinal, and urogenital systems. activity cycles.
Reproduced from Aerospace Med, 40, Aschoff J, Desynchronization and resynchronization of
Changes in the peripheral nervous system human circadian rhythms, pp. 847, Copyright (1969), with permission from Aerospace Medical
Association.
Muscle hypotonia
One of the cardinal features of sleep is progressive loss of muscle
[22]. When sleep–wake cycles and temperature cycles are dissoci-
tone as a subject transitions from wakefulness to NREM sleep and
ated from each other, for example when environmental cues such as
finally to REM sleep, where muscle hypotonia is most pronounced.
light are removed, the independent nature of the two becomes ob-
In NREM sleep, several factors seem to contribute to the mild hypo-
vious (Fig. 6.1). Body temperature follows a sinusoidal rhythm with
tonia; in particular, inhibition of noradrenergic locus coeruleus
a peak around 9:00 pm and a minimum (nadir) around 3:00 am as
and serotonergic midline raphe neurons, as well as mild hyperpo-
a result of circadian rhythmicity (Fig. 6.2). Thus, the core tempera-
larization of motor neurons in the brainstem and spinal cord [14].
ture nadir occurs 2–3 hours before habitual wake time, a fact that is
Additionally, during REM sleep, the near-complete paralysis of most
of crucial importance in the detection and treatment of circadian
voluntary muscles (with the exception of the diaphragm, extraocu-
rhythm disorders (see Chapters 21 and 22).
lar, and middle ear muscles) is thought to be due to activation of a
As with the sleep–wake circadian rhythm (see Chapter 3), the
specific group of neurons in the dorsal pontine tegmentum [15,16],
master clock for the temperature regulation rhythm is in the supra-
particularly pathways from the peri-locus coeruleus alpha and the
chiasmatic nucleus (SCN) of the hypothalamus, through its pro-
SLD causing disinhibition of cholinergic neurons, and inhibition of
jections to the thermosensitive neurons of the GABAergic median
noradrenergic and serotonergic neurons in the pons. The cholinergic
preoptic nucleus (MnPN) of the anterior hypothalamus (POAH).
neurons, in turn, excite pontine glutamatergic neurons projecting to
The MnPN and the ventrolateral preoptic (VLPO) nucleus of the
the glycinergic and GABAergic premotor neurons in the medullary
POAH are also responsible for generation of NREM sleep [23].
reticular formation, causing hyperpolarization of the motor neu-
Thus, the POAH region is responsible for both thermoregula-
rons and muscle paralysis during REM sleep [17]. The ventral SLD
tion and NREM sleep, explaining the close association of the two
sends both direct and indirect projections via the ventromedial me-
rhythms. However, this arrangement is subject to external influ-
dulla that hyperpolarize motor neurons in the brainstem and spinal
ences. Warmth-sensitive neurons of the POAH receive inputs from
cord through inhibitory GABAergic and glycinergic pathways.
peripheral cutaneous receptors and increase firing rates at sleep
Additional contribution to REM atonia comes from dysfacilitation
onset while decreasing the rates at sleep offset [24]. Peripheral heat
of lateral hypothalamic hypocretinergic neurons. At the cellular
level, the atonia of REM sleep is due to enhanced inhibitory postsyn-
aptic potentials (IPSPs). The abrupt, jerky, purposeless movements
seen intermittently during phasic REM sleep, manifested as muscle
twitching seen on EMG channels in PSG recordings and sometimes 36.8
clinically, are thought to be due to excitatory postsynaptic potentials
(EPSPs) in the motor neurons [18,19] mediated by the reticulospi- 36.6
Temp C
nal and vestibulospinal rather than the corticospinal and corticobul-

bar tracts [20]. The IPSPs and EPSPs are kept balanced during REM
sleep to ensure that voluntary muscles remain paralyzed as the brain 36.4
is active and dreaming; failure of this system results in pathological
dream-enacting behavior, as may occur with RBD [21].
0600 0900 1200 1500 1800 2100 0000 0300 0600

Thermal regulation in sleep
Body temperature regulation follows a circadian rhythm that is Fig. 6.2 Body temperature follows a sinusoidal rhythm with a peak around 9:00
closely linked to, but is independent of, the sleep–wake rhythm pm and a minimum (nadir) around 3:00 am as a result of circadian rhythmicity.

Chapter 6 physiological changes in sleep 45
loss, such as may occur with vasodilation after a hot bath, or even
Box 6.1 The respiratory muscles
just warming the feet, results in shortened sleep onset latency and
increased slow-wave sleep (SWS) [25–27]. Conversely, a rise in core Inspiratory muscles
body temperature, as occurs with vigorous exercise just before sleep, ◆ Diaphragm
has traditionally been thought to hamper sleep onset [28], although
◆ External intercostal
this concept has been challenged recently [29]. Temperature control
differs in NREM and REM sleep. The thermoregulatory responses Accessory inspiratory muscles
that occur during NREM sleep, such as sweating and panting, are
◆ Sternocleidomastoideus
absent in REM sleep, where thermoregulation is impaired [30].
There has been interesting research into the role of thermoregu- ◆ Scalenus (anterior, middle, posterior)
latory dysfunction or mismatch between thermoregulatory and
◆ Pectoralis major
sleep–wake cycles in patients with a number of sleep disorders. For
example, patients with sleep onset insomnia have delayed core body ◆ Pectoralis minor
temperature rhythms [31], suggesting that their sleep difficulties ◆ Serratus anterior
may be due to attempts to initiate sleep before the nocturnal dip in
◆ Serratus posterior superior
body temperature. Similarly, it has been suggested that age-related
impairment of the heat loss mechanism or phase advance in body ◆ Latissimus dorsi
temperature rhythm may partly explain sleep initiation or mainte- ◆ Alae nasi
nance difficulty in the elderly, and therefore behavior that enhances
◆ Trapezius
peripheral heat loss may improve sleep [32,33]. Jet lag and shift-
work disorder may similarly be a result of environmentally induced
Expiratory muscles
disruption of thermoregulation and SWS, causing sleep initiation
and maintenance problems, disorganization of sleep architecture, (These are silent during quiet breathing, but contract during
and poor daytime function [34]. Menopausal hot flashes may pos- moderately severe airway obstruction or during forceful and
sibly also be a disorder of thermoregulation during sleep as a result increased rate of breathing)
of POAH dysfunction; hot flashes may be more common in the ◆ Internal intercostal
first than the second half of the night when REM sleep dominates,
◆ Rectus abdominis
impairing the thermoregulatory mechanism [35,36].
◆ External and internal oblique
Respiration and sleep ◆ Transversus abdominis
Control of respiration in wakefulness and sleep Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic
Science, Technical Considerations, and Clinical Aspects (3rd ed), Copyright
The primary function of the respiratory system is to maintain (2009), with permission from Elsevier.
arterial homeostasis of the partial pressures of carbon dioxide
(pCO2) and oxygen (pO2). This requires adequate alveolar ven-
tilation, which in turn is dependent on central controllers of
respiration located in the medulla (with input from the cortex), nuclei (pneumotaxic center) and one in the dorsolateral region
peripheral chemoreceptors, and pulmonary and upper airway of the lower pons (apneustic center) [37,38] exert influences over
mechanoreceptors, the thoracic bellows (consisting of the rib- these medullary centers (Fig. 6.3). The rate and rhythm of breath-
cage, respiratory muscles, and their innervation), and the lungs ing are modulated by inputs to the medullary respiratory centers
(including the airways and the alveolar membrane where gas ex- that arise from peripheral chemoreceptors (the carotid and aortic
change occurs). Box 6.1 lists the respiratory muscles. The prin- bodies that are sensitive to hypoxia, hypercapnia, and alterations
cipal muscle of inspiration is the diaphragm (innervated by the in blood pH), the central chemoreceptors in the medulla (sensitive
phrenic nerve, formed by motor roots of C3, C4, and C5 anterior mainly to hypercapnia and increased blood pH), and pulmonary
horn cells), assisted by the external intercostal muscles (inner- mechanoreceptors, sensitive to stretching of the lungs. Inputs from
vated by the thoracic motor roots and nerves). Expiration is usu- these receptors travel via the glossopharyngeal and vagus nerves
ally a passive process, resulting from elastic recoil of the lungs. and synapse in the NTS. This system works in concert to ensure
However, during forced and effortful breathing (eg, dyspnea and homeostasis of blood gases, for example by increasing the rate and
orthopnea), accessory muscles of both inspiration and expiration depth of respiration in response to hypoxia or hypercapnia, or by
are activated. causing a cessation of breathing when pCO2 falls below a certain
The “pacemaker” for breathing is the dorsal respiratory group level (the apneic threshold) [39]. This system is referred to as meta-
(DRG) in the medulla, which mainly initiates inspiration and is bolic or autonomic control of breathing and is independent of voli-
responsible for the regularity, rhythmicity, and rate of breathing; tional control. In wakefulness, the reticular activating system and
the ventral respiratory group (VRG) lies in proximity and generally the cortex exert an additional influence and allow for the voluntary
is activated when active expiration is required. These centers pro- control of breathing as well as for phonation. However, in sleep,
ject to the anterior horn cells of spinal motor neurons innervating this voluntary control is lost, and respiration is controlled purely
the diaphragm and the intercostal muscles. Two centers in the ros- by the metabolic system [40]. This situation explains the changes in
tral pons, one in the region of the parabrachial and Kölliker–Fuse respiration that occur in sleep.

P Table 6.1 Summary of physiological changes in the respiratory system
PONS
occurring during sleep
A
Parameters Wakefulness NREM sleep REM sleep
DRG
MEDULLA
N
N
Botzinger
Respiratory rate Normal Decreases Variable, apnea
A A
N Pre-Botzinger may occur
N
R R VRG
G G Minute ventilation Normal Decreases Decreases further
Alveolar ventilation Normal Decreases Decreases further
PaCO2 Normal Increases Increases further
SPINAL CORD
slightly slightly
PaO2 Normal Decreases Decreases further
slightly slightly
SaO2 Normal Decreases Decreases further
To To slightly slightly
Inspiratory Expiratory
Hypoxic ventilatory Normal Decreases Decreases further
Fig. 6.3 Schematic representation of central respiratory neurons in the pons response
and medulla. DRG: dorsal respiratory group with projections to contralateral hypercapnic Normal Decreases Decreases further
predominantly inspiratory muscles; VRG: ventral respiratory group with
ventilatory response
projections to contralateral inspiratory and expiratory muscles; P: pneumotaxic
center; A: apneustic center. Upper airway Normal Decreases Decreases
Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic Science, Technical muscle tone slightly markedly or is
Considerations, and Clinical Aspects (3rd ed), Copyright (2009), with permission from Elsevier. absent
Upper airway Normal Increases Increases further
resistance
Respiratory changes in sleep
There is a progressive fall in respiratory minute ventilation by ap- Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic Science, Technical
Considerations, and Clinical Aspects (3rd ed), Copyright (2009), with permission from
proximately 0.5–1.5 L/min compared with wakefulness in NREM Elsevier.
sleep and 1.6 L/min in REM sleep (with the biggest reduction being
in phasic REM sleep). This is mainly due to a fall in tidal volume;
respiratory rate does not decrease, although respiration becomes ir- Table 6.1 summarizes the physiological changes that occur in the
regular in REM sleep, especially during phasic REM [41]. This fall respiratory system during sleep.
in tidal volume in sleep is due to a number of factors, chief among
which are hypotonia of all respiratory muscles except the diaphragm Cardiovascular system and sleep
(leading to hypoventilation, reduced tone, and collapse of the upper
airway dilators resulting in increased upper airway resistance) and Changes in cardiac and vascular function that occur in sleep are ul-
reduced chemosensitivity; these are more marked in REM than timately due to the control of the ANS (see the discussion earlier in
NREM sleep. This fall in alveolar ventilation in sleep causes a rise in this chapter). In phasic REM sleep, superimposed surges of sympa-
pCO2 by 2–8 mmHg, a fall in pO2 by 3–10 mmHg, and a decrease thetic activity occur. Knowledge of these changes in ANS function
in arterial oxygen saturation (SaO2) by less than 2% [42]. aids in the understanding of hemodynamic changes that occur in
Sleep-related changes in the upper airway, in particular, play an sleep. These changes are summarized in Table 6.2.
important role in the pathogenesis of sleep-disordered breathing. In
wakefulness, the activity of the upper airway inspiratory dilator mus- Changes in cardiac function during sleep
cles (Table 6.1) reflexively increases at the onset of inspiration due to Bradycardia during both NREM and REM sleep results from a
the negative intrathoracic pressure; this is a protective mechanism tonic increase in parasympathetic activity (sympathectomy has
guarding against upper airway narrowing. In sleep, this reflexive re- little effect). The heart rate decreases by 5–8% during NREM sleep,
sponse is blunted, making the upper airway susceptible to collapse. but becomes more intense during REM sleep, with frequent upward
This susceptibility is enhanced by agents that lower muscle tone, and downward swings resulting in bradytachycardia occurring in
including alcohol and benzodiazepines, and worsens with aging and phasic REM sleep due to superimposed spikes of sympathetic ac-
in the supine position [43]. The role of tongue muscles, particularly tivity [47–49]. Similarly, cardiac output falls progressively during
the genioglossus and geniohyoid muscles that protrude the tongue, sleep, with the greatest decrease occurring during the last sleep
in the pathogenesis of OSA is being increasingly recognized. EMG cycle, particularly during the last REM sleep cycle early in the
recordings have demonstrated that genioglossal muscle activity morning [50].
mildly decreases during NREM sleep, but markedly decreases dur-
ing REM sleep [44]. The resulting backward displacement of the Changes in the circulatory system during sleep
tongue partially or completely against the posterior pharyngeal wall Systemic blood pressure falls by approximately 10–20% during
restricts airflow and contributes to OSA. Several treatment modali- NREM sleep and swings up and down during REM sleep, with an
ties for OSA, including tongue-retaining devices [45] and hypo- overall increase by about 5% above that noted in NREM sleep. There
glossal nerve stimulation [46], target this phenomenon. is a sharp rise in blood pressure around the time of awakening [51].

Table 6.2 Summary of physiological changes in the heart and rate for glucose and oxygen decrease by 5–23% during NREM
circulatory system occurring during sleep sleep, whereas these values vary from 10% below up to 41% above
waking levels during REM sleep [61–63]. Functional neuroimag-
Physiological characteristic NREM REM ing techniques, including PET scans, reveal significant differences
in areas and levels of brain activation during wakefulness, NREM
Heart rate ↓ ↑↓
sleep, and REM sleep (see Chapter 13). During NREM sleep, there
Cardiac output ↓ ↓↓ is a global decrease in CBF, with regional decreases in the dorsal
Systematic arterial BP: pons, mesencephalon, thalami, basal ganglia, basal forebrain, ante-
rior hypothalamus, prefrontal cortex, anterior cingulate cortex, and
◆ Dippers ↓ ↓↑
precuneus [64–66] and regionally specific increases in activities
◆ Extreme dippers ↓↓ ↓↑ during SWS in the brainstem, cerebellum, ventral prefrontal cortex,
◆ Non-dippers ↓– ↓↑ posterior cingulate cortex/precuneus, and parahippocampal areas,
◆ Reverse dippers ↑ ↓↑
in addition to areas generating fast and slow spindles. These find-
ings suggest that during NREM sleep, the brain is actively involved
Pulmonary arterial BP ↑ ↑ in generating synchronized slow waves and spindles, which have
Peripheral vascular resistance –↓ ↓ important implications for memory processing [67]. In contrast,
Systematic blood flow:
the brain in REM sleep is far more globally active, with increased
blood flow and metabolism in the pontine tegmentum, thalamus,
◆ Cutaneous – ↓ amygdala, anterior cingulate cortex, hippocampus, temporal and
◆ Muscular – ↓ occipital regions, basal forebrain, cerebellum, and caudate nucleus,
◆ Mesenteric – ↑ and regional deactivation in the dorsolateral prefrontal cortex, pos-
terior cingulate gyrus, precuneus, and inferior parietal cortex [68].
◆ Renal – ↑ REM sleep-related activation of the pontine tegmentum, thalamic
Cerebral blood flow ↓ ↑ nuclei, and basal forebrain supports the REM sleep-generating
mechanisms in these regions [69].
↓ = Decreased; ↑ = Increased; ↓↑ = Uncertain; –= Unchanged.
Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic Science, Technical
Considerations, and Clinical Aspects (3rd ed), Copyright (2009), with permission from The gastrointestinal tract and sleep
Elsevier.
The activity of the gastrointestinal tract is controlled by both the
ANS and the enteric nervous system, an intrinsic autonomic system
within the walls of the visceral organs that works closely with the
This circadian variation in blood pressure, with an overall reduction ANS. Changes that occur in the gastrointestinal tract during sleep
during sleep and increase on awakening, is referred to as “dipping.” are summarized in Table 6.3.
Normal dipping of systolic blood pressure, such that the night-wake
ratio is between 0.8 but less than or equal to 0.9, is physiological, Changes in esophageal function and gastric acid
and these individuals are called “dippers” [52–54]. “Non-dippers” secretion during sleep
are subjects in whom the night-wake systolic blood pressure ratio There is a clear circadian rhythm to gastric acid secretion. During
is between 0.9 and 1, and “extreme dippers” are those in whom the wakefulness, gastric acid secretion depends on food ingestion,
ratio is less than 0.8. In “reverse dippers,” the blood pressure actu- increased salivation, and the activity of the vagus nerve. During the
ally increases during sleep (night-wake ratio greater than 1). Non- first 2 hours of sleep, there is a failure of inhibition of acid secretion,
dippers, extreme dippers, and reverse dippers are at higher risk for resulting in peak gastric acid secretion occurring between 10:00 pm
cardiovascular or cerebrovascular events causing infarctions and and 2:00 am. Vagotomy abolishes this rhythm [70]. Studies have
periventricular hyperlucencies on brain MRI [55–57]. failed to demonstrate any difference in gastric acid secretion be-
Pulmonary arterial pressure rises slightly during sleep. During tween NREM and REM sleep [71–73]. Esophageal motility and
wakefulness, the mean value is 18/8 mmHg; that during sleep is function are also affected by sleep. This is of particular importance
23/12 mmHg. Cutaneous, muscular, and mesenteric vascular blood for patients with gastro-esophageal reflux disease (GERD). There
flow shows little change during NREM sleep, but during REM sleep, are two esophageal sphincters that act as barriers to reflux: the
there is profound vasodilation in these splanchnic beds, resulting upper esophageal sphincter (UES) and the lower esophageal
in increased blood flow in the mesenteric and renal vascular beds. sphincter (LES). Although disputed by some authors [74], most
As a result, peripheral vascular resistance (PVR) generally remains studies have found that in normal individuals who experience epi-
unchanged during NREM sleep, but falls significantly during REM sodes of GERD, there is generally a reduction in LES pressure dur-
sleep [58]. ing sleep [75,76]. Similarly, sleep-induced loss of UES pressure may
promote reflux of esophageal contents into the pharynx and tra-
Changes in cerebral blood flow and metabolism cheobronchial tree. Also during sleep, reflux is cleared much slowly
during sleep than during wakefulness, and salivary flow and swallowing are
Cerebral blood flow (CBF) and metabolic rate are noted to be lower reduced, resulting in a longer acid–mucosa contact time. Proximal
in NREM than in REM sleep, lower at the end of the night compared migration of gastric contents and decreased esophageal peristalsis
with at the beginning of the night, and lower in post-sleep wake- in sleep (especially in SWS) also occur, and all of these factors pre-
fulness than in pre-sleep wakefulness [59,60]. CBF and metabolic dispose to development of esophagitis [77], Thus, patients with

Table 6.3 Summary of physiological changes in the gastrointestinal higher plasma levels of antidiuretic hormone (ADH) [88]. In add-
tract occurring during sleep ition to lower ADH levels, patients with OSA have increased atrial
natriuretic peptide, which suppresses plasma renin secretion; thus
Physiological characteristics Wakefulness Sleep there is an increase in nocturnal urine output. This often results in
patients with OSA complaining of nocturia and frequent awaken-
Swallowing frequency Normal Decreased
ings for micturition [89].
Salivary flow Normal Decreased
Esophageal acid clearance time Normal Prolonged Endocrine regulation and sleep
Lower and upper esophageal Normal Decreased While the characteristic pattern of hormone secretion by most
sphincter pressure endocrine glands is an episodic or pulsatile secretion every 1–2
Esophageal peristaltic Normal Decreased hours, suggesting an ultradian rhythmicity, the plasma concentra-
contractions tions of several hormones show circadian rhythms that in some
Gastric motility Normal Decreased cases are related to the sleep–wake cycle (Fig. 6.4). For example,
adrenocorticotropic hormone (ACTH), cortisol, and melatonin
Gastric acid secretion Depends on Peak secretion
rhythms are determined by the circadian clock, whereas growth
food ingestion between 10 pm
and 2 am hormone (GH), prolactin, thyroid-stimulating hormone (TSH),
and renin rhythms are sleep-related. It is evident from Fig. 6.4 that
Migrating motor complex Normal velocity Reduced velocity during the first part of the night, the plasma GH level is high and
(MMC) (recurs every 90 minutes)
the cortisol level low, whereas during the later part of the night, GH
Colonic motility Normal Decreased level is low and cortisol level high, suggesting a reciprocal inter-
Rectal motor activity and anal Normal Increased action of the hypothalamic–pituitary–adrenocortical axis and the
canal pressure periodic activity hypothalamic–pituitary–s omatostatin system. Thus there are
with retrograde 24-hour oscillations of circulating levels of various endocrine secre
propagation and tions, showing a time-of-day dependence. These are driven not
higher anal canal only by the endogenous circadian rhythms but also by sleep–
pressure wakefulness and behavioral or environmental factors.
Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic Science, Technical Melatonin, the “hormone of darkness,” is synthesized by the
Considerations, and Clinical Aspects (3rd ed), Copyright (2009), with permission from pineal gland and released directly into the bloodstream or cerebro-
Elsevier. spinal fluid. The maximum nocturnal secretion of melatonin has
been observed in young children, aged 1–3 years; secretion then
peptic ulcer disease and GERD may have repeated awakenings and begins to fall around puberty and decreases significantly in the eld-
arousals from nocturnal epigastric pain (“nightly heartburn”), par- erly [90]. Melatonin levels follow a circadian rhythm that is heavily
ticularly in the first few hours of the night. Concomitant OSA wors- influenced by environmental light, which suppresses its produc-
ens GERD, although the mechanism is unclear, and treatment with tion. In the absence of light as a major influence, melatonin begins
continuous positive airway pressure (CPAP) improves symptoms to rise in the evening, attaining maximum values between 3:00 am
[78]. Esophageal pH monitoring during polysomnography (PSG) and 5:00 am and then decreasing to low levels during the day (Fig.
may help in the evaluation and management of these patients. 6.4). A negative feedback mechanism exists to regulate melatonin
production; impulses from the retinal ganglion cells that perceive
Changes in gastrointestinal motility during sleep light are transmitted via the retinohypothalamic tract to the SCN,
There are contradictory reports in the literature about the effect of which then sends efferent fibers to the paraventricular nucleus of
sleep on gastric motility, with both inhibition and enhancement the hypothalamus and then to the intermediolateral horn cells of
of gastric motility having been described [79,80], and one group the upper thoracic spinal cord, and subsequently to the superior
reporting that gastroduodenal motility during sleep was related cervical ganglia, which in turn transmit impulses via the postgan-
to sleep-stage shifts and body movements [81]. In the stomach glionic efferent fibers to the pineal gland [91]. The SCN has two
and small intestine, a cyclical pattern of motor activity, called the melatonin receptors (MT1 and MT2). MT1 receptors inhibit SCN
migrating motor complex (MMC), recurs every 90 minutes and has neuronal activity and MT2 receptors phase-shift circadian firing
a circadian rhythm, with the lowest velocity occurring during sleep, rhythms in the SCN. Because of its hypnotic and chronobiologi-
although no consistent differences have been detected between cal properties, melatonin has found application in the treatment
NREM and REM sleep [82–86]. There is decreased colonic mo- of insomnia and circadian rhythm disorders. Melatonin admin-
tility in the transverse, descending, and sigmoid colon, and there is istered in the evenings has a phase-advancing effect, and when
retrograde periodic rectal motor activity during sleep, all of which administered in the mornings has a phase-delaying effect. Thus, it
serve to prevent passive escape of rectal contents during sleep [87]. has been used in the treatment of jet lag, shiftwork disorder, and
non-24-hour sleep–wake syndrome. The use of melatonin in the
treatment of insomnia is described in Chapter 20, and its use in
Renal function and sleep the treatment of circadian rhythm disorders in Chapters 21 and 22.
The volume of urine production generally decreases in sleep owing The secretion of GH, an anabolic hormone whose function is medi-
to decreased glomerular filtration, increased reabsorption of water, ated through hepatic insulin-like growth factor 1, is closely linked to
increased activation of the renin–angiotensin–aldosterone system SWS [92,93]. In addition to the secretion of GH itself by the anterior
(see the next section), decreased sympathetic activity and slightly pituitary gland, SWS enhances the release of GH-stimulating factors

100 primary insomnia. In patients with depression, the lowest point of

MLT cortisol level is advanced and cortisol secretion is not suppressed
0 by dexamethasone, although the latter is a nonspecific finding that
100 also occurs in healthy sleep-deprived individuals [103,104]. With
ADH sleep deprivation and sleep fragmentation (as may occur in OSA),
0
100
evening cortisol concentrations and sympathetic nervous system
activity are increased, resulting in impaired glucose tolerance and
ALD
negative cardiovascular consequences [105].
0
100 Prolactin is a hormone that mainly promotes lactation in women
TSH and is synthesized by the anterior pituitary gland. It is tightly linked
0 to sleep, with the highest levels occurring during sleep and the
100 lowest during wakefulness. The prolactin level begins to rise ap-
TES proximately 60–90 minutes after sleep onset and peaks in the early
0
100 morning hours from approximately 5:00 to 7:00 am. Prolactin se-
cretion does not appear to have an independent circadian rhythm
PRO
0
but vary in its secretion by sleep stage [106–109], although some
100 authors have suggested that an independent circadian rhythm
GDH becomes evident during sleep deprivation [110].
0 Gonadotropin-releasing hormone (GnRH) produced by the hypo-
100 thalamus stimulates the anterior pituitary gland to secrete the gonad-
COR otropins: luteinizing hormone (LH) and follicle-stimulating hormone
0 (FSH). In men, LH is the stimulus for the secretion of testosterone
100
by the testes, and FSH stimulates spermatogenesis. In women, the
GH
ovarian hormones estrogen and progesterone are secreted by the
0
ovaries in response to LH and FSH, which are also responsible for
Onset 1 2 3 4 5 6 7 8
ovarian changes during the menstrual cycle. The gonadotropins are
Hours of sleep
secreted in a pulsatile pattern throughout the 24-hour cycle, and no
Fig. 6.4 Schematic representation of the plasma levels of hormones in an relationship to the sleep–wake cycle has been demonstrated [111].
adult during 8 hours of sleep. Zero indicates lowest secretory episode and 100 However, in both late pre-pubertal and pubertal boys and girls, go-
indicates peak. MLT: melatonin; ADH: antidiuretic hormone; ALD: aldosterone; nadotropin levels appear to increase during sleep [112–116]. Plasma
TSH: thyroid-stimulating hormone; TES: testosterone; PRO: prolactin; testosterone levels do not appear to correlate with the pulsatile secre-
GDH: gonadotropic hormone; COR: cortisol; GH: growth hormone. tion of FSH and LH. Testosterone levels rise at sleep onset and con-
Reproduced from Chokroverty S (ed.), Sleep Disorders Medicine: Basic Science, Technical
tinue to rise during sleep at night, possibly related to REM sleep; this
Considerations, and Clinical Aspects (3rd ed), Copyright (2009), with permission from Elsevier.
sleep-related rise in testosterone levels attenuates with age [117–120].
In women, sleep appears to inhibit LH secretion in the early parts
such as hypothalamic GH-releasing hormone (GHRH) and ghrelin, of the follicular and luteal phases of the menstrual cycle, although
an appetite-stimulant gastric peptide. It is notable that stimulation the data are contradictory [121,122]. There is a suggestion that the
of the GABAergic hypothalamic GHRH neurons promotes both the shiftwork-related increased incidence of infertility in women may be
onset of SWS and the peak GH levels, and agents promoting SWS related to a sleep-related inhibitory effect on gonadotropin release
(eg, γ-hydroxybutyrate) enhance GH secretion, suggesting a recip- during the follicular phase of the menstrual cycle [123].
rocal link between SWS and GH secretion [94]. GH secretion occurs TSH secretion has a well-defined sleep-dependent circadian
shortly after sleep onset during SWS and is inhibited by awakenings rhythm. Sleep has an inhibitory effect on TSH secretion that
and sleep fragmentation. Conditions that fragment sleep, such as appears to be related to SWS; TSH levels are low during the day-
OSA and narcolepsy, cause diminished sleep-related GH secretion. time, increase rapidly in the early evening, peak shortly before sleep
In OSA patients, CPAP treatment increases GH secretion in sleep onset, and are followed by a progressive decline during sleep [124].
[95]. There is a natural decrease in sleep-related GH production in Sleep deprivation is associated with nocturnal increase of TSH, but
elderly populations, possibly related to the reduction of SWS and TSH is not inhibited by daytime sleep. TSH is thus controlled by
increased fragmentation of sleep with age. In acromegaly, a disorder both circadian clock and sleep homeostasis.
of unregulated GH synthesis, the relationship between sleep and The renin–angiotensin–aldosterone system plays a major role in
hormone secretion is lost [96]. maintaining hemodynamic stability in the face of decreased sys-
The 24-hour secretion pattern of the ACTH–cortisol system has temic blood pressure. The juxtaglomerular cells in the kidney sense
its own circadian rhythm, but one that is also modulated by the decreasing renal perfusion and secrete renin, which converts angi-
sleep–wake cycle. Cortisol secretion rapidly falls with sleep onset, otensinogen first to angiotensin I and then angiotensin II, which
most markedly with SWS, but then quickly rises in the later part in turn stimulates aldosterone production in the zona glomerulosa
of the night, being highest at awakening and subsequently declin- of the adrenal cortex. The end result is increased blood pressure
ing throughout the day. However, this rhythmicity is absent during and blood volumes, increased sodium reabsorption, and increased
sleep deprivation, and only occurs during nocturnal sleep [97,98]. potassium secretion. With the fall in blood pressure that occurs in
Awakenings causing sleep interruption will increase the pulsa- NREM sleep as a result of decreased sympathetic activity, plasma
tile cortisol secretion [99] and some [100,101], but not all [102], renin levels rise; in contrast, during REM sleep, which is associ-
studies have shown higher mean cortisol levels in patients with ated with fluctuating BP and intermittently increased sympathetic

activity, there is a significant decrease in renin levels [125]. Sleep- 10. Sleight P, La Rovere MT, Mortara A, et al. Physiology and
related aldosterone levels are higher than those found in wakeful- pathophysiology of heart rate and blood pressure variability in
ness, and do not appear to depend on fluctuations in plasma renin humans: is power spectral analysis largely an index of baroreflex gain?
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SECTION 2
Laboratory evaluation

CHAPTER 7
Polysomnography
Technique and indications
Nic Butkov
Introduction connections, or malfunctioning equipment. Artifacts can affect

bio-â•‰electrical signals, as well as signals derived from respiratory
Polysomnography (PSG) is defined as the recording, analysis, and transducers, oximetry, or any other devices applied to the patient.
interpretation of multiple physiological parameters during sleep. Paradoxically, recording artifacts were often easier to recognize in
The development of PSG began in the early 1970s, when a team the past when analog PSG systems were used, because these sys-
of researchers at Stanford University led by William C. Dement, tems had less capability of altering the data. With the advent of
Jerome W. Holland, and David M. Raynal combined tracings from digital PSG, there has been a tendency to “clean up” the record by
respiratory and cardiac sensors together with the electroencepha- selective filtering or by other forms of digital manipulation, which
logram (EEG), electromyogram (EMG), and electrooculogram can make it more difficult for the reader to discern between real
(EOG) in a simultaneous multichannel study. The concept was physiological data and artifacts that resemble physiological activity.
subsequently presented by the team in a 1974 publication titled This chapter provides an overview of the PSG recording process,
“Polysomnography: a response to a need for improved communica- with emphasis on obtaining accurate data with appropriate, but not
tion,” which helped establish PSG as the standard testing procedure excessive, signal manipulation. The latter segment of the chapter
for patients with suspected sleep disorders [1]â•„. Since then, PSG has describes and illustrates some of the more common recording arti-
become a worldwide gold standard in both clinical and research facts, with practical strategies for minimizing their impact on the
applications, and it continues to enhance our understanding of recording.
sleep and its disorders to the present day.
From a practical perspective, the main attribute of PSG is the
inclusion of physiological sleep measures that allow the reader Indications for PSG
to evaluate any suspected anomalies within the context of sleep The following clinical indications for PSG are based on guidelines
and wake physiology. This is especially important when studying published by the American Academy of Sleep Medicine (AASM) in
patients with complicated histories and comorbidities, where care- 2005 [2]â•„, which state that attended PSG is considered the standard
ful analysis of all recorded parameters becomes essential for accu- of practice for
rate and complete diagnosis.
◆ diagnosis of sleep-â•‰related breathing disorders (SRBD);
From a technological standpoint, PSG has undergone many
changes over the past several decades, most notably in the 1990s, ◆ positive airway pressure titration;
when analog polysomnographs were replaced with digital PSG ◆ preoperative assessment for snoring or obstructive sleep
recording systems. The transition to digital PSG has opened the apnea (OSA);
doors to many possibilities and has dramatically changed the way
◆ evaluatingresults of treatment for moderate to severe OSA with
in which PSG data are processed, stored, and analyzed. At the same
time, the development of digital PSG has increased the complexity oral appliances, surgery, or dental procedures;
of the recording process. Technologists who perform the studies ◆ treatment results requiring follow-â•‰up PSG for substantial weight
must not only be thoroughly familiar with the basic principles of gain or loss;
biophysiological signal recording, but also understand the effects of
◆ treatment
results when clinical response is insufficient or when
any digitally based signal manipulation on the quality and accuracy
symptoms return;
of the data.
Understanding the recording process is equally important for ◆ patients
with systolic or diastolic heart failure and nocturnal
those who score and interpret digital PSG. When reading a poly- symptoms of SRBD;
somnogram, it is essential to keep in mind that any form of bio- ◆ patients
whose symptoms continue despite optimal management
physiological data collection includes the potential for recording of congestive heart failure;
artifacts. This holds especially true when recorded subjects are
◆ neuromuscular disorders with sleep-â•‰related symptoms;
unrestricted in movement and are monitored for extended periods
of time. Artifacts can stem from dislodged sensors, patient move- ◆ narcolepsy (for which PSG is followed by the multiple sleep
ment, postural changes, perspiration, electrical interference, poor latency test, MSLT);

56 Section 2 laboratory evaluation
◆ periodic limb movement disorder in cases secondary to com- This is particularly useful for documenting and/or verifying infor-
plaints by the patient or by an observer. mation that might otherwise be undetected or inaccurately repre-
According to the AASM, PSG is not required to diagnose sented by body sensor tracings. This may include verification of
body position, description of breathing or snoring sounds, docu-
◆ parasomnias;
mentation of atypical behaviors, etc.
◆ seizure disorders;
◆ restless legs syndrome; The patient/equipment interface
◆ common, uncomplicated noninjurious events such as night- The application of electrodes and sensors to the patient repre-
mares, enuresis, sleep-talking or bruxism; sents the most essential, yet most vulnerable link in the entire
chain of connections between the patient and the data output.
◆ circadian rhythm disorders.
Despite advances in technology, the old adage: “garbage in = gar-
In recent times, PSG has increasingly been used for diagnosing and bage out” still stands, meaning that without a proper application
treating patients with complicated forms of SRBD requiring the use technique, the accuracy of the recorded data becomes question-
of advanced positive airway pressure (PAP) modalities that deliver able. Consequently, the best insurance against faulty data collec-
nocturnal noninvasive ventilation. PSG is essential for these stud- tion is to pay close attention to the integrity of the electrode and
ies, because it provides critical information regarding the patient’s sensor application. After the application has been completed, it
physiological responses to therapy during all phases of titration. is equally important to maintain signal quality for the duration
of the study.
EEG, EOG, EMG, and ECG data are obtained by applying sur-
PSG recording parameters face electrodes to the patient. EEG electrodes are applied according
In routine clinical practice, PSG includes (but is not limited to) the to the International 10/20 System of electrode placement (Figs. 7.1
following parameters: and 7.2) [3]‌, typically using gold-plated cup electrodes that are
◆ central, frontal and occipital EEG; adhered to the scalp using either collodion or EEG paste. The
AASM recommends using F4/M1 for recording frontal EEG activity
◆ recording of eye movements (EOG); (with F3/M2 as back-up), C4/M1 for recording central EEG activity
◆ recording of chin muscle activity (chin EMG); (with C3/M2 as back-up), and O2/M1 for recording occipital EEG
◆ recording of leg muscle activity (right and left anterior activity (with O1/M2 as back-up) [4].
tibialis EMG); EOG electrodes are placed in the proximity of the right and left
outer canthus, offset vertically to detect both vertical and hori-
◆ the electrocardiogram (ECG); zontal eye movements. The AASM recommends placing the right
◆ nasal and oral airflow; EOG electrode (E2) 1 cm directly above the right outer canthus
◆ respiratory
and the left EOG electrode (E1) 1 cm directly below the left outer
effort (based on chest and abdomen excursion);
canthus. EOG recordings are based on the electrical potential dif-
◆ pulse oximetry. ference between the cornea and retina of the eye. The cornea has
Depending on the intent of the study, or as indicated by individual a positive potential relative to the retina. When the eyes move,
laboratory protocols, additional PSG parameters may include voltage shifts occur in relation to electrodes placed in the vicinity
of each eye, generating corresponding deflections on the data dis-
◆ expanded number of EEG channels;
play. Following conventional EOG electrode placements, when the
◆ additional EOG leads (recommended for multiple sleep latency eyes move to the right or upward, a positive (downward) deflec-
testing); tion occurs in the right EOG channel and a negative (upward) de-
◆ snoring sensors; flection occurs in the left EOG channel. The opposite effect is seen
when the eyes move to the left or downward. The distinct out-of-
◆ body position sensors; phase deflections produced by this configuration should be easily
◆ esophageal pressure measurements; distinguishable from background frontal EEG activity recorded by
◆ esophageal
the EOG channels. EOG electrodes (and other facial electrodes)
pH measurements;
are usually attached with tape. A skin-tight connection is obtained
◆ recording of arm muscle activity; by using a double-sided adhesive electrode collar underneath the
◆ end-tidal or transcutaneous carbon dioxide (CO2) recordings; electrode cup and then covering the electrode with a small piece of
paper tape to firmly secure it in place.
◆ other parameters as indicated by individual protocols.
Chin EMG recordings are obtained from electrodes placed over
When interfacing PSG with PAP equipment, the recording should the mentalis and submental muscles. The AASM recommends pla-
include all relevant PAP data, such as pressure levels, leak values, cing one electrode on the midline, 1 cm above the inferior edge of
estimated tidal volumes, and inspiratory-to-expiratory ratios. the mandible, and two electrodes 2 cm below the inferior edge of
Contemporary PAP equipment designed for in-laboratory titration the mandible, offset 2 cm to the right and left of the midline, re-
provides this information by direct link to the computer that is used spectively. Two of the electrodes are referenced to each other in a
to collect the PSG data. bipolar derivation, while the third serves as a back-up. Some prac-
An important adjunct to PSG is audio/video monitoring com- titioners place the third electrode over a masseter muscle, to bet-
bined with direct behavioral observation by a trained technologist. ter detect bursts of bruxism. Chin EMG electrodes can be attached

Chapter 7 polysomnography: technique and indications 57
Nasion ECG recordings in polysomnography are generally limited to a

single modified lead II configuration, with additional leads used as
back-up or according to individual protocols. To record a modified
lead II ECG, one electrode is placed slightly below the right clavicle
Fpz and the other over the lower left thorax. An additional electrode
Fp1 Fp2
placed slightly below the left clavicle allows for recording a modi-
fied lead I and lead III ECG.
F7 F3 FZ F4 F8
Leg EMG recordings are obtained by applying a pair of electrodes
Preauricular Preauricular over the anterior tibialis muscle of each leg. The electrodes are
point point
spaced approximately 2–3 cm apart and referenced to each other in
a bipolar derivation. In the absence of leg muscle activity, leg EMG
T3 C3 CZ C4 T4
channels generally display a flat line, with bursts of EMG activity
seen when leg movements occur.
A single patient ground electrode is applied, typically on the
M1 T5 P3 PZ P4 T6 M2 patient’s forehead, just below the hairline. The purpose of a patient
ground is to divert excessive 50 or 60 Hz line frequency interfer-
ence from the patient’s body. To avoid the possibility of stray cur-
O1 O2
OZ rent passing through the patient, the ground input in the electrode
jack box must be isolated, and to avoid the possibility of a ground
Inion loop, only a single ground electrode should be used on the patient.
Fig. 7.1 The International 10/20 System of electrode placement (top view).

Reproduced from Butkov N, Atlas of Clinical Polysomnography, Second Edition, Copyright
Electrode site preparation and measuring
(2010), with permission from Synapse Media. electrode impedances
Before applying any surface electrode, the electrode site must be
with double-sided electrode collars and paper tape, or they can be cleaned and lightly scrubbed with a gel-based prepping solution.
glued in place if the patient has a beard. Recordings of the chin The reason for this is because the skin acts as a natural barrier to the
EMG should produce sufficient visible activity in the EMG channel passage of the extremely low, rapidly fluctuating voltages generated
even when the subject is relaxed in order to better detect the onset by the patient. The rate of opposition to these voltages is described
of REM sleep, when the chin EMG is expected to fall to the lowest as impedance, technically defined as a combined measure of resist-
level of the recording. ance and reactance (the reactance can be inductive or capacitive or
both). Scrubbing the skin with the prepping solution is intended to
lower impedance to an acceptable level, so as to preserve signal fi-
C2 delity. For optimal results, all electrode impedance readings should
be below 5000 Ω (5 kΩ). Impedance checks can be made either
FZ with a separate hand-held meter or by using an impedance measur-
ing option provided by the digital recording system.
PZ
When scrubbing the skin with a prepping solution, it is important
C3
F3 to only scrub an area no larger than the diameter of the electrode
P3 cup. Scrubbing large areas of the skin and/or spreading excessive
Fpz amounts of any conductive substance (including skin-preparation
Fp1 material) can cause electrical bridging and increase the probability
F7 OZ
T3 T5 O1 of artifacts.
Nasion
After the electrode sites have been adequately prepared, the elec-
trodes are carefully adhered to the skin directly over the scrubbed
Inion area. The electrode cups are filled with conductive gel, cream, or
EEG paste, which serves as the interface between the skin and the
Preauricular A1
point electrode. After completing the application, the electrode leads are
M1 bundled and neatly secured in a way that provides maximum mo-
bility for the patient, yet minimizes the chances of tangled wires
or dislodged electrodes. A final impedance check should be made
before initiating the study.
Application of respiratory sensors

One of the challenges of any form of sleep testing that includes re-
Fig. 7.2 The International 10/20 System of electrode placement (side view).
spiratory parameters is that precise respiratory measurements dur-
Reproduced from Butkov N, Atlas of Clinical Polysomnography, Second Edition, Copyright ing sleep are difficult to obtain. Pneumotachometry and esophageal
(2010), with permission from Synapse Media. pressure measurements are considered to be reference standards

for detecting respiratory airflow and effort, respectively; however, over the umbilicus. The belts should be comfortably snug, but not
both methods are intrusive and generally impractical for routine over-tightened. Proper adjustment of the belts should be made
clinical use. Instead, recordings of respiratory airflow are usually when the patient initially settles into bed, and further adjustments
obtained with thermal sensors and/or nasal air pressure transduc- should be made if signal distortion occurs later in the study due to
ers, while recordings of respiratory effort are usually obtained with body position changes and/or belt slippage.
piezoelectric or inductance plethysmography belts.
The two commonly used thermal sensors for recording airflow Oximetry
are thermistors and thermocouples. A thermistor is a temperature-
sensitive variable resistor that requires an external power source, Oximetry recordings are typically obtained by using either dispos-
either from a battery or from the electrode jack box interface with able or nondisposable finger probes. Alternatively, an earlobe probe
the recording system. In contrast, a thermocouple generates its own can be used, and may be preferable in some instances, particularly
voltage, based on the use of dissimilar metals within the sensor. Of if the signal from the finger probe proves to be faulty. Oximetry
the two, thermocouples tend to provide a more stable signal and measurements rely on partial absorption of light waves by the
are more sensitive to fluctuations in airflow. Both types of thermal patient’s hemoglobin from a light-emitting diode (LED) aimed at
sensors are available in a three-prong configuration, with two a receptor diode opposite the LED. Erroneous readings can result
prongs positioned under the nares and one over the mouth. It is if the LED is not properly positioned over the nail bed, if the light
important to position the sensors in such a way as to avoid direct path is blocked by nail polish or artificial nails, or if blood flow
contact with skin; otherwise the signal can be dampened by the is impeded by over-tightening the finger probe. Any questionable
skin temperature. oximetry readings should be checked and corrected by the attend-
A nasal air pressure transducer generates waveforms based on ing technologist. Problems often occur following body position
pressure changes at the nares, detected by a nasal cannula connected changes if a probe becomes partially or completely dislodged.
to a pressure sensor. Nasal air pressure transducers are more sen-
sitive to minor changes in airflow than thermal sensors (especially Additional recording parameters
when compared with thermistors); however, they are susceptible to Additional recording parameters may be added to the study as
signal loss when mouth breathing occurs. For this reason, nasal air deemed necessary by the ordering clinician. Most commonly, these
pressure transducers are usually combined with thermal sensors, include measures obtained from PAP therapy equipment. When
with the two derived signals recorded on separate channels. applying PAP therapy, the airflow signal is obtained from the PAP
An alternative method of recording airflow is with polyvinylidene flow sensor, which is generally superior to signals derived from
fluoride (PVDF) sensors. This is a patented technology that uses a thermocouples or nasal air cannulas. An added benefit of using the
specially processed flexible film that detects both pressure and tem- PAP flow sensor is that it can provide other essential PAP data, such
perature changes at the nares and mouth. as estimated air leak and estimated tidal volumes.
Piezoelectric belts have been commonly used to record respira-
tory effort, based on fluctuating voltages generated by a piezocrys-
tal film in response to chest and abdomen movement. Essentially Signal processing
motion sensors, piezoelectric belts can only be expected to provide The electrical signals obtained from the patient are extremely low
a surrogate representation of respiratory effort, but otherwise they in voltage and must be greatly amplified before they are converted
are easy to use and often provide a more reliable signal than other into visible tracings. The main challenge in the amplification pro-
forms of respiratory effort monitoring. An alternative to piezoelec- cess is to separate physiological signals of interest from unwanted
tric belts are PVDF belts, which have recently been approved by electrical interference, which can originate from the patient, from
the AASM as an acceptable method for recording respiratory effort. devices used on the patient, or from the surrounding environ-
Inductance plethysmography belts are used for recording re- ment. The most pervasive interfering signal in any recording
spiratory effort based on changes in body circumference associated environment is 50 or 60 Hz power line frequency, stemming from
with breathing. A small electrical current is applied to wires woven electrical equipment or wiring in the vicinity of the study. The
in a sinusoidal pattern within the belts, generating an oscillating primary method of eliminating 50/60 Hz interference, or other
signal in response to resistance variations associated with body cir- extraneous signals, is by a process known as common mode rejec-
cumference changes. Inductance plethysmography has often been tion. This requires the use of two inputs for each channel, with
promoted as a means for obtaining semiquantitative measures of signals from two sources applied to the two inputs and referenced
ventilation during sleep, based on calculations of the sum of the to each other.
thoracic and abdominal signals. However, from a practical per- For example, when recording EEG activity, signals derived from
spective, such measurements are unrealistic, because they rely on the C4 electrode are referenced to signals derived from the M1 elec-
calibrated values that are difficult to maintain during a sleep study. trode. The output from this derivation represents only those signals
Changes in body position and any displacement of the belts render that are dissimilar in voltage or polarity between the two inputs,
the calibrations inaccurate. In addition, inductance plethysmogra- while any identical, in-phase signals are rejected (these would
phy belts are generally less forgiving of belt displacement or de- include 50 or 60 Hz, or any other extraneous signals that are identi-
formation than piezoelectric belts and often require readjustments cal in both inputs). Common mode rejection is a function provided
by the attending technologist during the course of the study to by the use of differential amplifiers, which are specifically designed
maintain an adequate signal. to amplify only dissimilar signals from their two inputs (Fig. 7.3).
When applying respiratory effort belts, the thoracic belt is posi- In the past, these amplifiers were relatively large in size and consti-
tioned at the level of the nipples and the abdominal belt is placed tuted a major part of the polysomnograph, located in the laboratory

Input G1
Exploring electrode (C4) Signal

output
Input G2
Differential
amplifier
Reference electrode (M1)
Fig. 7.3 Diagram of input signals processed by a differential amplifier.

Reproduced from Butkov N, Atlas of Clinical Polysomnography, Second Edition, Copyright (2010), with permission from Synapse Media.
Input G1
C4
Input G2
M1
C4/M1
Fig. 7.4 Referential EEG recording (graphic simulation). By comparing an active EEG site with a relatively inactive reference (M1), the output signal amplitudes are
maximized.
control room. In the present day, the amplifiers have been minia- signals (Fig. 7.4). In this example, C4 is described as the exploring
turized and are typically integrated with the electrode jack box in electrode, whereas M1 is the reference electrode.
the patient’s room. An EEG derivation can be bipolar, in which case both inputs are
The two inputs to the differential amplifier are commonly identi- relatively active. An example of a bipolar EEG derivation is F4 refer-
fied as G1 and G2. By international agreement, EEG and PSG equip- enced to C4. Because of the close proximity of these two electrodes,
ment is configured to produce an upward deflection (as viewed on the signals applied to the two inputs of the differential amplifier are
a computer screen or on paper) when a negative voltage is applied very similar, resulting in tracings that are significantly attenuated
to the G1 input, with respect to G2. Because this configuration can (Fig. 7.5).
be changed within the system software, it is important to verify cor- In PSG, referential derivations are used to record EEG data rel-
rect polarity when viewing the PSG data. This can be accomplished evant to sleep stage and arousal scoring. By using a distant and
during standard calibration procedures, by applying a negative DC relatively inactive reference site (M1 or M2), the signals of inter-
calibration voltage to all channels and documenting appropriate est are optimally amplified while undesirable interfering signals
signal response. are rejected. EOG recordings are likewise referential, with each
EOG electrode referenced to an opposite mastoid.1 Bipolar EEG
Signal derivations derivations are primarily used in seizure montage recordings, for
The previously mentioned example of C4 referenced to M1 is

described as a referential derivation. This means that EEG signals 1 The AASM recommends referencing both EOG electrodes to the right
of specific interest (C4) are compared with a relatively inactive
mastoid (M2). However, referencing the right EOG electrode (E2) to the
EEG site (M1). This arrangement provides maximum amplifica- mastoid on the same side of the head can significantly attenuate the EOG.
tion of the signals of interest, by subtracting the relatively inactive Consequently, some sleep centers prefer using a contralateral reference to
(low-voltage) M1 signals from the more active (higher-voltage) C4 equalize the out-of-phase signal deflections seen with conjugate eye movements.

Input G1
F4
Input G2
C4 F4/C4
Fig. 7.5 Bipolar EEG recording (graphic simulation). When both input signals are similar, the output signal amplitudes are significantly attenuated.
the purpose of detecting dissimilar aberrant voltages between bandwidths after the amplified signals have been converted into
the two electrode sites and to localize their origin by comparing digital form.
multiple derivations with one another. Other examples of bipolar The use of digital filters has opened new possibilities, whereby
derivations used in PSG include the recordings of EMG and ECG raw data can be collected and stored with minimal filtering, while
signals. the data display can later be selectively filtered as deemed appro-
priate by the user. A cautionary note regarding any form of filter-
Gain, sensitivity, and digital data display ing is to avoid using filters as a means of “cleaning up” the study.
Excessive signal filtering, whether by system design or by incorrect
The term “gain” refers to the ratio of output signal level to input
filter settings, can lead to loss of detail in the recording and prevent
signal level, based on the number of times the raw signal from the
the operator from recognizing possible signal degradation. A com-
subject is amplified. On most contemporary recording systems, the
mon problem with excessive signal filtering is the absence of clearly
gain is a fixed value. Sensitivity refers more specifically to the ratio
identifiable artifacts (which are actually useful for identifying prob-
of input voltage to the vertical height of the signal display. This is a
lems with loose electrodes, high impedances, etc.). With excessive
variable value that can be adjusted by the user. In PSG recordings,
filtering, outside signal interference may take on the appearance
the sensitivity settings of the EEG, EOG and EMG channels are
of physiological data instead of artifact, effectively resembling the
usually set to either 50 or 70 µV/cm, depending on individual la-
EEG, EMG, ECG, etc., and consequently be misinterpreted by the
boratory protocols. Lower sensitivity settings (such as 100 µV/cm)
reader. For example, a poor-quality, over-filtered ECG recording
are generally used for pediatric studies, because of the considerably
can produce signals that resemble ectopy within a normal sinus
higher EEG amplitudes seen in children.
rhythm. Without the excessive filtering, a poor-quality signal can
Whereas in the past PSG tracings were presented in uniform size
instead be recognized by the presence of 50 or 60 Hz artifact, or by
on grid paper, contemporary PSG systems allow for infinite vari-
other obvious signs of signal distortion.
ability in terms of the actual dimensions and aspect ratio of the
The choice of filter settings for each recorded parameter is based
data display. Although this can be useful in many ways, it can also
on the information sought within that parameter. For example,
lead to potential problems, particularly when the data display is ex-
when scoring sleep stages, the EEG is generally read within a fre-
cessively attenuated. It is possible, however, to calibrate a computer
quency range of 0.5–25 Hz. To preserve each end of the frequency
screen to produce a visual display that approximates a paper-based
spectrum, the low-and high-frequency filters are set to a slightly
recording and allows for precise signal amplitude measurements. It
wider range (0.3 Hz and 30 or 35 Hz, respectively). Table 7.1 dis-
is also helpful to develop a standard workspace within a laboratory,
plays filter settings for various PSG parameters based on recom-
so that all who are involved in recording, scoring, or interpreting
mendations by the AASM.
the PSG are viewing the data in the same way.
In addition to low-and high-frequency filters, PSG recording
systems provide a 50 or 60 Hz filter to eliminate line frequency
Filters interference from the recording. It is recommended that each
Filters are used to isolate specific frequency bandwidths relevant channel have an individual on–off setting for this filter and that
to each recording parameter. This prevents localized signal inter- the filter only be applied when other means of correcting the
ference from obscuring the signals of interest. For example, when problem have failed. The reason for this is the same as described
recording EEG, localized signal interference may stem from DC previously, i.e., these filters should not be used routinely to “clean
voltages generated by the skin or from fast frequencies generated by up” the signal. This especially holds true for the EEG and EOG
muscle activity. By limiting the frequency bandwidth, these extra- channels, which already employ a high-frequency filter setting
neous signals are eliminated from the data display. The extent to below the 50–60 Hz range. It is reasonable, however, to use 50
which these signal are eliminated depends on the design and con- or 60 Hz filters in the leg EMG channels (if necessary), because
figuration of the applied filters. Whereas in the past, analog filters these channels are more likely to be affected by line frequency
were designed to attenuate undesirable frequencies according to interference due to the extra-long electrode leads, and because it
a specific frequency response curve during data collection, con- is sometimes difficult to obtain optimal impedance levels when
temporary digital filters use software algorithms to delete selected recording leg EMGs.

Table 7.1 Examples of filter and sampling rate settings for various PSG recordings, using higher sampling rates to preserve all essential de-
parameters based on recommendations by the AASM tail of the individual EEG waves; whereas EMG recordings can be
adequately sampled at the Nyquist rate, because EMG analysis is
Derivation Low- High-frequency Minimal Desirable largely based on relative amplitude changes, not individual wave
frequency filter (Hz) sampling sampling scrutiny.
filter (Hz) rate (Hz) rate (Hz)
EEG–F4/M1
(or F3/M2)
0.3 30–35 200 500
System referencing
System referencing is a feature offered by digital PSG recording sys-
EEG–C4/M1 0.3 30–35 200 500
(or C3/M2)
tems for selecting and changing input derivations. System referenc-
ing relies on a common reference electrode, which is usually placed
EEG–O2/M1 0.3 30–35 200 500 on the midline of the scalp (Cz). During data collection, signals
(or O1/M2)
from all the applied electrodes (including the standard reference
R. EOG–E2/M2 0.3 30–35 200 500 electrodes M2 and M1) are initially referenced to the Cz electrode.
L. EOG–E1/M2 0.3 30–35 200 500 This configuration is not seen by the operator, but instead it serves
as a framework for viewing any derivation of interest, either during
Chin EMG 10 100 200 500
data collection or during playback. For each derivation selected by
Right leg EMG 10 100 200 500 the operator, the computer subtracts the common reference (Cz)
Left leg EMG 10 100 200 500 from the chosen pair of input signals. For example, if the operator
chooses to view the derivation of C4/M1, the computer subtracts
ECG 0.3 70 200 500
Cz from both C4 and M1 and combines the two input signals to
Airflow 0.1 15 25 100 produce the C4/M1 derivation. By using a common reference, vir-
Nasal pressure DC or ≤0.03 100 25 100 tually any combination of input signals can be selected to create the
desired output derivation.
Chest movement 0.1 15 25 100
System referencing is a valuable tool that provides maximum
Abdomen 0.1 15 25 100 flexibility for reviewing the PSG data. It is especially suitable for
movement viewing full-montage EEG recordings, allowing the selection of any
Oximetry DC Not listed 10 25 desired EEG derivation either during or after the study. In routine
PSG, system referencing is primarily used to change derivations
when recording artifacts occur. For example, if both C4/M1 and
C3/M2 are displaying artifacts, a combination of either C4/M2 or
Analog-to-digital conversion C3/M1 can be used. Or, if one of the ECG electrodes becomes dis-
Unlike paper-based recording systems of the past that transformed connected during the study, an alternate ECG derivation can be
the continuous analog signals directly into mechanical pen move- obtained by re-referencing the remaining ECG electrode to a leg
ments, contemporary recording systems rely on analog-to-digital electrode, or to any other distant electrode on the body.
converters (ADC) to convert the analog physiological signals into The only drawback to system referencing is that all of the recorded
digital form. The ADC converts the signals by assigning a numeric data are dependent on a single common reference. If the reference
value to the amplitude of the analog waveforms at predetermined electrode (Cz) becomes disconnected, or becomes the source of
intervals. artifact, then all of the channels linked to Cz become affected. It is,
The number of binary units (bits) used to represent the numeric therefore, important to pay attention to the integrity of the system
value of each sampled interval determines the amplitude resolution electrode connection and to be able to recognize when a recording
of the digital recording. For optimal amplitude resolution, a 12-bit becomes compromised by a faulty system electrode.
or higher system is recommended.
The number of sampled intervals obtained in the span of one
second is defined as the sampling rate, which determines the fre-
Timescale
quency resolution of the signal. Different sampling rates can be Historically, the timescale used in PSG was based on the paper speed
applied to each individual channel; the choice being dependent on of the recording instrument, which was most commonly set to
the range of frequencies recorded by the channel. According to the 10 mm/s, establishing an epoch length (amount of time per page) of
Nyquist theorem, basic frequency resolution requires a sampling 30 s. Alternatively, a 20 s epoch length was used in conjunction with
rate that is twice the frequency sampled. Sampling rates less than a paper speed of 15 mm/s. In the present day, the use of digital tech-
the Nyquist rate result in signal distortion known as aliasing. nology allows for multiple timescale settings, which can be applied
While the Nyquist theorem defines minimum sampling rates either during recording or during playback (Figs. 7.6 and 7.7).
for basic frequency resolution, significantly higher sampling rates For the purpose of sleep stage scoring, the 30 s epoch is the estab-
(5–10 times the frequency rate or higher) are necessary to obtain lished standard; however, alternative timescales can be used for
an adequate graphic representation of the individual waves [5]‌. The analyzing sleep-related events. For example, an epoch length of
choice of an appropriate sampling rate for each channel is based on 10–15 s can be useful for more closely examining suspected EEG or
the highest frequency expected within that channel and according ECG abnormalities, whereas epoch lengths of 2–5 minutes are use-
to how important it is to obtain full graphic resolution of the signal ful for examining respiratory patterns, periodic limb movements
of interest. For example, full graphic resolution is desirable for EEG and oximetry trends.

Alpha rhythm Mixed-frequency EEG

C4/M1
O2/M1
E2/M2 Slow-rolling eye movements
E1/M2
Chin EMG Normally active chin EMG
ECG
50 µV
Stage 1 (N1) (EEG, EOG, and EMG)
1s
Fig. 7.6 PSG recording viewed in a 30 s epoch window. A timescale of 30 s per epoch provides a high level of detail in the EEG and EOG channels and is the standard
scale for scoring sleep stages and arousals.
C4/M1
O2/M1
E2/M1
E1/M2
NREM sleep
Chin EMG
ECG
Right leg EMG
Left leg EMG
Airflow Cheyne–Stokes respiration with central apneas
Chest
Abdomen
95.0 95.0 98.0 98.0 96.0 94.0 97.0 97.0 96.0 95.0 96.0 97.0 96.0 95.0 93.0 97.0 96.0 95.0 94.0 97.0
SpO2
30 s
Fig. 7.7 PSG recording viewed in a 5 min epoch window. After scoring sleep stages and arousals in 30 s epochs, the timescale can be compressed into 2–5 min epochs,
in order to better discern the respiratory patterns while correlating them to the patient’s sleep and wake physiology.

Electrical safety It is important to note that not all artifacts are undesirable.

Certain physiological artifacts can be useful in the interpretation
Because the patient is connected by conductive leads to electrical of the study and should not be arbitrarily removed. For example,
instrumentation, there is always a potential hazard of stray electri- “snoring artifact,” recorded by the chin EMG, is useful for confirm-
cal current passing through the patient. To minimize this hazard, ing that the patient snores. Muscle-generated artifacts occurring
contemporary medical devices, including PSG recording systems, with body movements helps confirm that the patient moved. It is
provide isolated inputs that meet strict patient safety guidelines. also important to understand that even undesirable artifacts serve
These inputs isolate the patient from ground, eliminating the possi- a purpose, because they alert the operator that a faulty signal is pre-
bility of leakage current reaching the patient from external sources sent and needs correction.
and from devices connected to the patient. Nonetheless, technolo-
gists working with these devices must be adequately trained in elec- 50/60 Hz artifact
trical safety and recognize any potential problems stemming from The presence of 50 or 60 Hz artifact in PSG stems from power-
improper use of equipment or improper wiring in the vicinity of line frequency in the vicinity of the study.* The primary method
the study. of eliminating line frequency interference is by common mode
rejection, as described earlier in this chapter. In addition, the pa-
Patient monitoring tient ground electrode is used to divert stray electrical interference
from the patient. Consequently, the presence of 50 or 60 Hz artifact
Regardless of how well the electrodes and sensors are initially
in the recording generally indicates that either impedance levels
applied to the patient, recording problems occurring during the
are too high or the ground connection has degraded, or there is a
course of an overnight sleep study are common. While monitoring
combination of both. Excessive electromagnetic fields within the
the patient, part of the job of a sleep technologist is to recognize
laboratory environment can further aggravate 50 or 60 Hz inter-
and correct these problems in order to preserve the integrity of the
ference, as can excessive leakage current, which can originate from
recording for its duration. The other aspect of patient monitoring
extension cords, power strips, lamps, televisions, electric beds, fans,
is to directly observe the patient, both for safety purposes and to
or any other electrical devices in the vicinity of the study.
document any information that can potentially enhance the inter-
It is easy to recognize 50 or 60 Hz artifact, because it is a fast,
pretation of the PSG.
uniform frequency that obscures the underlying tracings (Fig. 7.8).
It can be diminished or removed by the use of a 50/60 Hz filter;
Artifact recognition however, this should not be standard practice. Instead, the source
PSG artifacts are defined as extraneous signals appearing within of the problem should be identified and corrected, either by re-
any of the recorded parameters of the sleep study. Most recording referencing the channel or by reattaching the offending electrode.
artifacts can be readily identified by their exaggerated or distorted
High-frequency artifacts generated
appearance. However, in some cases, it may be difficult to discern
between artifacts and physiological signals of interest. One of the
by electronic devices
advantages of a multichannel recording is the ability to cross- High-frequency interference from electronic devices (commonly
examine the recording to see if the signals in question correlate described as “noise”) can resemble 50 or 60 Hz artifact, but does
with other parameters. For example, if questionable wave patterns not respond to a 50/60 Hz filter. Although common mode rejec-
are seen in an EEG channel but are not appropriately reflected in tion and the patient ground help minimize the presence of elec-
adjacent EEG or EOG channels, they are likely to be artifacts. By tronic noise, in some instances it might be necessary to identify
comparing adjacent channel tracings, one can also determine the the source of interference and either turn it off or move it to an-
origin of the artifact. For example, if an identical artifact is seen in other location.
two or more channels sharing the same reference (eg, C4/M1 and
E2/M1), it can be assumed that the source of artifact is the reference Muscle artifact
electrode. However, if an artifact appears in only one channel (shar- Muscle artifact appearing in the EEG or EOG is another high-
ing a common reference with other channels), then the problem frequency artifact that somewhat resembles 50 or 60 Hz artifact.
can be traced to the exploring electrode. However, unlike power line or electronic interference, muscle arti-
Because PSG recordings are conducted over an extended period fact is not uniform but irregular, and it may wax and wane with
of time (typically 7–8 hours) on patients who are unrestricted in increased or decreased muscle tension (Fig. 7.9). Muscle artifact is
movement, some degree of artifact can be expected in nearly every caused by localized muscle activity in the vicinity of the exploring
study. Part of the job of a sleep technologist is to minimize the or reference electrode. When seen in the EEG or EOG channels, the
occurrence of undesirable artifacts by utilizing proper electrode artifact often stems from a reference electrode that was placed too
application techniques and by making appropriate corrections or low or too far from the ear flap (pinna), and is in close proximity
adjustments to the study when artifacts occur. to the muscles of the neck. Repositioning the electrode over a firm
In some instances, corrections can be made by re-referencing a bony area close to the pinna can correct the problem. When muscle
channel to a back-up electrode (if available) or by using a back- artifact is only limited to one or two EEG or EOG channels, it can
up derivation (eg, C3/M2 instead of C4/M1). In other instances,
correcting a faulty signal requires entering the patient’s room to
replace or reposition a sensor (eg, a loose respiratory belt or dis- * Most European and Australasian countries use 50 Hz, while 60 Hz is used
lodged oximetry probe). in the United States, Canada, and many South American countries.

C4/M1
O2/M1
E2/M1
E1/M2
Chin EMG 60 Hz artifact
ECG
Right leg EMG
Left leg EMG
Airflow
Fig. 7.8 An example of 60 Hz artifact in the chin EMG channel caused by faulty electrode connection.
C3/M2
Muscle artifact
O2/M1
E2/M1
E1/M2
Muscle artifact
Chin EMG
Stage wake (W)
ECG
Fig. 7.9 Muscle artifact in the EEG and EOG. This is an example of muscle artifact appearing in the C3/M2 and E1/M2 channels. Because the artifact is identical in both
channels sharing the same reference, it is evident that the artifact originates from the M2 electrode.

usually be eliminated by re-referencing to a back-up derivation. bony area behind the ear, away from the soft fatty tissues of the
Muscle artifact also often disappears without any intervention as neck. In some instances, it may be advantageous to place these elec-
the patient relaxes and falls asleep. trodes slightly above the conventional mastoid process site, making
sure not to place them too high. It is also possible to reduce or elim-
ECG artifact inate ECG artifact in the EEG or EOG channels by linking the two
Unlike localized low-voltage EEG waves, strong ECG signals can reference electrodes M1 and M2. This can be accomplished if the re-
be detected from virtually any location on the body, including the cording system has re-referencing capabilities. When the EEG and
scalp. Based on the principle of differential amplification, the prob- EOG channels are double-referenced, this essentially creates three
ability of ECG artifact in the EEG or EOG channels increases in divergent ECG signals that cancel each other, thereby reducing the
proportion to the distance between the exploring and reference artifact. However, it is important to note that double-referencing
electrodes. Because of the relatively long inter-electrode distances may attenuate the signals of interest, and that it opens up the pos-
used in standard PSG referential recordings (such as C4 referenced sibility of other forms of artifact stemming from either of the com-
to M1), it is not unusual to see a small amount of ECG artifact in the bined reference electrodes to contaminate the recording. Therefore,
EEG and/or EOG channels. double-referencing should only be used when absolutely necessary,
While a small amount of ECG artifact in the EEG or EOG chan- and not as general practice.
nels is usually not problematic, excessive amounts of ECG arti- ECG artifact should not be expected in the EMG channels, be-
fact can make it difficult to read the study. In addition, excessive cause the distance between any pair of EMG electrodes is minimal.
amounts of ECG artifact generally indicate problems with the elec- The presence of ECG artifact in an EMG channel invariably indi-
trode application, such as improper placement or high impedance cates improper electrode placement or unequal impedance levels.
levels (Fig. 7.10). ECG artifact is especially common when study-
ing obese patients, who may have increased body fluids or fatty Slow-frequency artifacts
tissue in the vicinity of the neck and scalp. ECG voltages are also Slow-frequency artifacts in the EEG or EOG channels can be
seen more prominently when the electrode placement follows the caused by perspiration or by direct pressure against an electrode.
electrical orientation (axis) of the heart, which may be horizontally Perspiration induces chemical changes in the electrolyte interface
deviated in massively obese individuals. between the electrode and the patient’s skin, causing the appear-
To reduce the possibility of ECG artifacts in the EEG and EOG, ance of slowly oscillating waves in the EEG and/or EOG, com-
the reference electrodes (M1 and M2) should be placed over a firm monly described as “sweat artifact” (Fig. 7.11). A similar pattern,
C4/M1
O2/M1
E2/M1
E1/M2
Chin EMG
Stage wake (W)
ECG
Fig. 7.10 An example of excessive ECG artifact in the EEG and EOG channels. Although small amounts of ECG artifact are sometimes unavoidable, ECG artifacts can be
exacerbated by impedance imbalances between the EEG and EOG electrode connections or by poor placement of the mastoid reference electrode.

C3/M2
O2/M1
E2/M1
E1/M2
Chin EMG
Stage ?
ECG
Right leg EMG
Left leg EMG
Airflow
Chest
Abdomen
74.0 81.0 83.0 82.0 79.0 76.0 73.0 72.0 72.0 72.0 74.0 76.0 77.0 77.0 76.0
SpO2
Fig. 7.11 Slow-frequency artifacts in the EEG and EOG. The slow-frequency artifacts in this example are most likely caused by a combination of sweat and slight
rhythmic head motion associated with breathing. The artifacts are limited to the C3/M2 and E1/M2 channels. They are identified by their exaggerated appearance and by
lack of correlation with the O2/M1 and E2/M1 derivations.
although more pronounced and abrupt, can be caused by intermit- even the slightest movement. It is also important not to spread con-
tent pressure against an electrode or by tugging an electrode lead. ductive substances (including skin prepping materials) beyond the
This is commonly described as “popping artifact.” Popping artifact boundary of the electrode cup when preparing the electrode site
can also be caused by dirty or faulty electrodes or by electrodes that and when applying the electrodes.
are loosely attached to the skin. Even with proper electrode application technique, slow-wave
Any body movement can further aggravate the presence of slow- artifacts can be problematic when a patient perspires heavily or
frequency artifacts. A common phenomenon in PSG recordings is moves frequently during the study. When slow-wave artifacts are
the appearance of slow artifacts in the EEG and EOG channels that limited to the side of the head on which the patient is lying, they
appear synchronous with the patient’s respiratory patterns. This can be eliminated by re-referencing all the derivations to the op-
is most likely due to the slight movement of the head associated posite side of the head. Another strategy (especially when slow-
with each breath. Slow-frequency artifacts that appear synchronous wave artifacts appear in all EEG and EOG channels) is to attempt to
with breathing are often labeled as “respiration artifacts.” This term cool the patient with a fan or air conditioning. As a last resort, slow-
may be misleading, because the source of the artifact is not really frequency artifacts can be eliminated from the recording by chan-
respiration, but rather a combination of chemical and mechanical ging the low-frequency filter to a higher setting. This will effectively
instability of the EEG and EOG electrode/patient interface, which attenuate any slow frequencies within the channel, including sweat
can be further affected by any motion, including slight head motion or popping artifacts. At the same time, however, any physiological
associated with breathing. slow-wave activity, including slow EEG waves and slow eye move-
As with all artifacts, proper electrode application technique ments, will also be attenuated; therefore, this technique should be
helps minimize the potential for slow-wave artifacts in the EEG used sparingly, and not as routine practice. It is also important to
and EOG. More specifically, it is important to make sure that all note that using filters to remove slow-wave artifacts is only appro-
electrodes are well adhered, with a tight seal between the electrode priate if the underlying EEG and EOG signals are intact and have
and the patient’s skin. This prevents the electrodes from “floating” not been degraded by high impedance levels or faulty electrode
over the electrode sites, which can cause signal disruption from connections.

In the past, low-frequency filter settings in PSG recordings were application. To minimize the effects of body movement, it is
typically limited to 0.03, 0.3, 1, and 10 Hz. Contemporary digital fil- important to practice proper application technique, and to use
ters on some of the more advanced PSG systems can be set to almost strategies that prevent patients from excessively pulling or tug-
any configuration. This is advantageous, because the operator of the ging at the electrode wires.
equipment can select an appropriate filter setting that reduces the
artifact but has less impact on the physiological data. For example, Artifacts in the ECG channel
in the past, slow-wave artifacts were eliminated by changing the As with all bioelectrical recordings, the ECG relies on proper elec-
low-frequency filter from 0.3 to 1 Hz, which eliminated the artifact, trode application technique to ensure signal quality. Although
but also significantly altered the EEG. A more conservative filter much higher in voltage than the EEG, EOG, or EMG, the ECG is
change to a setting of 0.5 or 0.6 Hz can be made with contempo- nonetheless susceptible to artifacts caused by high electrode imped-
rary digital filtering, which effectively reduces the artifact, but at the ances, faulty connections, pressure against an electrode, sweat, and
same time preserves most of the underlying EEG data. patient movement. In some instances, artifacts in the ECG can re-
semble ectopic beats. To avoid misinterpreting the ECG, it is useful
Movement artifacts to compare any questionable tracings to alternative ECG deriva-
Movement artifact is a general term that describes any data dis- tions. If the recording equipment provides system referencing, an
tortion caused by body movement. When major body move- alternative ECG signal can be obtained from any two electrodes
ments occur, often a combination of slow and fast artifacts, as that are sufficiently distant from each other, such as the C4 elec-
well as generalized signal blocking, can be seen in the recording. trode referenced to one of the left leg electrodes (Fig. 7.12).
To some extent, movement artifacts are expected and are useful
for confirming that the patient moved. However, excessive signal Artifacts stemming from a faulty system reference
distortion occurring with every movement makes it difficult to As noted earlier in this chapter, the use of a system reference opens
interpret the study, and is usually an indication of poor electrode up many possibilities for reconfiguring input signal derivations.
C4/M1
O2/M1
E2/M1
E1/M2
Chin EMG Stage 2 (N2)
ECG
ECG (alternative derivation)
Right leg EMG
Left leg EMG
Airflow
Fig. 7.12 Artifacts in an ECG channel. In this example, the primary ECG channel is distorted with artifact. An alternative ECG derivation has been added to the recording
and demonstrates a normal sinus rhythm. The alternative derivation was obtained by referencing an ECG electrode to one of the left leg electrodes.

C4/M1
O2/M1
E2/M1
E1/M2
Chin EMG Stage ?
ECG
Right leg EMG
Left leg EMG
Airflow
Chest
Abdomen
90.0 90.0 90.0 90.0 89.0 89.0 89.0 89.0 90.0 90.0 90.0 90.0 90.0 90.0 90.0
SpO2
Fig. 7.13 Artifacts originating from the system reference electrode. In this example, a faulty system electrode connection is causing artifacts to appear in all of the
channels that are linked to the system reference.
However, if the system reference electrode becomes detached or evaluated within the context of sleep and wake physiology, and the
the signal is degraded, all of the channels that rely upon the system various channels can be cross-examined to confirm or refute the
reference are affected (Fig. 7.13). The only solution to this problem validity and/or etiology of any suspected event (Fig. 7.14).
is to properly reattach the system reference electrode.
Artifacts in the oximetry channel
Artifacts in the respiratory channels Inaccurate oximetry tracings can be caused by probe displacement,
As noted before, it is important to recognize that for practical rea- by over-tightening the probe on a patient’s finger, by poor perfu-
sons, most forms of respiratory monitoring during sleep rely on sion, by motion artifact, or by placing a probe over painted or artifi-
sensors that provide nonquantitative, indirect representations of re- cial nails. Although most contemporary recording systems provide
spiratory airflow and effort. As such, these representations are often some form of signal quality verification, none of these systems is
imprecise and subject to many forms of signal distortion. However, foolproof; therefore, it is essential for sleep technologists to be able
unlike bio-electrical recordings, inaccurate respiratory tracings do to recognize a questionable signal and make the necessary correc-
not necessarily demonstrate obvious signs of signal distortion; con- tions. Likewise, it is essential for the reader of the study to iden-
sequently, it can be easy to misinterpret the data, especially if one tify potentially false oximetry data, especially when interpreting
attempts to over-scrutinize each wave pattern individually without unattended sleep studies or overnight oximetry screens (Fig. 7.15).
correlating the tracings with other PSG parameters. In many
instances, artifacts in the respiratory channels can resemble physio-
logical respiratory events. Although every attempt should be made Summary
to maintain adequate respiratory tracings throughout the duration PSG is a complex procedure that requires extensive and systematic
of the sleep study, it is equally important for those who read the PSG training for those who perform, score, and interpret the studies.
data to be aware of the characteristics and limitations of respiratory When properly performed and accurately interpreted, PSG yields
sensors and interpret the study accordingly. A distinct advantage a wealth of information that is unattainable by other form of sleep
of multichannel PSG recordings is that all respiratory data can be testing. PSG provides an essential window into the physiology of

Fig. 7.14 Artifact in the airflow channel resembling an apnea. By examining the respiratory channels within the context of the patient’s sleep and wake physiology (as
documented by the top channels), it is evident that the apparent “absence of airflow” is actually an artifact caused by patient movement during an arousal. The flattening
of the airflow signal may have been caused by the patient’s mouth dropping open or by a dislodged airflow sensor. Note the continued attenuation of the airflow signal
following the arousal. This is an example of an artifact that could be erroneously scored as an apneic event.
Fig. 7.15 Artifact in the oximetry channel. Artifacts in the oximetry channel are common, and may be caused by a number of factors, including patient movement or sensor
displacement. It is important to identify and delete these artifacts during the scoring and interpretation process, to prevent false oximetry data from appearing on the final report.

sleep, offering optimal diagnostic capabilities for patients with sleep References
disordered breathing, narcolepsy, movement disorders, seizure dis-
1. Holland JV, Dement WC, Raynal DM. Polysomnography: a response
orders, medication effects on sleep, parasomnias, and other disor-
to a need for improved communication. Presented at the 14th Annual
ders that are undetectable during a person’s waking hours. Meeting of the Association for the Psychophysiological Study of Sleep,
In recent years, the scope of sleep medicine has expanded to- Jackson Hole, WY, June 1974.
ward treating increasingly complicated patients, many of whom 2. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters
require nocturnal noninvasive ventilation. Advances in bilevel for the indications for polysomnography and related procedures: an
positive airway pressure (PAP) technology have made it possible update for 2005. Sleep 2005;28:499–521.
to treat conditions that were previously refractory to conventional 3. Jasper HH. The ten twenty electrode system of the International
Federation. Electroencephalogr Clin Neurophysiol 1958;10:371–5.
PAP therapy. Combining this technology with digital PSG has
4. Berry RB, Brooks R, Gamaldo CE, Harding SM, Marcus CL, and
greatly enhanced our ability to effectively diagnose and treat com- Vaughn BV for the American Academy of Sleep Medicine. The
plex forms of sleep disordered breathing, as seen in patients with AASM Manual for the Scoring of Sleep and Associated Events: Rules,
congestive heart failure, COPD, neuromuscular disease, or obesity Terminology and Technical Specifications, Version 2.0. Darien
hypoventilation, patients who develop central apneas as a result of Illinois: American Academy of Sleep Medicine, 2012.
opioid use, and various other conditions that warrant a specialized 5. Hirshkowitz M. R&K manual update. Sleep Review, March 6, 2005.
approach to diagnosis and treatment. http://www.sleepreviewmag.com/2005/03/rampk-manual-update/.

CHAPTER 8
Scoring of sleep stages,

breathing, and arousals
Marco De Los Santos and Max Hirshkowitz
Introduction period. Chapters by various clinician-â•‰scientists in Guilleminault’s

(1982) Sleeping and Waking Disorders: Indications and Techniques
Behavioral and measurable bioelectrical correlates characterizing [7]â•„became the de facto manual for recording and scoring sleep-â•‰
sleep provide metrics for determining whether an individual is disordered breathing, periodic leg movements, gastroesophageal
asleep or awake. Thus, in a real sense, the question “what is sleep” reflux, chronobiological rhythms, and sleep in infants. In the 1990,s
serves to determine “when is sleep?” Behavioral approaches for several American Sleep Disorders Association task forces devel-
detecting sleep onset have involved monitored involuntary object oped and published standardized rules (eg, [8]), but information
dropping or releasing contact switches. Alternatively, the subject and sources remained fragmented. It was not until 2007 that the
might lapse during a signal detection task (eg, pressing a button in American Academy of Sleep Medicine (AASM) published rules,
response to sound or a visual target), and researchers have assumed terminology, and technical specifications for scoring sleep and its
that response cessation marks sleep onset. Armed with the assump- associated physiological events relevant to sleep medicine [9,10].
tion that sleep is a brain process, research breakthroughs followed Techniques outlined in this “cookbook” for clinical polysomnogra-
from recording brain electrical activity. Hans Berger, a German phy will be the main subject matter of this chapter.
physiologist and psychiatrist, and the inventor of electroencepha- This chapter’s aim is to summarize and clarify the main technical
lography (EEG), paired brainwave patterns with subject reports and procedural aspects of performing and reading PSG. The prin-
about sleep status. He described alpha-â•‰wave disappearance during ciples adopted in this chapter are based on the AASM guidelines for
relaxed wakefulness as a marker for when sleep occurred [1]â•„. scoring and staging sleep studies.
Less than a decade later and some 4000 miles away in Tuxedo
Park, New York, Alfred Lee Loomis and colleagues made the first
continuous, all-â•‰night EEG recordings in sleeping humans [2]â•„. They Sleep, wake, and central nervous
described sleep spindles, slow waves, K complexes (at that time system arousal
called random waves), and devised a scoring system to describe
the sleep process. Sleep involved multiple processes; “sleep” was Recording montage
no longer a single entity. These processes appeared to proceed in Attended polysomnography serves as the diagnostic test at the core
an orderly fashion and were basically similar in all healthy, young of traditional sleep medicine. The term originates from both Latin
adults. and Greek roots: the Greek polus meaning “many,” the Latin somnus
Equipped with EEG technology, scientists began exploring other referring to sleep, and the Greek graphein meaning “to write.” The
physiological processes and their alterations associated with sleep. sleep study, as it is commonly known, is without debate a costly,
Sleep’s biological portrait became more complete when Aserinsky labor-â•‰intensive, and time-â•‰consuming test. It requires skilled tech-
and Kleitman [3]â•„described periodic ocular motility episodes dur- nicians and specialty-â•‰trained physicians to interpret the results.
ing sleep correlated with dreaming. A sleep stage scoring system But even as the more affordable home sleep testing gains ground,
evolved to include what ultimately became known as rapid eye in-â•‰laboratory PSG remains the gold standard. The vast majority of
movement (REM) sleep [4,5]. An ad hoc committee established medically ordered sleep studies are used to diagnose or determine
standardized methods in 1968 for classifying sleep stages in human treatment for patients with sleep disordered breathing. Other med-
adults [6]. ically approved PSG indications include narcolepsy assessment and
Sleep medicine began to emerge as a subspecialty, and during differentiating parasomnias from nocturnal seizure disorder.
the next decade and a half, techniques to detect, characterize, and Frontal, central, and occipital lobe EEG, electrooculography
summarize breathing and movement pathophysiologies emerged. (EOG), and submentalis (chin) EMG serve as core parameters used
The resulting EEG, eye movement, respiratory, electromyographic to (a) differentiate sleep from wakefulness, (b) classify the type of
(EMG), snore sound, oxyhemoglobin saturation, and electrocardi- sleep, and (c) detect awakenings. Figure 8.1(a) illustrates recom-
ographic (ECG) recording array constitutes what is now called pol- mended electrode placements. Other signals recorded for specific
ysomnography (PSG). Most laboratories also include simultaneous diagnoses include: oxygen saturation, body position, ECG, anterior
video recording to capture the patient’s behavior during the sleep tibialis (leg) EMG, nasal–â•‰oral airflow, and respiratory effort. These

(a) (b)
Nasion
E
10%
20%
1 cm
1 cm
20%
F E
100%
100%
C (c)
M M 1 cm
2 cm
Vertex 2 cm
1
O 2 3
Inion
Fig. 8.1 EEG, EOG, and EMG electrode placements. (a) AASM recommended electrode positions based on the international 10-20 System. These include left mastoid
referenced (M1) right frontal lobe (F4–M1), central lobe (C4–M1), and occipital lobe (O2–M1) scalp derivations. Backup electrodes are place on the left frontal, central,
and occipital scalp positions referenced contralaterally (i.e, F3–M2, C3–M2, and O1–M2, respectively). (b) Electrode placements for EOG recordings. (c) Placements
recommended for recording submentalis EMG needed to classify REM sleep and detect CNS arousals from REM sleep.
parameters, when combined, recount the uninterrupted story of a vertical eye movements can be attained by placing the E1 and E2
sleeping patient. electrodes 1 cm below the outer canthi and using a forehead place-
ment as a reference site (Fig. 8.1b). However, this sacrifices easy
EEG recording
eye movement differentiation from frontal EEG activity using the
EEG electrode placement accords with the 10-20 System, an inter- in- versus out-of-phase paradigm).
nationally recognized standard for placing electrodes on the human
scalp. This method landmarks scalp placement of 21 electrodes. To EMG
determine specific sites, the method uses four reference points; the Three chin EMG electrodes are placed. The first is placed midline
nasion, inion, and auricular openings of left and right ears. The and 1 cm above the mandible’s inferior edge. The second is attached
nasion, anatomically, is the point where the nasal and frontal bones 2 cm to the right of the midline and 2 cm below the mandible’s
merge. The inion is the most prominent protuberance of the occipi- inferior edge. The third placement is 2 cm to the left of the midline
tal bone. With reference points well demarcated, the skull is meas- and 2 cm below the mandible’s inferior edge (Fig. 8.1c). These chin
ured in the transverse and median planes with electrodes placed EMG electrodes provide an uncalibrated muscle tone index used
by dividing these perimeters into 10% and 20% segments. Per rec- to appreciate REM-related atonia. Chin EMG activity increases
ommendations, PSGs involve continuous recording of central (C), also serve as part of the criteria for scoring CNS arousals during
frontal (F), and occipital (O) EEG leads. The suggested EEG deri- REM sleep.
vations are F4–M1, C4–M1, and O2–M1 (with backups at F3–M2,
C3–M2, and O1–M2), where M1 and M2 refer to the left and right Scoring
mastoid processes.
Sleep and wake
EOG recording We designate each successive 30 s snapshot of a sleep study as an
Electrodes placed near each eye’s outer canthus (E2 and E1, for epoch. Each epoch is classified as either sleep or wakefulness. Sleep
right and left eyes, respectively) will detect eye movement. Using epochs are further classified as rapid eye movement (REM) sleep
a neutral reference site (M1 or M2) provides the basis for record- or non-rapid eye movement (NREM) sleep. Finally, NREM epochs
ing positive corneal potentials moving toward and/or away from are also further categorized as stage N1, stage N2, and stage N3.
these electrodes. This recording arrangement produces robust out- Staging proceeds from the start of the study (lights out) to the end
of-phase (E1 versus E2) activity when horizontal eye movements of the study (lights on), and each epoch is exclusively assigned a
occur. Being out of phase, eye movements are easily differentiated single stage. When features characteristic of more than one stage
from frontal EEG activity inadvertently recorded by EOG elec- coexist within a particular epoch, the stage is designated according
trodes (which appears as an in-phase signal). The manual recom- to which sleep process (identified by specific waveforms) occupies
mends E2 placed 1 cm above and E1 placed 1 cm below the outer the majority of the time. Although scoring is systematic and gener-
canthus of the respective eyes. Staggering the electrode placements ally reproducible, ambiguities exist. Inter-rater reliability for sleep
slightly above and below each eye’s horizontal plane allows some staging (and scoring of respiratory events), varies somewhat with a
appreciation of vertical eye movement. Better visualization of scorer’s skill and experience level.

Chapter 8 scoring of sleep stages, breathing, and arousals 73
Table 8.1 Principal EEG waveforms and events for categorizing sleep Sleep staging rules
stages and wakefulness Stage W (wakefulness)
This is scored when alpha EEG activity occupies more than 50%
Term Definition of a given epoch; that is, more than 15 s duration. At first glance,
Alpha activity Rhythmic, sinusoidal-like EEG activity in the 8–13 Hz this would appear to be a simple, easy-to-follow, and straightfor-
frequency range. When recognizably present, alpha EEG ward rule, and in patients with well-formed alpha EEG activity, it
activity is the primary waveform used to differentiate sleep is (Fig. 8.2). However, EEG quality in many patients with sleep dis-
from wakefulness. On the scalp, alpha activity usually orders is poor, and alpha activity can be indistinct. To complicate
appears most prominently over the occipital region and matters further, approximately 10% of individuals lack a discerna-
predominates during relaxed wakefulness with eyes closed. ble alpha rhythm on eye closure. In such cases, differentiating sleep
Theta activity Groups of contoured or triangular EEG waves in the 4–7 Hz from wakefulness presents greater difficulty, and scoring must rely
frequency range. Theta activity usually has greater amplitude on other characteristics. Conjugate REMs and blinking help iden-
when recorded from central derivations. Although theta tify wakefulness. The appearance of vertex sharp waves, generalized
activity is not part of formal delineation rule criteria for sleep EEG flattening with some slowing into the theta bandwidth, sleep
stage scoring, it serves as a general confirmatory marker spindle or K-complex emergence, and delta activity indicate sleep.
that sleep is present. Also, a special type of theta, called
sawtooth theta, can help verify the presence of REM sleep. Stage N1 sleep
Sawtooth theta has a notched appearance resembling the This is established by the gradual waning of alpha activity to
serrated edge of a saw’s cutting blade—hence the name. the point where it occupies less than 50% of the 30 s epoch (see
Delta activity Rhythmic EEG activity with a frequency below 4 Hz. fig. 8.3, top panel). The alpha rhythm is replaced by low-voltage,
A subcategory of delta activity falling in the 0.5–2 Hz mixed-frequency (theta and beta rhythms) activity. In the absence
frequency range called “slow waves” are important in sleep. of REMs, when this low-voltage, mixed-frequency activity does
Slow waves are high-amplitude EEG waves (peak-to-trough not contain sleep spindle, K-complex, or delta activity, the epoch
amplitude >75 μV on monopolar central or frontally is scored as stage N1 sleep. The presence of slow rolling eye move-
derived recordings). Slow-wave activity duration within ments and vertex waves is characteristic of but not essential to N1
the 30 s time domain considered an “epoch” is used as a
sleep scoring criteria. As previously discussed, alpha EEG presence
criterion to differentiated N3 from N2 sleep.
and/or integrity can be compromised in some patients, making
Sleep spindle A greater than 0.5 s train of spindle-shaped waves with a stage N1 scoring difficult. Furthermore, because stage N1 sleep
center frequency of 11–16 Hz (or most commonly 12–14 criteria essentially represent “rules of exclusion” and N1 occupies
Hz). Sleep spindles are usually most prominent in recordings
so little of overall sleep time, inter-rater reliability is quite low
from central EEG derivations. Sleep spindles are used to
(18–42%).
differentiate stage N2 from stage N1 sleep and stage R sleep.
K-complex A greater than 0.5 s, high-amplitude, negative-going, EEG Stage N2 sleep
sharp wave that is immediately followed by a positive This is defined by the presence of sleep spindles and/or K-
component. K-complex waves stand out from the complexes (see fig. 8.3, middle panel). In contrast to stage W and
background EEG activity and are most prominent in central N1 scoring, stage N2 is easily identified, and scoring reliability
and frontal EEG derivations. K-complex waves are used is very high. Once a patient enters N2, the subsequent epochs
to differentiate stage N2 from stage N1 sleep and stage R are scored as N2 as long as there is evidence of K-complexes or
sleep. sleep spindle activity. Stage N2 scoring terminates when sufficient
slow-wave activity appears indicating a transition to N3, when the
sleeper ascends to stages N1 or W, or at the onset of a REM sleep
episode (see below).
Five main EEG waveforms direct classification of an epoch as
Stage N3 sleep
sleep or wakefulness or sleep and then subclassify sleep into one
This is scored when an epoch contains 6 s (or more) (i.e, ≥20%)
stage or another (see Table 8.1). Alpha activity, theta activity, delta
of slow waves (>75 μV waves in the 0.5–2 Hz bandwidth) (see
activity (also known as slow waves), K-complexes and sleep spin-
fig. 8.3, bottom panel). Stage N3 sleep is also called slow-wave
dles form sleep’s basic central nervous system (CNS) microarchi-
sleep (SWS) or delta sleep. The older R&K Manual previously
tecture. Staging is considerably easier when the microarchitectural
divided stage N3 sleep into NREM stage 3 and stage 4 sleep based
waveforms are clearly present, are well formed, and readily stand
on whether there was 20–50% or >50% slow-wave activity, respec-
out from background activity. It is worth remembering that sleep
tively; some sleep specialists still make this distinction. Sleep spin-
staging rules were developed as bioelectrical correlates in normal
dles occur during stage N3 sleep, but eye movements are absent.
healthy subjects. In clinical practice, patients are very often older
and infirm. Therefore, poorly formed and ambiguous features make Stage R sleep
it more difficult to score sleep and may reduce inter-rater reliability. The background EEG for this stage is similar to that for stage
While some problems may stem from poor recording technique, a N1 sleep; however, REM activity is also present. REMs appear as
sleep disorder itself often erodes the quality of EEG patterns and sharply peaked EOG channel deflections with an initial rise-time
events. Sometimes, successful treatment improves sleep’s basic lasting less than 0.5 s. Stage R sleep was originally called JEM sleep
microarchitecture and returns EEG quality to normal, a far more (jerky eye movement sleep) by its discoverer. Subsequently, this
impressive accomplishment than increasing one or another specific sleep process became most commonly known as REM sleep (named
sleep stage percentage. for the accompanying REMs). However REM sleep possesses

Sleep
onset E1-M2
E2-M1
F4-M1
C4-M1
O2-M1
Chin1
Fig. 8.2 Sleep onset. This figure represents a clear transition from wakefulness to sleep. The subject had well-defined alpha EEG activity that completely attenuates after
the first third of this epoch, giving way to low-voltage, mixed-frequency EEG activity.
multiple alternative monikers, including D-sleep (dreaming sleep), between phasic REM (epochs with REM or other activity bursts)
paradoxical sleep (because there is awake-like EEG activity and eye and tonic REM (quiescent periods). Figure 8.4 illustrates phasic
movements), desynchronized sleep, active sleep, and, most recently, and tonic REM sleep.
stage R sleep. Dreaming occurs during stage R sleep, and the eye
movements appear to be changes in direction of gaze associated CNS arousal
with dream content. Middle ear muscle activity, facial grimacing, CNS arousal scoring provides a sensitive index for sleep disturb-
twitching, penile erections, and sudden heart-rate alterations can ance. This microarchitectural feature differs from awakening with
also accompany REM sleep. Sawtooth theta waves and muscle ato- respect to its duration. An awakening involves transition from any
nia are also characteristic of the stage. Skeletal muscle atonia pre- sleep stage to stage W (wakefulness). Such a transition requires an
vents the sleeper from enacting dreams or behaviorally reacting to epoch to contain 15 s (or more) of alpha activity. Consequently,
the dream sensorium. Stage R sleep is easily recognizable during briefer sleep interruptions are not appreciated by sleep stage scoring.
epochs in which eye movements are present; however, a REM sleep It was for this reason that CNS arousal scoring rules were developed.
episode may continue for several minutes with ocular quiescence, CNS arousals include sleep interruptions ranging from 3 s up
only to be followed by subsequent bursts of REM activity. Once to, but not including, 15 s. The lower limit was established on the
stage R has commenced, REM scoring continues until a K-complex, basis of how brief an event could be reliably detected visually by
sleep spindle, chin EMG tone increase, or another scorable sleep or the original task force members developing the rules. CNS arous-
wake stage occur. In the past, many sleep specialists distinguished als can be evoked by external events (eg, noise), can be provoked
(a)
N1 E -M
E -M
F -M
C -M
O -M
Chin
(b)
N2 E -M
E -M
F -M
C -M
O -M
Chin
(c)
N3 E -M
E -M
F -M
C -M
O -M
Chin
Fig. 8.3 NREM sleep stages. (a) An epoch of stage N1 with low-voltage, mixed-frequency activity and slow rolling eye movements. (b) Stage N2 with clear well-defined
sleep spindle activity. (c) An archetypal example of slow-wave sleep in which slow-wave variants of delta EEG activity dominate the entire epoch.

(a)
Phasic
REM E1-M2
E2-M1
F4-M1
C4-M1
O2-M1
Chin1
(b)
Tonic E1-M2
REM
E2-M1
F4-M1
C4-M1
O2-M1
Chin1
Fig. 8.4 REM sleep. (a) An epoch of REM sleep during which phasic events (in the form of rapid eye movements) accompany low-voltage, mixed-frequency EEG
background activity with observable sawtooth theta waves. Additionally, submentalis EMG (chin) is virtually absent. (b) A quiescent epoch of REM sleep during which
no rapid eye movements are seen. EEG background remains low-voltage with mixed frequencies, and EMG activity remains absent.
by pathophysiologies (eg, apnea episodes), or can occur spontane- Breathing

ously (which can mean either that they were caused by an unde-
tected event or that they were truly spontaneous). Recording
In adults, arousal scoring proceeds from EEG and chin EMG sig- Diagnosing sleep-related breathing disorders and titrating positive
nals. In children, digital video and audio recording are also used. airway pressure constitute the most common applications for PSG.
Arousal-associated EEG changes are typically most prominent in Basically, the clinician must review airflow, respiratory effort, and
occipital leads. Although it seems obvious, it should be empha- the effect on oxyhemoglobin saturation. Information about carbon
sized that the patient must be asleep for a CNS arousal to be scored. dioxide levels, while often very helpful, is not required in routine
Preceding sleep must be 10 s or more. Arousals involve an abrupt practice for adults. In the following paragraphs, we will review the
increase in EEG frequency to bandwidths associated with alpha or essentials for recording and scoring sleep-related respiration.
theta (but not spindle) activity. The shift (sometimes referred to
as EEG speeding) must persist for a minimum of 3 s. The above Airflow
criteria hold for all NREM sleep stages (see fig. 8.5, top pane). In Airflow monitoring during sleep studies involves placing thermis-
contrast, CNS arousals from stage R sleep also require a concurrent tors, thermocouples, and/or pressure transducers at the nares and
brief increase in chin EMG activity (see fig. 8.5, bottom panel). near the mouth. Strictly speaking, thermistors and thermocouples
(a) CNS
arousal E1-M2
REM
E2-M1
F4-M1
C4-M1
O2-M1
Chin1
(b) CNS
arousal E1-M2
NREM E2-M1
F4-M1
C4-M1
O2-M1
Chin1
Fig. 8.5 CNS arousals. (a) A CNS arousal (boxed) from REM sleep. Note the sudden, prominent, and brief increase in alpha EEG activity, how it subsides after a few
seconds, and how sleep returns. Also note that a submentalis EMG (Chin1) increase accompanies the EEG change. (b) A CNS arousal from REM sleep, also marked by a
burst of alpha EEG activity but with little or no change in submentalis EMG.

do not measure airflow but rather sense changes in temperature. sleep disordered breathing than the consequences. It can be espe-
Comparatively cooler inspired ambient gases are warmed by the cially helpful in patients with lung disease, central sleep apnea, and/
corporal blood flow before they are exhaled. That variance in tem- or morbid obesity.
perature is calculable and can therefore be used as a surrogate to
determine airflow over this thermally sensitive resistor (i.e, ther- Scoring
mistor). These subtle fluctuations in temperature are measured at The main terms used in sleep study reports are: obstructive apnea
the nares and in front of the mouth. The sensors are advantageous (OA), central apnea (CA), obstructive hypopnea (OA), and res-
in that they are low current and relatively small, but have an ade- piratory effort related arousal (RERA). Each term has a specific
quate sensing area to provide reliable information. Thermocouples operational definition based on objective measurements. Accurate
achieve similar endpoints as thermistors by employing the differen- scoring of these events, however, ironically depends greatly on the
tial expanding properties of different metals in response to thermal PSG technologist’s experience and skill. Computerized scoring,
change. Both thermocouples and thermistors are commonly used although promising, cannot be relied upon.
in sleep study because of their ease of use and comfort for patients.
Similarly, nasal pressure transducers are used to index airflow. Apnea
The measurable difference between atmospheric pressure and the An apnea event is the quantifiable temporal interruption of percepti-
relatively positive pressure on exhalation or negative pressure on ble airflow. The time-based cutoff for an apnea in the adult is 10 s. In
inhalation produces a waveform that can be accurately recorded. pediatrics, apnea minimum duration criteria are set at a two-breath
As opposed to the thermal changes of thermistors, pressure trans- equivalent. We can further classify each apnea episode as obstruc-
ducers measure a different consequence of airflow. Moreover, the tive, central, or mixed, based on respiratory effort. Obstructive apnea
pressure signal changes are more sensitive than thermal changes. involves breathing cessation notwithstanding continuing (and often
Airflow can also be estimated from differential chest and abdom- increasing) respiratory effort. In contrast, when breathing stops
inal movement. When calibrated, some manufacturers boast the because no effort to breathe is present, we call this a central apnea.
ability to quantitatively measure tidal volume. Finally, the most As the name suggests, mixed apneas have a period without respira-
accurate, quantitative, and reliable technique for measuring airflow tory effort (usually at the episode’s initiation) followed by unsuccess-
requires a pneumotachometer or a body box. Neither of these latter ful attempts to breathe (because the airway is obstructed) indicated
two approaches are routinely used in clinical PSG. by respiratory effort. See Fig. 8.6 for illustrations of obstructive and
Respiratory effort central apnea events. The AASM Manual endorses the use of thermal
sensors to detect apnea-related airflow cessations. Table 8.1 provides
Chest and abdominal movements provide evidence for respira-
apnea event operational definitions according to current guidelines.
tory effort. Monitoring these movements may employ piezoelectric
transducers, inductance plethysmography, or strain gauges. The Hypopnea
downward contraction of the diaphragm creates a negative pres- AASM standards require nasal pressure sensors recordings to score
sure that pulls air into the lungs. This process creates measureable hypopnea. These sensors are more sensitive to flow changes than
differences in volumes by the expansion of the thoracic wall and thermistors or thermocouples. However, in its most literal sense,
increases in abdominal girth. An alternative approach for simply a hypopnea is merely a shallow breath. It is also worth emphasiz-
detecting an effort to breath involves measuring muscle activity. ing that tidal volume reductions are not intrinsically pathophysi-
EMG activity recorded on or near intercostal muscles can provide ological during wakefulness. They occur naturally while eating
a primitive but adequate indication of breathing effort. Because the and speaking. However, when an airflow reduction during sleep
electrodes are placed in the anterior chest, they tend to also contain induces a significant oxyhemoglobin desaturation, there may be
ECG artifact, sometimes making the results difficult to interpret. reason for concern. Furthermore, if the event provokes a CNS
Newer techniques using accelerometers hold promise. arousal, thereby disrupting sleep continuity, it qualifies as patho-
Gases physiological. In the early 1980s, sleep clinicians began focusing
Key to understanding sleep disordered breathing’s pathophysiology more on sleep disordered breathing events, and hypopneas were
is knowing oxyhemoglobin saturation level. Pulse oximetry provides generally regarded as airflow reductions associated with a 3% (or
information concerning the consequence of reduced ventilation. greater) oxygen saturation decline, a CNS arousal (or awakening),
Typically recorded from earlobe or finger, spectrographic analysis or both. Oxyhemoglobin desaturation threshold was typically
determines blood oxygen content by taking advantage of hemoglobin’s set at 3% because many oximeters had up to 2% variation (due
reddening when bound with O2. Recording from the earlobe (rather to “noise,” i.e, error variability). Consequently, 3% represented the
than the finger) shortens circulatory delay and is preferred by many detectability threshold. In contrast, no real quantitative justifica-
clinicians for laboratory studies. Pulse oximeters provide a readily tion could be spun for how much airflow reduction was mean-
available, affordable, and noninvasive method for uninterrupted oxy- ingful. Some clinicians used 50%, some used 30%, and still others
gen saturation (SaO2) monitoring. SaO2 is required for scoring hypo- used even less. Part of the problem revolves around the fact that
pnea, determining oxyhemoglobin nadir, and indexing the time spent percentage declines in the temperature-change-derived airflow
at or below 88% saturation (i.e, respiratory insufficiency). sensors are not proportional to tidal volume changes. Additionally,
Carbon dioxide (CO2) monitoring can also be helpful, but is not other factors alter percentage change.1 Thus, sleep specialists used
required for adult PSG according to current standards of practice.
In children, it is more important because SaO2 is not as sensitive. In 1 To make this point, M.H. used to be fond of asking new sleep fellows what
adults, CO2 represents the primary stimulus for ventilatory drive. they would expect an airflow signal to look like if the bedroom temperature
Thus, it informs the clinician more about the cause and dynamics of was 37°C?

(a) Obstructive apnea (b) Central apnea
E1-M2
E2-M1
Chin
F4-M1
C4-M1
O2-M1
EKG
RLEG
LLEG
Snore
Press
Therm
Chest
Abd
Fig. 8.6 Sleep apnea episodes. (a) An obstructive sleep apnea. Note how the airflow ceases according to nasal pressure (Press) and thermistor (Therm) recording
channels, while respiratory effort recorded with chest and abdominal (Abd) movements continues. (b) In contrast, in the central sleep apnea illustrated here, the
cessation of breathing is accompanied by cessation of respiratory effort.
to quibble about what percentage a PSG airflow tracing needed to more) oxyhemoglobin desaturation but paid no attention to sleep
drop in order score a hypopnea. The more pressing (and related) disruption. Thus, to a large extent, hypopneas became desaturation
issue, however, was scoring reliability. Without a standard to reign events (Fig. 8.7). Subsequently, the AASM attempted to restore the
in the wide variation in criteria, scoring reliability suffered. At one “sleep disruption” part of the hypopnea criteria—first by having
point, a group of sleep researchers attempted to create a standard; more than one definition for hypopnea included in the AASM
however, their work was accepted as research but not as providing Scoring Manual and later by revising the scoring manual’s defini-
clinical criteria [11]. As sleep medicine became more mainstream, tions. To date, however, such attempts have been futile because not
a standardized definition was forced on the clinical sleep com- using CMS criteria (when they exist) for Medicare and Medicaid
munity by Centers Medicare and Medicaid Services (CMS) [12]. patients is considered fraud. Furthermore, to prevent a two-tiered
Unfortunately the CMS definition for hypopnea required 4% (or medical system in the United States, CMS requires clinicians to use
(a) Hypopnea (b) RERA

E1-M2
E2-M1
Chin
F4-M1
C4-M1
O2-M1
EKG
RLEG
LLEG
Snore
Press
Therm
Chest
Abd
SaO2 94 94 93 93 92 92 91 90 90 91 92 95 95 95 94 94 95 95 95 95
Fig. 8.7 Hypopnea and respiratory effort related arousal (RERA). (a) A hypopnea episode showing decline prominently in the nasal pressure recording (Press) but less
clear in the thermistor (Therm) channel. The episode is also associated with a 4% decline in oxyhemoglobin saturation (SaO2). (b) In contrast, the RERA event illustrated
here shows decreased airflow accompanied by increased snoring sounds (presumably from increased airway resistance). The event is terminated by an arousal; however,
no significant change occurs in oxyhemoglobin saturation.

CMS criteria for all patients if even a single Medicare or Medicaid Table 8.2 Respiratory event criteria: definitions for the major
patient is serviced by their practice. To do otherwise is also con- sleep-disordered breathing events
sidered Medicare fraud. See Table 8.2 for both CMS and AASM
definitions for hypopnea. Event Definition and/or criteria
Respiratory-effort-related arousal Obstructive An obstructive apnea is a 10 s decrease in the peak signal

The concept of respiratory effort related arousal (RERA) originated apnea excursion by ≥90% of baseline. Measurement is ensured
because clinical researchers observed CNS arousals terminat- according to the type of study: via oronasal thermal sensor
(diagnostic study) or PAP device flow (titration study). The
ing very subtle respiratory perturbations. These events included
OA need not be associated with an arousal or desaturation.
extended inspiratory phase, paradoxical movement of the chest wall
and abdomen, and/or overall signal flattening. These sleep-related Central apnea The definition is similar to that of an obstructive apnea
breathing disorder events were not accompanied by obvious air- except that a central apnea has a cessation of respiratory
effort during the decrease in airflow.
flow reductions when standard clinical recording techniques were
used. However, when esophageal pressure recordings were made, Mixed apnea Mixed apneas are scored when a sleep disordered breathing
intrathoracic pressure increased until an arousal terminated the event meeting criteria for apnea occurs but during which
event. It appeared that increased airway resistance led to increased the initial portion shows no respiratory effort but is
followed by resumed inspiratory effort but still no airflow.
respiratory effort, and this sequence of events ultimately provoked
Overall, a mixed apnea is considered an obstructive-type
sleep fragmentation. Because these patients typically suffered from
event.
moderate to severe sleepiness, the condition was dubbed “upper
airway resistance syndrome” [13]. CMS Hypopnea is defined as an abnormal respiratory event
This conceptualization of RERA was short-lived. When CMS hypopnea lasting at least 10 s with at least a 30% reduction in thoraco-
abdominal movement or airflow as compared with baseline,
designated the term hypopnea to mean, to all intents and pur-
and with at least a 4% oxygen desaturation.1
poses, a sleep-related desaturation event, the term RERA was
commandeered to identify nondesaturating hypopnea episodes. AASM The 2013 version of the American Academy of Sleep
RERA became a way to identify and count those events that hypopnea Medicine definition for hypopnea has three parts as
follows:2
no longer met CMS hypopnea criteria—specifically, sleep dis-
ordered breathing events failing to provoke a 4% (or greater) (a) During diagnostic evaluation, airflow diminishes by 30%
(or more) on nasal pressure (preferred) or other airflow
oxyhemoglobin desaturation but were nonetheless terminated
sensor. During positive airway pressure (PAP) titration,
by a CNS arousal. See Table 8.2 for the operational definition machine flow oscillation declines by 30% (or more).
for RERA.
(b) This 30% (or more) airflow decline persists for at
least 10 s.
Data processing (c) A 3% (or greater) oxyhemoglobin desaturation is
Over the past half-century, technological advances have exten- provoked by the event or the event is terminated by a
sively changed the methods used to record sleep. Older analog CNS arousal.
sleep recorders have given way to newer multichannel digital RERA A respiratory effort related arousal or RERA is characterized
devices, with scoring now exclusively performed while viewing by either an increase in respiratory or attenuation of airflow
computer-generated displays rather than paper. Modern tech- associated with arousal from sleep.
nology has reduced data storage requirements from rooms filled Cheyne–Stokes A breathing pattern exhibiting a crescendo and
with paper PSGs to a few file cabinet drawers for DVD backup breathing decrescendo amplitude in successive breaths. During
disks. Computerization and widespread server technology have sleep, if the decrescendo phase is extended to the point of
greatly improved remote data accessibility. constituting a 10 s (or longer) respiratory pause, the pattern
Once a sleep study has been completed and data have been becomes Cheyne–Stokes breathing and central sleep apnea
archived, sleep staging, sleep disordered breathing, arousal scor- (CSB–CSA). This pattern is characteristic of patients with
ing, and leg movements can be identified and tabulated by a decompensated congestive heart failure. A diagnosis of
trained technologist (who can access data from anywhere in the CSB–CSA requires that the events must have a total of 5 or
more per hour of sleep.
world). Sleep parameters of interest usually include sleep effi-
ciency (total sleep time as a percentage of time in bed), latency to 1 This definition was taken verbatim from the CMS website; however, we assume (although
sleep onset, latency from sleep onset to the first REM sleep epi- it was not explicitly stated) that to score an event as a hypopnea, it must as a prerequisite
not qualify as an apnea.
sode, and the number of CNS arousals per hour of sleep. Sleep
2 Although not explicitly stated, we assume that to qualify as a hypopnea, the event must
stages are typically summarized as percentages of total sleep time.
first not qualify as an apnea.
Sleep-related respiratory parameters include the number of apnea
episodes per hour of sleep (i.e, the apnea index, AI), the ratio of
obstructive plus mixed apnea to central apnea, the number of to REM versus NREM stages and by supine versus nonsupine
apnea and hypopnea episodes per hour of sleep (i.e, the apnea– position. Arousals related to snoring can also be useful. To gauge
hypopnea index, AHI), and the number of apneas plus hypopneas hypoxemia, the SaO2 nadir and the time spent below 88% or 85%
plus RERAs per hour of sleep (i.e, the respiratory disturbance saturation are calculated. According to the AASM, an adult AHI
index, RDI). AI, AHI, and RDI are also usually sorted according of 0–5 is normal, 5–15 is mild sleep apnea, 15–30 is moderate

sleep apnea, and >30 is severe sleep apnea.2 The sleep special- 7. Guilleminault C. Sleeping and waking disorders: indications and
ist is also able to remotely access the PSG tracing and tabulated techniques. Menlo Park, CA: Addison-Wesley, 1982.
information in order to evaluate the patient’s sleep. During PSG 8. ASDA. Sleep Disorders Atlas Task Force. EEG arousals: scoring
rules and examples: a preliminary report from the Sleep Disorders
review, the clinician also should identify significant abnormal
Atlas Task Force of the American Sleep Disorders Association. Sleep
EEG activity, cardiac arrhythmias, and other PSG events not rou- 1992;15:173–84.
tinely quantified by standard scoring rules. 9. Iber C, Ancoli-Israel S, Chesson A, Quan SF; American
Academy of Sleep Medicine. The AASM manual for the scoring
of sleep and associated events: rules, terminology and technical
References specifications. Westchester, IL: American Academy of Sleep
1. Berger H. Ueber das elektrenkephalogramm des menschen. J Psychol Medicine, 2007.
Neurol 1930;40:160–79. 10. Silber MH, Ancoli-Israel S, Bonnet MH et al. The visual scoring of
2. Loomis AL, Harvey N, Hobart GA. Cerebral states during sleep, as sleep in adults. J Clin Sleep Med 2007;3:121–31.
studied by human brain potentials. J Exp Psychol 1937;21:127–44. 11. AASM. The Report of an American Academy of Sleep Medicine Task
3. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, Force. Sleep-related breathing disorders in adults: recommendations
and concomitant phenomena. Science 1953;118:273–4. for syndrome definition and measurement techniques in clinical re-
4. Dement W, Kleitman N. The relation of eye movements during sleep to search. Sleep 1999;22:667–89.
dream activity: an objective method for the study of dreaming. J Exp 12. Centers for Medicare and Medicaid Services. National coverage de-
Psychol 1957;53:339–46. termination for continuous positive airway pressure (CPAP) therapy
5. Williams RL, Agnew HW, Webb WB. Sleep patterns in young adults: an for obstructive sleep apnea (OSA) NCD #240.4. 2005. Available
EEG study. Electroenceph Clin Neurophysiol 1964;17:376–81. from: http://www.cms.hhs.gov.
6. Rechtschaffen A, Kales A, eds. A manual of standardized terminology, 13. Guilleminault C, Stoohs R, Clerk A, et al. A cause of excessive
techniques and scoring system for sleep stages of human subjects. NIH daytime sleepiness: the upper airway resistance syndrome. Chest
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2 AHI, however, is not an ideal index for severity. The duration of sleep
disordered breathing events and their consequences on oxyhemoglobin
saturation are also important. A patient with an AHI of 25 who never
desaturates below 88% is arguably less severely afflicted than a patient with
an AHI of 12 who spends 28 minutes at or below 85% SaO2 level.

CHAPTER 9
Other sleep laboratory

procedures (MSLT, MWT,
and actigraphy)
Fabio Pizza and Carlo Cipolli
Introduction period of the day and leading to unintended lapses into drowsi-
ness or sleep in inappropriate (and often potentially dangerous)
Polysomnography (PSG) has long been considered the gold stand- situations [1]â•„.
ard for the measurement of sleep because it provides objective To properly use the MSLT and MWT and interpret their results,
measures not only of wake and sleep time, but also (and above the clinician first has to evaluate the features of the sleepiness com-
all) of sleep architecture coupled with muscular and respiratory plaint, namely to ascertain, by means of an accurate history, not
parameters. However, PSG is limited by cost and inconvenience only the subjective feeling, but also the potential occurrence and
as a method for long-â•‰term, continuous sleep monitoring, and is characteristics of sleep episodes (eg, refreshing and/â•‰or associated
not able to provide any measure of the daytime sleepiness which with dream content). In particular, the clinician should consider
is a frequent and cardinal symptom of a number of sleep disorders. the time of day (i.e, circadian timing) of sleep episodes, the indi-
These two main limitations have prompted researchers and sleep vidual sleep habits (eg, misalignment of major sleep period from
clinicians to set up, tune, and apply other tools to obtain objective night–â•‰day cycle, chronic sleep deprivation, suggested by a signifi-
measures for the evaluation of sleep architecture, sleep habits and cant difference between sleep time during working days and that
sleepiness for longer periods (from days to weeks) and/â•‰or the diag- during holidays/â•‰weekends, and individual chronotype), as well as
nosis of specific sleep disorders. These tools, which have different other concomitant daytime and nocturnal symptoms suggesting
costs and practical limitations compared with PSG, appear comple- the presence of sleep disorders (eg, cataplexy, restless legs, sleep
mentary, rather than alternative, to both PSG and subjective meas- disordered breathing, and nocturnal awakenings). Finally, the cli-
ures of sleepiness and sleep duration and quality, given the different nician should ascertain the possible concomitance of other (psychi-
types of information they provide. atric, neurological, and/â•‰or medical) disturbances that can mimic
Objective measures of sleep and sleepiness can be obtained or cause hypersomnolence and of the chronic use of treatments
mainly by using actigraphy, the multiple sleep latency test (MSLT), potentially affecting sleep or vigilance. Indeed, hypersomnolence
and the maintenance of wakefulness test (MWT), which are record- can be either the cardinal symptom of several sleep disorders (eg,
ing techniques and standardized laboratory-â•‰based procedures with obstructive sleep apnea syndrome, central disorders of hypersom-
different functions compared with PSG. In this chapter, we will nolence), or the result of a wide range of medical disorders and
describe these techniques and their clinical applications in the light medication use, but can be also frequently confused with other
of current recommendations. conditions characterized by “decreased energy” or fatigue, such
as insomnia and depression. Fatigue differs from sleepiness as it
Sleep laboratory procedures to objectively refers to a cumulative disinclination toward a sustained effort that
assess sleepiness: MSLT and MWT can lead to reduced performance efficiency and resolves with rest,
whereas sleepiness resolves with sleep [2]â•„.
Overview Sleepiness can be measured also by means of subjective scales,
The MSLT and MWT are two laboratory procedures aimed at which evaluate sleepiness as a state (i.e, a contingent individual
quantifying sleepiness objectively, but the use of either is also rec- condition) [3,4] or a trait (i.e, as a stable individual characteristic)
ommended in specific clinical situations. Physiological sleepiness, [5]â•„. The subjective scales are commonly used to help the clinician
which is a subjective feeling expressing the inner desire to sleep and in the preliminary evaluation, by minimizing inter-â•‰individual dif-
is thus indicative of the biological need for sleep, differs substan- ferences in introspection, awareness, and, finally, ability to report
tially from hypersomnolence, which is a pathological individual sleepiness. State sleepiness refers to the subjective feeling in a spe-
trait resulting in an inability to stay awake during the major waking cific moment of the day: the subject rates his/â•‰her own feeling on

an ordinal scale where numbers are associated with a list of ver- (eg, coffee) or vigorous activities, including exposure to bright
bal descriptors ordered from the lowest level of sleepiness to that sunlight.
of imminent sleep. The Stanford Sleepiness Scale includes seven The MSLT requires the execution of five (or four) naps at
items ranging from “feeling active, vital, alert, or wide awake” two-hour intervals. The subject is not allowed to sleep between
(score = 1) to “no longer fighting sleep, sleep onset soon; having the nap opportunities, and the laboratory staff should control
dreamlike thoughts” (score = 7) [3]). The Karolinska Sleepiness patient’s activities (or continuously record them with ambula-
Scale encompasses 10 items ranging from “extremely alert” (score = 1) tory PSG) between naps. A light breakfast is recommended at
to “extremely sleepy, falls asleep all the time” (score = 10) [4]. Both least one hour before the first trial, and a light lunch is recom-
these scales, as well as the Visual Analogue Scale, where the subject mended immediately after the termination of the second noon
has to indicate the subjective sleepiness (or the alertness) level on trial. The MSLT montage includes two electroencephalographic
a 10 cm line [6], are useful in conjunction with sleep logs and/or (including central and occipital derivations: C3-A 2, C4-A 1,
actigraphy to track circadian fluctuations of sleepiness. They can O1-A2, O2-A1), two electrooculographic (right and left eyes
also be administered before each MSLT or MWT trial (see below) recorded by a lead referenced to the same mastoid), and one elec-
to evaluate the subjective awareness of sleepiness in parallel with tromyographic (mental/submental muscle) channels together
its objective measure. with electrocardiography according to technical requirements
Conversely, subjective trait sleepiness refers to a stable individual of sleep medicine [10]. Before undergoing each scheduled nap
characteristic over a prolonged period of time, lasting at least some opportunity, the subject should not smoke for at least 30 min-
weeks. To identify subjects with hypersomnolence, the most fre- utes, should avoid activities for 15 minutes, and should prepare
quently used tool is the Epworth Sleepiness Scale [1,5]. This is a to go to bed (including going to the toilet if necessary) 10 min-
self-administered questionnaire in which subjects rate the prob- utes before the trial start. Then, five minutes before the start of
ability of dozing off or falling asleep in eight common situations the recording, the technician performs the biocalibration, and,
encountered in daily life with a score ranging from 0 (“would never in the minute before the lights are turned off, the subject rates
doze off ”) to 3 (“high chance of dozing”). The final score ranges his/her subjective state sleepiness. During each nap opportu-
from 0 to 24; 11 is considered the threshold to identify pathological nity, the subject is recumbent in the sleep laboratory bed and is
sleepiness [5]‌. invited to “lie quietly, assume a comfortable position, keep your
To overcome the intrinsic limits of all subjective measures, the eyes closed, and try to fall asleep.” Then, the lights are turned
MSLT and MWT have been standardized and validated to quan- off (start of the trial), and the subject has 20 minutes to fall
tify different aspects of sleepiness. These tests, which require a sleep into sleep, defined as a 30 s epoch of any sleep stage, including
laboratory with a professional technician available for execution non-REM sleep stage 1 (sleep onset). If the subject falls asleep,
across the day, are based on the common assumption that the time the technician should continue the recording for 15 minutes in
needed to fall asleep reflects sleepiness. However, they have clear order to document the potential early occurrence of REM sleep
differences and specific clinical uses: the MSLT measures “sleep (sleep onset REM period, SOREMP). If the subject does not
propensity,” while the MWT quantifies the individual “ability to fall asleep, the nap opportunity is interrupted after 20 minutes.
maintain wakefulness” (or to resist sleep) [1,7]. For the MSLT trials without evidence of sleep onset, the sleep
latency is by convention considered to be 20 minutes. Events
The MSLT that represent deviations from the normal protocol should be
The MSLT was developed at the University of Stanford by reported by the technician in order to correctly interpret the
Carskadon and Dement, who evaluated the impact of sleep dep- results of the test. The MSLT report should include the start and
rivation on daytime sleep latency across pubertal development. end times of each nap opportunity, latency from lights-off to the
In 1986, the procedures to perform the MSLT were published, first epoch of sleep, mean sleep latency (arithmetic mean of all
and sleep laboratories worldwide de facto used the test as the nap opportunities), and number of SOREMPs. MSLT interpre-
gold standard measure of daytime sleepiness for both clinical tation is thus based on two key objective measures: the mean
and research purposes [8]‌. The huge amount of published data sleep latency and the number of SOREMPs (Table 9.1). A mean
on MSLT findings in different clinical contexts made apparent sleep latency below eight minutes is considered pathological,
the need for an extensive literature review [9], and this was fol- although 30% of the general population may fall below this
lowed by the release of new guidelines for MSLT execution and limit, and two or more SOREMPs (including any SOREMP pre-
interpretation by the American Academy of Sleep Medicine in sent during the nocturnal PSG performed the night before the
2005 [7]. These guidelines are reflected in the third edition of the MSLT) are required to confirm the diagnosis of narcolepsy (with
International Classification of Sleep Disorders [1]. In brief, the test and without cataplexy, now defined as type 1 and type 2 nar-
should start in the morning between 8 and 10 am, 1.5–3 hours after colepsy, respectively): according to this criterion, the execution
awakening from the major sleep period documented by nocturnal of the fifth nap is mandatory in specific clinical situations (eg,
PSG in the laboratory, with at least six hours of total sleep time, single SOREMP documented during the first four naps unless a
and possibly after one-week assessment of sleep–wake schedules SOREMP was observed in the previous night’s PSG recording)
carried out using sleep logs and/or actigraphy. Drugs potentially [1,7]. A modified MSLT protocol to measure sleep propensity
affecting sleep should ideally be stopped two weeks before; alterna- for research purposes requires awakening the subject after the
tively, their administration should be considered in the interpreta- onset of sustained sleep (i.e, at least three consecutive epochs of
tion of MSLT results. A drug screening in the morning of the test sleep stage 1 or one epoch of any other sleep stage) in order to
may be useful to rule out pharmacologically-induced sleepiness. avoid any influence of sleep on subsequent naps, and thus pro-
During the day, the subject should avoid stimulating substances vides only a mean sleep latency as result [8]‌.

Chapter 9 other sleep laboratory procedures (mslt, mwt, and actigraphy) 83
Table 9.1 Overview of the MSLT procedure
Timing Procedure Recommendation

−2 weeks Withdrawal of medications with stimulant or REM-suppressing effect Recommended
−1 week Regular sleep–wake schedules monitored by sleep logs/actigraphy Suggested
−1 day Nocturnal polysomnography documenting a total sleep time > 6 h and excluding significant sleep Recommended
disorders. Split-night sleep studies are not allowed
Not defined Withdrawal of other usual medications (antihypertensives, insulin, etc.) with sedating or stimulating Clinician decision
properties
At awakening Drug screening Clinician decision
All day Avoid vigorous activities, exposure to bright sunlight, and caffeinated beverages. Between MSLT Recommended
scheduled naps, the patient is out of bed and prevented from sleeping (staff observation)
1.5–3 h from awakening Start of the test with five trials scheduled every 2 h (four-nap version is reliable for narcolepsy diagnosis Recommended
only if two SOREMPs occurred)
Meals Light breakfast at least 1 h before the first trial, light lunch after the second trial Recommended
Trials
−30 min Stop smoking Recommended
−15 min Stop any stimulating activity Recommended
−10 min Comfort adjustments, including restroom visit Recommended
−5 min Biocalibration* Recommended
−1 min Subjective state sleepiness evaluation Suggested
−30 s Assume a comfortable position for sleep Recommended
−10 s “Please lie quietly, assume a comfortable position, keep your eyes closed, and try to fall asleep” Recommended
Time 0 (T0) Lights-off Recommended
T0 + 20 min Trial interruption (if no sleep occurs) Recommended
Sleep onset (SO) SO is defined as the first epoch greater than 15 s of cumulative sleep in a 30 s epoch of any Recommended
stage of sleep, including stage 1 NREM sleep
SO + 15 min Trial interruption (if sleep occurs) Recommended
Scoring
Sleep latency Time elapsed between T0 and SO. If no sleep is recorded, the conventional sleep latency is 20 min Recommended
REM latency Time elapsed between SO and the first epoch of REM sleep, within the first 15 min of sleep onset Recommended
Report
Start and stop times of each nap Recommended
Sleep latency of each nap and mean sleep latency across trials. A mean sleep latency < 8 min is Recommended
considered pathological
Number of SOREMPs. A number of SOREMPs ≥ 2 is highly specific for narcolepsy Recommended
Events/conditions representing deviations from the protocol Recommended
Recommendation Level rated as: recommended, suggested, or optional. *Instruction for biocalibration before each MSLT trial: “(1) Lie quietly with your eyes open for 30 seconds, (2) close
both eyes for 30 seconds, (3) without moving your head, look to the right, then left, then right, then left, right and then left, (4) blink eyes slowly for 5 times, and (5) clench or grit your
teeth tightly together.”
Source data from Sleep, 28(1), Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test,
pp. 113–21, Copyright (2005), Associated Professional Sleep Societies, LLC.
The MWT setting may not reliably reproduce the workplace conditions where
Along with the routine use of the MSLT in sleep laboratories worldsleep tendency usually manifests. Therefore, the individual ability
wide, the test showed limitations in documenting the treatment to resist sleep was proposed as an alternative objective measure of
effect in severely sleepy patients whose MSLT changes seemed sleepiness.
minimal compared with what was expected on the basis of patients’ The first proposed procedure required the subject, sitting in a
self-reports. The MSLT was also criticized because its laboratory comfortable chair in a quiet and dimly lit room, to stay awake in

four (or five) 20-minute trials performed every two hours across Comparison of and recommendations on
daytime [11]. Only in 1997 a normative study standardized differ- the MSLT and MWT
ent test procedures (i.e, four naps lasting 20 or 40 minutes) and
Even though both the MSLT and MWT measure sleepiness by
interpretation methods (sleep onset defined as first epoch of any
means of sleep latency, they are based on different conceptualiza-
sleep stage, or as three consecutive epochs of non-REM sleep stage
1 or a single epoch of any other sleep stage) leading to four differ- tions: in the MSLT, sleepiness is viewed as sleep propensity, but
ent MWT protocols [12]. Therefore the MWT could be performed in the MWT as a difficulty in maintaining wakefulness (and thus
with four 20 minutes trials and interpreted considering either the similar to alertness). When used in parallel on patient populations,
sleep latency to the first epoch of sleep or that to the occurrence the two tests provide data that are correlated, but this correlation
of sustained sleep (two protocols). Alternatively, the procedure can explain only a low percentage of the observed variability, thus
could be based on four 40-minute trials interpreted considering confirming that the tests measure different aspects of the sleepiness
either the sleep latency to the first epoch of sleep or that to the phenomenon [13]. Individual motivation during the tests is also
occurrence of sustained sleep (two protocols). Accordingly, a sleep crucial and should be taken into account when interpreting results,
latency cut-off was provided for each of the four procedures; how- as well as potential deviation from the established protocols. The
ever, this heterogeneity prevented the widespread use of the test. same subject can appear more sleepy during the MWT (trying to
After few years, and in parallel to the MSLT, the available data were fall asleep instead of remaining awake) or more alert during the
extensively reviewed [9]‌, and unambiguous guidelines for MWT MSLT (trying to remain awake instead of falling asleep), but the
execution and interpretation were published [7]. The current ver- opposite attitudes do not affect the test results. Therefore, the MSLT
sion of the MWT requires four 40-minute trials at two-hour inter- is a better measure of sleepiness (rather than alertness), and the
vals. The first session should begin after 1.5–3 hours from the usual MWT one of alertness [14]. Finally, the two tests also show different
wake-up time (approximately between 9 and 10 am), without, relations with performance measures, as suggested by the stronger
however, a formal need to either objectively document sleep time correlations between simulated driving performance and alertness
in the night before the test by means of PSG or verify sleep patterns (during the MWT) versus sleep propensity (during the MSLT) in
in the weeks before the test by means of sleep logs or actigraphy. At patients with severe obstructive sleep apnea syndrome [15].
each trial, the subject sits in bed with the back and head supported In the clinical practice of sleep medicine, the MSLT is a diag-
by the bedrest (many laboratories, however, prefer the use of a nostic tool recommended to characterize the central disor-
comfortable armchair), in a sound-attenuated laboratory, which ders of hypersomnolence (especially to document SOREMPs).
is also insulated from external light and has low illuminance (with Diagnostic criteria require a sleep latency below eight minutes
the light placed out of the patient’s field of vision, with 0.10–0.13 with two or more SOREMPs (including any SOREMP noted in
lux at the corneal level) and a temperature regulated to maximize the nocturnal PSG performed the night before the test) in both
patient comfort. The use or withdrawal of drugs, tobacco and caf- type 1 and type 2 narcolepsy, and a sleep latency below eight min-
feine is decided by the clinician, while a light breakfast and lunch utes with fewer than two or no SOREMPs in idiopathic hyper-
should be administered one hour before the first nap and imme- somnia [1]‌. Conversely, the MSLT should not be used to quantify
diately after the second one, respectively. The recording montage sleepiness in any other sleep disorder (eg, insomnia, circadian
is the same as for the MSLT [10]. Before each nap, the subject is rhythm sleep disorders, and sleep disordered breathing), given
asked about the need to go to the toilet or to have other adjust- the frequent occurrence of short sleep latencies in the general
ments for comfort. At the beginning of each trial, the technician population [1,7] and the existence of conditions with high sleep
performs the biocalibration, including a period of at least 30 sec-
ability in the absence of any sleepiness complaint [16]. However,
onds with eyes opened followed by another one with eyes closed.
despite the fact that MSLT is not indicated for quantifying sleepi-
Then, the subject is instructed to “sit still and remain awake for as
ness in the initial assessment of obstructive sleep apnea syndrome
long as possible, to look directly ahead of you and not at the light.”
or to assess treatment response, it can be performed in patients
Extraordinary measures (eg, singing) to stay awake are forbidden.
whose sleepiness level remains pathological after adequate treat-
However, the technician is not allowed to enter the room during
ment with continuous positive airway pressure. The test can also
the trial. The trial is interrupted after 40 minutes if the subject
stays awake, or after the occurrence of unequivocal/sustained be repeated in ambiguous cases of suspected narcolepsy with
sleep (i.e, three consecutive epochs of sleep stage 1 or an epoch of negative MSLT findings, as well as when the initial test execution
any other sleep stage). The sleep latency is calculated from lights- was influenced by extraneous circumstances or when it provided
off to the first epoch of any sleep stage defined as a period greater ambiguous results [1,7].
than 15 seconds of cumulative sleep within a 30 second epoch. Conversely, the MWT is not a diagnostic tool, and current guide-
The MWT report should include start and stop times for each lines recommend its use to test alertness in individuals such as
trial, sleep latency, total sleep time, stages of sleep achieved for professional drivers in whom the inability to maintain wakefulness
each trial, and the mean sleep latency (the arithmetic mean of the can constitute a personal or public safety issue and in patients with
four trials), together with events or conditions that may represent hypersomnolence to assess treatment response [1,7]. The mean
deviations from the normal protocol (Table 9.2). The definition sleep latency values of normal subjects are 30.4 ± 11.2 minutes, and
of normal values is even more controversial than in the MSLT: a thus the pathological threshold is considered 8 minutes (two stand-
mean sleep latency below eight minutes has been conventionally ard deviations below the mean). Indeed, considering as normal a
established as the cut-off for impaired vigilance, whereas a mean sleep latency of 30 or 40 minutes leaves to the clinician a huge “gray
value of 30 minutes or above is the cut-off established for normal area” of uncertain results that cannot be interpreted either as nor-
alertness (7). mal or as pathological.

Table 9.2 Overview of the MWT procedure
Timing Procedure Recommendation

Not defined Withdrawal of medications Clinician decision
Not defined Regular sleep–wake schedules monitored by sleep logs/actigraphy No consensus reached
−1 day Nocturnal polysomnography prior to MWT Clinician decision
Not defined Withdrawal of other usual medications (eg, antihypertensives, insulin, etc.) with sedating or stimulating Clinician decision
properties
At awakening Drug screening Clinician decision
All day Avoid caffeinated beverages Clinician decision
1.3–3 h from awakening Start of the test with four 40 min trials scheduled every 2 h starting between 9 and 10 am Recommended
Meals Light breakfast at least 1 h before the first trial, light lunch after the second trial Recommended
Trials
Not defined Stop smoking Clinician decision
Not defined Stop any stimulating activity Clinician decision
Not defined Comfort adjustments, including restroom visit Recommended
Not defined Biocalibration* Recommended
Not defined
Not defined Assume a comfortable position. The subject should be seated in bed with the back and the head Recommended
supported by a bedrest (bolster pillow) so that the neck is not uncomfortably flexed or extended
Not defined “Please sit still and remain awake for as long as possible. Look directly ahead of you, and do not look Recommended
directly at the light”
Time 0 (T0) Lights-off Recommended
T0 + 40 min Trial interruption (if no sleep occurs) Recommended
Sleep onset (SO) First epoch of greater than 15 s of cumulative sleep in a 30 s epoch Recommended
Unequivocal sleep Trial interruption, after the recording of three consecutive epochs of stage 1 sleep, or one epoch of any Recommended
other stage of sleep
Scoring
Sleep latency Time elapsed between T0 and SO. If no sleep is recorded, the conventional sleep latency is 40 min Recommended
Report
Start and stop times of each nap Recommended
Sleep latency of each nap and mean sleep latency across trials. A mean sleep latency < 8 min is Recommended
considered pathological. Values greater than this but less than 40 min are of uncertain significance
Stages of sleep achieved for each trial Recommended
Events/conditions representing deviations from the protocol Recommended
Recommendation Level rated as: recommended, suggested, or optional. *Instruction for biocalibration before each MSLT trial: “(1) sit quietly with your eyes open for 30 seconds, (2) close
both eyes for 30 seconds, (3) without moving your head, look to the right, then left, then right, then left, right and then left, (4) blink eyes slowly for 5 times, and (5) clench or grit your
teeth tightly together.”
Source data from Sleep, 28(1), Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test,
pp. 113–21, Copyright (2005), Associated Professional Sleep Societies, LLC.
Actigraphy sleep–wakefulness patterns with the key advantage of cost-effective

limited equipment (modern devices are as invasive as wristwatches)
Overview of the technique allowing prolonged recordings (from days to weeks) in the natural
Actigraphy is a minimally invasive objective monitoring technique environment, barely interfering with daily activities. It is thus opti-
that is able to record the occurrence of movements for prolonged mal to examine sleep patterns of those subjects who do not tolerate
periods of time. Its rationale is based on the fact that few move- the laboratory setting (eg, insomniacs, elderly demented patients,
ments occur during sleep, while active wakefulness is normally and children) and to accurately estimate their habitual sleep pat-
characterized by high motor activity. The actigraphic assess- terns across the 24 hours. However, it should be kept in mind that
ment of motor activity can provide a fairly accurate evaluation of actigraphy does not record sleep per se, but provides an indirect

evaluation of sleep quality and duration based on activity/inactiv- Apart from using actigraphy to evaluate sleep and wakefulness
ity as equivalent of wakefulness/sleep. Therefore, the interpretation measures, raw motor activity data can be directly analyzed to assess
of the collected data can be misleading in clinical situations where the circadian rhythm of motor activity. Indeed, data collected over
high motor activity occurs during the night (eg, patients with REM prolonged periods of time lasting for multiple circadian periods can
sleep behavior disorder) or low motor activity is noted during the also give chronobiological information by directly analyzing the raw
day (eg, hypersomnia), respectively. Conversely, actigraphy pro- activity data as a rest–activity rhythm. The most popular method is
vides good estimates of sleep–wake patterns in healthy subjects. the cosinor analysis, which allows computing the circadian rhythm
The first pioneering studies in which activity monitoring was quantified by the acrophase (time of peak activity), amplitude (peak-
applied to document sleep and wakefulness date back to the 1970s to-nadir difference) and mesor (mean) of the fitted curve of motor
and were conducted by the groups of Kupfer [17] and Colburn [18]. activity [23,24]. More sophisticated approaches (such as the five-
Soon thereafter, sleep parameters provided by actigraphy were vali- parameter extended cosinor analysis) have also been developed to
dated in comparison with PSG-defined sleep, and showed good better fit the mathematical function to the activity data when they
reliability for the quantification of minutes spent in sleep and wake- are poorly represented by the shape of a cosine curve [25]. However,
fulness during the sleep period [19]. also given the frequent nonsinusoidal waveform of rest–activity data,
While the first devices required a connection with a recorder to other nonparametric procedures such as 24-hour autocorrelations
store the data, modern tools have miniaturized accelerometers and can be applied to describe the circadian rest–activity rhythm [26,27].
solid memories able to record for long periods and are included in Actigraphy simply measures the motor activity of a limb, thus
an apparatus the size of a wristwatch. Several hardware and soft- showing potential discrepancies when compared with objective
ware methods have been developed to derive activity, and most sleep recording (by PSG) or subjective perception (by sleep logs or
of the currently available actigraphs analogically sample physical questionnaires). In more detail, actigraphy shows a strong reliabil-
activity several times per second and digitize the signal in a user- ity in distinguishing consolidated periods of sleep from wakeful-
defined time interval, with one minute being the most widely used ness [28], but generally underestimates sleep latency for the typical
epoch duration. Although the actigraph is mostly applied to the immobility at the transition between wakefulness and sleep [29,30],
nondominant hand, the clinician can decide to apply the device to and also suffers from a systematic tendency to underestimate short
other body segments (eg, dominant hand, trunk, or legs), and tailor periods of wakefulness within nocturnal sleep. Actigraphy thus
both sampling and epoch rates, or choose the digitizing approach if overestimates sleep time and efficiency [31]. Accordingly, acti-
necessary, according to the specific clinical application or research graphic measurements of sleep and wakefulness are less accurate
purpose. Three different strategies to digitize the analog signal are when sleep becomes more fragmented during nighttime, as well as
currently available, and some devices utilize more than one method when individuals spend prolonged motionless periods during day-
in parallel to increase data quality: (a) the “time above the threshold” time. Finally, the reliability of the sleep estimates increases in par-
mode counts the times per epoch when the motion signal is above a allel with the number of recorded days, with seven nyctohemeral
specific threshold (disregarding signal acceleration and amplitude); cycles being considered the minimal acceptable recording time [32].
(b) the “zero-crossing” approach counts the times per epoch when
the motion signal crosses zero (disregarding signal acceleration and Applications in the assessment of sleep
amplitude); and (c) “digital integration” calculates the area under the and sleep disorders
curve of the signal, thus reflecting its amplitude and acceleration, Over the last decades the technical evolution of actigraphy devices has
but not its duration or frequency [20]. Some devices can also record led to a progressive increase in its use for research and clinical purposes
light exposure and cutaneous temperature; moreover, most devices in both normal subjects and patients with sleep disorders (Fig. 9.1).
have an event button to be pushed in specific situations, for example Accordingly, each subsequent systematic literature review promoted
when the light is turned off. Although the newest actigraphs can be by the American Academy of Sleep Medicine produced guidelines
water-resistant and some have software able to estimate metabolic that continuously expanded the potential applications of actigraphy
measures from motor activity, the subject is generally instructed to from a research tool for the study of sleep, which is reliable in normal
remove the device while bathing as well as when engaged in strong subjects [33], to an objective monitoring technique increasingly use-
physical activity (eg, sport). To properly interpret the recording, ful for clinical diagnosis and management of several sleep disorders
it is crucial to ask the subject to keep a daily sleep/actigraphy log [34,35]. The latest guidelines stated that actigraphy should be used
with times of device removal, an overview of the activities per- in the following circumstances with different levels of recommenda-
formed across the 24 hours, and a self-evaluation of sleep quality. tion (namely, standard, guideline, and option) [35]: (1) to determine
Downloading the data every week is also prudent to minimize data sleep patterns in healthy adults (standard), as well as to monitor sleep
loss, especially when recording at high sampling frequency and time and treatment response in insomnia patients (guideline option)
across more weeks. Once data are downloaded on a personal com- [36]; (2) to evaluate patients with circadian sleep disorders, especially
puter, they should be manually edited using the information pro- advanced and delayed sleep phase syndromes, shift work disorder
vided by the daily log (or event-marked points). This procedure is (guideline) [37,38], as well as jet lag and non-24-hour sleep–wake syn-
crucial to correctly attribute periods of actigraphy removal to sleep, drome (option) ([39,40]; (3) to estimate total sleep time in the absence
wakefulness, or “missing data,” and also to set lights-off and lights- of PSG in obstructive sleep apnea syndrome, also in association with
on times into the scoring software. After the visual editing, several cardiorespiratory monitoring, to improve the accuracy of respiratory
software packages, by applying different algorithms to interpret the indices when normalized for sleep time instead of time in bed (stand-
rest–activity data, provide several quantitative parameters on the ard) [41]; (4) to characterize the circadian rhythms in patients with
sleep–wake cycle (namely, daytime and nocturnal total sleep times, insomnia complaints [42], also when associated with mood disorders
number of sleep episodes, sleep latency, and efficiency) [19,21,22]. (option) [43]; (5) to determine the circadian patterns and estimate

450 by means of actigraphy may provide a convenient alternative to

400 PSG for epidemiological studies (51).
350
Conclusion
300
The MSLT, the MWT, and actigraphy are objective techniques com-
250
plementary to clinical evaluation, PSG, and subjective reports. They
200 provide quantitative measures of sleep propensity, alertness, and cir-
150 cadian patterns of motor activity, with specific clinical applications in
100 the field of sleep medicine. Also, the application of these techniques for
research purposes has proved capable of gathering items of evidence
50
that are mirrored by their extended utilization in clinical practice.
0 Among recent research findings, it seems worth mentioning that
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
other measures apart from MSLT sleep latencies have led to promis-
ing results for the characterization of the sleep onset period in the
Fig. 9.1 Number of scientific publications per year retrieved by PubMed using differential diagnosis of central disorders of hypersomnolence. For
the search term “actigraphy.”
example, the order of sleep stages at sleep onset (sleep stage sequence
analysis) disclosed that SOREMPs in patients with narcolepsy are
more frequently preceded by non-REM sleep stage 1, whereas other
daily sleep time in patients with hypersomnolence complaint (option) forms of hypersomnia, such as insufficient sleep syndrome, reached
[44]; (6) to assess, together with sleep logs, sleep–wake schedules for also non-REM sleep stage two [52,53]. On the other hand, the wake-
at least seven days before the execution of the MSLT, in order to bet- to-sleep transition has been shown to be longer in patients with idio-
ter interpret its results (option) [1,7]; (7) to assess treatment response pathic hypersomnia than in patients with narcolepsy, as measured
(guideline) in patients with circadian rhythm sleep disorders [45] and by the combined application of two different sleep onset definitions
in insomniacs [46]; (8) to characterize sleep, circadian rhythm pat- (i.e, single epoch of sleep stage one versus sustained sleep) [54]. This
terns, and treatment outcome in older adults (guideline) either living sleep onset profile is similar to that of patients with obstructive sleep
in the community [47)] or chronically hospitalized [48], the former in apnea syndrome [55]. To date, this additional information, and the
association with other measures and the latter being typically difficult potential utility of documenting the features of daytime sleepiness
to be studied by means of PSG; and (9) to delineate sleep patterns and in settings closer to daily life by means of data obtained from con-
treatment responses in normal infants, children, and special pediatric tinuous PSG monitoring across 24 hours [56] or by analyzing the
populations (guideline) [49]. circadian rhythm of motor activity and immobility [57], have been
In line with the above recommendations, actigraphy is listed tested only in selected populations of sleep disorder patients. These
within the available techniques to measure sleep duration and sleep data thus require further validation before being applicable to the
patterns in the diagnostic criteria for several specific sleep disorders clinical practice of sleep medicine. Future studies using techniques
in the International Classification of Sleep Disorders, third edition different from PSG are expected to provide specific evidence to re-
[1]‌. Actigraphy (or sleep logs) is indeed primarily recommended fine the current objective measures for differential diagnosis of sleep
when sleep patterns must be assessed over time, making PSG im- disorders and predicting sleepiness-related risks.
practical, in the diagnostic approach to all circadian rhythm sleep
disorders except the jet lag syndrome, in order to document the
abnormal timing of the habitual sleep pattern. Similarly, actigra-
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CHAPTER 10
Scoring guidelines for

sleep-â•‰related movements
Michela Figorilli, Monica Puligheddu, and Raffaele Ferri
Leg movement activity during sleep the end of each event is identified by a decrease to ≤2 µV above
the resting EMG signal, lasting for at least 0.5 s. This duration cut-â•‰
Sleep-â•‰related movement disorders are characterized by usually ste- off has been introduced because an event may have one or more
reotyped and simple movements, disturbing sleep or its onset [1]â•„. periods where the EMG signal drops below the offset criteria for
Movements involving the lower limbs are most frequently studied. less than 0.5 s. The duration of a limb movement is from to 0.5 to
Leg movement activity during sleep has been analyzed by recording 10 s (15 s for research purposes). Leg movements are considered
of the surface electromyographic (EMG) activity of the tibialis ante- bilateral but counted as one event when these occur simultaneously
rior muscles. Recently, actigraphy has been proposed as an alterna- or are separated from each other (offset-â•‰to-â•‰onset) by less than 0.5 s.
tive diagnostic tool [2] in specific situations. The following sections An arousal and leg movement should be considered to be associ-
describe several lower limb activities recorded during sleep. ated when there is <0.5 s interval between the end of one event
and the onset of the other event, regardless of which is first. A leg
Periodic limb movements movement should not be computed as a PLM if it occurs at the
Periodic limb movements (PLM) are repetitive and somewhat ste- termination of an apnea or hypopnea, or the offset of the earlier
reotyped movements occurring in sleep (PLMS) or wakefulness event precedes the onset of the other by less than to 0.5 s. The inter-
(PLMW). PLM involve most frequently the lower extremities, and val between each event is measured from onset to onset, and the
are manifested by an extension of the big toe, often in combina- interval between two consecutive periodic events has to be from
tion with partial flexion of the ankle, the knee, and sometimes the 5 to 90 s. A PLM sequence is represented by a series of at least
hip [1]â•„. Lugaresi et al. [3] described for the first time in 1965 the four leg movements separated from each other by an interval last-
features of PLM in patients suffering from restless legs syndrome/â•‰ ing from 5 to 90 s. PLM can occur both during sleep and during
Willis–â•‰Ekbom disease (RLS/â•‰WED), characterizing their presence wakefulness, particularly during any stage of sleep, and a single
during both wakefulness and sleep. Originally, the quantification of sequence may continue across changes in sleep–â•‰wake state. The
PLM was based on the EMG recording of the tibialis anterior mus- basic analysis of PLM activity should always include the PLM index
cles [3]. In 1980, Coleman [4] laid the foundations for the scoring (number of PLM divided by number of hours of sleep), PLMS with
criteria of PLM, describing them in terms of duration, amplitude, arousal index (number of PLMS associated with arousals divided
and periodicity. Later, the criteria proposed by Coleman [4] were by number of hours of sleep), and PLMW index (number of PLMW
accepted by the American Sleep Disorders Association [5] and used divided by number of hours of wake). Moreover, it is recommended
for more than 20 years. Currently, rules for scoring PLM have been to differentiate the PLMS index during NREM sleep and that dur-
suggested based on algorithms for the automatic detection of leg ing REM sleep; the duration of PLMS (total, NREM, and REM) and
movements during polysomnography (PSG), including analysis of that of PLMW; and the inter-â•‰movement interval of PLMS (total,
several parameters, such as thresholds, intervals, amplitude, and NREM, and REM) and that of PLMW. Optionally, PLMS could be
periodicity [6–â•‰8]. The scoring guidelines for PLM were proposed reported by sleep stages and isolated leg movements.
first by a task force of the International Restless Leg Syndrome
Study Group (IRLSSG)/â•‰World Association of Sleep Medicine Time structure and periodicity of limb movements
(WASM) [9] and then incorporated by the American Academy during sleep
of Sleep Medicine (AASM) [10] in its guidelines. Separate clinical Non-â•‰periodic leg movements, during sleep or wakefulness, are
and research criteria were initially described. The first step in the present in patients suffering from RLS/â•‰WED, PLMD, or other con-
scoring of PLM should be a calibration of the EMG channel with ditions, as well as in normal controls [8,11]. Moreover, PLMS are
relaxed anterior tibialis muscles, in order to obtain a non-â•‰rectified usually combined with cortical and autonomic changes, which can
signal lower than ±5 µV (or 10 µV peak-â•‰to-â•‰peak) in clinical prac- be present also in non-â•‰periodic leg movements [12–â•‰14]. Therefore,
tice and ±3 µV (or 6 µV peak-â•‰to-â•‰peak) for research purposes. PLM the standard scoring features seem to be inadequate to better dis-
are identified on the EMG signal, obtained from the anterior tibialis criminate PLMS from non-â•‰periodic leg movements [15]. Three
muscles, showing repetitive contractions characterized by the fol- additional indices are useful: the total LM index, the periodicity
lowing features: the onset of each limb movement event is defined index (PI), and the time distribution of PLM throughout the night,
by an increase of the EMG signal ≥8 µV above resting baseline, and not counting PLMS related to respiratory events [15]. The first

movements in polysomnographic recordings, published in 2006.

Box 10.1 Limb movements
Each new standard rule has been classified with a level of evidence
◆ Onset: increase
[21]. The rules to detected leg movements have been substantially
of electromyographic (EMG) signal ≥8 µV
confirmed and only a new criterion for the morphology of leg move-
above resting baseline
ments, that applies only to computerized leg movement detection
◆ Offset: decrease of EMG signal ≤2 µV above resting baseline to better match expert visual detection, has been added. There have
(lasting at least 0.5 s) been two main changes introduced by these new rules: 1) Candidate
◆ Duration: 0.5–10 s leg movements (CLM), are any monolateral leg movement 0.5–10 s
long or bilateral leg movements 0.5–15 s long; 2) PLM are now
◆ Bilateral limb movements to be considered as single event if
defined by runs of at least 4 consecutive CLM with an intermove-
overlapping or the interval between movements (offset-to-
ment interval ≥10 and ≤90 s without any CLM preceded by an inter-
onset) is <0.5 s
val <10 s, interrupting the PLM series. There are also new options
◆ Limbmovements and arousal are associated when the interval defining leg movements associated with respiratory events; the
from offset to onset is <0.5 s scorer can choose one of two different options: the first is essentially
the same as in the previous standards [9] (leg movements overlap-
ping within ±0.5 s the end of a respiratory event) while the second,
indicates the total amount of limb movement activity recorded. The
more inclusive, is based on recent empirical data indicating that leg
PI represents the degree of periodicity, that is the ratio of the inter-
movements might be considered to be associated with a respiratory
movement interval lasting from 10 to 90 s (at least three consecutive
event when any part of the leg movement is between 2.0 s before
intervals) divided by the total number of intervals [8,15]. This index
and 10.25 s after the end of respiratory events [22]. PLMS should
can vary from 0, representing the absence of periodicity with none
first be quantified by ignoring all possible associations including
of the intervals having a length between 10 and 90 s, to 1, represent-
respiratory events and then determined after removing all leg move-
ing complete periodicity, with all intervals lasting from 10 to 90 s
ments associated with respiratory events. Reports and publications
and included in sequences of consecutive intervals all within this
should explicitly state which of these rules are used. Finally, special
range. The third essential feature of PLMS is the nighttime hourly
considerations for pediatric studies have been included. With these
distribution, showing in the majority of RLS patients a decrease of
new rules, the expert visual scoring of leg movements has only been
PLM from sleep onset to the morning awakening [15,16].
altered by the new standards to require accepting all leg movements
These three main parameters show clear age-related changes,
>0.5 s regardless of their duration, otherwise the technician scores
with particular features in children and in the elderly [13,17]. The
the leg movements as for the old standards.
elderly population shows a high degree of periodicity, and high
Box 10.1 summarizes the features of CLM. Box 10.2 reports the
total numbers of PLM, compared with children. Thus, normative
basic rules defining PLM.
values should be specific for different age groups [18].
These three parameters (total LM index, PI, and time structure) Actigraphy
help to distinguish “true” PLM, typical of RLS, from other clini-
Actigraphy has been used to examine the sleep–wake rhythm and
cal conditions associated with PLMS, such as narcolepsy [16] and
movements during sleep, especially using the shorter-term moni-
REM sleep behavior disorder (RBD) [19,20]. Finally, based on the
toring of rest–activity rhythm combined with PLM measurements
evidence accumulated in the last decade, very recently, a joint task
[23,24]. However, actigraphy has several limitations, including
force of the International and European Restless Legs Syndrome
an inability to distinguish wakefulness and sleep from each other
Study Groups and World Association of Sleep Medicine revised
because of the lack of EEG recording. Also, without a channel
and updated the prior standards [9] for recording and scoring leg
recording body position, PLM cannot be identified correctly.
Therefore, PLM may be both under-and over-estimated using
Box 10.2 Periodic limb movements (PLM) actigraphy. Some validation studies for actigraphy have been con-
ducted [24–26], but only small samples of PSG results have been
◆ PLM sequences are identified by at least four limb movements compared with actigraphy [24]. The filter settings of some acti-
◆ Interval between two consecutive PLM (onset-
to-
onset) graphic systems have a substantial impact on the PLM index [25];
is 90 s thus, it would be important to choose a model of actigraphy that
allows modification of its settings, such as duration of movement.
◆ Periodic
limb movements in sleep (PLMS) index: number of Actigraphy essentially uses an accelerometer to measure mechani-
PLMS divided by number of hours of sleep cally generated movements. This can be worn on the big toe, the
◆ Total LM index dorsum of the foot, or the ankle [27]. Conversely, in standard PSG,
◆ PLMS
PLM are evaluated as EMG activity of the tibialis anterior muscle,
with arousal index: number of PLMS associated with
not necessarily leading to any visible movement. Actigraphy may
arousal divided by number of hours of sleep
overestimate PLM because it can produce an output also in the
◆
Periodic limb movements in wakefulness (PLMW) case of passive movements. Nevertheless, actigraphy is more con-
index: number of PLMW divided by number of hours of wake venient and cheaper than standard PSG [2]‌, and it can be carried
◆ Periodicity index: ratio of consecutive inter-movement inter- out easily even in some populations, such as demented patients,
vals, all separated by 10–90 s (at least three intervals) divided dependent or frail seniors, and children, who are otherwise diffi-
by total number of movements cult to monitor. Further research studies are needed to find a more
convenient and reliable tool to monitor movements during sleep,
◆ Time distribution of PLMS throughout the night
such as PLM.

Chapter 10 scoring guidelines for sleep-related movements 91
Table 10.1 PSG features of alternating leg muscle activation (ALMA), hypnagogic foot tremor (HFT), and high-frequency leg movement (HFLM)
Frequency (Hz) Length of single Number of events in Sleep stages Burst series
event (ms) one series duration (s)
ALMA 0.5–3 100–500 4 Arousal, NREM, REM 20–30
HFT 0.3–4 250–1000 4 Transition wake/sleep, NREM 10–15
stage N1 and N2
HFLM 0.3–4 100–700 4 Wakefulness, NREM, REM 15–30
Other leg motor activities during sleep a more descriptive and neutral term. Table 10.1 synthesizes the
characteristics of the three sleep-related leg activities.
This section illustrates three sleep-related motor phenomena,
which are very similar to each other, represented by small motor
activations of lower limbs, short-lasting bilateral alternating or uni- Excessive fragmentary myoclonus
lateral activations (agonist/antagonist), occurring during sleep or Excessive fragmentary myoclonus (EFM) is characterized by brief,
wakefulness, often associated with arousals, usually in trains. These even invisible, muscle twitches that occur asynchronously, sym-
movements can be so small that they can be seen only when filming metrically, and bilaterally [31,32]. These movements involve distal
without any covering, such as a blanket, on the legs. muscles, like fingers, toes, and corners of the mouth, and occur at
the sleep–wake transition or during sleep. The EMG activities typi-
Alternating leg muscle activation cal of EFM can be recurrent and persistent, lasting from 75 to 150
Alternating leg muscle activation (ALMA) consists of brief alter- ms, without any clear clustering. A sequence of EFM is defined by
nating activation of the anterior tibialis muscles during sleep or at least five potentials per minute for at least 20 minutes of stage N2
arousal from sleep [1]‌. The frequency of the alternating EMG or N3 [32]. Another parameter to quantify EFM is the myoclonus
bursts is from 0.5 to 3.0 Hz, usually lasting for 100–500 ms; the index [33], identified as the number of 3 s mini-epochs containing
minimum number of discrete and alternating bursts of leg muscle at least one fragmentary myoclonus potential, included within each
activity needed to score an ALMA series is four [28] and a sequence 30 s epoch; the myoclonus index can vary between 0 and 10. EFM
of ALMAs lasts up to 20–30 s. This motor activity can arise from is more common in males and increases with age. It should be men-
all sleep stages, but especially during arousals [28,29]. ALMA may tioned that EFM can be found in patients suffering from other sleep
represent a benign phenomenon without clinical impact, but it disorders, including sleep-related breathing disorders [1]‌. Box 10.3
is not clear if it represents one of the nocturnal motor activities shows the main features of EFM. The definition of EFM will prob-
related to RLS/WED. ably be revised in the near future [34].
Hypnagogic foot tremor Propriospinal myoclonus at sleep onset

Hypnagogic foot tremor (HFT) is represented by a rhythmic move-
Propriospinal myoclonus (PMS) at sleep onset is a rare motor dis-
ment of the feet or toes occurring at the transition between wake
order, characterized by generalized and symmetric jerks, arising
and sleep or during NREM sleep stage N1 and/or N [23]. This phe-
first in spinal axial muscles of the trunk, neck, or abdomen and
nomenon is characterized by at least four recurrent EMG bursts, at
then propagating at low velocity to more rostral and caudal mus-
1–2 Hz (range 0.5–4 Hz) in one or both feet, lasting 250–1000 ms
cles, by means of slow propriospinal polysynaptic pathways [1,35–
and with a duration of one train at least of 10 s [10].
37]. PMS occurs during relaxed wakefulness or drowsiness, with
diffuse EEG alpha activity, and is typically inhibited by mental acti-
High-frequency leg movements
vation and sleep onset [1]‌. For these reasons, it can cause insomnia
High-frequency leg movements (HFLM) are identified as at least four [38], because the jerks appear several times during relaxed wake-
leg movements occurring with a frequency of 0.3–4 Hz, mostly uni- fulness or drowsiness and the patient cannot achieve stable sleep.
lateral, rather than bilateral [30]. HFLM can occur in all sleep stages PSM may resemble PLMW, longer and less periodic than PLMS;
and also, frequently, during wakefulness [1]‌. The sequences of HFLM however, generally during PSM, there is no urge to move or other
are in general longer than those of ALMA [1]. However, scoring cri-
teria are not yet available, and further studies are needed to establish
any possible relationship with RLS and their clinical relevance. Box 10.3 Excessive fragmentary myoclonus (EFM)
Do ALMA, HFT, and HFLM constitute a continuum? ◆ Burst duration: 75–150 ms

The three sleep-related leg activities that have been mentioned may ◆ Sequence of EFM: at least 5 bursts per minute
represent different manifestations of the same phenomenon along
◆ Minimum duration of a sequence: 20 minutes
a spectrum, since they have many common features.
Furthermore, their clinical impact and their association with ◆ Occurrence during NREM stage N2 or N3
RLS/WED are not clear. Further studies are needed to better out- ◆ Myoclonus index: number of 3 s mini-epochs containing at
line differences and similarities among these phenomena, and least one fragmentary myoclonus potential, included within
whether it would be possible to group them together in one entity. each 30 s epoch
They might be gathered together as HFLM [30], because this seems

Box 10.4 Propriospinal myoclonus at sleep onset (PMS) Box 10.5 Sleep bruxism (SB)
◆ Generalized and symmetric jerks, arising first in spinal axial ◆ Phasic or tonic increase of chin electromyographic (EMG)
muscles of trunk, neck, or abdomen and then propagating signal, at least twice the amplitude of the background EMG
slowly to more rostral and caudal muscles activity
◆ Occurrence during relaxed wakefulness or during drowsiness ◆ Tonic augmentation of the chin EMG signal lasting more
◆ Inhibited by mental activation and sleep onset than 2 s
◆ Phasic increases of chin EMG signal are also known as
rhythmic masticatory muscle activity (RMMA)
symptoms commonly seen during PLMW and RLS/WED. There ◆ RMMA include at least three consecutive contractions, with a
are no available quantitative PSG scoring criteria for PSM, and all frequency of 1 Hz
the descriptions are mainly qualitative [10]. The main features of ◆ Burst duration: 0.25–2 s
PSM are summarized in Box 10.4.
◆ Interval
between each episode of SB: 3 s of stable background
chin EMG signal
Neck myoclonus during sleep ◆ Polysomnographic (PSG) diagnosis: at least four episodes
Neck myoclonus during sleep, or head jerks, is a short “stripe- of SB per hour of sleep, or at least 25 individual masticatory
shaped” movement-induced artifact visible vertically over the EEG muscle bursts per hour of sleep associated with at least two
channels during REM sleep [39]. Frauscher et al. found this phe- audible episodes of tooth-grinding
nomenon in more than 50% of their patients, suffering from vari-
ous sleep disorders, during routine PSG, with low frequency during
the night (1.0 ± 2.8 episodes per hour of REM sleep), slightly more
prevalent in patients with RBD, and showing an inverse relation normal subjects [41], without any clinical implication. A new epi-
with age, being more frequent in younger patients [39]. However, sode of SB is scored if there is a preceding interval of at least 3 s of
further studies are needed to define a pathological cut-off for this stable background chin EMG signal [10]. According to the AASM
phenomenon, its prevalence in normal controls, and its relation- Manual, SB can be scored by a combination of audio and PSG, with
ship with RBD [39]. Another similar phenomenon is facio-man- a minimum of two audible tooth grinding episodes per night in
dibular myoclonus during REM sleep, which is more frequent in the absence of epilepsy [10]. PSG diagnosis of SB needs the pres-
the elderly, and is characterized by episodes of one to three con- ence of at least four episodes of SB per hour of sleep, or at least 25
tractions leading to awakenings, following biting of the tongue and individual masticatory muscle bursts per hour of sleep, associated
forceful jaw closings [40]. with at least two audible episodes of tooth grinding [1,10]. Box 10.5
shows the PSG features of SB.
Sleep bruxism
Sleep bruxism (SB) is identified as a repetitive jaw muscle activity
Rhythmic movement disorder
characterized by clenching or grinding of the teeth or by bracing or Sleep-related rhythmic movement disorder (RMD) is identified by
thrusting of the mandible, generally associated with arousal from repetitive, stereotyped, and rhythmic motor behavior that occurs
sleep [1]‌. According to the International Classification of Sleep mainly during drowsiness or sleep and may involve large muscle
Disorders, Third Edition (ICSD-3), the diagnosis of SB is based on groups, such as those of the head, neck, trunk, or limbs [1]‌. RMD
clinical features, such as reports of tooth grinding sounds during is differentiated from developmentally normal sleep-related move-
sleep, the presence of abnormal tooth wear, complaints of morn- ments when it leads to significant clinical consequences, such as
ing jaw muscle pain or fatigue, temporal headache, or jaw locking interference with sleep, important impairment of daytime per-
upon awakening [1]. PSG is indicated when the clinician suspects formance, or injuries caused by the behavior [1]. Episodes may
another sleep disorder, such as obstructive sleep apnea or RBD, last seconds or minutes, and may be present also during wakeful-
epilepsy, or other orofacial–mandibular disorders. In PSG, SB is ness preceding sleep or after sleep onset, with duration and fea-
represented by EMG artifacts recorded by the surface EEG chan- tures similar to the episodes arising from sleep. Most episodes of
nels, especially if the reference is the ear or mastoid. The scoring RMD occur during NREM sleep, stages N1 and N2, rarely SWS
manual of the AASM recommends placement of chin EMG elec- or REM sleep. Sometimes episodes have been associated with the
trodes for scoring SB; however, additional masseter or temporal cyclic alternating pattern [42,43] and respiratory arousal. There
electrodes should be included at the discretion of the investigator is a single case report indicating an epileptic etiology for RMD
or the clinician [10]. An episode of SB is identified by phasic and/or [44]. The suggested criteria for scoring RMD include (a) frequency
tonic elevations of chin EMG activity, at least twice the amplitude of ranging from 0.5 to 2 Hz, (b) presence of at least four rhythmic
the background EMG [10]. To be scored as SB, sustained contrac- movements, and (c) an amplitude of EMG bursts at least two times
tions have to last more than 2 s. Phasic augmentations of chin EMG the EMG background activity. A video-PSG is required to reach a
activity, known as rhythmic masticatory muscle activity (RMMA), correct diagnosis. Typically, RMD is seen in infants and children,
are scored as SB if they are composed by at least three contractions, but also in adults. The pattern of motor behavior may involve the
with a frequency of 1 Hz and a duration from 0.25 to 2 s. Bursts of head (headbanging or headrolling), but also the body (body rock-
chin EMG activity shorter than 0.25 s are scored as myoclonus, and ing) or occasionally the legs (leg rolling or leg banging) [1,42]. The
are observed in about 10% of SB cases. RMMA may occur also in clinical diagnosis of RMD is based on the history and, if they are

combined with bilateral phasic EMG activity in the flexor digitorum

Box 10.6 Rhythmic movement disorder (RMD)
superficialis muscles, with a cut-off of 32% of 3 s mini-epochs (and
◆ Occurrence
27% of 30 s epochs) [46]. Tonic chin EMG activity was scored simi-
mainly during drowsiness or sleep, or after sleep
larly to the Lapierre and Montplaisir method. Phasic EMG activity is
onset (mostly during stage N1 or N2)
scored in 3 s mini-epochs as any burst of EMG activity lasting from
◆ RMD may interfere with sleep, cause important impairment of 0.1 to 5 s with amplitude exceeding twice the background activity
daytime performance, or lead to injuries irrespective of its morphology [45]. The authors showed that these
◆ Episode duration variable: seconds or minutes cut-off values provide reasonable sensitivity, specificity values, and
correct classification of RBD [46,47].
◆ Frequency: 0.5–2 Hz
◆ Series of RMD: at least four rhythmic movements Automatic scoring of RSWA in RBD
◆ Amplitude of electromyographic (EMG) burst at least twice Recently, some authors have proposed some automatic scoring
the EMG background algorithms to quantify the amplitude of chin EMG activity [52–
54]. According to these automatic algorithms, the REM sleep
◆ Video-
polysomnography (video-PSG) is required to reach a
atonia index (RAI) can vary from 0 (complete absence of EMG
correct diagnosis, especially in doubtful cases
atonia) to 1 (stable EMG atonia). Initially, the threshold of the RAI
was chosen arbitrarily at 0.7, by Ferri and co-workers, because
normal controls rarely have values of RAI lower than this thresh-
available, home-and self-made video recordings. Video-PSG is old [53]. However, It should be kept in mind that normal controls
useful in doubtful cases or to rule out other sleep disorders, such may also have a RSWA without clinical RBD [55]. After a noise
as PLMS, ALMA, or motor seizures. Box 10.6 includes the PSG reduction, the threshold of the RAI was set at 0.8 (correct classifi-
features of RMD. cation 82.6%), while values of RAI between 0.8 and 0.9 indicated
a less evident (mild) alteration of atonia, and values above 0.9 are
found in normal controls [56]. Furthermore, RAI was compared
REM sleep behavior disorder between patients with Parkinson disease (PD) with or without
Visual scoring of REM sleep without atonia (RSWA) RBD, finding high sensitivity and specificity to detect the presence
According to the ICSD-3, video-PSG is mandatory to diagnose RBD of RSWA and RBD in this population [57]. The REM sleep Atonia
as well for the demonstration of REM sleep without atonia (RSWA), Index correlated considerably with the Lapierre and Montplaisir
as defined by the guidelines for scoring of RBD in the AASM Manual method to detect RSWA in RBD patients [58], with an agree-
[1]‌. The latest ICSD-3 introduces for the first time a clear suggested ment of 85% between the two methods. However, the RAI has
cut-off value for RSWA as any (tonic/phasic) chin EMG activ- been validated only in the submentalis muscle, and occasionally
ity combined with bilateral phasic activity of the flexor digitorum RBD patients may have normal REM atonia at the chin, while loss
superficialis muscles in >27% of REM sleep, scored in 30 s epochs, of atonia is observed in other muscle groups. Furthermore, this
based on the Sleep Innsbruck Barcelona (SINBAR) Group scoring index has been assessed in normal young and elderly controls, idi-
method [1,45–47]. Several studies have proposed different methods opathic RBD patients, and subjects with multiple system atrophy,
to analyze and quantify EMG activity during REM sleep [47–51]. PD, obstructive sleep apnea syndrome, narcolepsy, and idiopathic
The most widely accepted scoring system was published by Lapierre hypersomnia [53,56,57]. These results suggest that RAI could be
and Montplaisir [48,49] and differentiates between tonic and phasic used as a valid support for the diagnosis of RBD—so far for the
chin EMG activity, respectively assessed on 20 s sleep epochs, but detection and quantification of RSWA. Table 10.2 summarizes
also adapted to 30 s epochs and 2 s sleep mini-epochs. According visual and automatic scoring methods for RSWA.
to this method, a tonic REM epoch is defined by the presence of
tonic chin EMG activity for >50% of the epoch, with an amplitude at Video scoring of RBD episodes
least twice that of the background or greater than 10 µV; phasic chin The analysis of video-recorded behaviors is crucial in the diagnosis
EMG activity is identified by the presence of chin EMG bursts lasting of RBD [1]‌. Some studies have classified behaviors as simple or com-
0.1–10 s, with an amplitude exceeding four times the background plex [59], and others have distinguished between different severity
[49]. Lapierre and Montplaisir proposed a cut-off value ≥30% for the categories, like mild, moderate, and severe [60]. The severity has
tonic chin EMG activity (correct classification of 81.9%) and ≥15% been based on the excursion amplitude of the limbs and volume of
of 2 s mini-epochs containing phasic chin EMG activity (correct clas- vocalization [60]. Also, Frauscher et al. have published an extended
sification of 83.8%); when both cut-off values are satisfied, the correct analysis of all movement and behaviors, from the smallest motor
classification is 85.6% [49]. The SINBAR Group has evaluated differ- events and vocalization to the most complex and violent behaviors,
ent muscle combinations with the highest rate of REM sleep phasic including a detailed analysis about the relationship between abnor-
EMG activity in patients with RBD, finding the best combination in mal behaviors and REM sleep microstructure [61,62]. The video
the simultaneous recording of the mentalis, flexor digitorum super- scoring of RBD can be carried out in two ways: (a) a full analysis
ficialis, and extensor digitorum brevis muscles [45]. More recently, of the video in real time for all REM sleep epochs [61–64], which
the same group has published normative and cut-off values for EMG is time-consuming but necessary for research purposes, and (b) a
activity during REM sleep in 11 different body muscles, showing that selective screening of video and PSG recording epoch by epoch
adding the analysis of phasic EMG activity at the upper limb flexor (30 s epoch), which is more useful in clinical practice [65]. The latter
digitorum superficialis muscles improves sensitivity and specific- approach, the RBD Severity Scale (RBDSS) in particular, evaluates
ity for RBD diagnosis [46]. The SINBAR Group recommended the severity of motor behavior events during REM sleep on video-PSG
analysis of tonic and/or phasic EMG activity in the mentalis muscle recordings and grades them visually on an event-to-event basis.

Table 10.2 Scoring method for REM sleep without atonia
Lapierre and Montplaisir SINBAR RAI
Muscle Submental Mental, FDS Chin

EMG activity Tonic: Tonic: Tonic:
50% tonic 50% tonic ≥1 µV
>2 × background amplitude (or >10 µV) >2 × background amplitude (or >10 µV)
Phasic: Phasic:
>4 × background amplitude >2 × background amplitude
0.1–10 s 0.1–5 s
Any:
>2 × background amplitude
0.1 sec
Epoch duration 20/2 s mini-epochs 30/3 s mini-epochs 1s
Cut-off and combination Tonic: >30% Phasic chin: 16.3% RAI < 0.8
Phasic: >15% Any chin EMG (3 s): 18%
Any chin EMG + phasic FDS EMG (3 s): 32%
Any chin EMG + phasic FDS EMG (30 s): 27%
Specificity Tonic: 90% Phasic chin: NP 81%
Phasic: 87.5% Any chin EMG (3 s): NP
Both: 82.5% Any chin EMG + phasic FDS EMG (3 s): NP
Any chin EMG + phasic FDS EMG (30 s): NP
Sensitivity Tonic: 73.8% Phasic chin: NP 84%
Phasic: 80% Any chin EMG (3 s): NP
Both: 88.9% Any chin EMG + phasic FDS EMG (3 s): NP
Any chin EMG + phasic FDS EMG (30 s): NP
Correct classification Tonic: 81.9% Phasic chin: AUC 0.981 82.6%
Phasic: 83.8% Any chin EMG (3 s): AUC 0.990
Both: 85.6% Any chin EMG + phasic FDS EMG (3 s): AUC 0.998
Any chin EMG + phasic FDS EMG (30 s): AUC 0.999
SINBAR: Sleep Innsbruck Barcelona Group; FDS: flexor digitorum superficialis; EMG: electromyography; RAI: REM sleep Atonia Index; NP: not provided; AUC: area under the curve.
According to this scale, the location of movements is categorized need further refinement and validation before they can be consid-
as follows: 0 = no visible movement; 1 = slight movements or jerks ered for research and clinical applications.
2 = movements involving proximal extremities, including violent
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CHAPTER 11
Neuroimaging in normal
sleep and sleep disorders
Pierre Maquet and Julien Fanielle
Normal sleep thalamus, hippocampus, anterior cingulate cortex, temporo-â•‰

occipital areas, cerebellum, caudate nucleus, and basal forebrain
NREM sleep [2,10–â•‰12]. These data can be separated into areas that are impli-
Neuroimaging techniques have established that brain energy me- cated in the generation and the maintenance of REM sleep, such as
tabolism, as assessed by cerebral blood flow (CBF) as well as oxygen the pontine tegmentum and thalamus, and areas linked to limbic
or glucose metabolic rates, is decreased during non-â•‰REM (NREM) or paralimbic structures (amygdala, hippocampus, anterior cingu-
sleep in comparison with wakefulness and REM sleep: by 5–â•‰10% late cortex, etc.). Conversely, the precuneus, parietal cortex, pos-
during stage N2 and by 25–â•‰40% during slow-â•‰wave sleep (SWS) terior cingulate cortex, and dorsolateral prefrontal cortex are the
[1–â•‰3] (Fig. 11.1). In SWS, regional CBF (rCBF) decreases are par- least active brain regions during REM sleep [2,10,13]. Currently,
ticularly prominent in the basal ganglia, thalami, mesencephalon, the cellular mechanisms underpinning this peculiar regional activ-
dorsal pons, hypothalamus, precuneus, mesial part of the temporal ity pattern remain elusive, although the activation of pontolimbic
lobe, and prefrontal and anterior cingulate cortices [1,2]. areas and the quiescence of heteromodal associative cortices was
Regional brain activity during stages N1 and N2 (light NREM putatively related to oneiric activity [10,11,13,14].
sleep) shows a similar pattern, but the midbrain tegmentum main- Rapid eye movements are the hallmark of REM sleep, and their
tains an activity similar to wakefulness. Comparison of absolute generation is deemed different from saccades during wakefulness.
rCBF between light NREM sleep and SWS revealed that rCBF in REMs are more strongly associated during REM sleep than during
the pons, midbrain tegmentum, cerebellar vermis, caudate nucleus, wakefulness with an increase in regional blood flow in the lateral
and thalamus significantly decreased during SWS [4]â•„. geniculate bodies and striate cortex [15,16]. This finding suggested
The spatial distribution of regional brain activity during SWS that REMs are generated through mechanisms reminiscent of the
is usually thought to reflect the generation of sleep rhythms, es- ponto-â•‰geniculo-â•‰occipital waves typically recorded in animals just
pecially slow waves during SWS [3,5]. With the advent of event-â•‰ before or during REM sleep.
related functional magnetic resonance imaging (fMRI), it became Another characteristic of REM sleep consists of an autonomous
possible to directly probe this hypothesis. Spindles were shown to instability. Heart rate variability was more strongly associated dur-
be associated with responses in thalami, paralimbic areas (anterior ing REM sleep than during wakefulness with the activity in the
cingulate and insular cortices), and superior temporal gyri [6]â•„. right amygdala and less so with the activity in the right insula, an
Fast spindles (13–â•‰15 Hz) further recruited a set of cortical regions important cardiovascular regulator during wakefulness [17].
involved in sensorimotor processing, as well as the mesial frontal
cortex and hippocampus, whereas slow spindles (11–â•‰13 Hz) were Sleep disorders
associated with increased activity in the superior frontal gyrus.
Neural correlates of the slow oscillation (<1 Hz) were also Obstructive sleep apnea syndrome
reported [7]â•„. Significant decreases in activity were associated with Obstructive sleep apnea syndrome (OSAS) is known as a leading
these waves in several cortical areas, including the inferior frontal, cause of daytime sleepiness and results in variable degrees of cog-
medial prefrontal, precuneus, and posterior cingulate areas, all of nitive and performance deficits. However, the respective contribu-
which are considered as main hubs in the human brain [7,8]. These tions of sleep fragmentation and hypoxemia to the emergence of
results were independently confirmed by source reconstruction of these cognitive deficits are not yet firmly established. It is also not
high-â•‰density EEG signals [9]. yet known whether these deficits are reversible or whether OSAS
results in permanent alteration in brain structure or function.
REM sleep MRI voxel-â•‰based morphometry (VBM) or magnetic resonance
Brain energy metabolism during REM sleep is similar to that dur- spectroscopy (MRS) showed gray matter loss in the frontal, pari-
ing wakefulness and higher than during NREM sleep [1]â•„. However, etal, and anterior cingulate cortices, in the cerebellum, and in the
there are differences in the regional distribution of brain activity temporal lobe concerning the parahippocampal gyrus and in par-
between REM sleep and wakefulness. Activity has been repeat- ticular the hippocampus [18–â•‰21], which might account for altera-
edly shown to be elevated in the pontine tegmentum, amygdala, tions in memory, attention and executive functioning. A significant

Imaging of the D2 receptor using a selective antagonist (raclo-

pride) and positron emission tomography (PET) showed a mild but
Low Glucose metabolism High significant decrease in D2 receptor binding in the putamen in RLS
patients in comparison with healthy subjects [27]. However, the
decrease in binding was not related to symptom severity. Another
Wakefulness study using the same technique found lower D2 receptor binding in
REM sleep the nucleus accumbens and the caudate, but no significant differ-
Slow-wave sleep
ences in the putamen in an idiopathic RLS group of eight drug-naive
patients compared with healthy controls. After a 2-week treatment
with pramipexole, binding levels in the nucleus accumbens were
negatively correlated with clinical severity scores and positively
with the degree of post-treatment improvement in patients. These
findings implicate alterations in mesolimbic D2–D3 receptors in
RLS and show that baseline availability of these receptors is po-
Fig. 11.1 (See colour plate section) Schematic representation of the variations in
global cerebral glucose metabolism in resting wakefulness, slow-wave sleep, and REM
tentially predictive of clinical outcome after dopaminergic agonist
sleep. The images represent the cerebral glucose metabolism measured in a single treatment [28]. In contrast, there is no evidence for presynaptic
subject during three different sessions with [18F]fluorodeoxyglucose positron emission dopaminergic transporter impairment in RLS patients according
tomography (FDG-PET). Functional images are displayed at the same brain level and to a single-photon emission computed tomography (SPECT) study
using the same color scale. Similar rates of brain glucose metabolism are measured [29]. The decrease in D2 receptor binding might be explained by a
during wakefulness and REM sleep. Brain glucose metabolism is significantly decreased down-regulation or a dysfunction of the D2 receptors or by a local
during slow-wave sleep relative to both wakefulness and REM sleep. augmentation in the levels of synaptic dopamine saturating bind-
Adapted from Brain Res, 513(1), Maquet P, Dive D, Salmon E, et al, Cerebral glucose utilization
ing sites, the latter suggestion being supported by recent data [30].
during sleep–wake cycle in man determined by positron emission tomography and
[18F]2-fluoro-2-deoxy-D-glucose method, pp. 136–43, Copyright (1990) with permission Iron deficiency has also been implicated in the pathophysi-
from Elsevier. ology of RLS. In fact, low ferritin levels and high transferrin levels
were discovered in the cerebrospinal fluid (CSF) of idiopathic RLS
patients [31]. Interestingly, tyrosine hydroxylase, the rate-limiting
correlation was observed between maximum apnea duration and enzyme for dopamine synthesis, uses iron as cofactor, linking iron
cortical thinning in the dorsolateral prefrontal regions, pericentral deficiency to dopamine dysregulation [32]. Using phase MRI, iron
gyri, and insula [22]. Furthermore, resting-state functional con- content was shown to be decreased in the thalamus, pallidum,
nectivity was shown to be altered in cognitive and sensorimotor- substantia nigra, and putamen in a group of 15 RLS patients in
related brain networks in OSAS patients [23]. Some data suggest comparison with 15 healthy subjects [33]. However, these findings
that continuous positive airway pressure (CPAP) treatment might remain contentious, since another study did not find any difference
result in both improved cognition and regional increases in gray in brain iron content in RLS patients [34].
matter in the hippocampus and frontal areas [24]. Likewise, for the time being, functional and structural brain
Intriguingly, unilateral gray matter alterations were reported in abnormalities reported in RLS are inconsistent across magnetic res-
OSAS patients within the left ventrolateral prefrontal cortex and onance studies. Some VBM studies did not show any difference be-
cerebellum (areas involved in upper airway motor regulation) tween patients and control subjects [35–37], whereas others found
and the anterior cingulate [21]. Likewise, neural response to the heterogeneous data such as gray matter increase in the pulvinar
Valsalva maneuver is blunted in OSAS patients in regions with gray bilaterally [38], gray matter decrease in the middle orbitofrontal
matter loss that are involved in upper airway and diaphragmatic gyrus and left hippocampus [39], grey matter decrease in the pri-
motor control, breathing modulation, blood pressure regulation, mary somatosensory cortex bilaterally [40], or white matter volume
and sensory input integration of the oropharynx, such as the left reductions in small areas of the genu of the corpus callosum, the
inferior parietal cortex, superior temporal gyrus, posterior insular anterior cingulum, and the precentral gyrus [41]. Some argue that
cortex, cerebellar cortex, fastigial nucleus, and hippocampus [25]. these discrepant results arise from sample heterogeneity and meth-
Brain alterations in OSAS patients also involve white matter. odological differences (eg, statistical models) [37].
Diffusion tensor imaging showed extensive white matter alteration fMRI of RLS patients reported bilateral activation of the cere-
in fibers of the limbic system, pons, frontal, temporal, and parietal bellum and contralateral activation of the thalamus associated with
regions, and projections to and from the cerebellum [26]. unpleasant sensations in RLS [42]. In addition, there were also acti-
vations in the red nuclei and the brainstem close to the reticular for-
Restless legs syndrome mation during the symptomatic period, suggesting that subcortical
Restless legs syndrome (RLS) is a sleep disorder characterized by cerebral generators are involved in the pathogenesis of RLS [43].
an urge to move the legs, usually associated with uncomfortable
and unpleasant sensations in the legs that are relieved at least par- Narcolepsy
tially by movement. The symptoms are worse in the evening and are Several VBM studies have been conducted to characterize the al-
exacerbated by rest. teration in gray matter in patients with narcolepsy, with variable
The physiopathology of RLS is not completely understood, results. Some studies reported a bilateral decrease in hypothal-
but it is generally suspected that the dopaminergic circuits are amic gray matter in narcoleptic patients [44–46], consistent with
involved, because there is clinical improvement with dopaminergic the known loss of hypocretin neurons in the lateral hypothalamus
medications. of such patients [47,48]. Other VBM studies found decreases in

Chapter 11 neuroimaging in normal sleep and sleep disorders 99
cortical gray matter of limbic-related areas: the inferior temporal By contrast, a nigrostriatal dysfunction was consistently reported
and inferior frontal regions [46,49], the right prefrontal and fron- by SPECT and PET studies: dopaminergic innervation of the stri-
tomesial cortex [50], or the cingulate cortex [51–53]. Gray matter atum is significantly decreased in iRBD patients, emphasizing the
reduction was also observed in the right nucleus accumbens and continuum between iRBD and alpha-synucleinopathies [62–64].
in the cerebellar vermis [44] and, in narcoleptic patients with cata- One of the difficulties with iRBD patients is then to identify who
plexy, in both nuclei accumbentes [46]. Structural modifications in will eventually develop a neurodegenerative disorder. A SPECT
the limbic system are usually interpreted as a potential neural basis study published in 2012 found that patients with iRBD who devel-
for altered emotional processing in narcoleptic patients. oped PD or DLB had an rCBF increase at baseline in the hippo-
campus in comparison with iRBD patients with a stable condition
REM sleep behavior disorder who did not develop PD or DLB, which is the first step in estab-
REM sleep behavior disorder (RBD) is a disorder characterized by lishing a potential predictive biomarker for neurodegenerative
loss of skeletal muscle atonia during REM sleep while the patient is evolution in iRBD [65]. In conclusion, actual data suggest that the
generally dreaming, a condition associated with unusual and often etiopathogenesis of iRBD probably takes place in the brainstem and
impressive motor behavior during sleep. that associated neurodegenerative repercussions may be observed
RBD predates clinical manifestations of alpha-synucleinopathies in hippocampal regions and the striatum.
such as Parkinson disease (PD), dementia with Lewy bodies (DLB),
and multiple system atrophy [54]. For this reason, neuroimaging Insomnia
features in RBD are variable, depending on the clinical context set Insomnia is a frequent disorder defined as a subjective perception of
by the underlying neurodegenerative disorder. Consequently, we dissatisfaction with the amount and/or quality of sleep [66]. Major
will focus on neuroimaging features in idiopathic RBD (iRBD). complaints are difficulty in falling asleep, impaired sleep mainten-
The mesopontine tegmentum (MT) was one of the first regions ance, and early awakening. Insomnias are generally classified as
of interest to be considered with regard to RBD because of work comorbid insomnias, due to a medical or psychiatric disorder, and
on cats by Jouvet and his team since 1967, using a model of loss of primary insomnias that are not explainable by a comorbid condi-
skeletal muscle atonia during REM sleep as a result of MT impair- tion. Here, we will focus on primary insomnias because of the het-
ment involving the sublaterodorsal nucleus [55,56]. Moreover, case erogeneity of comorbid insomnias.
reports illustrated secondary RBD due to brainstem lesions [57,58]. Nofzinger et al. demonstrated in an FDG ([18F]fluorodeoxyglu-
Actually, few MRI studies are available on iRBD, and these gen- cose)-PET scan study that, compared with control subjects, insom-
erally involve small samples and sometimes contradictory results. niac patients had a smaller decrease in relative metabolism between
Nevertheless, two recent diffusion tensor imaging (DTI) studies wakefulness and NREM sleep in the ascending reticular activating
identified subtle anomalies in brainstem white matter, especially in system, hypothalamus, insular cortex, amygdala, hippocampus,
the pons and the midbrain, in iRBD patients versus control subjects and cingulate and medial prefrontal cortices [67]. This observa-
[59,60] (Fig. 11.2). tion is compatible with the hyperarousal theory of insomnia, which
Consistent with these results, gray matter density decreases in postulates that patients suffering from insomnia have inappropriate
the pontine tegmentum [61], although a gray matter increase has physiological arousal, with a diminution of the waking threshold
also been reported in both hippocampi in iRBD patients, for rea- and a sympathetic nervous system activation during sleep in com-
sons that remain unclear [60]. parison with normal subjects [68,69]. Moreover, in comparison
t=8
t=0
–13 –10 –7
LPT
PAG PAG
vIPAG
Fig. 11.2 (See colour plate section) Statistical parametric mapping (t) axial maximum intensity projection maps rendered onto a stereotactically normalized MRI scan,
showing areas of significant decreases of fractional anisotropy values (color code, yellow to orange) in a cohort of patients with idiopathic REM sleep behavior disorder
versus healthy control subjects. The number at the bottom right corner of each MRI scan corresponds to the z-coordinate in Talairach space. The schematic drawings
below the scans correspond to the MRI and visualize proposed nuclei involved in REM sleep control (modified from Boeve et al. [94]). The REM-off region is represented
by the ventrolateral part of the periaqueductal gray matter (vlPAG)/periaqueductal gray matter (PAG) and the lateral pontine tegmentum (LPT).
Reproduced from Annals of Neurology, 69(2), Scherfler C, Frauscher B, Schocke M, Iranzo A, Gschliesser V, Seppi K, Santamaria J, Tolosa E, Hogl B, Poewe W, White and gray matter abnormalities in
idiopathic rapid eye movement sleep behavior disorder: a diffusion-tensor imaging and voxel-based morphometry study, pp. 400–407, Copyright (2011), with permission from John Wiley and Sons.

with healthy subjects, patients suffering from insomnia showed also suggested between a decrease in gray matter density in the
hypometabolism in a large part of the frontal cortex bilaterally, in orbitofrontal area and altered caudate recruitment in insom-
the left hemisphere superior temporal, parietal, and occipital cor- niac patients due to attenuated input from orbitofrontal cortex
tices, and in the thalamus, hypothalamus, and brainstem reticular projections to the caudate nucleus. Finally, persistence of altered
formation [67] during wakefulness. Interestingly, the prefrontal caudate recruitment was observed even after successful treatment
hypometabolism seen in insomniac patients while awake is a fea- of insomnia, and, interestingly, attenuated caudate recruitment
ture that we also found in sleep-deprived subjects, and it might be was obtained in healthy subjects by SWS fragmentation [71] (Fig.
related to inefficient sleep in insomniac patients [67,70]. 11.3). In an fMRI study, during a verbal fluency task (letter fluency
Recently, executive function was probed using fMRI on a and category fluency), the left medial prefrontal and left inferior
sample of 25 patients suffering from primary insomnia and 14 frontal cortices responded significantly less in elderly patients
control subjects matched for age, sex, and education. Reduced suffering from isolated chronic primary insomnia in comparison
recruitment of the head of the left caudate nucleus was found with control subjects. This reduced activation was partly restored
during executive functioning, with an association between after nonpharmacological sleep therapy (cognitive–behavioral
caudate recruitment and hyperarousal severity [71]. A link was therapy, CBT) [72].
(a) TASK CONTRAST (ALL PARTICIPANTS, n = 37)

R
Z > 3.1, P < 0.05 cluster-corrected
MINI (–10, 18, 6) 3.1 Z 5.0
(b) INSOMNIA (n = 24) < CONTROL (n = 13)

R
Z > 3.1, P < 0.05 cluster-corrected

MINI (–10, 18, 6) 3.1 Z 5.0
(c) SLOW WAVE SUPPRESSED < NORMAL SLEEP (12 CONTROLS)

R
P < 0.05 vowel-corrected

MINI (–10, 18, 6) 0.05 P 0.0001
Fig. 11.3 (See colour plate section) Reduced caudate recruitment in insomnia and after slow-wave sleep fragmentation. (a) The head of the left caudate shows increased
BOLD signal during executive functioning relative to baseline trials across all participants. (b) Patients with insomnia show an attenuated task-elicited BOLD response in
the head of the left caudate nucleus when compared to controls (Zmax = 4.31 at MNI coordinates (−12, 18, 2); cluster size = 43 voxels = 344 mm3). (c) Controls show an
attenuated task-elicited BOLD response in the head of the left caudate nucleus after a night of slow-wave sleep suppression relative to a night of normal sleep (Zmax =
3.32 at MNI coordinates (−12, 18, 4); 36 of 43 voxels in the region of interest = 84%). Significant clusters (a and b) or voxels (c) are shown in a gradient from red to yellow
overlaid on the most informative orthogonal slices from the averaged MNI152 brain, displayed according to neurological convention (left = left). MNI coordinates for the
orthogonal slices, statistical thresholds, and a color bar indicating Z-value or significance level are shown at the bottom.
Reproduced from Brain, 137(2), Stoffers D, Altena E, van der Werf YD, Sanz-Arigita EJ, Voorn TA, Astill RG, Strijers RL, Waterman D, Van Someren EJ, The caudate: a key node in the neuronal
network imbalance of insomnia?, pp. 610–620, Copyright (2013), with permission from Oxford University Press, reproduced under the Creative Commons License 3.0.

Responses to a working memory task, as assessed by fMRI, were anterior caudate nuclei, the cingulate, and the premotor cortex
also reduced in insomnia patients, and their influence over default [86]. Hypersomnia, hyperphagia, and hypersexuality were deemed
mode areas was decreased [73]. It is argued that these findings to be related to the hypothalamic dysfunction, whereas frontal
partly explain cognitive complaints reported by patients suffering hypometabolism was thought to be involved in apathy and behav-
from primary insomnia. ioral changes, including hyperphagia. No metabolic decrease was
In a resting-state fMRI study, functional connectivity between the observed in the thalamus in these two patients, although previous
amygdala on the one hand and the thalamus, insula, and striatum studies had reported such a decrease in several cases of KLS [87,88].
on the other was reduced in insomniac patients. In contrast, func- This bilateral thalamic hypometabolism, observed with SPECT,
tional connectivity was increased between the amygdala and the was selectively seen during symptomatic episodes and disappeared
premotor and sensorimotor cortices in insomnia patients, suggest- during asymptomatic periods in all patients of a five-patient group
ing a dysfunction in emotional pathways in primary insomnia [74]. [87]. Hypoperfusion in the temporal, frontal, and occipital cortices
In patients complaining about having difficulties in falling asleep and in the basal ganglia was reported in some but not all patients
but not fulfilling the criteria for primary insomnia, functional con- [86,88,89]. Interestingly, some perfusion abnormalities persist in
nectivity was increased between primary sensory regions and supple- asymptomatic periods, especially after a long clinical evolution.
mentary motor regions, suggesting a sustained sensory processing of Concerning other SPECT imaging data, a reduction of striatal
environmental stimuli that potentially might delay sleep latency [75]. dopamine transporter availability was identified in KLS patients
VBM in insomnia patients yielded contentious results. A study during the symptomatic period in a SPECT study with [99mTc]
of 28 primary insomnia subjects and 38 good sleeper controls did TRODAT-1 [90] and, in a case report, SPECT imaging with [123I]
not identify any difference between the groups in VBM analysis of iomazenil showed a decrease in benzodiazepine binding to GABAA
gray and white matter volumes [76], whereas another study found receptors in the left mesial temporal lobe and the right frontal
a gray matter (decrease in the left orbitofrontal cortex correlated opercula [91].
with subjective severity of insomnia and a gray matter decrease in Finally, MRS data are controversial. One study suggested an
the anterior and posterior precuneus [77]. increase of glutamine metabolites in the left thalamus and in the
Likewise, the hippocampal volume (HV) in chronic insomnia basal ganglia in symptomatic compared with asymptomatic scans
was found to be reduced in insomnia patients in one study [78], but in a 20-year-old woman suffering from KLS [92], whereas a recent
not in another [79]. Interestingly, in the latter, actigraphic meas- study with 14 KLS patients and 15 healthy controls using fMRI
ures of poor sleep maintenance were still associated with smaller and MRS showed no difference in spectroscopic findings between
HV [79]. A third study did not observe any significant difference patients and controls, but did identify a negative correlation be-
in HV or intracranial volume between primary insomnia patients tween N-acetylaspartate levels and fMRI activity in the left thal-
and good sleepers, but in the patient group, bilateral HV was nega- amus in KLS patients, but not controls, while performing a working
tively correlated with duration of insomnia and arousal index and memory task [93].
positively correlated with recognition rates of visual memory [80].
An enlargement of the bilateral rostral anterior cingulate cortex
(rACC) was reported in patients with chronic primary insomnia
Conclusion
in comparison with good sleeper controls. Moreover, there was a Neuroimaging techniques, which are still in progress, contribute
positive correlation between rACC volumes and self-reported and to the comprehension of sleep mechanisms and sleep disorders in
objective determinations of poor sleep quality. It was postulated a minimally invasive way. A combination of such techniques with
that enlargement of rACC volumes might represent a compensa- electrophysiological devices provides great prospects for the future.
tory response to repetitive sleep disturbance and be a sort of marker But technical progress is not sufficient in the absence of a good
of resilience to developing a mood disorder [81]. methodology. In fact, real data from neuroimaging studies of sleep
Finally, a recent MRS study identified a reduction in and its disorders are too often controversial because of the small
γ-aminobutyric acid (GABA) levels in the anterior cingulate and size of the samples involved. That is why it is important to develop
occipital cortices of unmedicated primary insomnia patients by large-sample studies in the next few years with highly significant
33% and 21%, respectively, compared with age-and sex-matched statistical power.
healthy controls [82]. Similar phenomena were also described in
major depressive disorder (MDD) [83–85], which is interesting be-
cause of the strong relationship between MDD and insomnia.
References
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SECTION 3
Clinical science: general
introduction

CHAPTER 12
Clinical sleep medicine

An introduction
Jennifer â•‰A. Liebenthal and Christian Guilleminault
Sleep Medicine has now become a specialty in its own right, with Orofacial growth is rapid early in life. By six years of age, 60% of
many advances occurring over just a short time in recent years. the adult face is already formed, and many factors may negatively
Narcolepsy—â•‰now subdivided into type 1 with abnormally low cer- impact the width of the upper airway [5]â•„. Today we also have a bet-
ebrospinal fluid (CSF) hypocretin levels (and usually cataplexy) ter understanding of nonsyndromic genetic mutations that lead to
and type 2, lacking this key sign—â•‰is considered today as a poten- abnormal growth of bones supporting the upper airway. For exam-
tial model autoimmune disorder of the brain. The demonstration ple, in certain forms of Ehlers–â•‰Danlos syndrome associated with
of the association between HLA DQB1*0602 and a specific poly- only minor laxity of limb articulations, there may be a congenital
morphism of the T-â•‰cell receptor α in narcolepsy type 1, along with absence of teeth involved in the build-â•‰up of maxillary bone [6]. In
absent or pathologically low levels of hypocretin in the CSF, has led addition to nonsyndromic genetic mutations, there are functional
researchers in this direction. The finding of an abrupt and notably disorders related to abnormal suction, mastication, swallowing,
large increase in pediatric narcolepsy cases following a specific vac- and nasal breathing that may lead to mouth breathing and pro-
cination against the H1N1 virus in Nordic European countries, and gress to abnormal orofacial growth and nasal disuse. Recognition
the significant increase in the number of Chinese pediatric cases of such functional changes has led to routine evaluation of prema-
during the same H1N1 epidemic, have furthered our understand- ture infants and older individuals with such backgrounds, as well
ing of narcolepsy with cataplexy. Large-â•‰database studies from drug as systematic assessment for short lingual frenulum (leading to
companies and general population surveys have clearly indicated mandatory frenulum evaluation in the Federal State of Brazil). This
the general health impact of narcolepsy, particularly on the child- recognition has also encouraged increasing involvement of pediat-
hood and adolescent populations. Increases in obesity, cardiovas- ric dentists and orthodontists in the recognition and treatment of
cular disease, psychiatric syndromes, and early mortality have been abnormal oral cavities using rapid maxillary expansion, not only
observed. Now that we better understand the impact of hypocre- in children but now also in adults (through the use of mini-â•‰palatal
tin (orexin) neuron destruction in the lateral hypothalamus, many implants). Such recognition has also led to the worldwide devel-
types of knockout rodent models have explained the multiple opment of orofacial myofunctional therapists and the creation of
health consequences of the neuronal destruction [1–â•‰3]. an international society [7]. The efficacy of this approach has been
Obesity has become a significant health problem in recent dec- demonstrated in adults as well as in children.
ades, with a drastic impact on the regulation of metabolic func- Cardiologists have been reluctant to embrace the field of Sleep
tion, particularly during sleep. Obesity has a direct impact on brain Medicine for many years, even though large studies have demon-
function during sleep, but also induces changes in breathing dur- strated the important association of sleep-â•‰disordered breathing
ing sleep. However, it is difficult to distinguish between the conse- with recurrence of atrial fibrillation, despite standard medical ther-
quences directly related to obesity and those occurring secondary apy. In patients with heart failure, a comparison of patients treated
to breathing impairment during sleep. Obesity per se is responsible with adapt-servo-ventilation (ASV) during sleep [8] versus those
for cardiovascular, metabolic, and neurological changes. Invasion treated without ASV shows improved cardiac function and progno-
by adipocytes of the abdominal walls, the base of the tongue, and sis in those treated with ASV, although recent SERVE-â•‰HF clinical
the lateral pharyngeal walls may worsen the changes induced by trial results in Europe have led to some confusion in this regard [9].
obesity. Therefore, the many abnormal findings attributed to Restless legs syndrome (RLS) is a pain syndrome that continues to
obstructive sleep apnea in an obese subject cannot be solely due to be under-â•‰diagnosed and left untreated. This condition is particu-
abnormal upper airway narrowing during sleep, but may be direct larly difficult to recognize in young children, who have difficulty
consequences of obesity. These developments in understanding expressing symptoms. All too often, such symptoms are attributed
have led to revisions of therapeutic recommendations, emphasizing to “growing pains.” There seems to be a variable ethnic risk for RLS,
weight loss programs and bariatric surgery in addition to positive but new questionnaires have been constructed to help recognize the
airway pressure [4]â•„. syndrome. Additionally, several new therapeutic avenues are being
A clearer understanding of the growth and development of the investigated, particularly those that avoid the risk of augmentation.
orofacial region during early childhood has led to the recogni- The increasing number of medication options also means that the
tion of factors that increase the collapsibility of the upper airway. use of secondary drugs will become more widespread. However,

108 Section 3 clinical science: general introduction
one challenge involves the use of methadone and its potential progression of the neurodegenerative syndrome must include
impact on opioid neurons in the medulla, which are responsible for those individuals who may be the potential beneficiaries of any
controlling inspiration. If such therapy turns out to be an impor- new finding.
tant adjunct, particularly in medication-resistant older adults, then In many parts of the world, Sleep Medicine has been allo-
careful follow-up of breathing during sleep may be needed despite cated to different subspecialties, but such a division of labor is
the usually low dosages (5–10 mg) commonly prescribed. Iron detrimental to patient care and the advancement of research. A
infusion has also been a successful approach in adults [10]. multidisciplinary approach within a centralized location allows
Sleep Medicine is also becoming increasingly involved in deter- specialists to see the impact of a problem in its totality, such as
mining the role played in sleep and its disorders by the contem- the significance of sleep-disordered breathing on ophthalmologi-
porary wide use of cellphones, computers, and other electronic cal or otologic syndromes. The World Health Organization has
devices. Among younger individuals, sleep is becoming more and recognized this need. If ICD-10 is still lacking an independent
more restricted, and sleep disruption related to these gadgets is number for “Sleep/Wake Disorder,” this should not be the case
becoming more common. The consequent poor sleep and reduced with ICD-11.
total sleep time lead to impaired daytime functioning [11]. While
industrial accidents are a major concern in this regard, psychiatric
well-being is also significantly affected. Sleep restriction and distur- References
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marker of alpha synucleinopathies by years to decades is bring- behaviour disorder and relevance to neurodegenerative disease. Brain
ing more information [12]. Any drug trial aimed at slowing the 2007;130:2770–88.

CHAPTER 13
Classification of sleep disorders

Michael Thorpy
In 2013, the American Psychiatric Association published the Obstructive sleep apnea syndrome (OSA) is defined as an apnea
revised version of the Diagnostic and Statistical Manual of Mental hypopnea index (AHI) of at least 5 per hour along with typical noc-
Disorders, Fifth Edition (DSM-â•‰V) [1]â•„, which includes a section turnal respiratory symptoms, or daytime excessive sleepiness or
entitled “Sleep Wake Disorders,” an update of the DSM-â•‰IV sec- fatigue. Alternatively the diagnosis requires an AHI of at least 15
tion (Box 13.1). The intention of this classification system is to regardless of accompanying symptoms. Mild OSA is regarded as an
produce a classification for mental health and general medical cli- AHI of less than 15, moderate 15–â•‰30, and severe greater than 30.
nicians who are not experts in sleep medicine. The result is a clas- Central sleep apnea (CSA) requires the presence of 5 or more cen-
sification that differs from the International Classification of Sleep tral apneas per hour of sleep. Sleep-â•‰related hypoventilation has PSG
Disorders (ICSD-â•‰3) produced by the American Academy of Sleep evidence of decreased ventilation with either elevated CO2 levels
Medicine, which was updated in 2014 [2]. The presence of two or persistent oxygen desaturation unassociated with apneic/â•‰hypop-
competing classifications produces some confusion, especially for neic events. Idiopathic hypoventilation, congenital central alveolar
health insurance companies and for epidemiological research. The hypoventilation, and comorbid sleep-â•‰related hypoventilation can
International Classification of Diseases, Modified Version (ICD-â•‰10-â•‰ be specified.
CM) [3], adopted in the USA in 2014, contains a classification that Circadian rhythm sleep–â•‰wake disorders, with five subtypes,
more closely conforms to ICSD-â•‰3. is defined as a persistent or recurrent pattern of sleep disruption
due to an alteration or misalignment of the endogenous circadian
rhythm and the individual’s required sleep–â•‰wake schedule, along
DSM-â•‰V with symptoms of either insomnia or excessive sleepiness or both.
The first entry in the DSM-â•‰V is insomnia disorder; this diagnostic The subtypes are delayed sleep phase type, advanced sleep phase
entry requires the presence of at least one sleep complaint, such as type, irregular sleep–â•‰wake type, non-â•‰24-â•‰hour sleep–â•‰wake type, and
difficulty initiating sleep, that must be present at least three nights shiftwork type, none of which has any specific diagnostic criteria.
per week for at least 3 months. The diagnosis can be coded along The parasomnias are subdivided into five disorders; non-â•‰rapid
with other mental, medical, and sleep disorders. It is a little confus- eye movement (NREM) sleep arousal disorder, nightmare disorder,
ing that the diagnosis can be specified as being episodic if it occurs rapid eye movement (REM) sleep behavior disorder (RBD), restless
for at least 1 month, but acute and short-â•‰term insomnia that has legs syndrome (RLS), and substance/â•‰medication-â•‰induced sleep dis-
symptoms for less than 3 months should be coded as “other speci- order. NREM sleep arousal disorder is divided into two types by the
fied insomnia disorder.” typical features of either sleepwalking or sleep terrors. Confusional
Hypersomnolence disorder is a 3-â•‰month history of excessive arousals as defined in ICSD-â•‰3 are not included as a specific disor-
sleepiness in the presence of significant distress or other impair- der. The sleepwalking type can have sleep-â•‰related eating or sleep-â•‰
ment. Objective documentation is not required. This diagnosis can related sexual behavior (sexsomnia) specifications. Nightmare
be coded along with other mental, medical, and sleep disorders. disorder is defined as repeated occurrences of extended, dysphoric,
Narcolepsy is defined as recurrent episodes of sleep that occur for and well-â•‰remembered dreams that threaten the individual. Rapid
at least 3 months along with one of three additional features, such orientation and alertness follows the episode and causes significant
as cataplexy, hypocretin deficiency, or polysomnographic features, distress. RBD comprises recurrent episodes of arousal with vocali-
either a sleep onset REM period (SOREMP) on a nighttime poly- zation and /â•‰or complex movements from REM sleep that is docu-
somnogram (PSG) or a multiple sleep latency test (MSLT) showing a mented by either PSG or a history suggesting a synucleinopathy.
mean sleep latency less than 8 minutes and two or more SOREMPs. RLS is an urge to move the legs accompanied by uncomfortable
So narcolepsy can be diagnosed in DSM-â•‰V if just sleepiness occurs sensations in the legs with the typical features that occur at least
for 3 months and there is a SOREMP on the nocturnal PSG. This three times per week for at least 3 months. It is unclear from where
has the potential of leading to errors in diagnosis, since other disor- the definition of three times a week was derived. Sleep/â•‰medication-â•‰
ders, including obstructive sleep apnea syndrome (OSA), can pro- induced sleep disorder is a sleep disturbance either during or soon
duce similar features. Five subtypes are specified according to the after substance intoxication or after withdrawal, or when the sub-
following criteria: the presence or absence of hypocretin deficiency; stance is known to cause sleep disturbance. The substance should
autosomal dominant cerebellar ataxia, deafness, and narcolepsy be specified.
(ADCADN); autosomal dominant narcolepsy, obesity and type 2 Other specified insomnia disorder is specified when the insom-
diabetes (ADNOD); or secondary to another medical condition. nia does not meet the criteria for insomnia disorder, and other

hypersomnolence disorder when the excessive sleepiness does not

Box 13.1 DSM-V
meet the criteria for hypersomnolence disorder. Similarly, unspeci-
Sleep–wake disorders fied sleep–wake disorder is specified when the sleep–wake disorder
◆ Insomnia disorder does not meet the full criteria for the specified sleep–wake disor-
ders. Unspecified forms of insomnia disorder, hypersomnolence
◆ Hypersomnolence disorder disorder, and sleep–wake disorder exist.
◆ Narcolepsy
• Subtypes: ICSD-3
• Presence or absence of hypocretin deficiency ICSD-3 is a major revision of ICSD-2 and was published in March 2014
• Autosomal dominant cerebellar ataxia (Table 13.1). The main change was the simplification of the insomnia
Deafness and narcolepsy (ADCADN) disorders and an expansion of the sleep-related breathing disorders.
The organization of ICSD-3 produced a greater degree of stand-
• Autosomal dominant narcolepsy ardization between disorder texts. It includes information in all the
Obesity and type 2 diabetes (ADNOD) following categories where available:
• Secondary to another medical condition ◆ Alternate names
◆ Obstructive sleep apnea syndrome ◆ Diagnostic criteria

◆ Central sleep apnea ◆ Essential features
◆ Sleep-related hypoventilation ◆ Associated features
• Subtypes: ◆ Clinical and pathophysiological subtypes
• Idiopathic hyperventilation ◆ Demographics: prevalence, gender bias, racial/
ethnic bias,
• Congenital central alveolar hypoventilation cultural issues
• Comorbid sleep-related hypoventilation ◆ Predisposing and precipitating factors: risk factors, familial pat-
tern (genetics, familial clusters)
◆ Circadian rhythm sleep disorder
◆ Onset, course, and complications: medical, neurological, psychi-
• Delayed sleep phase type atric/social
• Advanced sleep phase type ◆ Developmental issues: pediatric, geriatric
• Irregular sleep–wake type ◆ Pathology and pathophysiology
• Non-24-hour sleep–wake type ◆ Objective findings: sleep logs, actigraphy, questionnaires,
• Shiftwork disorder polysomnography, multiple sleep latency test (MSLT), neuro-
• Unspecified type logical (electroencephalogram, cerebrospinal fluid (CSF), neu-
roimaging, electromyogram, autonomic), endocrine, genetic
◆ Parasomnias
testing
• Non-rapid eye movement sleep arousal disorder
◆ Physical findings: respiratory (arterial blood gas, pulmonary
• Subtypes: function, ventilatory response), cardiac (electrocardiogram,
• Sleepwalking type echocardiogram, cardiac catheterization), serum chemistry
• Sleep terror type Several disorders are now classified as isolated symptoms and
• Nightmare disorder normal variants, including excessive time in bed, short-sleeper,
snoring, catathrenia, long-sleeper, sleep-talking, excessive frag-
• Rapid eye movement sleep behavior disorder
mentary myoclonus, hypnagogic foot tremor and alternating leg
◆ Restless legs syndrome muscle activation, and sleep starts (hypnic jerks).
◆ Substance/medication-induced sleep disorder
◆ Other
Insomnia disorders
specified insomnia disorder
The insomnia disorders are characterized by one major disorder
◆ Other specified hypersomnolence disorder
termed chronic insomnia disorder. This recognizes the fact that the
◆ Unspecified sleep–wake disorder clinical features of insomnia can be the result of a primary or sec-
◆ Unspecified insomnia disorder ondary process, but the consequences are similar no matter what
the etiology [4]‌. The diagnosis rests upon a sleep symptom such
◆ Unspecified hypersomnolence disorder
as difficulty initiating sleep that occurs three times per week for at
◆ Unspecified sleep–wake disorder least 3 months and has daytime consequences. Psychophysiological
insomnia and insomnia disorders of ICSD-2 are mentioned as sub-
Source data from American Psychiatric Association, Diagnostic and
types of chronic insomnia disorder. The inclusion of short-term
Statistical Manual of Mental Disorders, 5th Edition DSM-5, Copyright
(2013), American Psychiatric Association. insomnia disorder with similar diagnostic criteria applies to insom-
nia that is less than 3 months in duration. Excessive time in bed

Table 13.1 ICSD-3 Table 13.1 Continued
ICD-9-CM code ICD-10-CM code ICD-9-CM code ICD-10-CM code

Insomnia disorders Central disorders of
hypersomnolence
Chronic insomnia disorder 342 F51.01
Narcolepsy type 1 347.01 G47.411
Short-term insomnia disorder 307.41 F51.02
Narcolepsy type 2 347.00 G47.419
Other insomnia disorder 307.49 F51.09
Idiopathic hypersomnia 327.11 G47.11
Isolated symptoms and normal
variants: Kleine–Levin syndrome 327.13 G47.13
Excessive time in bed Hypersomnia due to a medical 327.14 G47.14
disorder
Short sleeper
Hypersomnia due to a medication 292.85 F11–F19
Sleep-related breathing disorders
or substance (drug-induced)
Obstructive sleep apnea disorders:
291.82
Obstructive Sleep apnea, adult 327.23 G47.33 (alcohol-induced)
Obstructive sleep apnea, pediatric 327.23 G47.33 Hypersomnia associated with a 327.15 F51.13
psychiatric disorder
Central sleep apnea syndromes:
Insufficient sleep syndrome 307.44 F51.12
Central sleep apnea with 786.04 R06.3
Cheyne–Stokes breathing Isolated symptoms and normal
variants:
Central apnea due to a medical 327.27 G47.37
disorder without Cheyne–Stokes Long sleeper
breathing Circadian rhythm sleep–wake
Central sleep apnea due to high- 327.22 G47.32 disorders
altitude periodic breathing Delayed sleep–wake phase disorder 327.31 G47.21
Central sleep apnea due to a 327.29 G47.39 Advanced sleep–wake phase 327.32 G47.22
medication or substance disorder
Primary central sleep apnea 327.21 G47.31 Irregular sleep–wake rhythm 327.33 G47.23
Primary central sleep apnea 770.81 P28.3 disorder
of infancy Non-24-hour sleep–wake rhythm 327.34 G47.24
Primary central sleep apnea 770.82 P28.4 disorder
of prematurity Shiftwork disorder 327.36 G47.26
Treatment-emergent central 327.29 G47.39 Jet lag disorder 327.35 G47.25
sleep apnea
Circadian sleep–wake disorder not 327.30 G47.20
Sleep-related hypoventilation otherwise specified (NOS)
disorders:
Parasomnias
Obesity hypoventilation syndrome 278.03 E66.2
NREM-related parasomnias:
Congenital central alveolar 327.25 G47.35
hypoventilation syndrome Disorders of arousal (from NREM
sleep):
Late-onset central hypoventilation 327.26 G47.36
with hypothalamic dysfunction Confusional arousals 327.41 G47.51
Idiopathic central alveolar 327.24 G47.34 Sleepwalking 307.46 F51.3

hypoventilation Sleep terrors 307.46 F51.4
Sleep-related hypoventilation due 327.26 G47.36 Sleep-related eating disorder 327.40 G47.59
to a medication or substance
REM-related parasomnias:
Sleep-related hypoventilation due 327.26 G47.36
to a medical disorder REM sleep behavior disorder 327.42 G47.52
Sleep-related hypoxemia disorder: Recurrent isolated sleep paralysis 327.43 G47.51
Sleep-related hypoxemia 327.26 G47.36 Nightmare disorder 307.47 F51.5
Isolated symptoms and normal Other parasomnias:

variants: Exploding head syndrome 327.49 G47.59
Snoring Sleep-related hallucinations 368.16 H53.16
Catathrenia Sleep enuresis 788.36 N39.44
(continued)

Table 13.1 Continued and short-sleeper are included as isolated symptoms and normal
variants, not as specific disorders.
ICD-9-CM code ICD-10-CM code
Sleep-related breathing disorders
Parasomnia due to a medical 327.44 G47.54
disorder The sleep-related breathing disorders are organized into four main
categories: obstructive sleep apnea (OSA) disorders, central sleep
Parasomnia due to a medication 292.85 F11–F19 apnea (CSA) syndromes, sleep-related hypoventilation disorders,
or substance (drug-induced)
and sleep-related hypoxemia disorder. The CSA syndromes are
291.82 divided into eight types: two related to Cheyne–Stokes breathing
(alcohol-induced) (CSB), namely, high altitude and substance, three primary CSA dis-
Parasomnia, unspecified 327.40 G47.50 orders of which one is infancy and the other prematurity, and a new
entity entitled treatment-emergent CSA. The last category applies
Isolated symptoms and normal
variants: to central apnea that follows continuous positive airway pressure
(CPAP) administration.
Sleep talking OSA syndrome maintains the criterion of 5 or more respiratory
Sleep-related movement events per hour of sleep when studied in a sleep center or by out-
disorders of-center sleep studies (OCST), so long as typical symptoms are
Restless legs syndrome 333.94 G25.81 present; otherwise 15 or more predominantly obstructive respira-
tory events are sufficient to make the diagnosis. The OSA disorders
Periodic limb movement disorder 327.51 G47.61
are divided into adult and pediatric types. In the pediatric crite-
Sleep-related leg cramps 327.52 G47.62 ria, for those less than 18 years of age, only one obstructive event
Sleep-related bruxism 327.53 G47.63 is required per hour of sleep, so long as respiratory symptoms or
sleepiness are present; alternatively, obstructive hypoventilation
Sleep-related rhythmic movement 327.59 G47.69
along with symptoms is required.
disorder
CSA with CSB (CSA-CSB) is 5 or more central apnea or hypo-
Benign sleep myoclonus of infancy 327.59 G47.69 pneas per hour of sleep with a pattern that meets the criteria for
Propriospinal myoclonus at sleep 327.59 G47.69 CSB. CSA without CSB is diagnosed as CSA due to a medical dis-
onset order without CSB that occurs as a consequence of a medical or
Sleep-related movement disorder 327.59 G47.69 neurological disorder. CSA due to high-altitude periodic breathing
due to a medical disorder is central apnea attributable to high altitude of at least 1500 m but
usually above 2500 m. CSA due to a medicine or substance is most
Sleep-related movement disorder 292.85 F11–F19
typically due to an opioid or respiratory depressant not associated
due to a medication or substance (drug-induced)
with CSB. Primary CSA is 5 or more central apneas or central hypo-
291.82 pneas per hour of sleep in the absence of CSB and of unknown
(alcohol-induced) etiology. Primary CSA of infancy occurs in an infant with greater
Sleep-related movement disorder, 327.59 G47.69 than 37 weeks conceptional age with recurrent, prolonged (>20 s
unspecified duration) central apneas and periodic breathing for more than 5%
Isolated symptoms and normal of total sleep time during sleep. Primary CSA of prematurity occurs
variants: in an infant of less than 37 weeks conceptional age with similar
respiratory events.
Excessive fragmentary myoclonus
Treatment-emergent CSA is diagnosed when 5 or more obstruc-
Hypnagogic foot tremor and tive events during a PSG with CPAP that shows resolution of
alternating leg muscle activation obstructive events and presence of central apneas or hypopneas [5]‌.
Sleep starts (hypnic jerks)
Central disorders of hypersomnolence
Other sleep disorder 327.8 G47.8
There are eight central disorders of hypersomnolence. Narcolepsy
Appendix A has undergone a major revision with elimination of the disorder
Fatal familial insomnia 046.8 A81.83 name terms “with cataplexy” and “without cataplexy.” Type 1 nar-
Sleep-related epilepsy 345 G40.5 colepsy is that presumed to be due to hypocretin loss with either
measured reduction in CSF hypocretin or cataplexy with associated
Sleep-related headaches 784.0 R51 electrophysiological findings. Type 2 narcolepsy 2 is that which is
Sleep-related laryngospasm 787.2 J38.5 confirmed by electrophysiological studies in the absence of cata-
Sleep-related gastroesophageal reflux 530.1 K21.9 plexy or with a normal CSF hypocretin level. A major change in the
narcolepsy criteria is the inclusion of a SOREMP on the nocturnal
Sleep-related myocardial ischemia 411.8 I25.6 PSG as one of the two requirements for meeting the MSLT criteria
Appendix B of two SOREMPs for diagnosis. This amendment was based upon
ICD-10-CM coding for substance- F10–F19 a study indicating that the positive predictive value of a SOREMP
induced sleep disorders on the nocturnal PSG for narcolepsy is 92% [6]‌. Approximately
50% of patients with narcolepsy will have a SOREMP of less than
Source data from American Academy of Sleep Medicine, International classification of 15 minutes on the nocturnal PSG.
sleep disorders, 3rd ed., Copyright (2014) American Academy of Sleep Medicine.

Chapter 13 classification of sleep disorders 113
Idiopathic hypersomnia is now a single entity, with elimina- and/or complex motor behaviors, requires PSG evidence of REM
tion of the two ICSD-2 hypersomnia disorders that had specific sleep without atonia (RWA) [9]‌. RISP is a recurrent inability to
sleep duration criteria. The new idiopathic hypersomnia disor- move the trunk and all of the limbs at sleep onset or upon awaken-
der requires either an MSLT mean sleep latency of 8 minutes or ing from sleep that causes distress or fear of sleep. Nightmare disor-
less or a total 24-hour sleep duration of at least 660 minutes. The der is repeated occurrences of extended, extremely dysphoric, and
ICSD-2 category of recurrent hypersomnia has been reduced to well-remembered dreams that usually involve threats to survival,
a single entry, namely, Kleine–Levin syndrome, with a subtype security, or physical integrity.
of menstrual-related Kleine–Levin syndrome [7]‌. The sleepiness The section on other parasomnias includes three specific disor-
must persist for 2 days to 5 weeks and occur at least once every ders: exploding head syndrome (EHS), sleep-related hallucinations,
18 months. There can be only one symptom in addition to the and sleep enuresis. EHS is a complaint of a sudden noise or sense
sleepiness, namely, cognitive dysfunction, altered perception, eat- of explosion in the head either at the wake–sleep transition or upon
ing disorder, or disinhibited behavior. awakening during the night associated with abrupt arousal. Sleep-
Insufficient sleep syndrome is the new term for the previous related hallucinations are predominantly visual hallucinations that
more cumbersome term of behaviorally induced insufficient sleep are experienced just before sleep onset or upon awakening during
syndrome. The reduced sleep must be present most days for at the night or in the morning. Sleep enuresis is involuntary voiding
least 3 months. Extension of sleep time must result in resolution of during sleep at least twice a week in people older than 5 years of age.
symptoms. The other three items in the hypersomnia disorders sec- Parasomnias associated with medical disorders, and medication or
tion are hypersomnia related to a medical disorder, to medication substance and unspecific parasomnia, comprise the other entries
or substances, or to psychiatric disorder. in this category. Sleep talking is a normal variant that can occur in
Long-sleeper is no longer regarded as a disorder but as a normal both NREM or REM sleep and can be associated with parasomnias
variant. There are no diagnostic criteria, but a total sleep time of 10 such as RBD or DAs.
or more hours is suggested as being usually accepted.
Sleep-related movement disorders
Circadian rhythm sleep–wake disorders The sleep-related movement disorders (SRMDs) comprises seven
The circadian rhythm sleep–wake disorders (CRSWDs) com- specific disorders: restless legs syndrome (RLS), periodic limb
prise six specific disorders: delayed sleep–wake phase disorder movement disorder (PLMD), sleep-related leg cramps, sleep brux-
(DSWPD), advanced sleep–wake phase disorder (ASWPD), irreg- ism, sleep-related rhythmic disorder (RMD), benign sleep myo-
ular sleep–wake rhythm disorder, non-24-hour sleep–wake rhythm clonus of infancy (BSMI), and propriospinal myoclonus at sleep
disorder, shiftwork disorder, and jet lag disorder. These disorders onset (PSM). SRMDs are relatively simple, usually stereotyped,
arise when there is a substantial misalignment between the inter- movements that disturb sleep or its onset.
nal circadian rhythm and the desired sleep–wake schedule. Specific RLS (also known as Willis–Ekbom disease, WED) is an urge to
general diagnostic criteria are given for CRSWDs. A 3-month dura- move the legs, usually accompanied by or thought to be caused by
tion of symptoms is a requirement for diagnosing all these disor- uncomfortable and unpleasant sensations in the legs, and these
ders except for jet lag disorder, which has a requirement of jet travel symptoms begin or worsen during periods of rest or inactivity, are
across at least two time zones. A circadian rhythm disorder not partially or totally relieved by movement, and occur exclusively or
otherwise specified (NOS) is listed for patients who meet all the predominantly in the evening or night. In addition, these features
criteria for a CRSWD but not the specific types. are not solely accounted for as symptoms of another medical or
behavioral condition. The ICSD-3 criteria do not include any fre-
Parasomnias quency or duration criteria as is contained in the DSM-V criteria,
The parasomnias are divided into three groups: NREM-related par- but do include clinically significant RLS symptoms causing distress
asomnias, REM-related parasomnias, and other parasomnias. They or impairment of function, in contrast to International Restless
are defined as undesirable physical events or experiences that occur Legs Syndrome Study Group (IRLSSG) criteria.
during entry into sleep, within sleep, and during arousal from sleep. PLMD is defined by the polysomnographic demonstration of
The NREM-related parasomnias are defined based on general periodic limb movements (PLMS) of >5 per hour in children and
diagnostic criteria for the group heading of disorders of arousal >15 per hour in adults that cause significant sleep disturbance or
(from NREM sleep). Specific general diagnostic criteria are given impairment of functioning. Sleep-related leg cramps are pain-
for disorders of arousal (DA), and the detailed text applies to all ful sensations that occur in the leg or foot with sudden, involun-
of the DAs, since no text is presented for each of the specific DAs tary muscle hardness, or tightness. Sleep-related bruxism is tooth
except for diagnostic criteria. Sleep-related abnormal sexual behav- grinding during sleep that is associated with tooth wear or morn-
ior is listed as a subtype to be classified under confusional arousals. ing jaw muscle pain or fatigue. RMD is repetitive, stereotyped, and
Diagnostic criteria are given for three disorders; confusional arous- rhythmic motor behaviors involving large muscle groups that are
als, sleepwalking, and sleep terrors. The final NREM-related para- sleep related. BSMI is repetitive myoclonic jerking that involves the
somnia, sleep-related eating disorder (SRED), requires an arousal limbs, trunk, or whole body and occurs from birth to 6 months of
from the main sleep period to distinguish it from night eating syn- age during sleep. As PSM mainly occurs during relaxed wakeful-
drome (NES) disorder, which is excessive eating between dinner ness and drowsiness as the patient attempts to sleep, the term “at
and bedtime, and SRED requires an adverse health consequence sleep onset” has been added to the propriospinal myoclonus name.
from the disorder [8]‌. The three final categories are related to a medical disorder, medica-
The REM-related parasomnias include REM sleep behavior dis- tion of substance, and an unspecified parasomnia.
order (RBD), recurrent isolated sleep paralysis (RISP) and night- Isolated symptoms and normal variants include excessive
mare disorder. RBD, which is repeated episodes of vocalizations fragmentary myoclonus (EFM), hypnagogic foot tremor and

alternating muscle activation, and sleep starts (hypnic jerks). EFM

Box 13.2 Continued
is now regarded as a normal variant found on PSG EMG recordings
that are characterized by small movements of the corners of the G47 Organic sleep disorders
mouth, fingers or toes or without visible movement. Hypnagogic
foot tremor (HFT) is rhythmic movement of the feet or toes that G47.0 Insomnia
occurs in the transition between wake and sleep or in light NREM G47.00 Insomnia, unspecified
sleep, and alternating muscle activation (ALMA) is brief activation
G47.01 Insomnia due to medical condition
of the anterior tibialis in one leg with alternation in the other leg.
Sleep starts (hypnic jerks) are brief, simultaneous contractions of G47.09 Other insomnia
the body or one or more body segments occurring at sleep onset. G47.1 Hypersomnia
Other sleep disorder G47.10 Hypersomnia, unspecified
The final category in the ICSD-3 is a general other sleep disorder G47.11 Idiopathic hypersomnia with long sleep time
category for disorders that cannot be classified elsewhere. G47.12 Idiopathic hypersomnia without long sleep time
Appendices to ICDS-3 G47.13 Recurrent hypersomnia
Appendix A lists several disorders that are coded in sections of G47.14 Hypersomnia due to medical condition
ICD-10 other than the sleep sections, including fatal familial in- G47.19 Other hypersomnia
somnia, sleep-related epilepsy, sleep-related headaches, sleep-
related laryngospasm, sleep-related gastroesophageal reflux, and G47.2 Circadian rhythm sleep disorders
sleep-related myocardial ischemia (Box 13.2). Appendix B lists the G47.20 Circadian rhythm sleep disorder, unspecified type
ICD-10 sleep-related substance-induced sleep disorders. G47.21 Circadian rhythm sleep disorder, delayed sleep
phase type
Box 13.2 ICD-10-CM sleep disorders G47.22 Circadian rhythm sleep disorder, advanced sleep
phase type
F51 Sleep disorders not due to a substance or known physio- G47.23 Circadian rhythm sleep disorder, irregular sleep
logical condition wake type
F51.0 Insomnia not due to a substance or known physiological G47.24 Circadian rhythm sleep disorder, free running type
condition
G47.25 Circadian rhythm sleep disorder, jet lag type
F51.01 Primary insomnia
G47.26 Circadian rhythm sleep disorder, shiftwork type
F51.02 Adjustment insomnia
G47.27 Circadian rhythm sleep disorder in conditions clas-
F51.03 Paradoxical insomnia sified elsewhere
F51.04 Psychophysiological insomnia G47.29 Other circadian rhythm sleep disorder
F51.05 Insomnia due to other mental disorder G47.3 Sleep apnea
F51.09 Other insomnia not due to a substance or known G47.30 Sleep apnea, unspecified
physiological condition
G47.31 Primary central sleep apnea
F51.1 Hypersomnia not due to a substance or know physio
G47.32 High-altitude periodic breathing
logical condition
G47.33 Obstructive sleep apnea (adult) (pediatric)
F51.11 Primary hypersomnia
G47.34 Idiopathic sleep related nonobstructive alveolar
F51.12 Insufficient sleep syndrome
hypoventilation
F51.13 Hypersomnia due to other mental disorder
G47.35 Congenital central alveolar hypoventilation syndrome
F51.19 Other hypersomnia not due to a substance or known
G47.36 Sleep related hypoventilation in conditions classified
elsewhere
F51.3 Sleepwalking (somnambulism)
G47.37 Central sleep apnea in conditions classified elsewhere
F51.4 Sleep terrors (night terrors)
G47.39 Other sleep apnea
F51.5 Nightmare disorder
G47.4 Narcolepsy and cataplexy
F51.8 Other sleep disorders not due to a substance or known
G47.41 Narcolepsy
G47.411 Narcolepsy with cataplexy
F51.9 Sleep disorder not due to a substance or known physio
logical condition, unspecified G47.419 Narcolepsy without cataplexy, NOS
(continued)

Chapter 13 classification of sleep disorders 115
Box 13.2 Continued Conclusion

The new ICSD-3 is a major advance over previous versions, but it is
G47.42 Narcolepsy in conditions classified elsewhere unfortunate that some of the diagnostic criteria differ from those of
G47.421 Narcolepsy in conditions classified elsewhere with DSM-V, for example, the criteria for narcolepsy. However, DSM-V
cataplexy serves as an entry level classification, mainly for psychiatrists, and
G47.429 Narcolepsy in conditions classified elsewhere it is to be hoped that in the future the two classifications will be
without cataplexy merged into one that will cause less confusion not only for clini-
cians but also for agencies that reimburse for healthcare and pro-
G47.5 Parasomnia vide for treatment options.
G47.50 Parasomnia, unspecified
G47.51 Confusional arousals References
G47.52 REM sleep behavior disorder 1. American Psychiatric Association. Diagnostic and statistical manual
of mental disorders, 5th ed. (DSM-V). Washington DC: American
G47.53 Recurrent isolated sleep paralysis Psychiatric Association, 2013.
2. American Academy of Sleep Medicine. International classification
G47.54 Parasomnia in conditions classified elsewhere
of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep
G47.59 Other parasomnia Medicine, 2014.
3. International Classification of Diseases, Tenth revision, Clinical
G47.6 Sleep related movement disorders Modification (ICD-10-CM), National Center for Health Statistics.
G47.61 Periodic limb movement disorder Centers for Disease Control and Prevention (CDC), December
20, 2010.
G47.62 Sleep-related leg cramps 4. Edinger JD, Wyatt JK, Stepanski EJ, et al. Testing the reliability and
G47.63 Sleep-related bruxism validity of DSM-IV-TR and ICSD-2 insomnia diagnoses: results
of a multi-method/multi-trait analysis. Arch Gen Psychiatry
G47.69 Other sleep-related movement disorders 2011;68:992–1002.
5. Westhoff M, Arzt M, Litterst P. Prevalence and treatment of central
G47.8 Other sleep disorders
sleep apnoea emerging after initiation of continuous positive airway
G47.9 Sleep disorder, unspecified pressure in patients with obstructive sleep apnoea without evidence of
heart failure. Sleep Breath 2012;16:71–8.
Z72 Problems related to lifestyle 6. Andlauer O, Moore H, Jouhier L, et al. Nocturnal REM sleep latency
Z72.8 Other problems related to lifestyle for identifying patients with narcolepsy/hypocretin deficiency. JAMA
Neurol 2013;6:1–12.
Z72.82 Problems related to sleep 7. Arnulf I, Lin L, Gadoth N, et al. Kleine–Levin syndrome: a systematic
Z72.820 Sleep deprivation study of 108 patients. Ann Neurol 2008;63:482–93.
8. Brion A, Flamand M, Oudiette D, et al. Sleep related eating disorder
Z72.821 Inadequate sleep hygiene versus sleepwalking: a controlled study. Sleep Med 2012; 3:1094–101.
Z73 Problems related to life management difficulty 9. Schenck CH, Howell MJ. Spectrum of RBD (overlap between RBD and
other parasomnias). Sleep Biol Rhythms 2013;11(Suppl 1):27–34.
Z73.8 Other problems related to life management difficulty
Z73.81 Behavioral insomnia of childhood
Z73.810 Behavioral insomnia of childhood, sleep onset
association type
Z73.811 Behavioral insomnia of childhood, limit setting
type
Z73.812 Behavioral insomnia of childhood, combined
type
Z73.819 Behavioral insomnia of childhood, unspecified
type
Source data from World Health Organization, International Classification

of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), Copyright
(2010), World Health Organization.

SECTION 4
Hypersomnias

CHAPTER 14
Narcolepsy with cataplexy
Gert Jan Lammers
Introduction with abnormal expressions of REM sleep on the multiple sleep

latency test (MSLT) [6]â•„. Some of this group will develop narco-
Narcolepsy with cataplexy is usually described as a syndrome char- lepsy with cataplexy later on, and some may represent a “forme
acterized by excessive daytime sleepiness (EDS), cataplexy, hypna- fruste” of narcolepsy with cataplexy. These patients may have a
gogic hallucinations, sleep paralysis, and disturbed nocturnal sleep. less severe hypocretin cell loss than narcolepsy with cataplexy
Although this is in itself correct, simply listing these symptoms patients. Post-â•‰mortem brain studies, performed in a very limited
does not convey what it means to suffer from narcolepsy. The key number of patients, support this view [7]. However, probably a
problem of these patients, relentlessly present each and every day larger percentage represents both patients with a real hypersom-
of their lives, is their inability to remain fully alert or even awake nia of undetermined cause (at least not caused by a deficient
during longer periods of the day, paradoxically accompanied by hypocretin transmission) and subjects with a lifestyle-â•‰induced
difficulty remaining asleep during the night. In addition, the strict hypersomnia. The existence of these last groups raises the ques-
physiological boundaries of specific components of wake and sleep tion of whether the ICSD-â•‰3-â•‰required PSG/â•‰MSLT findings for nar-
stages are fluid. This leads to partial expressions, particularly of colepsy type 2 are specific and consistent enough to be useful.
identifiable REM sleep, explaining such symptoms as cataplexy, There are indications that chronic sleep deprivation or shiftwork
hypnagogic hallucinations, and sleep paralysis. The loss of state in otherwise healthy individuals may be enough to cause the
boundaries leads to more symptoms that are not always emphasized MSLT abnormalities, and repeated testing may show occurrence
in textbooks, such as automatic behavior, memory complaints, and and disappearance of sleep onset REM sleep on MSLT testing [8–â•‰
dream delusions. Moreover, those who suffer from narcolepsy with 10]. At any rate, most cases of narcolepsy without cataplexy do
cataplexy clearly bear a risk for obesity, fatigability, and psychiatric not develop cataplexy later on, so it is not simply an early stage of
comorbidities such as anxiety, depression, and possibly also eating narcolepsy with cataplexy.
disorders. The disorder has a severe negative impact on daily func-
tioning and quality of life. It is more detrimental when it starts dur-
Epidemiology
ing childhood than adulthood because of the additional negative
impact on social development and achievements at school. Narcolepsy with cataplexy has an estimated prevalence of 25–â•‰50
Narcolepsy can be divided into narcolepsy with and without per 100 000. The incidence is estimated to be 0.74–â•‰1.37 per 100 000
cataplexy [1–â•‰4]. In the most recent International Classification person-â•‰years [11–â•‰13]. There are no reliable prevalence or incidence
of Sleep Disorders, these have been rephrased as narcolepsy type estimations of narcolepsy without cataplexy.
1 and narcolepsy type 2, with the only difference being that if a Age of onset is usually between 15–â•‰35 years, but it may start at
patient who suffers from narcolepsy without cataplexy turns out any age. EDS is the first symptom to occur in the vast majority of
to be hypocretin-â•‰deficient, that patient is labeled as suffering from patients [14]. In less than 10%, the first symptom is cataplexy. In
narcolepsy type 1 [5]â•„. Narcolepsy with cataplexy is considered to more than 40% of patients, cataplexy appears within weeks from
be a homogeneous disease entity, a “morbus sui generis,” of which the start of EDS, and in 85% within 3 years. Nevertheless, appear-
the pathophysiological hallmark is a loss of hypocretin (also called ance many years or even decades after the first symptoms is possi-
orexin) cells in the hypothalamus (Fig. 14.1). A very small percent- ble. During the last few years, a growing number of childhood cases
age of these patients (less than 2%) suffer from a familial or sympto- have been diagnosed.
matic form. “Symptomatic” in this context means that that there is
a known cause, in contrast to the majority who suffer from what is The symptoms
also called “idiopathic” narcolepsy (in fact, this chapter is about the
98% of idiopathic narcolepsy patients). Symptomatic cases may also Excessive daytime sleepiness
be labeled as “narcolepsy with cataplexy due to medical condition”. EDS is the leading symptom of narcolepsy (Fig. 14.2). It usually
Possible causes are a tumor in the hypothalamic area, paraneoplas- develops over weeks to months, but may also start more acutely.
tic or Niemann-Pick disease type C. The majority of these cases also After its occurrence, it is relentlessly present daily [1–â•‰3,5].
show other symptoms beyond the known symptoms of narcolepsy. EDS is characterized not just by an inability to stay awake, but also
In some hypocretin cells may remain intact, and hypocretin-1 lev- by a subjective feeling of sleepiness that is expressed in a difficulty
els in the CSF may remain normal. In these cases a disturbance of in concentrating and in sustaining attention, leading to impaired
hypocretin transmission on a different level is presumed. performance while seemingly being awake [15]. Performance defi-
Narcolepsy without cataplexy may be no more than a hetero- cits and sleep(iness) typically occur during monotonous activities
geneous group of disorders characterized by EDS in combination such as watching television, reading a book, attending a meeting, or

120 Section 4 hypersomnias
Fig. 14.1 Narcolepsy is caused by selective cell loss in the hypothalamus.

Illustration made by Guillermo Rodilla Marin.
being a passenger in a car. In more severe cases, sleep attacks may over ten each day, depending not only on the severity of the nar-
also occur when patients are more active, such as during dinner, colepsy but also on the circumstances. Physical activity reduces
while walking, or even when riding a bicycle. Sleep attacks tend to the chance to fall asleep. Although falling asleep during the day is
be short, usually less than 20 minutes, sometimes only several min- labeled as “sleep attacks,” the onset of sleep is typically insidious
utes, and refreshing for some time. However, longer sleep attacks over at least seconds and often more than half a minute, and not
do not exclude the diagnosis. The number may vary from one to very sudden/acute.
Fig. 14.2 Postcards made by Julie Flygare, who runs the website Julieflygare.com. Julie is a narcolepsy advocate and is affected with narcolepsy.
Julieflygare.com

Chapter 14 narcolepsy with cataplexy 121
Narcolepsy patients do not actually spend a greater portion of complete attack to build up, most patients are able to take coun-
their time asleep across the 24 hours of the day when compared termeasures and prevent injury. Jerks and twitches may occur,
with people who do not have narcolepsy. This is mainly explained usually in the face. Mirth is the most typical trigger, which usually
by recurring wake periods during their nocturnal sleep. There are involves laughter. Laughing out loud, telling a joke, and making
some indications that if narcolepsy starts abruptly, there may be a a witty remark are typical triggers [18]. Although laughter is the
significantly increased need for sleep in the early stage of the dis- strongest trigger, various emotions may induce an attack, includ-
ease, disappearing over weeks to months. ing, for example, the unexpected meeting of an acquaintance and
EDS must be distinguished from tiredness or fatigue. The last two anger [18].
conceptions refer to an experience related to exhaustion. This may The cataplexy phenotype differs widely between patients, but
be a complaint of narcolepsy (as in many other chronic conditions, usually is stereotypical within a patient. If complete attacks occur,
including depression), but is not a (core) symptoms of narcolepsy they usually start as the typical partial attack of the individual. Also,
[16]. Fatigue without sleepiness is not compatible with narcolepsy. the frequency of attacks varies widely from dozens a day to less than
When fatigue is present, it may aggravate the complaint of EDS, be- once a month. Most attacks last seconds to half a minute, some-
cause it is usually associated with less (physical) activity. times up to 2 minutes, but only rarely longer. If longer, these are
Automatic behavior is another expression of EDS: the perform- usually sequential attacks when the trigger remains. Partial attacks
ance of a semi-purposeful, inadequate daytime activity. A patient tend to be shorter than complete ones, the majority even (much)
may for instance continue to write in a state of drowsiness, resulting less than 10 seconds. Patients may avoid situations in which cata-
in illegible handwriting, or put the laundry in the tumble dryer in- plexy may occur. A so-called “status cataplecticus” may be induced
stead of the washing machine. by acute withdrawal of medication, such as tricyclics and mazin-
In childhood cases, behavioral abnormalities including hyper- dol, or when initiating prazosin treatment for concomitant hyper-
active or aggressive behavior may accompany EDS and may even tension. It is characterized by an almost continuous succession of
be more pronounced problems than EDS, at least for parents [17]. cataplectic attacks, in part without identifiable trigger, that may last
This behavior is not seen in adult cases, although in adulthood EDS from hours to days. Although cataplexy is the only truly specific
may be accompanied by irritability. feature of narcolepsy, it is the first symptom to appear in less than
10% of cases, and it may appear many years or even decades after
Cataplexy developing EDS.
Cataplexy is the only specific symptom of narcolepsy. It is char- During childhood, a different phenotype may develop, char-
acterized by a sudden bilateral loss of skeletal muscle tone, with acterized by prominent facial involvement with a droopy expres-
preserved consciousness, elicited by emotions [2,5,18]. All stri- sion, eyelid ptosis, and paroxysmal episodes of mouth opening and
ated skeletal muscles can be involved, except the extraocular and tongue protrusion, also called “cataplectic facies.” This predomi-
respiratory muscles. Cataplexy may be complete, indicating com- nant facial hypotonia may be accompanied by prolonged periods of
plete loss of activity of all muscle groups. But more often it is par- hypotonia presenting as a paroxysmal gait disorder that may mimic
tial, only affecting control over the knees, face, and neck. Neck cerebellar ataxia [17,19,20]. Frequently there are superimposed
weakness, producing head drop, is common, whereas facial weak- active motor phenomena that can be confused with tics, chorea,
ness may lead to sagging of the jaw and dysarthria (Fig. 14.3). or dystonia. Typical triggers for children include watching a funny
Although respiratory muscles are not involved, patients some- movie and playing (video) games. However, an emotional trigger
times describe shortness of breath during an attack. Complete may be hard to identify or may even be absent in young children,
attacks may cause falls. Because it takes several seconds for a particularly close to disease onset.
Fig. 14.3 A partial cataplectic attack in the face and neck (lateral view). Stills from a video footage. A family member is telling a joke. Laughter starts after approximately
5 s, the punchline is reached after 25 s. First image: neutral; second: start of laughter; third: start of attack about 1 s before reaching the punchline. Fourth to sixth
images: 2, 3, and 3.5 s later, respectively.

Because patients rarely have attacks during consultation, the Sleep paralysis occurs as a symptom on its own and is therefore
presence of cataplexy needs to be established based on the clinical not specific for narcolepsy.
interview alone. In the exceptional case that an attack is observed, it
may be relevant to try to elicit the deep tendon reflexes, which will Disturbed nocturnal sleep
transiently disappear during an attack, including during a partial Sleep latency in narcolepsy is typically very short: patients usually
attack. fall asleep as soon as they lie down and their heads touch their pil-
low. They do not stay asleep, however, which is reflected in frequent
Hypnagogic hallucinations awakening, which is often labeled as “sleep fragmentation” [24].
Hypnagogic hallucinations (HH) are very vivid dreamlike expe- Most awakenings are brief, but some last for more than an hour.
riences that occur during the transition from wakening to sleep, The first hours of nocturnal sleep are usually the most consolidated.
but may also occur on awakening (hypnopompic). The content Comorbid parasomnias and periodic leg movements are more fre-
varies, but often they are extremely unpleasant and frightening. quent than in the normal population (see the next section). The
In 85% of the hallucinations, multiple senses are simultaneously total duration of nocturnal sleep is by and large comparable to the
involved: visual, auditory, and tactile [21]. The hallucinations may situation before the patient developed narcolepsy. In a minority of
be “pasted” over the actual environment, i.e, the room in which the cases, nocturnal sleep time increases temporarily or structurally.
patient is located—for example, someone they know seems to enter
that room. Patients may see and feel animals walking on their skin
or scratching it with their nails. However, people may also experi- Comorbidity
ence being in a totally different surrounding. Usually, narcolepsy Obesity
patients recognize immediately after the event that the experience About 30% of patients have a BMI of at least 30 kg/m2, which
was not real, which helps distinguish HH from hallucinations in a is about twice as much as in the general population [25]. The
psychiatric context. Their occurrence during the transition between explanation is probably complex, and the pathways are not fully
wakefulness and sleep also helps the diagnosis, since hallucinations understood. Part of the explanation may be decreased activity or
in psychiatric disorders can occur at any moment. There is no rea- increased caloric intake, but, since it typically occurs in hypocretin-
son to think that HH point towards a psychotic disorder: psychotic deficient patients, this seems to be a direct consequence of hypocre-
disorders do not occur any more frequently in narcolepsy patients tin deficiency and not part of the “sleep phenotype.” There are no
than in the general population [21]. convincing indications that basal metabolism is changed in narco-
HH are not specific for narcolepsy with cataplexy, since they are lepsy, although several studies point to a slightly lower (daytime)
also present in the general population and in other sleep disorders body temperature [26]. Probably diabetes type 2 is more frequent
[22]. However, the prevalence, and probably also the frequency, are when compared with the normal population, but not when com-
higher in narcolepsy. pared with age-and BMI-matched subjects [27].
Dream delusions Fatigue

Dream delusions are memories of a dream experience that are Fatigue differs qualitatively from EDS and it is therefore important
taken for a real event, forming sustained delusions, sometimes to differentiate between them. Fatigue is the experience of mental
about significant events. This is a symptom of narcolepsy that has and physical exhaustion that does not disappear after a period of
only recently been identified and that should be separated from HH sleep. In can be found in up to 60% of patients and is usually more
[23]. As opposed to the fleeting characteristic of an HH during the resistant to therapy than EDS [16]. Severe fatigue may increase the
sleep/wake transition, dream delusions are false memories induced impact of EDS, since it impairs daytime activity, which is a major
by the experience of a vivid dream, which lead to counterfactual countermeasure to combat EDS.
beliefs that may persist for days or weeks. For example, a man, after
dreaming that a young girl had drowned in a nearby lake, asked Sleep apnea, periodic limb movements,
his wife to turn on the local news in full expectation that the event and parasomnias
would be covered. Or a woman who experienced sexual dreams Obstructive sleep apnea (OSA) is reported in up to 30% patients
of being unfaithful to her husband believed that this had actually diagnosed with narcolepsy with cataplexy [28,29]. Treatment of
happened and felt guilty about it until she had a chance to meet the sleep apnea in these patients is problematic, and its necessity has
“lover” from her dreams to realize they had not seen each other in been questioned. Patients often do not experience benefit or can-
years and had not been romantically involved. not endure the treatment [28,29]. Therefore, in general, it is recom-
mended to treat the narcoleptic symptoms first. However, severe
Sleep paralysis comorbid sleep apnea may be treated first. When treating the nar-
Sleep paralysis is the inability to move or speak on awakening coleptic symptoms first, it must also be kept in mind that sodium
or when falling asleep while being subjectively awake and con- oxybate treatment may aggravate the apneas [30].
scious. The paralysis may be complete, so patients are unable to Periodic limb movements in sleep have been described in up to
raise as much as a little finger. Attacks presumably last up to sev- two-thirds of the subjects with narcolepsy, although it is unclear
eral minutes. Sleep paralysis has similarities with both cataplexy whether they really contribute to the impaired quality of noctur-
and HH: the timing resembles that of HH, whereas the pattern of nal sleep [29]. Patients usually only experience benefit from treat-
affected muscles resembles that of complete attacks of cataplexy. ment of the periodic limb movements if there are coexisting RLS
Sleep paralysis may occur simultaneously with HH. complaints.

Parasomnias number of subjects without a complaint of EDS, may show the

REM sleep behavior disorder (RBD) has a significantly higher prev- abnormalities that are considered to be diagnostic for narcolepsy
alence compared with the general population, affecting 12–36% of [9,10]. Also the test–retest variation seems not to be high, at least
patients [31,32]. Specific treatment is hardly ever necessary. Other in subjects without cataplexy [8]‌. Most likely, the majority of these
parasomnias such as nightmares and sleepwalking are probably MSLTs are false positives due to factors such as shiftwork, insuffi-
also more frequent. cient sleep, and, to a lesser extent, sleep apnea. Insufficient sleep as a
cause of EDS is supported by published case reports showing sleep
Anxiety and depression extension to “cure” the complaint and MSLT abnormalities [34].
Anxiety disorders, especially panic attacks and social phobias, often The occurrence of sleep stage N2 before the occurrence of REM on
affect patients with narcolepsy [33]. MSLT testing may be a marker for insufficient sleep as a cause of
Since depression may cause complaints of EDS and lack of energy, the abnormal result.
as well as neurophysiological abnormalities that may resemble nar- The MSLT may also be falsely negative in subjects clinically sus-
colepsy, it can be difficult to diagnose depression as a comorbid pected to have narcolepsy with cataplexy. In a recent study, 7% of
disorder. Nevertheless, depression is considered to have a higher patients with typical complaints of narcolepsy with cataplexy did
prevalence than in the general population; 5–30% of patients are not show the typical findings [35]. The false-negative rate for nar-
reported to fulfill the criteria for depression. Major depression is colepsy without cataplexy is unknown, since the MSLT results are
probably not more common [33]. part of the definition. Sometimes the MSLT may be negative owing
to poor sleep induced by environmental factors, anxiety, older age,
Memory complaints or medications that interfere with sleep.
Many patients have memory complaints. It is not clear if these Age influence the MSLT results in patients with narcolepsy. With
are due to impaired sustained attention and impaired executive advancing age, the number of SOREMPs decreases and the mean
function only, or if there is a dysfunction of the memory system sleep latency increases [36]. For instance, mean sleep latency is
itself or both. Standardized memory tests usually do not show lower in adolescents with narcolepsy (3.6 minutes) compared with
abnormalities. narcolepsy patients above 65 years (5.2 minutes). Also, the use or
discontinuation of medication, particularly antidepressants, may
significantly impact the occurrence of REM sleep. How to deal
Diagnosis: criteria, classifications, with all these potential confounders is not discussed in any formal
and limitations of diagnostic tests guidelines about the use of the MSLT.
Despite all these limitation, the MSLT is the best test we currently
ICSD-2 versus ICSD-3
have to quantify sleepiness in a considered objective way.
In the second edition of the International Classification of Sleep
Disorders, ICSD-2, published in 2005, the criteria to diagnose Hypocretin-1 measurement
narcolepsy with and without cataplexy are mainly based on clini- Hypocretin-1 deficiency, measured in cerebrospinal fluid (CSF), is
cal symptomatology [4]‌. Clinical criteria define cataplexy. If there the most specific and sensitive diagnostic test for narcolepsy with
is no cataplexy, the MSLT “decides.” In the context of a complaint cataplexy [37] (Fig. 14.4). Additional advantages are the lack of
of EDS, either with or without the presence of cataplexy, an MSLT influence of age, medication use or discontinuation, or lifestyle.
with a mean sleep latency < 8 minutes and two or more sleep onset In patients with typical cataplexy, who are positive for histocom-
REM periods (SOREMPs) is considered to be diagnostic for nar- patibility leukocyte antigen (HLA) DQB1*06:02, nonfamilial and
colepsy. In contrast, the ICSD-3 criteria, published in 2014, are asymptomatic (these are more than 95% of diagnosed patients),
mainly based on the presumed pathophysiology, i.e, the presence hypocretin-1 concentration in the CSF is low or undetectable in
of hypocretin deficiency [5]. Narcolepsy types 1 and 2 are distin- about 98% of cases [38]. The specificity of a low or undetectable
guished. A measured hypocretin deficiency, or, if no measurement hypocretin-1 is even higher than 98%.
has been performed, a very high a priori chance of hypocretin defi- For narcolepsy without cataplexy, the situation is more com-
ciency, defines type 1. All other cases without a clear other cause plex: the sensitivity of low or absent hypocretin-1 is low, 20–33%,
for EDS that show the typical MSLT abnormalities are labeled depending on a cut-off of 110 or 200 pg/mL,* but remains very
as type 2. Another difference is the calculation of the number of specific [5]‌. In ICSD-3, all patients with complaints of EDS and
SOREMPs: if a SOREMP occurs during the night preceding the who show hypocretin-1 deficiency in their CSF, irrespective of
MSLT, it may be added to the number of SOREMPs found during the presence of cataplexy, are labeled as having type 1 narcolepsy.
the MSLT. So, if the MSLT shows a mean sleep latency < 8 minutes ICSD-3 defines values below 110 pg/mL as deficient, rather than
and only one SOREMP, it can still be diagnostic for narcolepsy if a the 200 pg/mL that has recently been advocated by the Stanford
SOREMP has been identified on the PSG during the night preced- group [39].
ing the MSLT.
MSLT * The currently available commercial kit for the hypocretin-1

radioimmunoassay (RIA) has a large inter-assay variation, and therefore
Both ICSD-2 and ICSD-3 heavily rely on the MSLT. Unfortunately,
reference samples must always be included. Many centers use reference
the MSLT has significant limitations as a diagnostic test for narco- samples from Stanford and convert their values to the Stanford values.
lepsy. There are several recent studies that show that the specific- The values mentioned in ICSD-3 and in this chapter are based on Stanford
ity of the MSLT for narcolepsy is very low because up to several values. Levels below 40 pg/mL (in crude CSF) are usually below the
percent of people in the normal population, even in a substantial detection limit of the RIA and therefore called “undetectable.”

800 Controls Narcolepsy/hypersomnia Other sleep disorders
700
600
CSF hypocretin-1 (direct assay, pg/mL)
500
400
47 17 194 10 22 4 4 18 28 6 2 15 15 10 12
300
200
0 0 30 3 2 1 0 0 1 1 1 0 0 0 0
100
0 0 4 88 5 2 5 3 0 0 0 3 0 0 0
0
im
e
m
e ers xy xy ex
y nd xy nia nia nia ies ea m
e nia
ayt h tti o rd a ple a p l e tapl o ba a ple o m o m o m o log a pn d ro o m
g is t t a r t rs rs r s i p n s
D Ni ld lc
a
lc
a
ec ily
p ca pe pe pe ye
t
l ee sy In
g ica p ica p ica a tiv am No c hy d hy c hy d ar ives l e gs
o Ty y g F i te i n t ss
ol At ne ath rio
d co uc tle
ur A- en Se str
Ne L d iop u m Pe b R es
H I c O
do
Un
Fig. 14.4 Cerebrospinal fluid hypocretin-1 levels (direct assay) across various disease categories. Each dot represents a single patient. Diagnostic categories are as detailed
in Box 14.1. Hypocretin-1 values of 110 pg/mL or less were determined as the best cut-off point to diagnose narcolepsy as defined by the International Classification of
Sleep Disorders. A second cut-off point of 200 pg/mL best determines healthy control values. The number of subjects with hypocretin values below or equal to 110 pg/mL,
above 200 pg/mL, and between these two values is indicated for each category.
Reproduced from Arch Neurol., 59(10), Mignot E, Lammers G J, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H, Nishino S, The Role of Cerebrospinal
Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias, pp. 1553–1562, Copyright (2002), with permission from the American Medical Association.
HLA Differential diagnosis

Narcolepsy is tightly associated with HLA-DQB1*06:02, which is Cataplexy must be differentiated from cataplexy-like episodes in
in linkage disequilibrium with HLA-D QA1*01.02. Worldwide, normal subjects (“weak with laughter”), and from “drop attacks.”
about 85–95% of narcolepsy with cataplexy patients carry this Falls and sudden muscle weakness in the context of seizures, psy-
DQB1*06:02–DQA1*01:02 haplotype, compared with 12–38% of chogenic attacks, and transient ischemic attacks are usually simple
the general population. For nonfamilial cases and those with typi- to be differentiated from cataplexy by history [40].
cal cataplexy, the association may exceed 95% [38]. Therefore, car- EDS and MSLT findings resembling narcolepsy can be seen par-
rying this haplotype is thought to represent an almost certain risk ticularly in patients with shiftwork, sleep deprivation, and sleep
factor for developing narcolepsy. Since the prevalence in the gen- apnea [10].
eral population is relatively high, HLA typing is not of use in diag-
nosing narcolepsy. HLA positivity barely increases the likelihood Pathophysiology
of the diagnosis. It might be argued that HLA typing can be used
to exclude narcolepsy as a diagnosis. However, this also is of lim- State boundary control and the hypocretin system
ited usage, because cases with typical cataplexy are almost always All symptoms of narcolepsy can be explained by a state instability
DQB1*06:02-positive, but, in contrast, less typical and rare familial for which the term “loss of state boundary control” was introduced
or symptomatic cases more often are HLA-negative, but may still be by Broughton in 1986 [41] . “Loss of state boundary control” results
diagnosed as narcolepsy [5]‌. in two qualitatively different phenomena. The first is that no sleep
or wake state can be maintained for a normal length of time: when
Current diagnostic criteria awake, patients fall asleep easily, and when asleep, they awaken
See Box 14.1. easily. The second is that various phenomena that normally occur

together in a certain sleep stage now occur out of context. Muscle

Box 14.1 Types of narcolepsy
atonia that physiologically occurs during REM sleep is occurring
Narcolepsy type 1 during wakefulness in the form of cataplexy and sleep paralysis.
Criteria A and B must be met HH are considered to be intrusions of dream imagery into wakeful-
ness or drowsiness. Other findings in narcolepsy can be explained
A. The patient has daily periods of irrepressible need to sleep or in a similar manner. Nowadays, the hypocretin system (also named
daytime lapses into sleep occurring for at least three months.1 the orexin system) is considered to represent the natural “glue” for
B. The presence of one or both of the following: state boundary control [42]. Its loss causes a loss of state boundary
1. Cataplexy (as defined under Essential Features in ICSD-3, control and the symptoms of narcolepsy.
reference 5) and a mean sleep latency of ≤8 minutes and Hypocretin-producing cells are found solely in the lateral hypo-
two or more sleep onset REM periods (SOREMPs) on an thalamus. The system consists of the peptides hypocretin 1 and
MSLT performed according to standard techniques. A 2 (orexin A and B), derived from the same precursor, prepro-
SOREMP (within 15 minutes of sleep onset) on the pre- hypocretin [43,44]. The cells project throughout the neuraxis, and
ceding nocturnal polysomnogram may replace one of the hypocretin receptors (receptor 1 and 2) are found accordingly
SOREMPs on the MSLT.2 throughout the neuraxis [44]. These wide projections fit with the
hypothesis that the hypocretin system has a “state control” function.
2. CSF hypocretin-1 concentration, measured by immuno-
reactivity, is either ≤110 pg/mL or <1/3 of mean values Risk factors and cause
obtained in normal subjects with the same standardized Genetic and environmental factors
assay.
Narcolepsy with cataplexy is currently viewed as a disorder arising
Notes from the interaction of a genetic predisposition and environmental
1. In young children, narcolepsy may sometimes present as excessively factors, causing an autoimmune response that leads to a selective
long night sleep or as resumption of previously discontinued daytime
destruction of hypothalamic hypocretin-producing cells. Although
napping.
2. If narcolepsy type I is strongly suspected clinically but the MSLT criteria
the cell loss has been proven, the autoimmune mechanisms pro-
of B1 are not met, a possible strategy is to repeat the MSLT. posed are still waiting for proof [46,47].
HLA DQB1*06:02 is by far the most important genetic risk factor
Narcolepsy type 2 for hypocretin-deficient narcolepsy with cataplexy, among others that
Criteria A–E must be met were identified in recent genomewide association studies [38,48,49].
All identified polymorphisms have a link to the immune system.
A. The patient has daily periods of irrepressible need to sleep or Many environmental triggers have been considered—most consist-
daytime lapses into sleep occurring for at least three months. ently, infections and head trauma. Based on the apparent increase in
B. A mean sleep latency of ≤8 minutes and two or more sleep incidence of narcolepsy in 2009 and 2010 during the H1N1 pandemic
onset REM periods (SOREMPs) are found on an MSLT and the vaccination campaign, the most convincing environmen-
performed according to standard techniques. A SOREMP tal factor is vaccination for or infection with influenza (particularly
(within 15 minutes of sleep onset) on the preceding noc- H1N1) [50–52]. Streptococcus pyogenes is another candidate, since
turnal polysomnogram may replace one of the SOREMPs on patients show increased antigen titers close to disease onset [53].
the MSLT. Involvement of the immune system
C. Cataplexy is absent.1 The identified genetic and environmental risk factors point to
D. Either CSF hypocretin-1 concentration has not been meas- an autoimmune cause for the loss of hypocretin cells. A T-cell-
ured or CSF hypocretin-1 concentration measured by immu- mediated destruction of hypocretin cells is likely. A mimicry
noreactivity is either >110 pg/mL or >1/3 of mean values between the identified hypocretin epitopes and HA epitopes of
obtained in normal subjects with the same standardized H1N1 influenza virus has been proposed as an explanation for the
assay.2 increased numbers of diagnosed new-onset narcolepsy cases in
2009 and 2010, but has not been proven up to now [51,52].
E. The hypersomnolence and/or MSLT findings are not bet- A role of B-cells and auto-antibodies in the proposed autoim-
ter explained by other causes such as insufficient sleep, ob- mune mechanism is unclear. Anti-tribbles homolog 2 autoantibod-
structive sleep apnea, delayed sleep phase disorder, or the ies and IgG abnormalities were reported in narcolepsy; however,
effect of medication or substances or their withdrawal. these antibodies may also be secondary to hypocretin cell loss [54].
Notes
1. If cataplexy develops later, then the disorder should be reclassified as Treatment
narcolepsy type 1.
2. If the CSF hypocretin-1 concentration is tested at a later stage and found Unfortunately, we currently have only symptomatic treatment for
to be either ≤110 pg/mL or <1/3 of mean values obtained in normal narcolepsy. However, although symptomatic, it may lead to pro-
subjects with the same assay, then the disorder should be reclassified as found improvement. There are two known effective treatment
narcolepsy type 1. modalities: behavioral modification and pharmacological therapy.
Source data from American Academy of Sleep Medicine, International As a rule, both are needed to achieve sufficient improvement.
classification of sleep disorders, 3rd ed., Copyright (2014) American Before starting treatment, it is of paramount important that
Academy of Sleep Medicine. patients and their relatives be informed about the consequences of

this chronic disease and learn to accept the diagnosis. This greatly as assessed in groups is therefore of relative importance for
facilitates the implementation of the behavioral modifications and individuals.
decreases the burden of the disease. A supportive social environ- ◆ Pharmacokinetic aspects, i.e, short-and fast-acting versus slow-
ment (eg, family members, friends, employer, colleagues, patient and long-acting drugs, may be more important than the expected
group organizations, and support groups) is also valuable. efficacy.
Behavioral modification Treatment of EDS
Patients should be advised to live a regular life, go to bed at the Stimulants are the mainstay of treatment of EDS [57,58].These
same hour each night, and get up at the same time each morning, include dextroamphetamine (5–60 mg/day, usually in one or two
as much as possible. Scheduled daytime naps, usually less than doses per day), methylphenidate (10–60 mg/day, usually in two
20 minutes, may temporarily alleviate and prevent daytime sleepi- to four doses per day), and mazindol (1–6 mg/day, usually in one
ness, and a short nap just before certain activities demanding a high or two doses per day, but not available in the USA). Side effects
degree of attention may facilitate the proper completion. The opti- and tolerance are drawbacks to the use of stimulants. The most
mal frequency, duration, and timing of these naps has to be estab- important side effects include irritability, agitation, headache, and
lished on an individual basis [55]. peripheral sympathetic stimulation. These are usually dose-related.
Because narcoleptic patients are probably more sensitive to the Although addiction does not seem to be a problem in narcolepsy,
sleep-inducing properties of carbohydrates, they should not eat some patients tend to increase their dosage because they prefer high
large carbohydrate-rich meals [56]. For similar reasons, alcohol alertness [59]. Tolerance develops in about one-third of patients
consumption should preferably be avoided. [59,60]. Mazindol has been withdrawn in most countries owing to
observed uncommon, but severe, side effects in related drugs that
Pharmacological treatment suppress appetite, in particular fenfluramines. The side effects were
Despite these behavioral measures, the majority of patients will pulmonary hypertension and valvular regurgitation [61]. However,
have residual complaints, requiring adjuvant pharmacological as some patients respond better to mazindol than to any other drug,
treatment. it may be considered, provided that treatment is closely monitored.
A variety of substances may be used in the treatment of narco- Modafinil (100–400 mg/day, usually in one or two doses) is usu-
lepsy. This observation indicates that there is not one drug that ally grouped with the stimulants, but is chemically unrelated to
is efficacious in all. As most drugs predominantly address either amphetamine. Its efficacy is probably equal to that of the stimulants,
EDS or cataplexy, combinations are often needed to control both although direct comparisons are lacking [62]. The clinical impres-
symptoms. The only available drug that may improve all major sion is that all the described side effects of stimulants, including tol-
symptoms of narcolepsy is sodium oxybate (SXB). Combinations erance, may occur during treatment with modafinil, but, in general,
of SXB with, for example, stimulants may have a synergistic effect less frequent and less severe. More specific side effects of modafinil
for the amelioration of EDS, and may therefore be preferred over are headache and nausea; however, they usually disappear after 2–3
monotherapy. weeks of treatment. Armodafinil is the R enantiomer of modafinil
The following should be kept in mind when choosing a drug and has very similar effects but also has sustained duration. It is not
or drug combination for an individual patient and evaluating its available in most European countries.
efficacy: Long-acting agents (modafinil, armodafinil, dexamphetamine,
and methylphenidate controlled release) are generally better toler-
◆ Sleepiness will never be completely alleviated in any patient,
ated than the short-acting ones. The quick-and short-acting ones,
whereas cataplexy may completely disappear in some. Long-term
such as methylphenidate, can be used to good effect when “tar-
improvement of nocturnal sleep can only be achieved with SXB.
geted” at social events or difficult periods during the day. For this
Patients must be made aware of this, and this knowledge must
reason, combinations of stimulants may be tailored to the circum-
guide physicians in trying new drugs or combinations of drugs and
stances. Unfortunately, there are no studies assessing the advan-
in deciding on the right balance between efficacy and side effects.
tages or disadvantages of combinations of stimulants.
◆ History taking from both patients and partners/relatives is the Sodium oxybate, the sodium salt of γ-hydroxybutyrate, has been
best way to guide therapy. shown to be effective in reducing EDS. The usual starting dose is
◆ Improvement of daytime performance is a much more impor- 2.25 g twice a night. The dose must be gradually increased, keeping
tant treatment goal than a reduction in the total amount of in mind that the optimal daytime effects are reached after weeks.
daytime sleep. A relevant improvement of EDS is in most patients achieved with
higher dosages (6–9 g/night). The effect on EDS of higher doses is
◆ Improvement of cataplexy is not simply defined by a reduction in similar to that of modafinil, and side effects are, if present, usually
the number of attacks. Its severity also depends on several other mild [63]. The combination of both therapies is even more effec-
features: the duration, the number of muscles involved, and, very tive. The most frequent side effect is nausea, and the most disabling
important, the threshold. The threshold may determine whether are enuresis and sleepwalking. Lowering the dose may solve these
patients try to avoid situations in which attacks may occur. If problems. Weight loss may occur [64].
patients feel that it is safe for them be involved in any upcoming In follow-up studies, there is no indication that tolerance develops,
daily activity, despite continuing attacks, this may indicate a huge and abrupt cessation does not induce rebound cataplexy. However,
improvement. long-term clinical experience shows that a substantial proportion
◆ Individual differences in efficacy, side-effects and tolerabil- of patients may develop tolerance for the sleep-promoting effects,
ity appear to be large. Knowledge about the efficacy of a drug although efficacy for the other symptoms remains.

SXB should not be used in conjunction with other sedatives or Treatment of disturbed nocturnal sleep
alcohol. If patients have consumed alcohol in the evening, they Disturbed nocturnal sleep can be a major complaint of patients.
should omit one or both doses afterwards. In patients with comor- Unfortunately, treatment options are limited, since SXB is the only
bid OSA, treatment should be closely monitored, since SXB may drug with a proven long-term effect on nocturnal sleep [70]. Short-
worsen OSA. Co-treatment with continuous positive airway pres- term beneficial effects of benzodiazepines have been described
sure (CPAP) may be indicated [30]. [71]. Although nocturnal sleep may (temporarily) be improved
Unfortunately, there is concern for misuse. Although potential with benzodiazepines, improvement of EDS is not the rule.
threats related to misuse may result in hesitation among patients
to take, and physicians to prescribe, it is important to realize that Treatment in children
when the drug is properly used, it is safe and bears no risk of Treatment of children suffering from narcolepsy does not differ sig-
dependence [65]. nificantly from treatment in adulthood, although hardly any treat-
Caffeine may alleviate sleepiness, but has a weak effect: the alert- ment studies have focused on children. Behavioral problems only
ing effect of six cups of strong coffee is comparable to that of 5 mg occur at a young age, and there are indications that treatment of
of dexamphetamine [59,60]. EDS may have a positive impact on behavior as well, but studies
focusing in this important symptom are urgently needed.
Treatment of REM sleep dissociation phenomena
Most studies concerning the treatment of REM dissociation phe- Treatment of associated symptoms and comorbidities
nomena have focused on cataplexy. Amelioration of cataplexy Obesity is an associated symptom, for which there is no treatment
is generally associated with improvement of HH and sleep par- other than the usual advice for any obese person. However, some
alysis. SXB and tricyclic antidepressants are the most effective patients are happy to lose weight during treatment with SXB [64].
treatments. The different tricyclic antidepressants all inhibit the Fatigue or lack of energy may occasionally improve during treat-
reuptake of norepinephrine and serotonin and are potent REM ment with stimulants or SXB. There is no other therapy with a
sleep inhibitors. The most commonly used are imipramine (10– proven effect for this complaint.
100 mg/day) and clomipramine (10–150 mg/day) [2,57,58]. As Treatment of sleep apnea usually does not improve the EDS, and
with stimulants, side effects are a drawback. These are largely due compliance with CPAP and other treatments is a problem. Whether
to the anticholinergic properties; the most frequently reported are there is an indication for treatment is controversial [28,29].
dry mouth, increased sweating, sexual dysfunction (impotence, Treatment with SXB may facilitate the acceptance of CPAP treat-
delayed orgasm, and erectile and ejaculatory dysfunction), weight ment. However, since SXB may worsen the course of sleep apnea, it
gain, tachycardia, constipation, blurred vision, and urinary reten- is important in these cases that patients be compliant [30].
tion. However, very low doses, up to 20 mg, may often be remark- Treatment of periodic limb movements must be considered if
ably effective and are seldom accompanied by significant side there is coexistent RLS, otherwise only in very severe cases.
effects. Therefore, many consider clomipramine to be the treat- Treatment for RBD is rarely indicated, and in those cases clonaz-
ment of choice [66]. The most relevant drawback even with low epam and melatonin may be effective.
dosages is the possible occurrence of tolerance. Tricyclic antide- Anxiety and depression should be treated separately if they are
pressants should never be stopped abruptly, because of the risk of severe. Psychotherapy as well as pharmacological treatment may be
severe aggravation of cataplexy, which may even lead to a status considered.
cataplecticus. Recommendations for the initiation of pharmacological
Many alternative antidepressants have been studied, espe- treatment
cially selective serotonin reuptake inhibitors (SSRIs) and more The scheduled daytime naps should be continued. One should al-
selective noradrenergic reuptake inhibitors such as fluoxetine, ways start with a single medication at a time. It is usually best to
zimelidine, viloxazine, femoxitine, fluvoxamine, and paroxetine treat the most incapacitating symptom(s) first. If this is clearly the
in a relatively higher dosage than the tricyclics [2,58,67]. They EDS, then one should start with a stimulant; if it is clearly cataplexy
are usually not as effective in low doses as clomipramine is. or HH, then one should start with a low dose of clomipramine. If
The side effect of these higher dosages seems not to be favor- both disturbed nocturnal sleep and cataplexy are severe, then SXB
able when compared with the side effects with low dosages of may be considered as first choice. One should always start with a
clomipramine. These substances seem to act mainly via less se- low dose, and increase the dose based on history taking, keeping in
lective desmethyl metabolites [68]. In recent years, venlafaxine mind the trade-off between efficacy and side effects.
and atomoxetine have become very popular in the treatment of
cataplexy, although there are no randomized placebo controlled
studies available. Future pharmacological treatments
SXB is the best studied drug and is a very potent inhibitor of Several histamine-3 receptor (H3) antagonists are currently being
cataplexy [69]. It has never been compared with any antidepres- studied for the treatment of EDS. Pitolisant, a selective H3 antag-
sant, so it is difficult to know whether it is really more effective than onist, has recently been submitted to the EMA to become available
the antidepressants. However, its relatively mild side effect profile in Europe. Published studies showed encouraging results particu-
makes it a more favorable drug, even independent of the beneficial larly regarding improvement of EDS, but also, to a lesser extent,
effect of SXB on other symptoms. regarding improvement of cataplexy [72].
Several drugs may theoretically be expected to aggravate cata- Immune-based therapies are controversial, and if used should be
plexy, but the only one for which this is reliably documented is pra- given close to disease onset. Although an autoimmune cause is very
zosin, an α1 antagonist used to treat hypertension. probable, there is no convincing evidence that immune modulating

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CHAPTER 15
Idiopathic hypersomnia,
Kleine–â•‰Levin syndrome, and
symptomatic hypersomnias
Michel Billiard and Yves Dauvilliers
Besides the most prevalent obstructive sleep apnea syndrome second edition (ICSD-â•‰2) reverted to a division into two forms,
(OSAS) and the emblematic narcolepsy, which have been the topics namely, idiopathic hypersomnia with and without long sleep time
of multiple articles and books, there are a number of other causes [5]. Finally, in March 2014, the third edition (ICSD-â•‰3) was released
of excessive daytime sleepiness (EDS). They include idiopathic [6], and, in the absence of specific symptoms in idiopathic hyper-
hypersomnia, Kleine–â•‰Levin syndrome (KLS), and several symp- somnia with and without long sleep time, the division into two
tomatic hypersomnias. These conditions are less familiar to sleep forms was again abandoned, awaiting the discovery of consistent
specialists and are often neglected by internists and psychiatrists. biological markers.
Moreover, their less rich symptomatology may be the cause of
delayed diagnosis, and their treatment is not as well standardized Epidemiology
as in the case of sleep-â•‰related breathing disorders and narcolepsy. Owing to uncertainty regarding the nosological limits of idio-
Yet, these sleep disorders may seriously impact the quality of life of pathic hypersomnia, no prevalence study has ever been conducted.
patients. In this chapter, we will focus on idiopathic hypersomnia Instead, ratios of idiopathic hypersomnia to narcolepsy in cohorts
and KLS, reviewing clinical features, polysomnography (PSG) and of patients published by different sleep disorder centers are avail-
other objective findings, differential diagnosis, pathophysiology, able (Table 15.1). These ratios span from 9.2% to 47.2%, obviously
and treatment, and then mention the key points of symptomatic reflecting the lack of common diagnostic criteria. The onset of the
hypersomnias condition is most often during adolescence or young adulthood.
According to some cohorts, there is a higher prevalence of idio-
Idiopathic hypersomnia pathic hypersomnia in women [11,22,23].
Apart from these evaluations, a recent study has developed the
Historical background concept of “excessive quantity of sleep” (EQS), defined as a main
Idiopathic hypersomnia was progressively identified, beginning sleep period or 24-â•‰hour sleep duration ≥ 9 hours accompanied
with the description of sleep drunkenness by Roth in 1956 [1]â•„and by complaints of impaired functioning or distress due to exces-
ending with the publication by the same Roth in 1976 of a series sive sleep [24]. This study used the Sleep-â•‰EVAL expert system to
of 642 personally observed cases, including 368 patients with nar- ask questions on life and sleeping habits, health, and sleep, mental,
colepsy and 274 with hypersomnia, of which 103 had “idiopathic and organic disorders, according to the Diagnostic and Statistical
hypersomnia, polysymptomatic form,” 71 “idiopathic hypersom- Manual of Mental Disorders, fourth edition, (DSM-â•‰IV-â•‰TR) [25],
nia, monosymptomatic form,” 12 hypersomnia with disorders of in a nonselected population sample of 15 929 individuals. EQS was
breathing during sleep, and 5 neurotic hypersomnia [2]. Idiopathic observed in 1.6% of the sample, and the prevalence of DSM-â•‰IV
hypersomnia polysymptomatic form was characterized by exces- hypersomnia disorder was 0.5%. These results are of major interest,
sive diurnal sleep, prolonged night sleep of a duration of 12–â•‰18 even if DSM-â•‰IV hypersomnia based on subjective reports cannot
hours, and great difficulty awakening in the morning, while idi- be equated with idiopathic hypersomnia based on clinical, poly-
opathic hypersomnia monosymptomatic form was characterized somnographic, and MSLT criteria.
by the most prominent symptom of diurnal sleep of a duration of
one to several hours, not as irresistible as in narcolepsy. In 1979, the Predisposing factors
Diagnostic Classification of Sleep and Arousal Disorders referred A familial background has been found in up to 40% of idiopathic
to idiopathic hypersomnia as one of the disorders of excessive hypersomnia patients in an earlier study [26], but more rigorous
somnolence [3], and in 1990, the first edition of the International studies with direct clinical interview and sleep studies in relatives
Classification of Sleep Disorders (ICSD) referred to idiopathic are warranted. Precipitating factors like head trauma, viral illness,
hypersomnia as one of the intrinsic sleep disorders [4]. Neither and general anesthesia have been reported, but are less convincing
classification retained the division into two forms. In 2005, the than in narcolepsy.

Table 15.1 Series of patients with narcolepsy and idiopathic An MSLT performed according to standard techniques shows
hypersomnia published by various sleep disorder centers, and ratios fewer than two sleep onset REM periods (SOREMPs), or no
of idiopathic hypersomnia to narcolepsy SOREMP if the REM latency on the preceding PSG is 15 minutes
or less [6]‌.
Authors Narcolepsy Idiopathic Idiopathic Finally, one of the following should be present: a mean sleep la-
hypersomnia hypersomnia/ tency of 8 minutes or less on the MSLT, or a total 24-hour sleep
narcolepsy (%) time of 660 minutes or more documented on a 24-hour PSG or on
Roth [2]‌ 104 64 47.2 a 7-day wrist actigraphy performed in a period of unrestricted sleep
(eg, holidays) in association with a sleep diary [6]‌.
Van den Hoed et al. [7]‌ 41 17 41.4
In addition, psychiatric evaluation should be performed in sub-
Baker et al. [8]‌ 257 74 28.7 jects suspected of having a psychiatric disorder, mainly bipolar dis-
Aldrich [9]‌ 67 26 38.8 order II, major depression disorder, or schizoaffective disorder, and
neuroimaging in case of neurological signs.
Bruck and Parkes [10] 50 18 36.0
Bassetti and Aldrich [11] 258 42 16.2 Course
Billiard et al. [12] 380 35 9.2 Once established, fluctuations in disease severity may be observed
as documented by changes in MSLT results at several-year inter-
Kanbayashi et al. [13] 67 26 38.8
vals [29]. Moreover, cases of spontaneous disappearance have
Vignatelli et al. [14] 108 42 37.6 been reported [10,11,30]. At first sight, the complications of
Heier et al. [15] 54 10 18.5 idiopathic hypersomnia appear similar to those of narcolepsy,
including poor performance at school or at work, sleeping during
Martinez-Rodriguez 42 8 19.0
et al. [16] recreational activities, and car and work accidents. However, in the
case of patients complaining of long sleep time and difficulty on
Kanbayashi et al. [17] 67 26 38.7 awakening, complications have some peculiarities. These patients
Coelho et al. [18] 54 14 25.9 report arriving late at work, receiving negative comments from
Tanaka and Honda [19] 159 28 17.6 their employer, and often being dismissed as a consequence.
Second, the lengthy time these patients spend in bed is hardly tol-
Pizza et al. [20] 51 16 31.3 erated by family members over the long term. Third, in contrast
Dauvilliers et al. [21] 83 11 13.2 to narcoleptic patients, idiopathic hypersomnia patients rarely
benefit from extended night sleep, to the extent that they never
feel refreshed. Finally, EDS is most often amenable to stimulant
medications, whereas difficulty in awakening is often resistant to
Clinical features treatment [31].
EDS is the key symptom of idiopathic hypersomnia. It is gener-
ally considered as more continuous and less irresistible than in Pathophysiology
narcolepsy type 1. Naps tend to be long and nonrefreshing in Several non-mutually exclusive hypotheses have been proposed,
half to three-quarters of patients [6]‌. Night sleep is abnormally but understanding is still limited.
long in at least a third of patients [6]. Waking up in the morn-
ing or at the end of naps may be difficult or even present itself as Neurochemistry
sleep drunkenness, consisting of difficulty in coming to complete More than 40 years ago, Petitjean and Jouvet reported hypersomnia
wakefulness, accompanied by confusion, disorientation, poor with proportional increase of NREM and REM sleep suggestive of
motor coordination, slowness, and repeated returns to sleep [27]. idiopathic hypersomnia, after destruction of noradrenergic neu-
Headache, orthostatic hypotension, and Raynaud-like symptoms rons of the rostral third of the locus coeruleus complex or of the
are sometimes present. In addition, subjective symptoms such as noradrenergic bundle at the level of the isthmus, in the cat [32].
being more alert in the evening than in the morning, difficulty Subsequently, in the 1980es, a series of studies measuring mono-
in focusing more than one hour, complaints of attention and amine metabolites in the cerebrospinal fluid (CSF) of idiopathic
memory deficit, mental fatigability, and hyperactivity helping hypersomnia patients were performed. However, biological meth-
to resist sleepiness have also been reported [28]. Altogether, the ods for measuring monoamine metabolites have been criticized,
phenotype of idiopathic hypersomnia is not unitary—hence the and none of these studies has ever been replicated.
successive suggestions of nosological separation of the condition More recently, it has been shown that CSF hypocretin-1 con-
into two or three forms. centrations are normal in patients with idiopathic hypersomnia
[13,33,34]. Reduced CSF histamine levels have been observed in
Diagnostic tests hypocretin-deficient narcolepsy with cataplexy, in hypocretin
PSG followed by a multiple sleep latency test (MSLT) is manda- nondeficient narcolepsy and in idiopathic hypersomnia, but not
tory [6]‌. PSG generally demonstrates a normal architecture of sleep. in OSA syndrome [17]. These findings led to the suggestion that
Obstructive sleep apneas (OSA) should theoretically be fewer than CSF histamine is a biomarker reflecting the degree of hypersomnia
5 per hour and respiratory-effort-related arousals (RERAs) fewer of central origin. However, using a new validated method of CSF
than 10. Moreover, periodic limb movements should be fewer than histamine and tele-methylhistamine (t-MHA) measurement [35],
10 per hour. Dauvilliers et al. did not find any CSF histamine or t-MHA level

Chapter 15 idiopathic hypersomnia, kleine-levin syndrome and symptomatic hypersomnias 133
differences between the various etiologies of central disorders of compared with increases in IgG3 and IgG4, a decrease in IgG2,
hypersomnolence (narcolepsy type 1 and 2, idiopathic hypersom- and an IgG1/IgG2 imbalance in idiopathic hypersomnia patients,
nia, and unspecified excessive daytime sleepiness) and neurological thus favoring immunological differences between narcolepsy and
controls [21]. idiopathic hypersomnia. However, no other clinical or biological
Another perspective comes from a recent experiment which study has supported an immunopathological process in idiopathic
showed that CSF from hypersomnolent subjects (excluding known hypersomnia.
causes of excessive sleepiness) contains a small (500–3000 Da),
Homeostatic and circadian regulation
not yet identified, trypsin-sensitive substance that stimulates the
in vitro function of selected γ-aminobutyric acid (GABA) recep- In a study comparing the level of slow-wave activity (SWA) in
tors, only in the presence of GABA, relative to the stimulation the first two NREM–REM sleep cycles, this level was significantly
obtained with CSF from control subjects [36]. Notably, flumaze- lower in idiopathic hypersomnia patients than in controls [39].
nil, a drug that is generally believed to antagonize the sedative– Thus, patients with idiopathic hypersomnia may need prolonged
hypnotic action of benzodiazepines, reversed enhancement of sleep time because of a lower intensity of their NREM sleep. Two
GABAA signaling by hypersomnolent CSF in vitro. However, other studies compared the sleep spindle index in idiopathic hyper-
this recent discovery requires replication, since CSF alone from somnia and controls [40] and in idiopathic hypersomnia and
hypersomnolent patients had no effect on GABAA signaling. narcolepsy [41]. They documented an increased spindle index pre-
Furthermore, no differences were observed between different dominating by the end of night sleep in idiopathic hypersomnia,
diagnostic categories, and no correlation was found between which might explain the symptoms of difficulty waking up or of
GABA potentiation and objective measures of sleepiness. In con- “sleep drunkenness.”
trast, a recent study using the Xenopus oocyte assay found an ab- In addition, a disturbed circadian rhythm has been hypoth-
sence of GABA-A receptor potentiation with CSF from patients esized on the basis of a phase delay in the rhythm of melatonin
with central hypersomnolence disorders, with no significant and cortisol secretion in 15 patients with idiopathic hypersom-
differences between hypocretin-and non-hypocretin-deficient nia with long sleep time [42]. In a more recent study, Horne
patients compared to controls. The major discrepancies between and Östberg scores were lower in idiopathic hypersomnia sub-
these results may have arisen from differences in the phenotyping jects than in controls, consistent with a delayed sleep phase in
of patients affected with hypersomnolence, sample size, control idiopathic hypersomnia [43]. Moreover, investigations of the
group selection, lumbar puncture procedure, or treatment intake, dynamics of the expression of circadian clock genes in dermal
as well as methodological issues in the GABA-A response assess- fibroblasts of idiopathic hypersomnia patients in comparison
ment [37]. with those of healthy controls have shown that the amplitude
of rhythmically expressed BMAL1, PER1, and PER2 was sig-
Genetics nificantly dampened in dermal fibroblasts of idiopathic hyper-
Before the eventual identification of idiopathic hypersomnia in somnia patients compared with healthy controls, suggesting an
1976, a series of 23 probands with “essential hypersomnia,” with aberrant dynamics in the circadian clock of idiopathic hyper-
data from 190 family members of these probands, was published somnia patients [44].
by Czech authors [27]. A familial occurrence was found in nine
families (39.1%), and an autosomal dominant mode of inheritance Differential diagnosis
was suggested. In 2001, in a series of 35 idiopathic hypersomnia Differentiating idiopathic hypersomnia from other conditions is
patients, 25 with the polysymptomatic form and 10 with the mon- not always an easy task. This is reflected in the establishment in sev-
osymptomatic form, a familial history was found in 10 patients eral countries of reference centers with specialized clinicians and
with the polysymptomatic form (40%), including 3 with several access to long-term PSG or actigraphic monitoring.
relatives, and in 3 subjects with the monosymptomatic form (30%),
including 1 with several relatives [12]. Recently, a report of three OSAS
adolescent-onset cases of idiopathic hypersomnia assessed clinic- Idiopathic hypersomnia may be confused with OSAS, especially
ally and by use of ad libitum PSG was published, arguing for a gen- when RERAs rather than apneas/hypopneas are predominant. In
etic origin in this family [38]. The pedigree was compatible with an case of any doubt, a continuous positive airway pressure (CPAP)
autosomal dominant inheritance. Incidentally, no report of twins trial should be proposed.
affected with idiopathic hypersomnia has ever been published.
Narcolepsy type 2
Given these observations, there has been an early interest in po-
This is not easy to distinguish from idiopathic hypersomnia. First,
tential HLA markers in idiopathic hypersomnia, but no consistent
the ICSD-3 clinical criteria, A and C of narcolepsy type 2 and
findings have emerged so far.
A and B of idiopathic hypersomnia, are similar [6]‌. Second, nar-
Immunology colepsy type 2 is supposed to differ from idiopathic hypersomnia
Tanaka and Honda assessed immunoglobulin G (IgG) profiles by the presence of two or more SOREMPs on the MSLT, but the
in Japanese narcolepsy–cataplexy patients positive for the HLA- distinction between two SOREMPs or more for narcolepsy type 2
DQB1*0602 allele, idiopathic hypersomnia patients with long sleep and fewer than two SOREMPs for idiopathic hypersomnia sounds
time, and healthy controls [19]. The distribution of serum IgG was both arbitrary and subtle, since the number of SOREMPs may
significantly different among healthy controls, narcolepsy patients, vary from one MSLT to another in the same individual, depending
and idiopathic hypersomnia patients [19]. Decreases in IgG1 and on the disease process and age [29]. Third, a total sleep time of
IgG2 levels, a stable expression of IgG3, and an increase in the 660 minutes or more is not a compulsory PSG criterion for idio-
proportion of IgG4 were found in narcolepsy–cataplexy patients, pathic hypersomnia but a criterion in balance with a mean sleep

latency of 8 minutes or less. Thus, the distinction between the two As for consecutive clinical cohorts, the first one tested
conditions still awaits further clarification. the benefits and risks (habituation and adverse effects) of
modafinil in 104 patients with idiopathic hypersomnia and
Delayed sleep phase syndrome 126 patients with narcolepsy with cataplexy [48]. Modafinil
This is another diagnosis to consider, given the major difficulty had an excellent benefit/r isk ratio in idiopathic hypersomnia,
waking up in the morning. However, these subjects do not com- similar to its effects on narcolepsy–c ataplexy, as estimated by
plain of EDS in the afternoon and evening, and their total sleep patients and clinicians. Loss of efficacy and habituation were
time is usually normal. rare in both groups. However, idiopathic hypersomnia patients
Chronic fatigue syndrome reported more frequent adverse effects with modafinil than
This is characterized by persistent or relapsing fatigue that does narcolepsy patients. The second study compared quality of
not resolve with sleep or rest. The disabling fatigue is accompa- life, Epworth Sleepiness Scale (ESS) scores, and items con-
nied by joint and muscle pain, headache, poor concentration, cerning psychosocial and environmental variables in patients
impaired short-term memory, disturbed sleep, recurrent sub- with narcolepsy with cataplexy (83 on psychostimulants and 28
jective feverish feelings, and sore throat [45]. PSG shows reduced drug-naive), patients with narcolepsy without cataplexy (48 on
sleep efficiency and may include alpha intrusion into sleep psychostimulants and 27 drug-naive), patients with idiopathic
EEG [46]. hypersomnia without long sleep time (54 on psychostimulants
and 82 drug-n aive), with Japanese normative data [49]. All
Long sleeper three diagnostic groups had significantly lower scores for most
A long sleeper is an individual who consistently sleeps more in 24 Short Form 36 (SF-3 6) domains compared with the Japanese
hours than the typical person of his or her age group. The main normative data, and the ESS scores were significantly reduced
difference with idiopathic hypersomnia is the absence of any com- with treatment.
plaint of EDS or difficulty in awakening as long as sufficient sleep Recently, two randomized, double-blind, placebo-controlled
is obtained to fulfill the sleep need [6]‌. A consistent daily pattern, trials have been published. The first, a multicenter study, was per-
documented by a carefully kept sleep diary (preferably confirmed formed in 31 adult patients with idiopathic hypersomnia without
by actigraphy) showing 9 hours or more of sleep per night over a long sleep time, 14 of whom were on modafinil and 17 on pla-
minimum of 7 days is desirable for the identification of the long cebo [50]. Modafinil 200 mg given in the morning improved ESS
sleeper. and clinical global impression (CGI) compared with placebo and
led to a nonsignificant increase in the mean sleep latency on the
Other differential diagnoses maintenance of wakefulness test (MWT). The second, a crossover
These, which include hypersomnia due to a medical disorder, study, was conducted in 13 narcolepsy patients and 14 idiopathic
hypersomnia due to a medication or a substance, hypersomnia hypersomnia patients receiving modafinil (400 mg) or placebo
associated with a psychiatric disorder, and insufficient sleep dis- [51]. Modafinil improved driving performance judged on the mean
order, will be considered later in this chapter. number of inappropriate line crossings and standard deviation of
lateral position of the vehicle compared with placebo, as well as the
Treatment mean sleep latency on the MWT, equally in patients with narco-
Behavioral treatment lepsy and idiopathic hypersomnia.
Behavioral treatment of idiopathic hypersomnia is not as successful Another treatment, mazindol, a tricyclic non-amphetamine
as for narcolepsy. Naps are nonrefreshing, and extension of sleep stimulant, was evaluated in a retrospective analysis of the files of 37
time for several days to saturate the patients’ sleep need does not idiopathic hypersomnia patients refractory to modafinil, methyl-
bring relief on the long term. phenidate, and sodium oxybate, in three different hospitals [52].
Patients received an average dose of 3.6 mg/day. The benefit on
Conventional pharmacological options sleepiness, measured as the difference between the final ESS score
Up to now, although EDS may not have the same character in nar- and the one before starting treatment, was 4.8 ± 4.7 (p < 0.0001).
colepsy and in idiopathic hypersomnia, the same pharmacological Treatment was stopped in 5 patients (13.5%) owing to loss of effi-
options, namely, stimulants, including amphetamines and methyl- cacy, in 4 patients (11%) owing to adverse effects, and in 10 patients
phenidate, and eugregorics (from the Greek ευ meaning “good” and owing to other reasons (difficulties in obtaining the drug, preg-
γρηγοροσ meaning “which is watchful”), including modafinil and nancy, unknown). Selective serotonin reuptake inhibitors and tri-
armodafinil, have been used in both conditions. cyclic antidepressants may have a positive effect.
The first trial with modafinil in idiopathic hypersomnia was per- Of note, in view of a possible alteration of circadian regulation,
formed in an open-label study in 1988 [47]. Eighteen patients par- an improvement in half of 10 idiopathic hypersomnia patients
ticipated in the study. Modafinil was administered in the morning treated with melatonin (2 mg of the slow-release form at bedtime)
and at noon. The number of drowsiness and sleep episodes dur- has been reported [53].
ing daytime was significantly reduced in 15 patients. It then took Finally, a recent chart review of 46 patients with idiopathic
20 more years to have large observational studies and consecu- hypersomnia and 47 patients with narcolepsy type 1 treated with
tive clinical cohorts available. Among the first are two studies, one sodium oxybate, with smaller doses in idiopathic hypersomnia
by Anderson et al. [30] and one by Ali et al. [23], which showed patients than in narcolepsy type 1 patients, showed similar changes
that only 50–75% of patients remained on the prescribed drug, in excessive daytime sleepiness in idiopathic hypersomnia and nar-
modafinil or methylphenidate, and only 60–70% of those remain- colepsy type 1, and an improvement of severe morning inertia in 24
ing on the drug were good responders. of 34 patients with idiopathic hypersomnia [54].

Newer therapies his own, which he described in depth [66]. He gave the definition of
Levothyroxine, 25 μg/day, has been orally administered to nine “a syndrome composed of recurring episodes of undue sleepiness
patients with idiopathic hypersomnia with long sleep time [55]. lasting some days, associated with an inordinate intake of food, and
Mean total sleep time was 12.9 ± 0.3 hours and ESS was 17.8 ± 1.4 often with abnormal behavior.” In addition, he emphasized four
before treatment. After treatment, mean total sleep times were hallmarks: (1) sex incidence whereby males are preponderantly
9.1 ± 0.7 and 8.5 ± 1 hours at 4 and 8 weeks, respectively, and mean if not wholly affected; (2) onset in adolescence; (3) spontaneous
ESS scores were 8.8 ± 2.3 and 7.4 ± 2.8, respectively. No adverse eventual disappearance of the syndrome; (4) the possibility that the
effects were noted. One patient dropped out during the second megaphagia is in the nature of compulsive eating, rather than bu-
week owing to poor effect. limia. Following this publication, several reviews were published,
Flumazenil, an antagonist of the sedative–hypnotic action of with the emphasis being put on clinical features.
benzodiazepines, was first used in idiopathic hypersomnia after the In 2005, the second edition of the ICSD published diagnostic
nearly complete reversal, even if controversial, of the effect of hyper- criteria of recurring hypersomnia and gave a definition of KLS
somnolent CSF on GABAA receptor-mediated chloride currents in modifying Levin’s and Critchley’s views, in that hyperphagia was
vitro by co-application of 10 μmol/L GABA [36,37]. Subsequently, no longer necessary for the diagnosis, but only one of the possible
flumazenil improved psychomotor vigilance and subjective alert- symptoms of the syndrome [5]‌.
ness in seven hypersomnolent patients, two with a diagnosis of Following this publication, several large reviews appeared, allow-
idiopathic hypersomnia, two with a diagnosis of narcolepsy type ing quantitative evaluations of predisposing factors, circumstances
2, and three habitually long sleepers [36]. However, flumazenil has at onset, symptoms, physical signs, and comparisons of symptoms
a number of potential adverse effects, including dizziness, nausea, in men and women [67–69]. One of these reviews was a most valu-
headache, anxiety, confusion, and hyperphagia. able cross-sectional, systematic evaluation of 108 new cases and
To get round of these limitations, clarithromycin, a mac- comparison with matched control subjects [68]. Finally, the third
rolide antibiotic acting through an endogenous enhancement of edition of the ICSD changed the word “recurrent hypersomnia” to
GABAA receptors, has been tested in a group of 39 “hypersom- “KLS” [6]‌.
nolent patients” [56]. A subjective improvement was obtained in
34. Of these 34 patients, 23 chose to use clarithromycin on a long- Epidemiology
term basis: 16 used it on a daily basis, 4 on an intermittent basis, KLS is a rare disorder. No systematic prevalence study is available.
while 3 discontinued it after a mean of 5 months. More recently, Only large series of patients originating from single sleep disorder
a 5-week, randomized, placebo-controlled, double-blind, crossover centers (Table 15.2) and comprehensive reviews of the world lit-
trial of clarithromycin conducted in 20 patients with hypersom- erature [67,69] have been published. The number of reported KLS
nolence syndromes (excluding narcolepsy type 1), some of them patients is high in Israel [70] and, in one American series, there
already treated with psychostimulants, and evidence of abnormal were six times more Jewish patients than expected, all Ashkenazi,
CSF potentiation of GABAA receptors, showed a significant im- suggesting a founder effect in this population [68].
provement of subjective measures of sleepiness (ESS and Stanford Age of onset is predominantly adolescence and young adulthood,
Sleepiness Scale), but not on an objective measurement of vigi- with only 10 patients (3.7%) starting their condition before the age
lance (a psychomotor vigilance test being the primary outcome of 10 years and 16 (5.4%) starting their condition after the age of
measure) [57]. 30, in a population of 293 patients [69]. Familial cases are not ex-
Pitolisant, an inverse agonist of H3 histamine receptors, has ceptional, with 5 of 104 patients (4.8%) in one series [68] and 9 of
been effective in patients with narcolepsy type 1 [58]. A recent 297 patients (3%) in another [77]. Among these nine families, three
retrospective analysis of 78 patients with idiopathic hypersomnia included more than two affected relatives [78–80].
evaluated the benefits and risks of pitolisant. The median ESS score
decreased from 17 (range 15.5–18.5) to 14 (range 12–17), and by Predisposing and precipitating factors
more than 3 in 35.4% of patients [59]. Most frequent side-effects,
An increased frequency of the HLA-DQB1*02:01 allele had been
in 16–12% of patients, included epigastralgia and abdominal pain,
reported in a multicenter group of 30 unrelated patients with KLS
increased appetite, weight gain, headache, and insomnia.
[81]. However, in a later American series of 108 patients and 108
matched controls, HLA-DR and -DQ alleles did not differ between
Kleine–Levin syndrome patients and controls [68]. Factors precipitating the first episode
are mentioned in all series, consisting most frequently of an upper
Historical background airway infection or a flu-like illness and less frequently of an emo-
The name KLS was coined in 1942 [60]. However, “a syndrome tional stress, alcohol intake, head trauma, anesthesia, vaccination,
of periodic somnolence and morbid hunger” had been described or exhaustion.
in detail as early as 1936 [61], reports of patients with episodes of
hypersomnia, gluttony, odd behaviors and cognitive symptoms had Clinical features
been published in the 1920s [62–64], and scattered reports of the KLS is characterized by relapsing–remitting episodes of severe
condition were available even earlier, with one dating back to the hypersomnolence in association with cognitive, behavioral, and
eighteenth century [65]. psychiatric disturbances. The episodes begin within a few hours,
In 1962, Critchley published a masterpiece article “Periodic or gradually over a period of one to three days, with patients
hypersomnia and megaphagia in adolescent males,” in which he becoming extremely tired, muzzy and detached. Hypersomnia is
collected 15 “genuine” instances from the literature and 11 cases of the major symptom present in each episode. Patients lie in bed,

Table 15.2 Largest series of patients with Kleine–Levin syndrome The episodes of hypersomnia may end abruptly or insidiously
originating from single sleep disorder centers over a few days. In up to a third of cases, the episode is followed
by amnesia of the past events and elation with insomnia, as if the
Authors Country Number Males Females patient were trying to catch up for lost time, for one or two days.
of cases
Diagnostic tests
Critchley [66] England 11 11 0
The diagnosis of KLS is purely clinical. Routine blood tests, includ-
Takahashi [71] Japan 28 21 7
ing blood count, plasma electrolytes, urea, creatinine, and hepatic
Roth [72] Czechoslovakia 15 ? ? function, are normal. Static and dynamic hormonal tests (growth
Smolik and Roth [73] Czechoslovakia 14 5 9 hormone, prolactin, thyroid-stimulating hormone, testosterone,
and cortisol) are normal. Agents responsible for upper airway infec-
Gadoth et al. [70] Israel 34 28 6
tion, flulike illness, or other infections are rarely identified. CSF
Arnulf et al. [68] USA 108 82 26 white blood cell counts and protein levels are normal in all patients,
Huang et al. [74] Taiwan 30 26 4 ruling out infectious meningitis. Immunoelectrophoresis is also
normal. Routine EEG is remarkable for a general slowing of back-
Li et al. [75] China 42 ? ?
ground activity. Bursts of synchronous, generalized, moderate-to
Kas et al. [76] France 41 23 8 high-voltage, 5–7 Hz waves 0.5–2 sec in duration, mainly in the
bilateral temporal or temporofrontal areas, are frequent and a cause
of misdiagnosis with epilepsy. PSG is not easy to organize from one
day to the next and is difficult to interpret, given the frequent evolu-
sometimes with restlessness and untidiness. Vivid dreams may tion of sleep patterns throughout an attack. Altogether, the duration
occur. Usual sleep duration ranges from 12 to 18 hours, especially of recorded sleep is often shorter or much shorter than the behav-
during the first days. Patients wake up spontaneously to void. They ioral sleep as observed by parents or nurses. Sleep efficiency is poor,
may be irritable or even aggressive when awakened or prevented while SOREMPs are frequent. MSLT is of questionable interest in
from sleeping. view of the frequent limited cooperation of patients. Structural brain
Cognitive symptoms may be severe, such as altered perception imaging (computerized tomography or magnetic resonance imag-
(with people and objects appearing as distorted, distant, or unreal), ing) is normal in primary forms of KLS. Psychological interview and
confusion, delusions, or hallucinations, or less impressive, such as testing should be performed during and after the episode.
abnormal speech, impaired concentration, impaired memory, or
apathy. Course
Behavioral symptoms include compulsive eating, disinhibited KLS is characterized by episodes lasting a median of 9 days (range
sexuality, and odd behaviors. Patients do not necessarily look for 1–180 days) in men and of 8 days (range 1–60 days) in women and a
food, but cannot refrain from eating food within reach, in a com- cycle length (time elapsed from onset of one episode to the onset of
pulsive manner, such as in the case of an 18-year-old ordinary sea- the next episode) lasting a median of 106 days (range 14–1095 days)
man “who ate about a dozen large helpings of suet pudding (in in men and 60 days (range 15–1460 days) in women [69]. KLS van-
addition to his own heavy meal), the pudding having been rejected ishes spontaneously within months or years. However, the duration
by the majority of sailors as being underdone and too stodgy for of the condition is variable, and in some patients may exceptionally
consumption” [66]. A preference for sweets is common. Increased last up to 20–30 years. It is commonly assumed that the episodes of
drinking is sometimes associated. In some cases or in some epi- KLS decrease in frequency, severity, and duration with time before
sodes, compulsive eating may be replaced by anorexia. Sexual disin- fading out. However, this was clearly evidenced in a limited num-
hibition can take the form of overt masturbation, sexual advances, ber of cases only in one series [69].
or shamelessly expressed sexual fantasies. Sexual disinhibition is
apparently less frequent in women than in men, although it could
Clinical variant
assume a less visible expression such as fantasies of being “chat-
ted up” by men or experiencing love affairs. Odd behaviors, also Menstrual-related KLS is a very rare disease characterized by epi-
designated as compulsive behaviors, are very special to KLS. They sodes of hypersomnia, plus or minus other symptoms and physical
include stereotyped behaviors (repetitive and excessive), disinhib- signs of KLS, which occur in association with the menstrual cycle
ited social behavior, childish behavior, aggression, loss of decency, and sometimes with puerperium [69]. The condition occurs for the
bizarre postures, or imaginative actions. first time within the first months after menarche or later.
Psychiatric symptoms include depression during the episodes,
more often in women than in men, and, less frequently, anxiety, Differential diagnosis
equally reported by men and women. The most important differential diagnosis is a psychiatric condi-
KLS is remarkable for the absence of any neurological sign. On tion, such as psychotic disorder, depressive disorder, bipolar disor-
the other hand, autonomic symptoms such as profuse sweating, der, somatic symptom, and related disorder, due to the cognitive,
reddish, congestive, or puffy face, low or high blood pressure, brad- behavioral, and psychiatric symptoms. However, the onset and off-
ycardia or tachycardia, and intense body odor or nauseating urine set of symptoms are less abrupt than in KLS and the episodes of
are found in about 20% of men and women. In addition, weight longer duration.
gain of a few kilograms may be observed during the attacks and is Another frequently evoked diagnosis is epilepsy, given the
much more frequent in women than in men [69]. frequent bursts of synchronous, generalized, moderate- to

high-voltage, 5–7 Hz waves on the EEG, but the symptomatology drug, modafinil. Proper evaluation of these drugs is rather unre-
does not fit well with epileptic seizures. liable because of the spontaneous eventual disappearance of the
Less common differential diagnoses are brain tumors developing symptoms after a few days of evolution. In addition, psychostimu-
inside the third ventricle (colloid cyst, epidermoid cyst, or choroid lants are of poor efficacy in treating the symptomatic periods, since
papilloma) responsible for paroxystic blockages to the drainage of cognitive and behavioral problems will remain potentially poorly
CSF. In this case, the onset of sleep is generally preceded by sud- tolerated after normalization of the vigilance state. In contrast, pro-
den headaches, which may be associated with vomiting and vague phylactic treatments based on mood stabilizers (lithium and antie-
sensory disorders. Other intraventricular tumors in the fourth ven- pileptic drugs) are easier to evaluate, based on the recurrence (or
tricle, craniopharyngioma, or pinealoma may give rise to the same not) of symptomatic episodes. Lithium is effective in some cases.
symptomatology. Diagnosis in all these cases is based on brain A recent large, prospective, open-label study provides class IV evi-
imaging. dence that for patients with KLS, lithium decreases the frequency
Other possible diagnoses are encephalitis, head trauma, recur- and duration of KLS episodes [98]. Risks of thyroid and kidney
rent stupor, porphyria, and Lyme disease. insufficiency must be considered, however. Among antiepileptic
drugs, valproic acid may be the most effective. Recently, two trials
Pathophysiology of clarithromycin have been carried out in patients with KLS: in
Neuropathological examinations have been performed in three the first, a short-term effect was noted in one patient [99], while
cases of typical KLS [82–84] and in one case of KLS secondary to the second showed a partial response in four patients, although the
a presumptive brain tumor [85]. They have shown various abnor- optimal timing of treatment was not determined [100].
malities in different locations of the brain, but have not led to con-
sistent conclusions. Hypersomnia due to a medical disorder
Neuroimaging studies performed during symptomatic periods
and asymptomatic intervals have documented modifications in A direct cause of EDS is a coexisting medical disorder. In most
tracer perfusion or metabolism in different regions of the brain, cases, EDS only stands as an associated symptom, to the extent
particularly in the thalamus, hypothalamus, basal ganglia, and that it is often neglected as far as it does not compromise the vital
frontotemporal areas [74,76,86–90]. However, conflicting results prognosis.
have been recorded concerning the topography and direction of
Neurological disorders
changes, which may be due to the use of different imaging meth-
ods, small sample sizes, imaging at different stages of disease evolu- Brain tumors
tion, clinical symptoms during scanning, and delay from episode Clinically, sleepiness tends to be continuous, interspersed with
onset [91]. brief arousals, whether spontaneous or provoked. Sleepiness may
Based on the generally young age at onset, the recurrence occur in any intracranial hypertension syndrome, or more rarely
of symptoms, the frequent infectious trigger, and a significant result from tumors of the diencephalon or peduncular region with
increased frequency of the HLA-DQB1*02:01 allele in the multi- no associated intracranial hypertension. These tumors include glio-
center group of 30 unrelated patients with KLS, an autoimmune mas or hamartomas affecting the posterior hypothalamus; poste-
origin of KLS has been suggested [81]. rior and superior suprasellar craniopharyngiomas compressing the
Similar to narcolepsy with cataplexy, 3% of cases are familial, floor of the third ventricle; and pinealomas or teratomas affecting
suggesting that the familial risk of KLS is high, given the low preva- the posterior part of the third ventricle. A fair number of cases of
lence of the disease [77]. Moreover, two cases of monozygotic twin narcolepsy symptomatic of brain tumors affecting the hypothala-
pairs concordant for KLS have been published [92,94] supporting mus or midbrain regions have been reported [101].
a strongly genetic basis for the condition. Finally, rare multiplex Stroke
families suggest an autosomal Mendelian inheritance, indicating
EDS is often a transient state between confusional state, agitation,
that single-gene mutations may cause KLS [77]. However, none has
or even coma, marking the initial period of the stroke. Among the
been identified up to now.
most typical causes of sleepiness of vascular origin are paramedian
Given the role of hypocretin neuropeptides in both sleep–wake
uni or bithalamic infarcts characterized by vertical ocular paresis,
regulation and feeding, hypocretins seemed good candidates to be
“skew deviation,” paresis of the third cranial pair, dysarthria, and
involved in KLS. Effectively, according to several investigations,
instability in walking; paramedian pedunculothalamic infarcts
CSF hypocretin-1 might be temporarily decreased during hyper-
characterized by altered ocular motility due to paresis of the third
somnia episodes at least in some patients [34,75,94–96].
or of the sixth cranial pair; and tegmental infarcts affecting the pon-
Treatment tine tegmentum and the reticular formation of this region [102].
Most patients do not require any treatment when episodes are suf- Neurodegenerative disorders
ficiently spaced out and do not have major social impact. EDS affects 16–50% of Parkinson disease patients [103], a find-
A Cochrane Database Systematic Review did not find any ran- ing that is, however, rarely confirmed by the gold standard MSLT
domized controlled trials of pharmacological treatments in KLS evaluation [104]. It may precede Parkinson disease by several years
[97]. Therefore, one is left with individual cases or small series in and often worsens after the introduction of dopaminergic treat-
which one or several drugs have been administered and clinically ment. A degeneration of hypocretinergic neurons and monoamin-
evaluated. There are two types of treatment: symptomatic and pro- ergic neurons may be involved. It is of concern that the occurrence
phylactic. Symptomatic treatments are mainly based on stimulants of sudden irresistible sleep episodes is facilitated by the intake of
(amphetamine or methylphenidate) and on the wake-promoting dopaminergic agonists [105].

Multiple system atrophy gives rise to EDS in 25 –30% of patients and low CSF hypocretin levels need to be ruled out, since rare cases
[106]. However, the mechanism is not the same as in Parkinson dis- of narcolepsy with EDS and several SOREMPs, with or without
ease. It often depends on OSAS, present in 15–37% of patients [107]. cataplexy, secondary to bilateral hypothalamic lesions and hypo-
EDS is common in Alzheimer-type dementia. It is often a com- cretin levels below 40 pg/mL have been reported [120,121].
ponent of a more profound sleep–wake disturbance with frequent
awakenings at night. The symptom of EDS is accounted for in Infectious and parasitic diseases
several ways: sundowning syndrome, which affects roughly one- Infections caused by Epstein–Barr virus and other viruses
quarter of subjects with dementia, psychotropic medications, de- In the aftermath of infectious mononucleosis, most subjects feel
pression, and OSAS [108]. intense asthenia and lengthening of total sleep time, difficulty
Neuromuscular diseases awakening, and EDS, evoking idiopathic hypersomnia [122]. This
Any neuromuscular disease—motoneuron disease, motor neur- type of transient hypersomnia also develops following viral pneu-
opathy, neuromuscular junction disorder, or muscular disease—is mopathy, hepatitis B viral infection, and Guillain–Barré syndrome,
likely to be accompanied by sleep-related breathing impairment probably through the same mechanism.
resulting in EDS. A typical example is myotonic dystrophy char- Encephalitis caused by viruses
acterized by weakness of limb, facial, and respiratory muscles, Disorders of wakefulness and/or consciousness are found in virtu-
myotonia, cardiomyopathy, endocrinopathy, frontal baldness, ally all patients affected by viral encephalitis. However, in the ab-
neuropsychological deficits, and cataract. Myotonic dystrophy is sence of PSG studies, it is very difficult to define the border between
the chronic neuromuscular disease entailing the highest prevalence wakefulness disorders and disorders affecting consciousness. Two
of self-reported EDS, with up to 70–80% of patients being affected nosological entities are worthy of mention, arboviruses and epi-
with this condition [109]. Available clinical, neurophysiological, demic encephalitis.
and histopathological evidence supports the hypothesis that EDS The arboviruses represent a heterogeneous group of viruses whose
most often stems from a primary central nervous system (CNS) common characteristic is that they are transmitted by arthropod
disturbance, and possibly from a central dysfunction of sleep regu- vectors. Infections by the various arboviruses share the same ini-
lation leading to REM sleep alteration. tial symptoms, evoking a fairly severe flu-like state with high fever,
Post-traumatic sleepiness headache, and myalgias. Encephalitic signs then develop, which
In addition to residual symptoms such as focal neurological deficit, vary according to the agent responsible. Sleepiness is a fairly char-
post-traumatic epilepsy, movement disorder, hormonal disturb- acteristic feature of European tick-borne encephalitis [123].
ance, cognition deficit, and psychotic disorder, subjects with trau- First appearing in Europe in 1917, epidemic encephalitis affected
matic brain injury (TBI) may develop sleep–wake disturbances, tens of thousands of subjects in the 10 years that followed. Its cause
including excessive daytime sleepiness. According to Baumann has never been fully identified, even though the pathological lesions
et al., subjective post-traumatic sleepiness (as assessed with the and inflammatory sites located mainly in the gray matter of the di-
ESS) was found in 28% of 65 consecutive patients 6 months after encephalon and basal ganglia strongly suggest a viral infection. The
traumatic brain injury and objective post-traumatic sleepiness (as most common form, referred to as the lethargic form, consisted of
assessed with the MSLT) in 25% [110]. Another prospective study a febrile flu-like condition, rapidly complicated by sleepiness culmi-
conducted in 87 subjects, at least 3 months after TBI, found post- nating in a permanent state of sleep, stupor, and coma, associated
traumatic sleepiness in 25% of subjects [111]. Imaging studies may with frequent oculogyric crises with nystagmus. This clinical picture
reveal various findings: lesions affecting the hypothalamic region, corresponded to lesions in the posterior hypothalamus and midbrain
the midbrain, or the pontine tegmentum, or more often an absence tegmentum [124]. Sporadic cases are still exceptionally reported.
of any significant lesion. The etiology of post-traumatic sleepiness Acquired immunodeficiency syndrome (AIDS)
has yet to be elucidated, and it is likely that multiple factors, both
Subjects infected by the human immunodeficiency virus (HIV)
physical and psychological, may be involved.
sometimes complain of EDS. Darko et al. found that HIV-
Epilepsy infected patients were significantly more likely to sleep more, nap
Although epilepsy can be the cause of sleepiness, the association of more, and have diminished midmorning alertness in comparison
epilepsy and sleepiness is not straightforward. Some studies have with noninfected subjects [125]. More recently, poor nighttime
demonstrated EDS in 17–28% of patients with epilepsy [112,113], sleep was significantly correlated with fatigue intensity and EDS
while others have found no difference in ESS scores in patients with in a sample of 128 individuals in a longitudinal study [126].
epilepsy and in controls [114,115]. The location of the ictal focus
African trypanosomiasis (sleeping sickness)
likely influences the expression of sleepiness; patients with frontal
lobe epilepsy have increased sleep fragmentation, which may lead African trypanosomiasis is a subacute or chronic parasitic disease
to EDS [116]. Moreover, many antiepileptic drugs (although not caused by the inoculation of a protozoon, Trypanosoma brucei,
lamotrigine) are known to induce sleepiness. transmitted by the tsetse fly. It is endemic to certain regions of trop-
ical Africa. The form found in West and Central Africa is due to
Multiple sclerosis T. brucei gambiense. It causes over 98% of reported cases. The form
There is conflicting evidence regarding sleepiness in multiple scler- found in East Africa is caused by T. brucei rhodesiense.
osis (MS), with some study reporting sleep disturbances and EDS The West and Central African form is divided into three succes-
in MS patients compared with non-MS groups [117] and others re- sive stages. Several hours after the fly’s bite, a hot, edematous and
vealing ESS scores in the upper normal range [118,119]. In the case erythematous tender nodule, referred to as the chancre, appears
of severe sleepiness in MS, the presence of hypothalamic lesions around the inoculation point. After a phase of inoculation varying

from several days to several months, the invasion of the blood and disorder, most often OSAS, but it may also be due to a primary
lymphatic organs by multiple trypanosomes constitutes the hemo- wakefulness dysfunction. A comprehensive review of these syn-
lymphatic stage 1. This stage lasts until the appearance of the parasite dromes has been published [133] and the present subsection will
in the CSF, referred to as the meningo-encephalitic stage 2, charac- review only the most common genetic disorders accompanied
terized by exacerbated headaches and fatigue, mental disturbances, by EDS.
and a wealth of neurological signs, including disorders of tone and
Chromosomal abnormalities
mobility. Sleep and wake alterations consist of sleep episodes ran-
Autosomal abnormalities
domly spread over 24 hours, causing a loss of the circadian alterna-
Down syndrome is the most common autosomal abnormality.
tion of sleep and wakefulness and the occurrence of SOREMPs in
Most cases result from trisomy 21, although less commonly Down
several sleep episodes [127]. Demyelinating encephalitis ends the
syndrome occurs when part of chromosome 21 becomes attached
time course of the disease, along with apathy, dementia, epileptic
to another chromosome (translocation Down syndrome), and a
seizures, incontinence, and death in a state of cachexia.
very small percentage of patients with Down syndrome have an
Multisystem diseases extra copy of chromosome 21 in only some of the body cells (mo-
saicism of trisomy 21). EDS is frequent. It is connected with OSAS,
Sarcoidosis, a chronic multisystem disease, most frequently affects
the prevalence of which is higher than 50%, or with sleep fragmen-
the lungs. However, CNS involvement is thought to occur in about
tation and arousals, independently of respiratory events and peri-
10% of cases. Neurosarcoidosis can affect any part of the CNS, es-
odic limb movements.
pecially the hypothalamus and pituitary gland, and in that case
includes symptoms of sleepiness, hyperphagia, polydipsia, and Chromosomal anomalies in various dystrophic syndromes
variations in body temperature. Prader–Willi syndrome is due to a lack of expression of the pater-
Systemic lupus erythematosis is another chronic multisystem nally active genes in the q11–13 region of chromosome 15. EDS
disorder that may be associated with EDS. is the most common sleep-related symptom in Prader–Willi syn-
drome. Although OSAS may have a role to play in some patients,
Endocrine disorders the primary cause of EDS is thought to lie in hypothalamic dys-
EDS has been associated with several endocrine disorders, in part function, with comorbid symptomatic narcolepsy in some cases.
due to the co-occurrence of OSAS. Smith–Magenis syndrome is associated with a deletion of
chromosome 17 (17p11.2). Most patients exhibit sleep attacks
Hypothyroidism occurring at the end of the day, as the expression of an inversion of
Several studies have demonstrated that OSAS is more prevalent the melatonin circadian rhythm.
among patients with hypothyroidism than among control subjects Norrie disease is a rare genetic form of blindness and variable
[128]. However, a primary effect of hypothyroidism on sleep is also mental retardation due to an Xp11.3–p11.4 microdeletion. Features
possible, with potential benefit from thyroid stimulants [129]. of narcolepsy including irresistible episodes of sleep and attacks
Acromegaly resembling cataplexy have been described in three related boys in
Sleep-disordered breathing is common in acromegaly, and is con- North America [134].
nected with the insidious onset of facial features, bony proliferation,
Inherited neurometabolic disorders
and soft tissue swelling. In a study involving 17 patients (11 women
and 6 men) diagnosed with acromegaly, ten patients (58.8%) These diseases result from a single mutant gene coding for an en-
had an apnea–hypopnea index (AHI) greater than 10, nine had zymatic protein mostly involved in the catabolic pathways. Most
OSAS and one had central sleep apneas [130]. Seven (five with an striking sleep disorders are found in lysosomal storage disorders
AHI >10 and two with an AHI < 10) reported EDS with an ESS including glycogenoses, mucopolysaccharidoses, and sphingolipi-
score greater than 10. doses. Pompe disease results from an acid α-glucosidase deficiency.
Diaphragm weakness responsible for respiratory insufficiency or
Diabetes sleep apnea may appear in any stage of the disease and be asso-
Diabetes and OSAS share a high prevalence in industrial nations. ciated with EDS. Mucopolysaccharidoses are heterogeneous syn-
The presence of OSAS seems to promote the development of dia- dromes involving mental and physical retardation. OSAS is often
betes mellitus and vice versa. associated with self-reported EDS. Niemann–Pick disease type C
There are limited data regarding EDS in type 2 diabetes patients, is a lysosomal storage sphingolipidosis with four main forms: early
with huge a confounder in between, namely, obesity. In one study infantile, late infantile, juvenile, and adult. Cataplexy may be pre-
involving 614 type 2 diabetes patients, EDS, as measured by ESS, sent in 25–50% of late infantile and juvenile forms, even in the ab-
occurred in 8.5% of patients [131]. However, apneas were assessed sence of hypocretin deficiency. Total sleep time, sleep efficiency,
by the Sleep Disorders Questionnaires using sleep apnea subscales REM sleep amount, and delta sleep amount are decreased on PSG
only, and the relationship between apneas and EDS was not specif- in comparison with age-matched controls, and MSLT shows short-
ically assessed. In another study involving 110 patients with type 2 ened mean sleep latency [135].
diabetes, EDS was found in 55.5% of patients, in association with
depressive symptoms in 44.5% individuals [132].
Hypersomnia due to a medication
Genetic disorders or substance
EDS is highly prevalent in patients suffering from diverse genetic Patients with this disorder have excessive nocturnal sleep, daytime
syndromes. It is often the consequence of nocturnal breathing sleepiness, or excessive napping that is attributable to sedating

medications, alcohol, or drugs of abuse, or to withdrawal from depressive disorders; bipolar I and II disorders in the class of bi-
amphetamines and other drugs. polar and related disorders; and schizoaffective disorder in the class
This sleep disorder has become a public heath concern, owing to of schizophrenia spectrum and other psychiatric disorders.
the consequences of somnolence not only on driving, but also on As a rule, EDS is not systematically present in these disorders.
occupational activities and thus on productivity. First, the accompanying sleep symptom is either insomnia or ex-
cessive daytime sleepiness; second, the sleep symptom is part of
Sedating medications a list of symptoms, a certain number of which have to be present
These medications lead to “a state of calm or reduced nervous during the same 2-week period and represent a change from pre-
activity” (Collins English Dictionary) which may eventually re- vious functioning; third, and above all, most psychiatric disorder
sult in EDS. They cause sedation via effects on the neural sys- studies addressing EDS have assessed daytime sleepiness using ESS
tems involved in sleep–wake regulation, primarily by increasing or other subjective tests, but rarely objective sleepiness as measured
GABA or inhibiting histamine, norepinephrine (noradrenaline), by MSLT, actigraphy, or continuous PSG [137]. Moreover, the few
or serotonin. Important factors affecting the degree of sedation studies using objective sleepiness tests have failed to demonstrate
include receptor binding profile, dose, half-life, and time of ad- objective EDS. However, clinical experience shows that subjects
ministration, as well as age and association with multiple medi- with psychiatric disorders often spend hours in bed during the
cation ingestion. These medications include benzodiazepine daytime. Thus, it is of the utmost importance that future studies
and non-b enzodiazepine hypnotics, anti-anxiety drugs, some measure both EDS and total sleep time per 24 hours outside of psy-
antidepressants, first-generation antihistamines, antipsychotics, chotropic medication use.
antiepileptic drugs, opiates, anticholinergics, and skeletal muscle
relaxants. Insufficient sleep syndrome
Another frequent source of excessive somnolence is the use of
some dopamine agonists such as pramipexole and ropinirole. “Insufficient sleep syndrome occurs when an individual persistently
Excessive somnolence may less frequently be caused by various fails to obtain the amount of sleep required to maintain normal lev-
other medications, including antihypertensive drugs, mostly els of alertness and wakefulness” [6]‌. As a consequence, the subject
α2 agonists, (eg, clonidine) and less frequently nonselective is abnormally sleepy, with daily periods of irrepressible need to sleep
β-antagonists (eg, propranolol) and α1 antagonists (eg, prazosin), or daytime lapses into sleep. The patient’s sleep time, established by
nonsteroidal anti-inflammatory drugs, and antispasmodic drugs. personal or collateral history, sleep diary, and actigraphy, is usually
Of note, this adverse effect occurs only in a fraction of patients shorter than expected for age. Sleep time is markedly extended on
using these drugs and its severity can vary considerably. In some weekend nights or during holidays compared with weekday nights.
cases, failure to provide treatment with the incriminated drug may Depending upon the extent of sleep loss, individuals are at risk for
be more disruptive than EDS. a range of neurobehavioral deficits, including lapses of attention,
slowed working memory, reduced cognitive function, depressed
Substance abuse mood, and fatigue.
This syndrome was systematically investigated for the first time
EDS can occur with abuse of alcohol, benzodiazepines, barbi-
in 1983, in a population of 59 adults (37 men and 22 women) with
turates, γ-hydroxybutyrate acid, opiates, and cannabis. Alcohol
mean age 40.8 ± 12.2 years [138]. Since then, studies have been car-
intoxication typically causes sedation for 3–4 hours and then in-
ried out mainly among adolescents [139,140], except for a Japanese
somnia, whereas intake of caffeine or cocaine causes insomnia, and
study based on interviews with 1243 patients referred to a sleep
their withdrawal sedation. Sedation is a common adverse effect of
disorder outpatient clinic for complaint of excessive daytime sleepi-
opioid medication. The degree of sedation may depend on the spe-
ness: the combination of insufficient sleep and EDS was about 7.1%
cific drug, dosage, and duration of use, as well as the severity of the
of the sample [141]. However, no differential diagnosis was applied.
underlying disease.
Positive diagnosis is primarily based on interview, sleep diaries
Cannabis use may be associated with EDS, sluggishness, giddi-
maintained for more than a week, and actigraphy. PSG and MSLT
ness, and inability to concentrate.
are not required to establish a diagnosis of insufficient sleep syn-
Stimulant withdrawal drome. Rather, sleep time is extended first and the patient is clin-
ically reevaluated. If the symptoms disappear, insufficient sleep
EDS is common with abrupt discontinuation of stimulants. In syndrome is confirmed.
chronically heavy amphetamine users, EDS peaks during the first If unchecked, insufficient sleep syndrome may predispose to de-
week of withdrawal and can persist for up to several weeks. In pression and other psychological difficulties, as well as poor work
people consuming caffeine daily, discontinuation can produce EDS performance or traffic accidents. Differential diagnosis includes
and fatigue for several days. mainly central disorders of hypersomnolence, mood disorders, and
long sleepers. Treatment relies on a longer major sleep episode or,
Hypersomnia associated with if the patient’s professional life does not allow this, one or several
a psychiatric disorder daytime naps.
EDS can be a symptom of psychiatric disorders belonging to dif-
ferent diagnostic classes of the Diagnostic and Statistical Manual Conclusion
of Mental Disorders, fifth edition (DSM-5) [136]: major depressive In addition to OSAS and narcolepsy, etiologies of EDS are nu-
disorder, persistent depressive disorder, premenstrual dysphoric merous. Some of them, namely, idiopathic hypersomnia, Kleine–
disorder, and other specified depression disorders in the class of Levin syndrome, and insufficient sleep syndrome, are well known

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CHAPTER 16
Obstructive sleep
apnea and upper airway
resistance syndrome
Cristina Embid and Josep M. Montserrat
Introduction of Pickwickian syndrome. The spectrum of sleep disordered breath-

ing as presently understood is much broader, with different types of
In recent decades, the existence of sleep disordered breathing, its patients and patients with different characteristics involved, such as
clinical consequences, and its high prevalence have been progres- elderly people, children, non-â•‰obese patients, and the non-â•‰clinical
sively recognized and have become to be considered a major health population (Table 16.1).
problem [1,2]. The apneas result in a number of different patho- On the other hand, in addition to apneic events, the study by the
physiological and biological changes, leading to a variety of clinical group led by Douglas of the airflow reduction or hypopnea due to
features (Fig. 16.1). Initially, attention focused just on sleep apnea, partial upper airway (UA) collapse revealed the same disturbances
through studies of the classical picture of Pickwickian syndrome as occur incomplete apnea [3]â•„, and both these events are now con-
involving groups of obese patients who presented a large number sidered together. The apnea hypopnea index (AHI) has become the
of apneas during sleep. However, our concept of sleep disordered most appropriate measure to quantify events of sleep disordered
breathing has substantially changed since these early descriptions breathing. Furthermore, upper airway resistance syndrome (UARS),
Adaptive and maladaptive responses

APNEA NORMAL exist, as well as modulators
SYMPTOMS
Genetic risk
Somnolence
Asphyxias
Fatigue
Other
*
Physiological Arousal * Systemic biological changes
changes
EEG
Gene susceptibility
Large negative
intrathoracic Inflammation
Flow pressures
Oxidative stress
Effort Neurovegetative Endothelial dysfunction
activity
SaO Adipokines, free fat,….
Hypoxemia
RISK FACTORS
Cardiovascular
Metabolic
Risk factors Cognitive

Ambient, ageing, gender, obesity, alcohol.. * Intermediate mechanisms Others
Fig. 16.1â•‡ Physiological, biological, and clinical changes that occur as a consequence of sleep apnea. Adaptive or maladaptive responses, as well as different risk factors,
modulate the clinical consequences.

Table 16.1 Characteristics of the patients Table 16.2 Different definitions related to sleep apnea
Typical patients Actual patients Definitions

Pickwickian syndrome Elderly and children Apnea: Cessation of breathing flow for more than 10 s.
Obesity Pregnancy Hypopnea: Discernible reduction of flow for more than 10 s with arousal or a
3% decrease in oxygen saturation.
Heavy snoring Fibromyalgia
Other definitions of hypopnea: (1) Reduction in flow (30%) plus 3%
Breathing pauses Uvulopalatopharyngoplasty (UPPP)
decrease in oxygen saturation; (2) reduction in flow (50%) plus 4% decrease
Maxillomandibular problems in oxygen saturation. However, sensors to analyze flow are not qualitative, and
therefore these definitions are difficult to apply in practice.
Bariatric surgery
RERA (or UARS event): Short period of flow limitation (but > 10 s), ending
Cardiovascular/resistant hypertension
with an arousal (frequently scored as hypopnea).
Non-clinic population
Apnea and hypopnea index (AHI): number of apneas and hypopneas
Mild symptoms recorded per hour of sleep.
Neurological/psychiatric disease RDI: number of apneas and hypopneas plus RERAs recorded per hour of
sleep.
Myopathies and metabolic disorders
Short period of flow limitation (but > 10 s) without consequences: This
is not scored as an event.
also known as respiratory-effort-related arousal (RERA), has been Prolonged period of limitation without consequences: This is not scored
described, with pathophysiology similar to that of hypopnea. In this as an event.
case, the respiratory disturbance index (RDI), which is the sum of Severity of sleep apnea
the numbers of apneas, hypopneas, and RERAs per hour, is used to Mild OSA: AHI 5–15/h; moderate OSA: AHI 15–30/h; severe OSA: AHI > 30/h.
express the total spectrum of sleep respiratory events (Fig. 16.2(a)).
Table 16.2 summarizes different definitions related to sleep-related Clinical entities that have to be treated (sleep apnea–hypopnea syndrome)
breathing disorders (SBDs). SBDs have been described as forming Sleep apnea–hypopnea syndrome with AHI > 5–15/h plus mild
a continuous range of disorders, from snoring, through RERA and symptoms: General measures (Personalize).
then hypopneas to sleep apneas. From the pathophysiological point of Sleep apnea–hypopnea syndrome with AHI > 15–30/h plus symptoms:
view, these correspond to UA vibration (snoring), dynamic obstruc- General measures before CPAP (Personalize).
tion (hypopnea and RERA) (see below), and finally static obstruction
Severe sleep apnea with AHI > 30/h plus minor symptoms: General
(apnea). Of course, depending on the phenotype of the patient, the
measures and CPAP.*
continuity of this process is artificial, at least in part. Figure 16.2(b)
illustrates the definition of the AHI, for events when RERAs and *Some authors use a cut-off point of AHI >15/h instead of AHI > 30/h for more rigorous
hypopneas are considered together, (frequently all obstructive res- treatment (straight to CPAP).
piratory events are scored in this way. We consider RERAs and hypo-
pneas as the same respiratory event, scoring the obstructive load as
the sum of apneas and hypopneas (i.e, the AHI) (Fig. 16.2(b)). tends to decrease the size of the pharyngeal airway lumen (crani-
It should be mentioned that around 20% of the population ofacial structure, UA body fat, and tongue disproportion between
have an AHI of around 5–10 events per hour but without symp- container and content) and the activity during sleep of the UA
toms. From 4% to 8% or more of the population have more than muscles that maintain airway patency. When these anatomical
five events per hour with symptoms, which defines sleep apnea– factors are not compensated by increased neuromuscular activ-
hypopnea syndrome (SAHS) [1,2]. Repeated episodes of UA ity, an increase in UA collapsibility occurs that induces apneas or
obstruction trigger cortical arousals, large negative intrathoracic hypopneas (Fig. 16.3(b)). The absence of compensation occurs
pressures, an increased neurovegetative response, and finally a only during sleep, because these patients when awake have a
hemoglobin oxygen desaturation [4]‌. Intermittent hypoxia leading normal or even an increased muscle activity that eliminates UA
to increased oxidative stress, systemic inflammation, and sympa- obstruction.
thetic activity coupled with intrathoracic pressure changes leading The critical closing pressure Pcrit [10] is commonly used to quan-
to excessive mechanical stress on the heart and large artery walls, tify pharyngeal collapsibility, which depends on two factors: UA
together with arousal-induced reflex sympathetic activation with wall tissue compliance and UA muscle tone. Pcrit is defined as the
resultant repetitive blood pressure rises, are responsible for the minimum pressure inside the airway that allows the airway to
symptoms and the cardiovascular, neurocognitive, and metabolic remain patent. Figure 16.4 shows three examples of the possible
effects [5–9] (Fig. 16.1). Other forms of sleep apnea include central spectrum of Pcrit: (a) a fully open airway; (b) total obstruction; and
and complex apneas. (c) partial obstruction. When the UA has normal compliance or
when the activity of the UA tone is high, Pcrit is negative, meaning
that a very negative intraluminal pressure is required to close the
Pathophysiology UA. Very negative values of Pcrit suggest a stable UA, and therefore
As can be seen in Fig. 16.3, obstructive sleep apnea (OSA) occurs normal breathing is allowed. In the apnea group, the high compli-
when there is an imbalance between the anatomical factors that ance of the low muscle tone of the UA tends to close it, thereby

Chapter 16 obstructive sleep apnea and upper airway resistance syndrome 147
(a)
RDI Physiopathology
Vibration Dynamic obstruction Static obstruction
Snoring RERAS Hypopnea Apnea
Sound Mild flow Moderate flow Absence of flow

No other symptoms reduction reduction Desaturation or
ended with an arousal ended with arousal
Non heavy obesity desaturation Somnolence
Somnolence Somnolence
Clinical
(b)
AHI Physiopathology
Vibration Dynamic obstruction Static obstruction
Snoring Hypopnea Apnea
Sound Flow reduction Absence of flow

No other symptoms ended with an arousal or desaturation Desaturation or arousal
Somnolence Somnolence
Clinical
Fig. 16.2 (a) Definition of the respiratory disturbance index (RDI). (b) Definition of the apnea–hypopnea index (AHI). In the latter case, the upper airway resistance
syndrome (UARS, or RERAs) and hypopneas are scored together.
inducing airway collapse and thus apnea (static occlusion). In considered here specifically in relation to respiratory events. Sleep
Fig. 16.4(c), the intraluminal pressure is just above Pcrit. In this disorder breathing changes may not be recognized if the devices
situation, inspiratory flow itself decreases intraluminal pressure used to analyze and quantify airflow are not sensitive enough.
below Pcrit, and then the UA partially collapses during inspiration. Guilleminault [12] clarified the relationship between increased
This situation is called dynamic occlusion, because the obstruction respiratory resistance, snoring, and sleep fragmentation on the one
depends in part on the inspiratory flow [11]. Depending on the hand and daytime sleepiness on the other, thereby providing fur-
magnitude of this dynamic UA obstruction, among other effects, ther insight into this complex situation. In 1991, he produced an
ventilation may be reduced substantially (hypopnea) or slightly initial report on the effect of increased respiratory load during sleep
(RERAS). in children with symptoms similar to those of sleep apnea. Along
The Harvard group has recently described different traits such these lines, he identified heavy snoring as a cause of excessive
as the open loop or the arousability that contribute markedly daytime sleepiness [12]. Together with co-workers, Guilleminault
to the upper airway collapsibility and even can open up differ- reformulated the concept of sleep disordered breathing with a
ent therapeutic options, as summarized in Fig. 16.5. This figure description of the UA resistance syndrome (UARS/RERA) [13].
shows the basic pathophysiological abnormalities of SAHS, dif- They focused their attention on a group of subjects with complaints
ferent phenomena that contribute to the upper airway collapsibil- of excessive daytime sleepiness (EDS) presenting a trivial number
ity (open loop, low arousal threshold, and upper airway muscle of obstructive events as currently scored during full polysomnogra-
response), as well different possible alternatives of treatment of phy (PSG). However, these events were measured using a thermis-
these phenomena. tor, which has a very poor frequency response, and therefore it was
not possible to measure the dynamic obstruction accurately. This is
Sleep studies to measure respiratory events why Guilleminault had to measure esophageal pressure with a bal-
loon. Sleep fragmentation with short repetitive arousals secondary
Oronasal flow to increased UA resistance in the absence of apnea and hypopnea
The chapters in Section 2 of this volume describe various meth- was observed and was related to EDS. Some of the patients had
ods of sleep evaluation. However, some important aspects must be maxillomandibular abnormalities. Reversal of sleep fragmentation

(a) Upper airway mechanoreceptors

Negative pressure
Vibration
BRAINSTEM
UPPER AIRWAY
CENTERS
PATENCY/COLLAPSE
UPPER AIRWAY UPPER AIRWAY

FACTORS: MUSCLES
ANATOMIC
Obesity, retrognatia…
Normal breathing
COLLAPSABILYTY
Shape
Tissue properties
(b) Upper airway mechanoreceptors

Negative pressure
Vibration
UPPER AIRWAY BRAINSTEM

PATENCY/COLLAPSE CENTERS
UPPER AIRWAY
MUSCLES (–)
UPPER AIRWAY
FACTORS: (++)
ANATOMICAL
Obesity, retrognatia… Apnea
COLLAPSABILITY
Shape
Tissue properties
Fig. 16.3 Physiopathology of upper airway obstruction. (a) Normal balance between the anatomical factors that tend to decreases the size of the pharyngeal airway and
the activity of the upper airway muscles during sleep. (b) An imbalance of the anatomical factors tends to decrease the size of the pharyngeal airway and the activity of
the upper airway muscles during sleep, promoting respiratory events.
and sleepiness was achieved with nasal continuous positive airway of thermistor-type flow-measuring devices for detecting hypopneas
pressure (CPAP), providing further evidence that abnormal UA has been questioned [14]. Farré et al. [14] assessed the accuracy of
resistance is responsible for the disorder. Therefore, it is credible thermistors/thermocouples as devices for detecting hypopneas in
that UARS is not an independent disorder from hypopneas but is sleep studies (Fig. 16.6). They demonstrated that thermistors were
perhaps a subgroup with particular identifiable traits in the spec- only qualitative sensors, with strongly nonlinear characteristics,
trum of SAHS, which, like hypopneas, requires appropriate tech- and greatly underestimated flow reductions: a 50% reduction in the
nology for its diagnosis. The gold standard device to measure flow real flow resulted in only an 18% reduction in the thermistor signal.
is the pneumotachograph; however, its use during sleep requires The example in Fig. 16.6 clearly shows that a thermistor is not
the patient to wear a nasal or full-face mask, and for this reason it able to accurately measure the real flow or reproduce the mor-
is not suitable for routine diagnostic sleep studies. Therefore, non- phology of the inspiratory flow. Therefore, the use of thermistors
obtrusive sensors to detect breathing flow are especially suitable to quantify hypopneas may lead to considerable underdetection
for this application. Two types of small and simple devices, placed of respiratory periods of increased UA resistance. Another tech-
close to the airway opening, are used to provide surrogate flow sig- nical aspect is the concept of the morphology of the inspiratory
nals: thermistors/thermocouples and nasal prongs. The ventilation flow as a simple and easy way to detect increases in UA resistance.
disturbances caused by obstructive sleep events are also monitored However, this cannot be determined by the thermistor. Therefore,
indirectly by means of thoraco-abdominal bands. In fact, the use to recognize dynamic obstruction, hypopneas, and UARS events,

(a) Normal breathing Pcrit < Patm and nasal flow, while nasal prongs only measure nasal flow. When
conventional NPs similar to those designed for long-term oxygen
therapy are inserted into the nostrils and connected to a pressure
transducer, it is possible to measure the pressure fluctuations that
occur during breathing. These oscillations are used as a surrogate
for the nasal flow [15,16]. The set-up is simple and this method has
(b) Apnea–static obstruction Pcrit > Patm an excellent dynamic response. NPs work as follows: the tip of the
cannula is inside the nostril while the other side of the pressure
transducer is open to the atmosphere, and so there is a drop in pres-
sure between cannula tip and atmosphere during breathing, due to
the resistance of the nostrils. As the flow is turbulent, the relation-
ship between pressure changes, flow, and resistance is nonlinear,
and so NPs provide only a qualitative estimate of the flow, although,
(c) Hypopnea / UARS–dynamic obstruction Pcrit ≈ Patm in contrast to a thermistor, because of the quadratic pressure–flow
relationship, they overestimate flow reduction [15,16] (Fig. 16.6)
Nevertheless, the NP signal can be linearized [15,16] to obtain an
excellent surrogate flow signal (Fig. 16.6).
However, even when linearized, the NP signal may not provide
an absolutely accurate reading of total airflow over the entire night.
end-expiration inspiration Changes in the position of the cannula, periods of partial oral venti-
lation, and obstruction of the cannula by nasal secretions make the
Fig. 16.4 Dynamic and static occlusion of the upper airway: (a) normal breathing; linearized NP signal a less accurate measure of flow over the entire
(b) apnea; (c) hypopnea. Pcrit: critical pressure; Patm: atmospheric pressure; night [14–16]. As with thermal sensors, the changes in breathing pat-
UARS: upper airway resistance syndrome
Reproduced from Sleep Breath, 5(4), Montserrat JM, Farré R, Navajas D, New technologies
tern detected in a given sleep event should be compared with the
to detect static and dynamic upper airway obstruction during sleep, pp. 193–206, Copyright signal in the previous normal cycles. The major advantage of NPs
(2001), with permission from Thieme. is their fast response. This permits the detection of flow limitation,
since the device can track the details of the inspiratory waveform con-
tour, particularly if the signal is linearized. NPs have been used not
other devices than thermistors are needed. Pneumotachography just to detect reductions in the flow signal, like thermal devices, but
or esophageal pressure measurements would be ideal, except for also, more importantly, to detect and assess dynamic flow limitation.
the fact that they are inconvenient to use in clinical practice and The American Academy of Sleep Medicine (AASM) scoring manual
are therefore confined to research studies. The use of nasal prongs recommends nasal–oral thermal sensors for the detection of apnea
(NPs) and measurement of total thoraco-abdominal movement and NP sensors (with or without square root transformation of the
are appropriate in most cases. Thermal devices measure both oral signal) for the detection of hypopnea [17]. The simultaneous use of
both NPs and nasal–oral thermal sensors is recommended, provid-
ing the additional advantage of a backup sensor if one of the airflow
Defining Phenotypic Causes of Obstructive Sleep Apnea. detection devices fails. Tables 16.2 and 16.3 summarize the criteria
Identification of novel therapeutic targets and recommendations for detection of sleep disordered breathing.
Obesity, Tonsils, Nose problems, UA oedema, Allergy,
Maxilo/mandibular problems, Shape of the UA and tissue properties
Thoraco-abdominal motion
Thoraco-abdominal bands are used to analyze thoracic and
abdominal excursions, although the magnitudes of these excur-
Bad relationship CONTAINER/CONTINENT
sions are not proportional to swings in esophageal pressure. These
bands are only semiquantitative and sometimes may even misclas-
sify obstructive events as central. They analyze the amplitude of
(Surgery, DAM) Anatomical abnormalities
motion of the thoracic and abdominal compartments, as well as
Low arousal (Sedatives,
the synchrony between the movements of these compartments.
(Acetazolamide Loop gain
Oxygen) threshold Trazodone) Piezoelectric bands have frequently been used [18]. Currently,
UA COLLAPSIBILITY the AASM recommends the use of respiratory inductive plethys-
mograph (RIP) bands [17,19]. Other options are polyvinylidene
Poor UA
(Training, drugs) muscle
Apnoeas/Hypopnoeas fluoride (PVDF) sensors (excellent, but still not widely used) and
response (CPAP)
pneumatic bands, which have been used in the past with acceptable
Fig. 16.5 Different anatomical elements that contribute to the upper airway
and more economical results in many cases. However, discrepan-
collapsibility that, together with an absence of upper airway muscle response at cies have been observed in the assessment of thoraco-abdominal
night, results in apneas or hypopneas. Other traits such as changes in the open asynchrony, depending on the choice of respiratory movement sen-
loop or the arousability also contribute markedly to increase the upper airway sors. The literature contains a number of references to the RIP, but
collapsibility and therefore increase the number of respiratory events. As can be surprisingly, hardly any to other older systems. Figure 16.7 shows
seen in this Figure, these traits can open up different therapeutic options. the correlations between the esophageal pressure and the inspira-
Reproduced from Eckert.
tory flow contour (representing the degree of flow limitation) and

(a) Nasal prongs–Pneumotachograph (b) Thermistor–Pneumotachograph
PNEUMOTACHOGRAPH
(a) (b) (c)
0.5
Flow
ν L.s
0.0
NASAL PRONGS
–0.5
Flow (d) 0.5 (e) (f)
L.s
LINEARIZED NASAL PRONGS 0.0
ν
Flow –0.5
0 2 4 6 0 2 4 6 0 2 4 6
Time s Time s Time s
0 10 20 30 40
Time (sec)
Fig. 16.6 Flow measurement. (a) Nasal prongs overestimate the reduction in the pneumotachograph flow signal but correctly analyze the shape of the flow. Taking the
square root of the nasal prongs measurement provides an optimized result. (b) Comparison between a pneumotachograph and a thermistor. The thermistor does not
respond properly when the pneumotachograph signal decreases to 50% (it underestimates the drop). The thermistor does not correctly analyze the shape of the flow
signal. In summary, thermistors underestimate and nasal prongs overestimate the real reduction of flow.
Reproduced from Eur Respir J, 11(1), Farre R, Montserrat JM, Rotger M, Ballester E, Navajas D, Accuracy of thermistors and thermocouples as flow-measuring devices for detecting hypopnoeas,
pp. 179–182, Copyright (1998), with permission from European Respiratory Society.
between the esophageal pressure and the degree of coordination assessment of sleep apnea are (a) the most common symptoms and
of the thoracic bands. In both cases the correlation is acceptable, the physical examination (Fig. 16.8 and Table 16.3), (b) the risk
although it is better in the case of the inspiratory flow contour. factors and the associated diseases that present a high risk for OSA
(Table 16.4), and (c) the results of the sleep study (Tables 16.2 and
Other techniques 16.3) [17,23].
The diagnostic criteria for SBD have already been shown in
The forced oscillation technique (FOT) superimposes on spon-
Table 16.2, while Table 16.3 shows those specifically for SAHS.
taneous breathing a small pressure oscillation through a nasal
EDS, the most common SAHS symptom, may develop gradually,
mask attached to the patient. Respiratory impedance Z is derived
with the patient being unaware of the change. Other patients, espe-
online from pressure and flow signals recorded at the nasal mask.
cially women, complain of related fatigue instead of EDS, while
The potential application of FOT for the assessment of airway
obstruction in SAHS has been confirmed in a model study[20].
Its clinical applicability to assess airflow obstruction in real time Table 16.3 Sleep apnea: definition criteria of the AASM
during CPAP treatment has also been demonstrated in a limited
number of patients in comparison with measurements of esopha- A patient with obstructive sleep apnea–hypopnea syndrome must fulfill
geal pressure [21]. However, further research on FOT is needed criteria A and B or just criterion C:
to assess sensitivity and specificity in the detection of increased A) At least one of the following complaints:
UA resistance before it can be introduced as a routine clinical
procedure. • Excessive daytime sleepiness that is not better explained by other
factors, unrefreshing sleep, daytime, or fatigue.
The pulse transit time (PTT) method [22] is capable of detect-
ing increased respiratory effort and neurological activation (either • Awakenings with asphyxia, choking, or gasping.
arousal or autonomic arousal). • Bed partner reports louds snoring and apneas during sleep.
B) Sleep study:
Clinical findings Five* or more obstructed breathing events per hour during sleep.
Diagnosis of sleep apnea requires a combination of various clini- C) AHÍ >15.**
cal findings and the presence of an abnormal number of apneas
The sleep disorder should not be explicable by another sleep entity such as
and hypopneas per hour of sleep [4,6,17,23]. According to cur-
central sleep apnea or hypoventilation.
rent diagnostic criteria, a large number of abnormal respiratory
events with or without minor abnormal symptoms are necessary. *Some authors prefer 10 events/h.
The main points that have to be considered in the diagnosis and **Some authors prefer 30 events/h.

(a) (b) Flow-contour T-A bands
Normal
60 1
Esophageal pressure (cmH2O)

50
2
40
30
3
20
Inspiratory flow
Bands 4
Abnormal
10
0
1 2 3 4
Flow and bands morphology score Flow shape and T-A bands coordination
Fig. 16.7 (a) Evaluation of inspiratory flow and thoraco-abdominal (T-A) motion score characteristics related to esophageal pressure measurements. There is an acceptable
correlation between the esophageal pressure and the T-A bands and between the esophageal pressure and the flow shape signals. (b) Definitions of qualitative variables and
the score assigned to them. The inspiratory flow contour (upward direction) is classified as follows: 1 = well-contoured; 2 = partially limited; 3 = severely limited; 4 = no flow.
The degree of thoraco-abdominal motion paradox is classified as: 1 = no paradox; 2 = slight partial paradox; 3 = partial paradox; and 4 = complete paradox.
Reproduced from Am J Respir Crit Care Med, 155(1), Montserrat JM, Farre R, Ballester E, Felez MA, Pasto M, Navajas D, Evaluation of nasal prongs for estimating nasal flow, pp. 211–215, Copyright
(1997), with permission from American Thoracic Society.
others experience an impairment in social functioning [24,25]. The Typical symptoms are snoring, witnessed apneas, night asphyxias,
clinical expression of the disease may differ from patient to patient, and daytime somnolence or fatigue (Figs 16.8 and 16.9 and
with some experiencing only snoring and respiratory pauses with- Table 16.3) not explained by other entities (Table 16.5). Sometimes,
out EDS or other significant symptoms, while others are prone to the symptoms are not as clear and specific. It is important to inquire
sleepiness during driving [26]. Therefore, two patients with the about the patient’s consumption of alcohol, sedatives, and other
same AHI can have different clinical phenotypes or arterial oxygen drugs. Gastroesophageal reflux should be ruled out. Moreover, it
desaturation. is essential to question the patient about other common causes of
SYMPTOMS PHYSICAL EXAMINATION
DAYTIME NIGHTTIME ANTHROPOMETRIC CRANIOFACIAL OROPHARYNGEAL

Somnolence Loud snoring • Obesity • Thyromental • Enlargement of
Nonrestorative sleep Witnessed apneas distance shorten the tonsils,
• Neck < 1.5 cm tongue and uvula.
Fatigue Choking circumference,
Cognitive changes Body movements men > 43 cm; • Maloclusion • Stage 4 of both
Morning headaches women > 40 cm associated with item of the
retrognatia Friedmen
High blood pressure • Waist-to-hip classification
ratio men > 1; • High-erched
women > 0.85 palate • Nose problems
1 2 1 2
A B
A: Palatal position B: Tonsils

3 4 3 4
Friedman classification
Fig. 16.8 Suggested initial basic clinical assessment of patients with sleep apnea.

Table 16.4 The three main clinical features of sleep apnea sleepiness, such as depression, insufficient sleeping time, and inad-
equate sleeping routines (Table 16.5).
Patients at risk Risk factors SAHS, high pretest Sleepiness can be assessed in different ways. The easiest is to
(not so clear in females) ask the patient if EDS affects daily life in passive or active situa-
tions, including driving, in ways that cannot be explained by other
Obesity Lack of exercise Heavy snorer
diseases or circumstances. There are different questionnaires that
Resistant Male and elderly Witnessed apneas attempt to quantify sleepiness and other sleep complaints, although
hypertension Nocturnal choking there is no relationship with the physiological variables. There
Pulmonary Maxillomandibular Maxillomandibular alterations are three representative questionnaires: the Epworth Sleepiness
hypertension and ENT Scale (ESS) [27], the Functional Outcomes of Sleep Questionnaire
abnormalities (FOSQ) [28] and the QUEBEC [29] questionnaire, which analyze
Retrognathia different sleep complaints, and finally the EURO-COL, a very sim-
ple tool that assesses general quality of life [30]. The ESS, the most
Metabolic Postmenopausal ENT abnormalities commonly used scale, is a subjective estimation of the propensity
disturbances
to doze off in eight situations.
Enlargement of the tonsils and A complete examination (Fig. 16.8) with especial attention to
adenoids and nasal obstruction nasal problems, craniofacial abnormalities, macroglossia, den-
Arrhythmia Alcohol Waist circumference <102 cm tal malocclusion, enlarged tonsils, BMI, neck circumference, the
(men), <88 cm (women) waist-to-hip ratio, and cardiac, neurological, and metabolic fea-
Stroke and Tobacco Enlarged neck circumference tures, has to be performed. Blood tests are needed if there is a clini-
cardiac failure (men: <43 cm; women: <37 cm) cal suspicion of hypothyroidism or significant metabolic or cardiac
problems. SBDs are associated with an increased rate of road traf-
Myopathies Sedatives Systemic hypertension
fic accidents, although effective therapy is capable of reducing this
Hypothyroidism Genetic Daytime fatigue or somnolence risk [26]. Sleep apnea is a risk factor for significant cardiovascular
Acromegaly that disturb life (no other cause disease and new onset of arterial hypertension [31,32], congestive
found) cardiac failure, atrial flutter, and stroke [4–6]. SAHS is also related
PATIENTS WITH SYMPTOMS DIFERENTIAL DIAGNOSIS
• Snoring • Bad sleep hygiene or restriction

• Witnessed apneas • Narcolepsy, RLS
• Nocturia • Insomnia, d epression
CLINICAL
• Table 3… • Drugs or neurological disease
• Compressive history and
• examination
Patients that need to be evaluated Management • Broad ENT examination
• Basic blood test with
PATIENTS AT HIGH RISK glycosylated Hb
INTENSITY OF THE SYMPTOMS
• Check for reflux
• Hypertension (resistant)
• Somnolence that disturbs life • Rule out other disease
• Obesity (BMI >35 kg/m2),
• Somnolence while driving
• Pulmonary hypertension
• Choking……Table 3
Table 3….
Sleep study SAHS suspicion

CPAP + general measures IAH > 30 + clear symptoms
Home portable High pre-test
** sleep monitoring
CPAP + general measures IAH > 15–30 + clear symptoms
HPSM
Mild-moderate suspicion
General measures ** No difficult patients No
IAH > 15–30 + no clear symptoms
HPSM or PSG severe comorbilities
*
General measures + CPAP IAH > 30 no symptoms Difficult patients
Polysomnography Severe comorbilities
(PSG) Neurological diseases
Always consider DAM, surgery. * Individualization. ** Personalization.
Fig. 16.9 Suggested approach to management of patients with sleep apnea.

It should be mentioned that the AHI taken in isolation is only a guide and the final therapeutic decision has to be made on the basis of overall evaluation (clinical
features and cardiovascular comorbidities).

Table 16.5 Differential diagnosis and other sleep disorders pauses. At present, it is estimated that 50–90% of people with the
condition remain undiagnosed. Heavy snoring, breathing pauses
Daytime Bad sleep hygiene, shiftwork, sleep apnea, depression, with asphyxia, and an increased neck or waist circumference point
somnolence narcolepsy to the possibility of sleep apnea (Table 16.3, in bold).
Narcolepsy Cataplexy: sudden and transient episodes of loss of After the clinical interview and examination, a sleep study will
muscle tone triggered by emotions generally be performed. Depending on patient characteristics, a
simplified study, normally carried out at home, or a full PSG will
Restless legs Need to move the legs that improves on moving
syndrome (RLS)
be performed (Fig. 16.9). Tables 16.2 and 16.3 summarize the dif-
Can cause insomnia or somnolence
ferent definitions of the respiratory events that can be identified in
Depression Lack of interest and pleasure in daily activities a sleep study and the recommended classification of SAHS severity
Negative thoughts as per the AASM recommendations [17]. SAHS is graded as mild
Insomnia Difficulty in initiating (20 min) or maintaining sleep, with when AHI is between 5 and 15 events per hour, moderate between
perception of poor quality 15 and 30 events per hour, and severe with more than 30 events per
Very stressful in some patients
hour [23]. Table 16.3 presents the sleep apnea hypopnea syndrome
as defined by clinical criteria and sleep study characteristics as per
Somnolence Antianxiety agents, some antidepressants or the AASM.
induced by drugs antihistamines, narcotics, and pramipexole
Central sleep apnea (CSA) is much less common than OSA [33].
Neurological Infections, tumors, Steinert disease (myotonic dystrophy It is caused by loss of ventilatory motor output. There is no flow or
diseases type 1), stroke thoraco-abdominal motion. Common causes, clinical findings and
REM behavior Singular, usually violent, behaviors during sleep treatment, are shown in Table 16.6.
disorder In some cases, precedes degenerative brain diseases An especially important cause is cardiac failure (crescendo–
decrescendo pattern) because of its prognostic significance for
Classical Somnambulism, nocturnal terrors, nightmares
cardiac disease and narcotics use. Patients who have obstruc-
parasomnias
tive apnea may also develop episodes of central apnea in the
Chronobiological Very important to be considered nowadays transition from awake to sleep. The pathophysiology is related
diseases to ventilatory instability (Cheyne–Stokes) or depression of the
respiratory centers (by opiates or sedatives). Treatment requires
an optimization of the disease, O2 supplementation in the ven-
tilatory instability group, and mechanical ventilation. Complex
to diabetes and the metabolic syndrome [8]‌, independent of other
sleep apnea can appear during CPAP titration in patients with
cardiovascular risk factors such as obesity or lipid disorders, which
OSA [34]. Usually, this is transitory and is eliminated after 4–
are highly prevalent in these patients. CPAP treatment for SAHS
8 weeks of CPAP therapy. In some patients bilevel positive air-
has been shown to cause a risk reduction in fatal and nonfatal car-
way pressure (BiPAP) or assisted support ventilation (ASV) is
diovascular events [5] (Some controversies exist after the SAVE
needed. To use ASV it is necessary to have a heart ejection frac-
study). Table 16.4 shows the different groups of patients at risk for
tion of more than 45.
developing sleep apnea, in most of whom a sleep test has to be
performed, especially if the complaint is snoring with respiratory
Management, including non-CPAP
treatments
Table 16.6 Central sleep apnea (CSA) Management
SBD, as a common chronic condition, ideally requires a multidis-
Causes Clinical Treatment ciplinary approach for its management [35–38]. Figure 16.9 shows
features
what should be the most appropriate approach to diagnosis and
Hypercapnic: Somnolence Treatment of the management.
Idiopathic central hypoventilation Fatigue underlying disease Figure 16.10 shows the most appropriate sensors to detect the
Arnold–Chiari Headache Noninvasive different SBD events. Figures 16.11 and 16.12 show a recommen-
Neuromuscular disease
ventilation dation relationship between the primary care physician and sleep
Narcotics
centers. Typical sleep apnea patients without severe associated dis-
ease can be managed by non-reference centers (Fig. 16.12) while
CSA is also associated with more difficult patients must be managed at the sleep unit. An ade-
obstructive sleep apnea at sleep quate follow-up to improve adherence (compliance) to CPAP treat-
onset, in which case CSA events
ment is a key point.
are common
Non-hypercapnic: Insomnia ASV
Cheyne–Stokes (cardiac failure) Fatigue BiPAP
Non-CPAP treatment
High altitude Dyspnea Oxygen Although CPAP is generally a very effective therapeutic modality,
Brain disorders Asphyxias at Acetazolamide
a significant percentage of patients cannot tolerate this treatment.
night In addition, in patients with mild to moderate SAHS, non-CPAP
Renal failure
treatments can play an important role, although the degree of

INCREASED UPPER AIRWAY

EVENTS SENSORS PHYSIOPATHOLOGY (UA) COL.LAPSABILITY
STATIC
APNEA Thermistor
OCCLUSION Total UA
obstruction
SIMILAR MANAGEMENT
Partial UA
obstruction
(flow limitation)
HYPOPNEA DYNAMIC
Nasal prongs
or UARS OCCLUSION
Slight UA
obstruction
(flow limitation)
SAME PHYSIOPATHOLOGY
Fig. 16.10 Suggested sensors for use in understanding the physiology of respiratory events.
Table 16.7 Non-CPAP treatment of sleep apnea

Multidisciplinary teams
u Weight reduction
Sleep specialist
u Positional therapy
General specialist
u Lifestyle modification: exercise, increased sleep time
Family physicians
u Intraoral protrusion devices: mandibular advancement devices,
Nurses Network Non-network tongue-retaining devices
Medical providers Optimal conditions Non-optimal conditions
Cost-effective Not cost-effective u Surgical: nose, craniofacial structures and upper airway soft tissue (UPPP,
tongue base and hypopharynx, multilevel)
Fig. 16.11 The most appropriate approach for the management of SAHS, is the
u Others: drug therapy, training the upper airway muscles, neurostimulation,
development of a network with different medical levels on.
oxygen, measures to decrease upper airway edema and treatment of
esophageal reflux
Special patients (non-serious diseases, insomnia,
depression, or suspicion of neurological entities)
Sleep unit
Reference hospital and bariatric surgery. The results are variable. The Task Force
Sleep unit Difficult
Non-reference hospital patients Multidisplinary team Committee of the AASM [41] concluded that effective dietary
SAHS suspicion Fully equipped
Family physicians RP management may improve AHI in obese patients with OSA,
or other specialist Can diagnose and manage a with a few cases even achieving recovery, and therefore die-
significant number of patients tary management must be combined with a primary treatment
(CPAP, intraoral devices, or surgery of the UA). Moreover, the
Fig. 16.12 Recommended algorithm for choosing between primary care
physicians and sleep center. Tertiary hospitals can solve a significant number of AASM states that bariatric surgery may play a role in the treat-
patients, using simple devices in accordance with guidelines. ment of patients with SAHS and morbid obesity, in combina-
tion with a primary treatment such as CPAP. Exercise, sufficient
amount of sleep, avoidance of alcohol and sedatives, and treat-
evidence for the effectiveness of each of these varies greatly [39] ment of gastroesophageal reflux are general measures that have
(Table 16.7). to be implemented in all cases.
Treatment of obesity and lifestyle modifications Postural treatment

Obesity is a major risk factor for SAHS. Weight loss increases It is well know that respiratory events are worse in the supine posi-
the size of the pharynx and reduces collapsibility, which often tion. The term “postural treatment” usually refers to prevention
results in an improvement of the SAHS [40]. The usual proce- of supine position during sleep, for which various methods have
dures for loss of weight in SAHS patients are dietary treatment been used; the tennis ball technique, the use of vests and special

pillows, or positional alarms. Postural treatment is used in patients rhinitis. However, the reviews do not recommend the use of other
with positional SAHS, which is generally defined as an AHI at least drugs in the treatment of SAHS [41,45].
two times higher in the supine than the lateral position. Veasey
et al. [41] and Oksenberg et al. [42] in their reviews mentioned sev- Surgical treatment
eral studies in which postural treatment produced clinical or PSG A wide variety of surgical techniques have been used in the treat-
improvement in AHI, especially in young but not obese patients, ment of SAHS as an alternative to CPAP and MADs, in order
with mild to moderate SAHS, but more studies are needed. The to reduce or eliminate the anatomical obstruction at the nose,
AASM [41] stated that postural treatment is an effective secondary the oropharynx, or hypopharynx or, in the case of tracheotomy,
treatment or may be a supplement to primary treatment in patients bypassing the pharyngeal part of the UA. The results are unpre-
with positional OSA. dictable and depend on various circumstances, particularly the
criteria used for selection of patients, the type of technique used,
Intraoral devices and the experience of the surgeon. The main patient-related fac-
Intraoral devices together with surgery in selected cases are tors that influence the success of the intervention are the follow-
the main alternative to CPAP, but are currently underutilized. ing: age, BMI, location of the obstruction, and severity of SAHS.
Mandibular advancement devices (MADs), which act by moving For selection of the surgical technique and localization of the site
the jaw and tongue forward, are the types most commonly used of obstruction, a clinical examination and lateral cephalometric
[43,44]. Other intraoral devices, such as tongue-retaining devices fiberoptic nasopharyngoscopy are needed. If patients are appro-
that keep the tongue in a forward position by suction, are used very priately selected, surgery may have a clear role in sleep apnea
little. The AASM [41] recommend MADs in patients with mild treatment. There are different surgical procedures: maxilloman-
to moderate OSA as an alternative to CPAP. Patients with severe dibular advancement, tonsillectomy in patients with tonsillar
SAHS should initially receive CPAP treatment. It is essential to hypertrophy, radiofrequency procedures at different levels, or
carry out a process of re-evaluation and titrating MADs in a new soft palate implants [46,47]. Regarding the uvulopalatopharyn-
sleep study performed with the intraoral device, since the improve- goplasty (UPPP) as an isolated procedure, the guidelines are very
ment of symptoms does not predict accurately the degree of reduc- restrictive, and it is only recommended in a few selected cases.
tion in the AHI. Finally, multilevel surgery is considered an acceptable option in
patients with multilevel obstruction of the UA as a last resort in
cases where CPAP and other conservative measures do not have
Drug treatment good results. An adequate selection process means satisfactory
There are many drugs that have been studied in clinical trials as results.
potential treatments for SAHS, and this topic has been the subject
of several reviews [41,45]. Most of these have concluded that evi-
dence regarding the pharmacological treatment of SAHS is lack-
SAHS as a chronic disease
ing. The AASM recommends modafinil in the treatment of patients Patients with SAHS often have multiple comorbidities, so a rational
with SAHS with residual sleepiness after adequate CPAP treatment approach to disease management should include coordination with
and topical nasal steroids when the condition is associated with physicians treating the comorbidities, and in most cases through
SLEEP
SYMPTOMS
TS ICS
C T IEN RIST
A H RO PA CTE INE NT
S NIC A M E
AI DIS AR ER EM
OS EA S C DET NAG
H
Well-being E A
EM
Exercise–nutrition TH
Associated diseases: ATE ENTS
DEQU F PATI
obesity, diabetes, When a disease is common, all A O t)
ON in
depression the medical levels must be
LECTI ey po
involved, SE (k
with appropriate technology
(networking)
Compliance PSG
Is the key point SIMPLIFIED
DIAGNOSIS. FOLLOW UP METHODS
SLEEP SPECIALIST HOME SLEEP LAB
OTHER SPECIALIST (virtual)
FAMILY PHYSICIAN, NURSES
Fig. 16.13 SAHS has to be considered as a chronic disease and therefore is needed to treat all the associated comorbidities. This slide summarizes all the levels and
strategies that may be involved in the appropriate management of SAHS patients.

the primary care physician. SAHS therapeutic strategies can be 8. Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep
divided into three categories: general health measures and medical apnea and type II diabetes: a population-based study. Am J Respir Crit
and surgical treatment. Considering that SAHS is a chronic disease, Care Med 2005;172:1590–5.
9. Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, et al. Spanish
there are different elements that should all be included in the com-
sleep and breathing network. Effect of continuous positive airway
prehensive strategic plan of SAHS management [48]. They can be pressure on the incidence of hypertension and cardiovascular events
summarized as follows: in nonsleepy patients with obstructive sleep apnea: a randomized
u Patient education on healthy lifestyle. Counsel the patient to controlled trial. JAMA 2012;307:2161–8.
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u Choice and adaptation of specific treatment for each patient
12. Guilleminault C, Stoohs R, Duncan S. Snoring (I). Daytime sleepiness
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ness. All patients with SAHS, which is a chronic disease, should 13. Guilleminault C, Stoohs R, Clerk A, Simmons J, Labanowski M. From
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with SAHS, and resolution of symptoms. Patients who have had of thermistors and thermocouples as flow-measuring devices for
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surgery or lost weight should be followed to monitor modifi-
15. Farre R, Montserrat JM, Navajas D. Noninvasive monitoring of
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symptoms. 16. Montserrat JM, Farre R, Ballester E, et al. Evaluation of nasal prongs
u Specifically, treatment with CPAP should be accompanied by for estimating nasal flow. Am J Respir Crit Care Med 1997;155:211–15.
17. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory
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very effective in terms of performance and achieving increased Sleep and Associated Events. J Clin Sleep Med 2012;8:597–619.
hours of nightly use (over at least 5 hours/night). 18. Pennock BE. Rib cage and abdominal piezoelectric film belts to
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19. Sackner MA, Adams JA. Piezoelectric sensor vs. respiratory inductive
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CHAPTER 17
Positive airway pressure therapy

Dirk Pevernagie
Introduction Treatment of SDB may aim at different outcomes. To achieve

adequate symptomatic control is the principal goal, as it promotes
Medical conditions characterized by impaired breathing dur- the patient’s quality of life. To reduce or normalize the apnea–â•‰
ing sleep are collectively referred to as sleep disordered breathing hypopnea index (AHI) is a means to monitor treatment efficacy,
(SDB). These disorders are heterogeneous and may result from dif- but not necessarily a treatment objective. There is only a weak cor-
ferent pathogenetic mechanisms. Inhibition of respiratory rhythm relation between symptomatic control and reduction in AHI [6]â•„.
generation in the central nervous system underlies central sleep Additional objectives are to prevent comorbidities and to prolong
apnea (CSA), whereas obstruction of the upper airway (UA) due to life expectancy. Adequate therapeutic control of AHI improves car-
muscle atonia in sleep is causal to obstructive sleep apnea (OSA). diovascular outcomes in patients with severe OSA [5]. Whether the
Disorders of impaired pulmonary ventilation, whether associated same holds true for patients with mild to moderate OSA, or CSA,
with lung diseases, obesity, or neuromuscular/â•‰skeletal diseases, are has not been confirmed yet.
designated as alveolar hypoventilation. Typically, sleep is the time
where alveolar hypoventilation emerges at first and deteriorates
later on in the course of the respiratory disease. Combinations of Physiological mechanisms of PAP treatment
these impaired breathing patterns are frequently observed in clini- The principal effect of CPAP is to increase intraluminal pressure
cal practice. Yet, it is customary to decide in the individual patient in the UA. The results of CPAP application in patients with sleep-â•‰
whether SDB is mainly central, obstructive, or related to hypoven- related UA obstruction were first published by Sullivan et al. in
tilation. A classification of SDB according to these pathophysiologi- 1981 [7]â•„. It was shown that with nasal pressure ranging from 4.5 to
cal conditions is presented in the International Classification of 10 cmH2O, sleep-â•‰related collapse of the UA could be abolished in
Sleep Disorders (ICSD-â•‰3) [1]â•„. five OSA patients. There is empirical evidence to show that the ele-
SDB may be associated with significant symptoms such as insom- vated pressure acts as a pneumatic splint supporting the action of
nia, unrefreshing sleep, excessive daytime sleepiness (EDS), fatigue UA dilating muscles that becomes insufficient during sleep. Passive
and decreased neurocognitive performance [2]â•„. These symptoms, collapse of the UA during sleep is prevented when the intraluminal
as well as health-â•‰related quality of life, may improve significantly pressure exceeds the critical closing pressure of the UA [8,9] (Fig.
with effective therapy [3,4]. Moderate to severe OSA is causally 17.1). Imaging of the UA has shown that increasing nasal CPAP
related to arterial hypertension, cardiovascular comorbidity, and progressively enlarges the cross-â•‰sectional area of the pharyngeal
decreased life expectancy [5]. Again, appropriate treatment may airway and that this effect is most obvious in the lateral as com-
redress these adverse outcomes, and therefore adequate medical pared with the anteroposterior dimension [10] (Fig. 17.2).
management of SDB is paramount. Besides stabilizing the UA on the basis of mechanical splinting,
Given their heterogeneity, respiratory sleep disorders cannot CPAP may exert other effects on the respiratory system. Elevated
be addressed by a generic approach. Some general principles are intrapulmonary pressure may increase lung volume [11], which
important, including advice on behavior and lifestyle and treatment in turn may decrease collapsibility of the UA through a caudal tug
of underlying or comorbid diseases. Pharmacological therapy, treat- on the central airways [12,13]. Possible other effects of CPAP are
ment with oral devices, or surgical interventions may be appropri- improved stability of the central respiratory drive, decreased work
ate in individual patients. Those treatment modalities are outside of breathing, and improved cardiac function due to reductions in
the scope of this chapter: the interested reader should consult other preload and afterload. These factors could play a role in the gradual
literature sources for further reference. Treatment of SDB with posi- attenuation of CSA that is observed in some patients with chronic
tive airway pressure (PAP) devices has been around for more than heart failure (CHF) treated with fixed CPAP [14].
three decades now. Continuous PAP (CPAP) is the cornerstone in Bilevel PAP devices deliver a preset pressure support (inspira-
the management of OSA and some types of CSA as well. Bilevel PAP tory PAP: IPAP) on top of a preset positive end-â•‰expiratory pres-
is indicated for the treatment of alveolar hypoventilation. Adaptive sure level (expiratory PAP: EPAP). As with CPAP, the EPAP should
servo-â•‰ventilation (ASV) is a sophisticated PAP treatment mode be sufficient to stabilize the UA. Setting IPAP at higher levels will
for Cheyne–â•‰Stokes respiratory pattern with CSA (CSR-â•‰CSA.) This increase tidal volume and minute ventilation, the aim of which is to
chapter will focus on indications, physiological effects, modalities, compensate for hypoventilation. The pressure support is triggered
and outcomes of PAP therapy. Since treatment must be tailored to by spontaneous breaths. Bilevel PAP machines also feature a timed
the individual patient’s requirements, combining different therapeu- mode that provides IPAP/â•‰EPAP cycles at a preset frequency when
tic options can be considered at any time in the course of treatment. the patient stops breathing.

4 PAP devices and interfaces
CSA of UA (cm2)
3
Treatment with PAP is based on delivery of pressurized airflow,
generated with fan-driven or turbine systems, adjustable by varying
2 valve diameter or turbine speed [15]. To this end, a blower device
is used that is connected to the UA via a hose and an interface. The
1 interface is a mask that transmits the pressure to the nasal or oro-
0 * * nasal airways (Fig. 17.4).
–5 0 5 10 15 20
Intentionally, PAP should be used every night, either at or
Airway pressure (cmH2O)
away from home (eg, during trips). Therefore, PAP devices must
be versatile with respect to power supply (eg, 110–230 V) and
Fig. 17.1 Compliance of the upper airway (UA) in a subject with OSA (full line) should be comfortable in terms of portability and ease of use.
and a normal control (dashed line) presented in a pressure–area plot. The cross- Contemporary PAP machines are lightweight and quite silent.
sectional area (CSA) of the upper airway is smaller in the OSA patient for any With modern electronic technology, monitoring of compliance,
given intraluminal airway pressure, indicating that the UA is less compliant. The air leakage, and effects on AHI has become a standard. Regular
critical closing pressure (Pclose, *) is the intraluminal airway pressure at which CSA updates of this machine-derived information may assist the prac-
is reduced to 0 cm². Pclose is positive in the OSA patient, whereas negative suction
titioner with ongoing patient education and fine-tuning of the
pressure in needed in the normal subject to close the airway.
Source data from J Appl Physiol, 82(4), Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T,
PAP settings.
Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects, The available literature on the physiological effects of CPAP is
pp. 1319–26, Copyright (1997), The American Physiological Society; J Appl Physiol, 105(5), based on the use of nasal masks. This is an important reality, because
Younes M, Role of respiratory control mechanisms in the pathogenesis of obstructive sleep delivery of positive pressure via the nose exerts a direct stabilization
disorders, pp. 1389–405, Copyright (2008) The American Physiological Society. of the velopharynx, i.e, the retropalatal segment of the UA, which
has an important role in the pathogenesis of OSA. Application of
–5 cmH2O CPAP via the oral or oronasal route may have less potent or even
adverse effects on the stability of the velopharyngeal airway, which
0 cmH2O could lead to persistence of respiratory events, even in the presence
of higher pressure levels [16,17].
5 cmH2O Based on this evidence and because the nose is the default
physiological route for tidal breathing, PAP should primarily be
administered via the nasal airway [18]. The oronasal route may be
10 cmH2O
considered in cases of impaired nasal breathing, but medical or sur-
gical treatment of nasal obstruction should always be considered
15 cmH2O
prior to switching from a nasal to an oronasal mask. There is no
convincing argument to use oral masks. Interface technology has
Fig. 17.2 Reconstruction of cross-sectional area (CSA) and shape of the
velopharyngeal airway at different intraluminal pressures obtained by CT scan in thrived in recent years. With the introduction of inflatable or mold-
an awake normal subject. able mask cushions, patients’ comfort has improved a lot. A broad
Adapted from Am J Respir Crit Care Med, 1996, 154(4), Schwab RJ, Pack AI, Gupta KB, Metzger LJ, variety of nasal and oronasal interfaces is currently on the market.
Oh E, Getsy JE, et al, Upper airway and soft tissue structural changes induced by CPAP in normal A venting mechanism to remove exhaled carbon dioxide is an inte-
subjects, pp. 1106–16, Copyright (1996), with permission from American Thoracic Society. gral part of the interface. A small hole or array of minuscule perfo-
rations in the mask is sufficient for this purpose.
ASV is a special type of bilevel PAP therapy. ASV devices pro- The interface should be optimally adjusted to fit the anatomical
vide adaptive pressure support that is inversely proportional to the configuration of nose (and also the mouth in the case of full-face
instant spontaneous tidal volume. The difference between IPAP and masks). It is important to prevent air leakage from the edges while
EPAP is minimal during normal breathing and particularly during not strapping the interface too tightly to the facial structures. Sores,
hyperpneic periods, whereas it automatically and proportionally especially on the nasal bridge, may be caused by excessive clamping
increases during the waning phases of respiration (Fig. 17.3). The of the mask, and this may be a reason for PAP discontinuation. The
aim is to counteract periodic breathing and to reduce overall min- final choice of the type of interface depends on anatomical char-
ute ventilation. acteristics, but also on personal preferences. It is not uncommon
Fig. 17.3 The principle of adaptive servo-ventilation (ASV): effects of ASV on Cheyne–Stokes respiration with central sleep apnea (CSA-CSR). During the increasing
phase of respiration, pressure support decreases to a minimum, whereas during the waning phase and especially during apneas pressure support reaches a maximum.

Chapter 17 positive airway pressure therapy 161
As the aim of CPAP treatment in OSA patients is to ensure

unimpeded breathing during sleep, the fixed pressure must warrant
sufficient patency of the UA in all sleep stages and body postures.
CPAP is effective when all apneas, hypopneas, respiratory effort-
related arousals, and snoring events are controlled. The American
Academy of Sleep Medicine (AASM) used to advocate in-lab man-
ual pressure titration to determine the effective CPAP level [20].
However, methods based on autotitrating CPAP (APAP) [21] and
CPAP prediction formulas [22,23] may also be effective in this
respect. A comprehensive multicenter trial from the Spanish Sleep
and Breathing Network nicely demonstrated that different titration
techniques yield similar results [24]. Masa et al. randomized 360
CPAP-naive patients with severe OSA and EDS, into three parallel
groups, characterized by different CPAP initiation modes: standard
manual titration, APAP initiated at home or fixed CPAP assessed
with a prediction formula. After 3 months, a comparable improve-
ment in AHI, subjective sleepiness and compliance was found in
all three groups. Obviously, effective CPAP can be determined in
different ways, and there is increasing evidence for non-superiority
of the different assessment strategies [25]. The preference for a cer-
tain method is linked with patient-related characteristics including
severity of OSA, the presence of obesity or comorbid diseases, as
Fig. 17.4 PAP equipment. A blower device is connected to an interface via a well as social and psychological intricacies.
tube. The interface is fixed to the external nasal or oronasal airway with headgear, No guidelines exist for setting effective CPAP in CSA. Evidence
consisting of adjustable straps. In this drawing, a classical nasal mask (top left),
for pressure-dependent control of central respiratory events is lack-
nasal pillows (top right), and full-face mask (bottom right) are shown.
Reproduced courtesy of http://www.fotosearch.com/CSP813/k8137593/
ing, whereas it has been shown that the CSA index may dimin-
ish over time with continued CPAP use [14]. A short-term trial of
CPAP may be insufficient to draw conclusions regarding its treat-
having to try several masks in the early phase of PAP treatment, ment efficacy in CSA. It is recommended to empirically start CPAP
but regular nasal masks or nasal pillows are suitable for most PAP at low pressure levels and to reexamine the AHI after 6 and 12
indications in common practice. weeks of treatment in this patient category.
Bilevel PAP and ASV must be started in a supervised setting. To
Initiation of PAP treatment elaborate on these procedures is outside the scope of this chapter.
Therapy with PAP can be initiated either in a clinical environment

or at home. The former option ensures adequate supervision for Clinical results of PAP therapy
purposes of education and dedicated nursing support. Remedying Nasal CPAP is the gold standard for the treatment of moderate to
adverse side effects right from the start is favorable for better com- severe OSA [26]. Satisfactory clinical effects appear soon after com-
pliance in the long term (see the discussion further in this chap- mencement of therapy, often already following the first nights of
ter). However, admission to the sleep laboratory or hospital ward successful CPAP use. Sleep quality is positively affected. Rebound of
is expensive and labor-intensive. Economic constraints have pro- slow-wave sleep and REM sleep may be observed in the first nights
moted alternative approaches requiring fewer staff or enabling of CPAP treatment. Moreover, this apparent change in sleep archi-
commencement of PAP therapy at home. Which of these manage- tecture seems to correlate with subjective improvement in sleep
ment strategies is superior in terms of medical outcomes is uncer- quality [27]. EDS may recover substantially, as has been shown in
tain. Contemporary information and communications technology several randomized controlled trials [28,29]. Partial improvement
hold promise for telemonitoring of PAP utilization and may offer in cognitive performance has been reported, and a significant effect
a compromise between these two methods for initiating PAP treat- on attention seems most noticeable [30]. Drowsy driving is a haz-
ment [19]. ard in untreated OSA patients. They have a significantly elevated
The supervised setting offers the advantage of having the possi- risk of motor vehicle accidents [31], which is reduced after success-
bility to start up and titrate CPAP in the second half of an overnight ful treatment with CPAP [32].
polysomnographic (PSG) procedure. A so-called split-night study CPAP therapy also has favorable effects on cardiovascular sta-
combines diagnosis of OSA and commencement of CPAP treat- tus and prognosis. Blood pressure may be significantly reduced
ment in one session. The split-night approach seems feasible for in patients with moderate to severe OSA. A recent meta-analysis
patients with moderate to severe OSA. PSG all-night trends may found a mean net reduction in systolic blood pressure of 2.6 ±
show dramatic improvements of sleep architecture and cardiorespi- 0.5 mmHg and in diastolic blood pressure of 2.0 ± 0.4 mmHg [33].
ratory variables (Fig. 17.5). Manual upward pressure titration is car- Moreover, a higher baseline AHI was associated with a greater mean
ried out as in full-night titration studies. However, insufficient time net decrease in systolic blood pressure. In a recent study including
to assess the effective pressure level or issues with adaptation to the patients with OSA and resistant hypertension, CPAP treatment for
PAP equipment are salient limitations to this intervention [20]. 12 weeks compared with control resulted in a decrease in 24-hour

100
75
100
75
50
W
R
1
2
3
00:00 01:00 02:00 03:00 04:00 05:00
23:11 00:00 01:00 02:00 03:00 04:00 05:00
Fig. 17.5 All-night trends from a split night study. This demonstrates all-night trends from a split-night study in a patient with severe OSA. From top to bottom are
shown oxygen saturation from pulse oximetry (SpO2, %), instantaneous heart rhythm derived from the ECG (bpm), and the hypnogram (showing stages wake, REM
sleep, and NREM sleep 1, 2, and 3). The left part represents spontaneous breathing with untreated severe OSA. There are marked SpO2 dips, cardiac arrhythmias, and
severely disrupted sleep. At 02:00, CPAP was started with a pressure of 8 cmH2O. As a consequence, SpO2 and cardiac rhythm become remarkably stable and there is a
rebound of slow-wave sleep and REM sleep.
mean and diastolic blood pressure and in an improvement of the trial), CPAP attenuated CSR-CSA and improved CSA index, noc-
nocturnal blood pressure pattern [34]. Untreated severe OSA has turnal oxygenation, ejection fraction, norepinephrine (noradrena-
been shown to be a strong independent predictor for cardiovascu- line) levels, and six-minutes-walking distance [43]. However, CPAP
lar events and all-cause mortality. In a long term follow-up study, treatment was not associated with a better transplant-free survival.
effective CPAP treatment was associated with markedly improved While these data did not support the use of CPAP to extend life in
cardiovascular outcomes in this category of OSA severity [35]. To patients with CHF and CSA-CSR, a post hoc analysis demonstrated
what extent CPAP may prevent cardiovascular complications in improvement of cardiac function and transplant-free survival rates
patients who are not somnolent or who have only mild disease in CHF patients in whom AHI was effectively reduced by CPAP as
remains equivocal [36,37]. compared with CPAP-resistant controls [44].
Besides obesity and arterial hypertension, OSA is also associated The application of bilevel PAP seems to bring no advantage over
with disturbed glucose metabolism, insulin resistance, diabetes CPAP treatment in patients with CSA and CHF [45]. In contrast,
mellitus and hyperlipidemia/hypercholesterolemia, and elevated deterioration of SDB has been reported in CSA patients on bilevel
serum markers of systemic inflammation. This cluster of symptoms PAP therapy, presumably because of excessive minute ventilation,
and signs is commonly referred to as metabolic syndrome [38]. which tends to worsen hypocapnia and the associated periodic
Several trials have studied the effects of OSA and CPAP treatment breathing pattern [46]. With the introduction of ASV about a dec-
on glycemic control and insulin resistance. In non-diabetic patients, ade ago, a convenient treatment modality for CSR-CSA became
a significantly improved insulin resistance was found when patients available. ASV has been proven superior in reducing the CSA-
with moderate to severe OSA were treated with CPAP [39]. In index in CHF patients, as compared with other treatment options,
male patients with type 2 diabetes and OSA, therapeutic CPAP did including CPAP, bilevel PAP, and oxygen supplementation [47]. In
not significantly improve measures of glycemic control or insulin addition, treatment compliance with ASV may be better than with
resistance as compared with placebo [40]. Neither does CPAP seem CPAP [48]. Although it was observed that ASV may improve left-
to reduce hemoglobin A1c levels in patients with or without type ventricular ejection fraction in patients with CHF and CSR-CSA
2 diabetes [41]. Effects of CPAP on markers of systemic inflamma- [49], a large controlled trial with this therapeutic modality failed
tion are uncertain and as yet still controversial [42). to show any significant effect on salient clinical outcomes (SERVE-
Data on effects of CPAP in CSA have predominantly been HF study) [50]. There were no improvements regarding mortal-
obtained in patients with CHF. In one large survey (the CANPAP ity, need for lifesaving cardiovascular interventions, or unplanned

hospitalization for worsening heart failure. Moreover, there was Table 17.1 Adverse side effects of PAP therapy and proposed remedies
evidence that all-cause and cardiovascular mortality were both
increased with this therapy. As a consequence, it is advised not to Adverse side effect Proposed remedies
prescribe ASV to patients with CSR-CSA and CHF if the ventricu-
Rhinitis and nasal congestion Apply heated humidification; prescribe
lar ejection fraction is less than 45% [50].
topical steroids; consult ENT surgeon
Sores (ulceration) of nasal Change mask type; loosen straps or
Optimizing adherence and compliance bridge or other facial structures headgear
with PAP therapy Eczema, irritation of skin Change mask type
Difficulties with acceptance and tolerance are commonly seen as
Streaks on face (visible upon Change type of mask and/or headgear
the main disadvantages of PAP treatment. While adherence means awakening in the morning)
continuing the treatment, and compliance refers to using PAP for
a certain amount of time, both terms are used interchangeably in Ectopic insufflation of air Reduce pressure settings; change to
(bloating, ructus, flatus) non-PAP therapy
the literature. Although the definition of adequate compliance is
arbitrary, between 46% and 83% of unselected OSA patients have Air leaks at boundaries of Tighten headgear or use other type
been reported not to meet the requirement of using CPAP at least interface of mask
4 hours per night for at least 70% of nights [51]. Certain measures Mouth leakage Reduce pressure settings; use chin straps;
can be taken to optimize PAP use, the goal of which should be change to non-PAP therapy
to use PAP for at least 6 hours every night [52]. Indeed, in OSA Noise of apparatus (machine Check sealing of mask; check operational
patients, a dose–response relationship has been found between and/or mask) aspects of CPAP device
time used and improvement of EDS [53], as well as effects on arte-
Water condensation in mask Increase bedroom temperature; use
rial hypertension [54].
and circuit heated CPAP hose
Factors determining adherence and compliance
Several factors are related to compliance with CPAP therapy in
OSA patients. Improvement of sleep quality and REM rebound is The manufacturing industry has made serious efforts to upgrade
predictive of adherence [55,56]. Socio-economic status, age, and systems with air conditioning and adaptive pressure modalities.
gender have not been reported to be important, whereas OSA To enhance the comfort of nasal breathing, heated humidifica-
severity and daytime dysfunction are associated with better treat- tion has been added to most commercially available PAP devices.
ment outcomes [51]. Appropriate usage at the start of treatment is Indeed, conditioning the inspired air with heat and moisture may
also a good indicator for adequate long-term adherence to CPAP prevent or relieve symptoms of rhinitis. While recent evidence con-
[57]. Therefore, technical troubles and annoying side effects should firms that CPAP-associated inflammation of the nasal mucosa may
be tackled early on. be alleviated with heated humidification [60], it is unclear whether
Besides assuring optimal treatment comfort, appropriate patient this addition may improve long-term adherence.
education may enhance therapeutic results. Extensive information To tackle complaints of pressure intolerance, modifiable pressure
provided at the outset of CPAP treatment does not seem to increase settings have been introduced. Most CPAP machines feature a ramp
compliance, whereas supportive interventions to continue CPAP facility allowing a gentle increase of pressure to the preset level over
therapy may be helpful [58]. Cognitive–behavioral therapy aiming 20 minutes or so. This mode may be helpful to allow the patient to
at accepting and thinking positively about CPAP therapy may boost get accustomed to the external pressure sensation, especially at the
compliance when compared with care as usual [59]. beginning of PAP treatment. Adapting the pressure profile in the
course of the respiratory cycle is another means to enhance breath-
Adverse side effects and their management ing comfort. Expiratory pressure relief (EPR) may improve toler-
ance to the administration of higher levels of inspiratory pressure,
Because the PAP device is connected to the UA by an interface, side
effects may arise from the physical impact of the mask and/or the
insufflation of air into the respiratory tract (and sometimes the gas- Table 17.2 Psychosocial issues related to PAP therapy and suggestions
trointestinal tract). These side effects may be bothersome but are as for management
a rule not serious or life-threatening. Any nuisance or complication
of PAP therapy should be managed appropriately and promptly as Psychosocial issues Management
to preserve optimal treatment compliance. Some hints to correct Unable to tolerate mask owing to Carry out assisted training sessions
common side effects are detailed in Table 17.1. claustrophobia during daytime; psychotherapy
Psychological problems with respect to accepting treatment may
Not fancying the idea of being Increase educational efforts; cognitive–
also adversely affect adherence and compliance. Table 17.2 lists dependent on a machine “for the behavioral therapy; involve partner or
some frequently reported psychosocial issues and how they can be rest of my life” relatives
managed.
Interference with talking and Schedule activities; do not put on mask
Adaptations of PAP technology to intimacy in bed except when preparing to go to sleep
improve compliance Having to disclose PAP equipment Put equipment in luggage to be
from carry-on bags at security checked in
In recent years, several adjustments have been made to commercial
checks
PAP machines in order to enhance versatility and comfort of use.

Pressure 3. Jing J, Huang T, Cui W, Shen H. Effect on quality of life of continuous

20 positive airway pressure in patients with obstructive sleep apnea
15 syndrome: a meta-analysis. Lung 2008;186(3):131–44.
cmH2O
10 4. Sanchez AI, Martinez P, Miro E, Bardwell WA, Buela-Casal G.

CPAP and behavioral therapies in patients with obstructive sleep
5
apnea: effects on daytime sleepiness, mood, and cognitive function.
0 Sleep Med Rev 2009;13(3):223–33.
0 1 2 3 4 5 6 7
Time (h) 5. Sanchez-de-la-Torre M, Campos-Rodriguez F, Barbe F. Obstructive
sleep apnoea and cardiovascular disease. Lancet Respir Med
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treatment. Some OSA patients who restart CPAP therapy after with obstructive sleep apnea and in normal subjects. J Appl Physiol
previous treatment failure may benefit from this adaptive pressure (1985) 1997;82(4):1319–26.
9. Younes M. Role of respiratory control mechanisms in the
mode [61].
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Equipment for autotitrating CPAP (APAP) has been commercial- 2008;105(5):1389–405.
ized for about two decades now. These devices change the required 10. Schwab RJ, Pack AI, Gupta KB, et al. Upper airway and soft tissue
CPAP level based on feedback from various variables such as airflow, structural changes induced by CPAP in normal subjects. Am J Respir
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Appropriate detection of respiratory anomalies and adequate airway pressure effects on central sleep apnoea in patients with chronic
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pressure response to these events is fundamental to APAP technol-
15. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the
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PLoS One 2013;8(5):e64382.
Accordingly, the performance of APAP devices cannot be checked,
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CHAPTER 18
Central sleep apnea and

hypoventilation syndromes
Mithri R. Junna, Bernardo J. Selim,
and Timothy I. Morgenthaler
Pathophysiology ventilatory response to changes in PaCO2 and PaO2; (2) the plant

gain, which is the ventilatory response to changes in pulmonary
Normally, ventilation during sleep is carefully regulated to main- capillary PaCO2 and PO2; and (3) the mixing gain, which is the cir-
tain homeostasis of blood pH and blood oxygen content by the culatory time needed for changes in PaCO2 and PO2 in pulmonary
central nervous system response to anatomic detectors of pH (most capillaries to be detected by the chemoreceptors (effective circula-
prominently chemoreceptors on the ventrolateral surface of the tory time) [3]. Disorders such as idiopathic CSA, Cheyne–â•‰Stokes
medulla oblongata) and oxygen content (detected predominantly respiration (CSR), and high-â•‰altitude CSA are considered to be
in carotid and aortic bodies). These chemoreceptors, in propor- the result of high “loop gain” of the respiratory control system.
tion to higher PaCO2 (lower serum pH) and low oxygen content, Because of the dependency on a PaCO2-â•‰driven ventilatory response,
stimulate activity of the pontomedullary pacemaker, which in turn these breathing disorders are generally exclusive to NREM sleep,
activates inspiratory thoracic muscles with augmentation of venti- where the ventilatory pattern is particularly influenced by chemical
lation. The resultant increased ventilation tends to ameliorate the drive. In REM sleep, ventilatory pattern is influenced by a combi-
initially detected disturbance in homeostasis, re-â•‰establishing the nation of chemical and other nonmetabolic influences, producing
desired pH and oxygen set points. [Recall that ventilation has an lower ventilatory responsiveness to hypercapnia and hypoxia, and
inverse relationship to PaCO2 (and, to a lesser extent, the oxygen less tendency to over-â•‰or under-â•‰react to transient perturbations in
content of the blood), and that pH in turn has a reciprocal relation- ventilation.
ship to PaCO2 (so that a higher PaCO2 is associated with a lower
pH)]. In general, the ventilatory response to PaCO2 is thus propor-
tional, and is blunted in NREM and REM sleep. Sudden changes Alveolar hypoventilation syndromes
from sleep to wake or vice versa can result in sudden changes in This group of disorders are defined by an elevated nocturnal PaCO2
the desired PaCO2 set point, with resultant instability in ventila- level (>45 mmHg), which may extend into the daytime. The main
tory patterns. Such instability is particularly notable when PaCO2 respiratory abnormality resides anywhere along the brainstem res-
is normal or low, and less likely to occur in conditions where it is piratory control center (e.g., congenital central alveolar hypoven-
high [1]â•„. In central sleep apnea (CSA) syndromes, apnea events tilation syndrome), throughout the respiratory motor output unit,
generally result from temporary cessation of pontomedullary pace- from the motor neuron to the innervated respiratory muscle.
maker activity. Considering the mechanism(s) and the resulting Because the causes of alveolar hypoventilation with or without
tension of carbon dioxide in blood (PaCO2), CSA may be grouped central apneas are multiple, a clinical classification based upon
into (1) non-â•‰hypercapnic CSA (the most prevalent category) and the patient’s pulmonary function can help to differentiate abnor-
(2) alveolar hypoventilation syndromes. malities of the ventilatory drive (autonomic/â•‰metabolic respira-
tory control system) associated with normal pulmonary function,
Non-â•‰hypercapnic CSA versus abnormalities of pulmonary mechanics with subsequent
The most prevalent forms of CSA fall into this category. If meas- abnormal pulmonary function. Pulmonary function is commonly
ured, the PaCO2 is either normal (35 mmHg ≤ PaCO2 ≤ 45 mmHg) evaluated based upon information obtained in a pulmonary func-
or low (PaCO2 < 35 mmHg). In non-â•‰hypercapnic CSA, apneic tion test (PFT), further narrowing the differential diagnosis in
events are most often the result of over-â•‰response or under-â•‰response hypoventilation. Patterns of volume and flow changes observed
of the respiratory control system to minimal changes in nocturnal via spirometry and lung volumes can support an obstructive (e.g.,
PaCO2 (high “loop gain”) [2]â•„. Loop gain is an engineering term chronic obstructive pulmonary disease, COPD) or restrictive (eg,
that describes the degree of response, in this case, of the respiratory neuromuscular-â•‰skeletal diseases) physiology. Information from
control system, after a ventilatory disturbance. The higher the loop the diffusion capacity of carbon monoxide (DLCO) can point to
gain, the higher the overventilation or underventilation response, changes in the surface of gas exchange (e.g., emphysema) or vas-
resulting in respiratory instability. Loop gain comprises three com- culature (e.g., pulmonary hypertension). When neuromuscular
ponents: (1) the controller gain, which is the chemoreceptor-â•‰driven diseases are in question, maximal respiratory pressures can reflect

Table 18.1 Chronic alveolar hypoventilation syndromes and with frequent nocturnal awakenings and consequent nonrestora-
evaluations tive sleep and daytime sleepiness.
Evaluation Brainstem Respiratory Thoracic cage Diagnosis

respiratory motor output or pulmonary During diagnostic polysomnography (PSG), five or more central
control center unit failure* disease apneas or hypopneas per hour of sleep must be demonstrated, and at
failure
least 50% of the total number of apneas and hypopneas seen during
PaCO2 , or may be   the diagnostic PSG must be central apneas or hypopneas. The pat-
 by voluntary tern of ventilation should fulfill criteria for Cheyne–Stokes breath-
hyperventilation ing defined as a crescendo–decrescendo pattern, typically of length
Chest X-ray N, or signs of N, low lung N or abnormal, 45–60 s (Fig. 18.1). The disorder should not be better explained by
pulmonary volumes, or depending a concurrent sleep disorder or medication or substance use.
hypertension hemidiaphragm on underlying
elevation disease Treatment
Diaphragmatic N N or N If underlying heart failure is present, optimal medical management of
fluoroscopy paradoxical this condition is recommended through diet, lifestyle, and pharma-
(“sniff test”) upward cological therapies. Assistive devices such as continuous positive air-
movement of way pressure (CPAP) and adaptive servo-ventilation (ASV) devices
hemidiaphragm remain the mainstay of treatment. Attended PSG is recommended
Nerve conduction N  or absence N to determine effectiveness for either device. Contradictory informa-
study of phrenic tion exists regarding survival (transplant-free survival) and cardiac
nerve action function with the use of CPAP. If used, it should be titrated to ensure
potential control of sleep disordered breathing [4]‌. Retrospective studies, or
Diaphragmatic N Abnormal N subgroup analysis of prospective studies, show that patients with sys-
EMG tolic heart failure on treatment with ASV have long-term improve-
Pulmonary N Restrictive Restrictive (e.g., ments in respiratory events, cardiac NYHA functional class, and
function test kyphoscoliosis) cardiopulmonary exercise tolerance parameters, and a decrease in
(PFT) or obstructive the number of cardiac events (cardiac death and re-hospitalization)
(e.g., COPD) at 6-month follow-up. A similar profile of improvements has also
MIP/MEP or Pdif N  N
been shown in patients with diastolic CHF-CSR on ASV [5], as well
as CHF patients with obstructive and central sleep apnea occurring
Ventilatory Abnormal N or slightly N or slightly concurrently within the same night [6], independent of the severity
response to CO2 blunted blunted
of sleep disordered breathing [7]. However, prospective randomized
and O2
control trials are needed to confirm the impact of ASV on mortality
Polysomnography Hypoventilation Hypoventilation Hypoventilation rates and transplantation-free survival rates [8]. A word of caution
with sustained with sustained with sustained is needed regarding ASV treatment in systolic heart failure in view
oxyhemoglobin oxyhemoglobin oxyhemoglobin of the recent SERVE-HF clinical trial report [9] showing increased
desaturations, desaturations, desaturations,
mortality in patients with ejection fraction ≤ 45%.
more severe worse in REM. worse in REM
during slow- Presence of
wave sleep, less central or CSA due to drug or substance use
in REM. Variable obstructive
presence of apneas Clinical presentation
central apneas This disorder occurs in those using long-term opioid medications,
most often methadone, although also others. Bed partners may
*Respiratory motor neurons, spinal cord, phrenic nerves, respiratory muscles.
report nocturnal snoring, gasping, and apneas. Patients may report
N: normal; EMG: electromyogram; MIP: maximal inspiratory pressure; MEP: maximal
expiratory pressure; Pdif , transdiaphragmatic pressure; REM, rapid eye movement. sleep maintenance difficulties, with frequent nocturnal awakenings
and consequent nonrestorative sleep and daytime sleepiness.
changes in inspiratory and expiratory respiratory muscle strength Diagnosis

(Table 18.1). During diagnostic PSG, five or more central apneas or hypopneas
per hour of sleep must be demonstrated, and at least 50% of the
CSA with Cheyne-Stokes breathing total number of apneas and hypopneas seen during the diagnostic
PSG must be central apneas or hypopneas. Cheyne–Stokes breath-
Clinical presentation ing pattern must be absent. The breathing pattern must be due to
This disorder tends to occur in older men, particularly those with use of an opioid or other respiratory depressant. Other irregular
atrial dysrhythmias, diastolic or systolic congestive heart failure patterns of ventilation such as ataxic or Biot’s patterns may be noted
(CHF), or stroke. Bed partners may report nocturnal snoring, gasp- (Fig. 18.2). The disorder should not be better explained by a con-
ing, and apneas. Patients may report sleep maintenance difficulties, current sleep disorder.

Chapter 18 central sleep apnea and hypoventilation syndromes 169
LOC-Fz
ROC-Fz
Fz-Cz
Cz-Oz
C3-A2
Chin EMG
Leg EMG
ECG
ON flow
Nasal P
Sono
SaO2
Sum
Chest
Abd
HR
Fig. 18.1 Cheyne–Stokes breathing. This PSG segment obtained from a patient with compensated systolic heart failure shows 10 epochs of 30 s. Each heavy vertical
line demarks 30 s. The thermal sensor channel (ON flow) shows the presence of apneic events as a drop of ≥ 90% of peak thermal sensor signal from baseline. The nasal
pressure signal (Nasal P) denotes episodes of ≥ 3 consecutive central apneas separated by a crescendo and decrescendo change in breathing amplitude with a cycle
length of ≥ 40 s. LOC-Fz and ROC-Fz are left and right electro-oculograms. Fz-Cz, Cz-Oz, and C3-A2 are frontal, occipital, and central EEG montages, respectively. Chin
EMG and Leg EMG represent submental and pre-tibial EMGs. The electrocardiogram (ECG) shows sinus rhythm. Sono is a snoring microphone, and is unremarkable.
Abd and Chest are abdominal and chest respiratory impedance plethysmography signals that demonstrate changes in circumference at those levels, usually taken to
represent muscular effort. The Sum signal is the arithmetic summation of deflection of Abd and Chest signals, and parallels tidal volume when calibrated. HR is the pulse
rate, as read.
Treatment to provide ventilatory support in hypoventilation syndromes, but

As the effect of opioids on central apneas is dose-dependent, dis- only a slight hypoventilatory target from baseline values.
continuation or reduction of the dose of opioid, as tolerated, is
recommended [10]. Primary CSA
There are limited data to support the use of assistive devices. Clinical presentation
Attended PSG is needed to determine effectiveness. CPAP may This rare disorder is considered to be idiopathic, or of unknown eti-
reduce the number of respiratory events, but frequently does not ology, often occurring in middle-aged to older adults. Bed partners
result in effective control of sleep disordered breathing. There are may report nocturnal snoring, gasping, and apneas. Patients may
conflicting data about the role of ASV in this group of patients. One report sleep maintenance difficulties, with frequent nocturnal awak-
study that did not show ASV efficacy did not titrate therapy accord- enings and consequent nonrestorative sleep and daytime sleepiness.
ing to protocol. In two other studies with appropriate titrations, ASV
was effective in the majority of cases. At this point, if efforts at reduc- Diagnosis
ing or eliminating opioids are not fruitful, the use of ASV is probably During diagnostic PSG, five or more central apneas or hypopneas
appropriate. However, caution must be used, as ASV is not designed per hour of sleep must be demonstrated and at least 50% of the total

LOC-Fz
ROC-Fz
Fz-Cz
Cz-Oz
C3-A2
Chin EMG
Leg EMG
ECG
ON flow
Nasal P
Sono
SaO2
Chest
Abd
HR
Fig. 18.2 Opioids and ataxic breathing. This PSG segment obtained from a patient on chronic opioid medications shows 10 epochs of 30 s. Each heavy vertical line
demarks 30 s. The thermal sensor channel (ON flow) and the nasal pressure signal (Nasal P) denote an ataxic or irregular breathing pattern with clustering. Note that
most apneas here are central, but there is no clear period. Not discernible from this level of scrutiny, most of these apneas are not associated with arousals, despite the
clear oxyhemoglobin desaturation (see the signal labeled SaO2). LOC-Fz and ROC-Fz are left and right electro-oculograms. Fz-Cz, Cz-Oz, and C3-A2 are frontal, occipital,
and central EEG montages, respectively. Chin EMG and Leg EMG represent submental and pre-tibial EMGs. The electrocardiogram (ECG) shows sinus rhythm. Sono
is a snoring microphone, and is unremarkable. Abd and Chest are abdominal and chest respiratory impedance plethysmography signals that demonstrate changes in
circumference at those levels, usually taken to represent muscular effort. The Sum signal is the arithmetic summation of deflection of Abd and Chest signals, and parallels
tidal volume when calibrated. HR is the pulse rate, as read.
number of apneas and hypopneas seen during the diagnostic PSG should be obtained to ensure that ventilation is not worsened with
must be central apneas or hypopneas. Cheyne–Stokes breathing supplemental oxygen.
pattern must be absent. There should be no evidence for daytime
or nocturnal hypoventilation. The disorder should not be better Treatment emergent central apnea (also
explained by a concurrent sleep disorder, medical or neurological
disorder, or medication or substance use.
called complex sleep apnea syndrome)
Clinical presentation
Treatment This disorder is thought to occur in 5–20% of individuals under-
There are limited data to support pharmacological use of acetazola- going initial titration with positive airway pressure treatment for
mide, zolpidem, or triazolam. predominantly obstructive sleep apnea. Bed partners may report
There are limited data to support the use of assistive devices in the nocturnal snoring, gasping, and apneas. Patients may report sleep
form of CPAP, bilevel PAP with a back-up respiratory rate (BPAP- maintenance difficulties, with frequent nocturnal awakenings and
ST), or ASV [4]‌. consequent nonrestorative sleep and daytime sleepiness.
Oxygen supplementation may decrease respiratory controller
gain and stabilize breathing, but may worsen respiratory acidosis Diagnosis
associated with alveolar hypoventilation. Therefore, it should be During therapeutic PSG with the use of a positive airway pres-
tried first under monitored conditions, and an arterial blood gas sure device without a back-up rate, (1) resolution of obstructive

(a) Diagnostic stage (b) CPAP titration
Loc-Fz Loc-Fz
ROC-Fz ROC-Fz
Fz-Cz Fz-Cz
Cz-Oz
Cz-Oz
C3-A2
C3-A2
Chin EMG
Chin EMG
Leg EMG
Leg EMG
EKG
EKG
ON Flow
Nasal P Nasal P
Sono
SaO2
SaO2 Sum
Sum Abd
Abd Chest
Chest HR
HR
Fig. 18.3 Treatment emergent central (complex) sleep apnea. (a) This diagnostic PSG segment obtained from a patient with complex sleep apnea shows 5 epochs of
30 s with obstructive sleep apnea events. Each heavy vertical line demarks 30 s. The thermal sensor channel (ON flow) shows a drop of ≥ 90% of peak thermal sensor
signal from baseline. LOC-Fz and ROC-Fz are left and right electro-oculograms. Fz-Cz, Cz-Oz, and C3-A2 are frontal, occipital, and central EEG montages, respectively.
Chin EMG and Leg EMG represent submental and pre-tibial EMGs. The electrocardiogram (ECG) shows sinus rhythm. Sono is a snoring microphone showing reopening
of the upper airway with reinstitution of airflow at the end of the apneic event. Abdominal (Abd) and chest (Chest) respiratory impedance plethysmography signals
demonstrate paradoxical respiratory efforts. HR is the pulse rate, as read. (b) The CPAP titration trial shows elimination of obstructive apneas followed by emergence
of central apneas. The thermal sensor channel (ON flow) shows a drop of ≥ 90% of peak thermal sensor signal from baseline. Abdominal (Abd) and chest (Chest)
respiratory impedance plethysmography signals demonstrate absence of respiratory efforts during apneic events.
disordered breathing events must be demonstrated and (2) emer- certain patients [12]. Given the current limited data, patients with
gence of central apneas must be seen (Fig. 18.3). During this por- this disorder should probably be initially treated with ASV, or if
tion of the study, there must be five or more central apneas and good follow-up is assured, it may be reasonable to try CPAP for up
hypopneas per hour of sleep, and at least 50% of the total number of to 30 days and reassess.
apneas and hypopneas seen must be central in nature. The disorder
should not be better explained by another CSA disorder. Obesity hypoventilation syndrome
Treatment Clinical presentation
Treatment of complex sleep apnea syndrome is currently somewhat This disorder is seen in obese individuals and often coexists with
controversial. Even though the disorder most often becomes appar- obstructive sleep apnea. Patients may complain of sleep mainte-
ent during titration of CPAP, many advocate a more protracted nance difficulty and nonrestorative sleep, but, more consistently,
trial of CPAP. Retrospective studies suggest that as many as 95% of they complain of early morning headaches, confusion, and day-
patients will stabilize their breathing patterns on CPAP. These retro- time sleepiness, often correlating with their degree of nocturnal
spective studies are potentially biased by significant drop-out rates. hypercapnia.
A prospective trial has shown that only two-thirds of such patients
resolve, while over 90% of those treated with ASV show both ini- Diagnosis
tial and long-term control of sleep disordered breathing [11]. The Patients are noted to be obese, as defined by a body mass index
data available up until now discourage the use of BPAP-S mode (BMI) over 30 kg/m2. During wakefulness, there is presence of
in complex sleep apnea syndrome. The BPAP-ST mode may offer hypoventilation, as measured by arterial PaCO2, end-tidal CO2,
an alternative to CPAP or ASV in controlling respiratory events, or transcutaneous PCO2 > 45 mmHg. Diagnostic PSG demon-
even though the consolidation of sleep may still be suboptimal in strates worsening of hypoventilation during sleep if PaCO2 or other

noninvasive estimates are used. The hypoventilation should not be Diagnosis

due to underlying lung disease, chest wall disorder, neuromuscular
Daytime hypoventilation may or may not be present. However,
disorder, medication use, or congenital central alveolar hypoventi-
sleep-related hypoventilation is present as measured by arterial
lation syndrome.
PaCO2, end-tidal CO2, or transcutaneous PCO2 > 45 mmHg.
Mutation of the PHOX2B gene is present.
Treatment
Weight loss is an important long-term goal in the management of Treatment
obesity hypoventilation syndrome and may be pursued by medical Most patients require ventilatory assistance during sleep.
or surgical/bariatric means.
Assistive devices are considered first-line treatment modalities in
this condition. CPAP may be effective in many patients, especially Summary
those associated with increased upper airway obstruction. A trial Sleep disordered breathing may occur in a variety of ways. While
of CPAP is indicated before BPAP-S or -ST therapy is tried. If nonobstructive sleep apnea is the most common, we have reviewed here
invasive mechanical ventilation fails, tracheostomy for mechanical the most common types of sleep disordered breathing that occur
ventilation may be required. independently of upper airway obstruction. In many cases, there
is concurrent upper airway obstruction and neurological respira-
Congenital central alveolar tory dysregulation. Thus, along with attempts to correct the under-
lying etiologies (when present), stabilization of the upper airway
hypoventilation syndrome is most often combined with flow generators (noninvasive positive
Clinical presentation pressure ventilation devices) that modulate the inadequate venti-
This is a rare genetic disorder of autonomic dyscontrol of breathing, latory pattern. Among these devices, when CPAP alone does not
due to a mutation in the PHOX2B gene, often presenting at birth, allow correction of sleep disordered breathing, ASV is increasingly
but sometimes not until adulthood, in the presence of a stressor used for non-hypercapnic CSA types, while BPAP-ST is more often
such as anesthesia or respiratory illness. Patients may present with reserved for hypercapnic CSA/alveolar hypoventilation syndromes
cyanosis, an apparent life-threatening event, cor pulmonale, or res- (Table 18.2). Coordination of care among neurologists, cardiolo-
piratory failure. gists, and sleep specialists will often benefit such patients.
Table 18.2 Positive airway pressure (PAP) devices
Type Indications Set-up Disadvantages

CPAP CSA with Cheyne–Stokes breathing Single pressure setting, most often No ventilatory support in
Continuous PAP CSA due to drug or substance determined during attended hypoventilation syndromes
polysomnography
Device that applies the same constant Primary CSA
level of positive airway pressure during Obesity hypoventilation syndrome
inhalation and exhalation
BPAP Primary CSA (BPAP-ST mode) Inspiratory pressure (IPAP), BPAP-S may generate central
Bilevel PAP Treatment emergent CSA expiratory pressure (EPAP). apneas in CSA with Cheyne–
(BPAP-ST mode) Stokes breathing and treatment
Device that delivers a higher inspiratory Spontaneous (S) mode: no
emergent CSA
pressure (IPAP) and a lower expiratory Obesity hypoventilation syndrome back-up rate
pressure (EPAP), potentially increases (BPAP-S or BPAP-ST) Spontaneous-timed (ST) mode:
tidal volumes, and hence alveolar back-up respiratory rate for patients
ventilation with impaired respiratory drive or
neuromuscular disease with insufficient
triggering of IPAP
ASV CSA with Cheyne–Stokes breathing Maximum and minimum inspiratory Not designed to provide
Adaptive pressure support (except symptomatic congestive heart pressures ventilatory support in
servo- ventilation failure patients with ejection fraction End-expiratory pressure hypoventilation syndromes;
≤ 45% [9]‌) device designed to provide
Feedback control system with self- Back-up ventilatory rate and flow
CSA due to drug or substance slight hypoventilatory target
adjustable pressures that target an characteristics may also be set, but
from baseline values
average ventilation or inspiratory flow Primary CSA default values are provided
Treatment emergent CSA

7. Takama N, Kurabayashi. M. Effectiveness of adaptive servo-ventilation

References for treating heart failure regardless of the severity of sleep-disordered
1. Nakayama H, Smith CA, Rodman JR, et al., Effect of ventilatory drive breathing. Circ J 2011;75:1164–9.
on carbon dioxide sensitivity below eupnea during sleep. Am J Respir 8. Yoshihisa A, Shimizu T, Owada T, et al. Adaptive servo ventila-
Crit Care Med 2002;165:1251–60. tion improves cardiac dysfunction and prognosis in chronic
2. Khoo MC, Kronauer RE, Strohl KP, Slutsky AS. Factors inducing heart failure patients with Cheyne–Stokes respiration. Int Heart J
periodic breathing in humans: a general model. J Appl Physiol Respir 2011;52:218–23.
Environ Exerc Physiol 1982;53:644–59. 9. Cowie M, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation
3. Khoo MC. Determinants of ventilatory instability and variability. for central sleep apnea in systolic heart failure. N Engl J Med
Respir Physiol 2000;122:167–82. 2015;373:1095–105.
4. Aurora RN, Chowdhuri S, Ramar K, et al. The treatment of central 10. Ramar K. Reversal of sleep-disordered breathing with opioid
sleep apnea syndromes in adults: practice parameters with an evidence- withdrawal. Pain Pract 2009;9:394–8.
based literature review and meta-analyses. Sleep 2012;35:17–40. 11. Morgenthaler T, Kuzniar TJ, Wolfw LF, et al. The Complex Sleep
5. Bitter T, Westerheide N, Faber L, et al. Adaptive servoventilation in Apnea Resolution Study: a prospective randomized controlled trial
diastolic heart failure and Cheyne–Stokes respiration. Eur Respir J of continuous positive airway pressure vs. adaptive servoventilation
2010;36:385–92. therapy. Sleep 2014;37:927–34.
6. Koyama T, Watanabe H, Kobukai Y, et al. Beneficial effects of 12. Allam JS, Olsen EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive
adaptive servo ventilation in patients with chronic heart failure. Circ J servoventilation in treatment of complex and central sleep apnea
2010;74:2118–24. syndromes. Chest 2007;132:1839–46.

SECTION 5
Insomnias

CHAPTER 19
Insomnias
Classification, evaluation,
and pathophysiology
Simon D. Kyle and Colin A. Espie
“When you lose sleep, you lose the better part of yourself. You’re not all there—â•‰as insomniacs
know, as we say with the terms we use for ourselves: zombies, the living dead, nobody home. It
seems ironic that sleep is feared as the loss or disappearance of the self, when it may actually
be the way we become most fully ourselves, maintain the continuity of past and present selves,
retain our identities through time and change, become our most creative, intelligent, and alive.
Sleep is how we manage to be all there. You might even say, I sleep, therefore I am.”
Greene (2008, p. 48)
Insomnia: defining features edition of the ICSD identified several different subtypes of insom-
nia disorder, including four primary insomnia phenotypes (each
The core symptoms of insomnia, specified in major disease and with key defining features; see Table 19.2). However, thorough
sleep disorder classification manuals (ICSD-â•‰2 in 2005 [2]â•„, ICSD-â•‰3 assessment, by three clinician pairs, of 352 adults reporting insom-
in 2014 [3], DSM-â•‰5 in 2013 [4], and ICD-â•‰10 in 1992 [5]), corre- nia revealed low levels of reliability and validity for the psychophysi-
spond to difficulties with initiating sleep, maintaining sleep, waking ological, paradoxical, and inadequate sleep hygiene phenotypes [15].
up early (with an inability to resume sleep) or nonrestorative sleep Such data has influenced the latest revision of ICSD, published
(i.e. poor quality, unrefreshing sleep). To achieve disorder “status,” in 2014, which has dropped the primary insomnia subtypes and
sleep disturbance must not be a function of restricted sleep oppor- refined the number of insomnia categories to three: chronic insom-
tunity (eg, voluntary curtailment) or environmental perturbation nia disorder, short-â•‰term insomnia disorder and other insomnia dis-
(bed-â•‰partner snoring, traffic noise, etc.). Notably, the diagnosis of order [3]â•„. This refinement is also consistent with recent revisions to
insomnia disorder is made only when impairment to daytime func- DSM-â•‰5. Previous editions, including DSM-â•‰IV [13,14], listed “pri-
tion is present, which is linked attributionally to nighttime sleep mary insomnia,” essentially an exclusionary diagnosis ruling out
difficulties. Daytime impairments may be measured with reference comorbidity, and “secondary insomnia,” indicating that poor sleep
to isolated symptoms, such as fatigue, impaired concentration, is a consequence of a so-â•‰called primary condition. Taking heed of
poor memory, and low mood [6,7], but also more global dysfunc- evidence that insomnia is involved in the onset, maintenance, and
tion, for example, in areas of occupational, relationship, or social exacerbation of mental and physical illness and that causality is
functioning [8]. It is often these daytime concerns that drive treat- often difficult, if not impossible to determine in clinical practice
ment-â•‰seeking in those with insomnia [9,10]. Additional markers [16], DSM-â•‰5 [4] replaces “primary” and “secondary” insomnia with
of insomnia severity refer to the frequency and length (persis- the more encompassing term, “insomnia disorder.” The American
tence) of insomnia symptoms, which, for an insomnia diagnosis, is Psychiatric Association notes: “… this change underscores that
usually set at greater than or equal to three nights per week [11,12], the individual has a sleep disorder warranting independent clini-
being present for at least a 1-â•‰month period [2,6,13,14]. Of note, the cal attention, in addition to any medical and mental disorders that
most recent editions of the Diagnostic and Statistical Manual of are also present, and acknowledges the bidirectional and interactive
Mental Disorders (DSM-â•‰5) [4] and the International Classification effect between sleep disorders and coexisting medical and mental
of Sleep Disorders (ICSD-â•‰3) [3] have updated this duration crite- disorders” [4].
rion to a minimum of 3 days per week for 3 or more months (see
Table 19.1 for DSM-â•‰5 and ICSD-â•‰3 criteria for insomnia disorder). Insomnia prevalence, natural history,
DSM-â•‰5 and ICSD-â•‰3 have also eliminated the nonrestorative sleep
subtype, owing to its lack of specificity for insomnia and poorly and associated risk factors
defined features. Numerous epidemiological studies have been conducted to
Historically, the two main diagnostic manuals for categorizing assess insomnia symptom and disorder prevalence rates [17,18].
insomnia (ICSD and DSM) varied with respect to level of symp- Estimates naturally depend on the definition used, but insomnia
tomatic detail and subtype classification. In particular, the second symptoms are estimated to affect one-â•‰third of the population, while

178 Section 5 insomnias
Table 19.1 Criteria for insomnia disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) [4]‌and
the International Classification of Sleep Disorders, Third Edition (ICSD-3) [3]
DSM-5: insomnia disorder ICSD-3: chronic insomnia disorder

Sleep A predominant complaint of dissatisfaction with sleep The patient reports (or the patient’s parent or caregiver reports)
quantity or quality, associated with one (or more) of the marked concern about or dissatisfaction with sleep, comprising
following symptoms: one or more of the following:
1. Difficulty initiating sleep 1. Difficulty initiating sleep
2. Difficulty maintaining sleep, characterized by frequent 2. Difficulty maintaining sleep
awakenings or problems returning to sleep after awakenings 3. Waking up earlier than desired
3. Early morning awakening with inability to return to sleep 4. Resistance to going to bed on the appropriate schedule
5. Difficulty sleeping without the parent or caregiver present
Consequences The sleep disturbance causes clinically significant distress or The patient reports (or the patient’s parent or caregiver reports)
impairment in social, occupational, educational, academic, one or more of the following as being associated with the nighttime
behavioral, or other important areas of functioning sleep difficulty:
1. Fatigue
2. Mood disturbance
3. Interpersonal problems
4. Reduced cognitive function
5. Reduced performance
6. Daytime sleepiness
7. Behavioral problems (eg, hyperactivity, impulsivity, aggression)
8. Reduced motivation/initiative
9. Proneness to errors/accidents
Frequency The sleep difficulty occurs at least 3 nights per week The sleep disturbance and associated daytime symptoms occur at
least 3 times per week
Chronicity The sleep difficulty is present for at least 3 months The sleep disturbance and associated daytime symptoms have been
present for at least 3 months
Exclusions The sleep difficulty occurs despite adequate opportunity The reported sleep/wake complaints cannot be explained purely
for sleep by inadequate opportunity (i.e, enough time is allotted for sleep)
The insomnia is not better explained by and does not occur or inadequate circumstances (i.e, the environment is safe, dark, quiet,
exclusively during the course of another sleep/wake disorder and comfortable) for sleep
The insomnia is not attributable to the physiological effects The sleep/wake difficulty is not better explained by another primary
of a substance sleep disorder
Coexisting mental disorders and medical conditions not
adequately explain the predominant complaint of insomnia
Reproduced from ChronoPhysiology and Therapy, 2014(4), Miller CB, Espie CA, Kyle SD, Cognitive behavioral therapy for the management of poor sleep in insomnia disorder, pp. 99–107,
Copyright (2014), reproduced under the Creative Commons License 3.0.
insomnia disorder (core sleep symptoms plus daytime impairment) found that 6.6% of the general population met criteria for DSM-IV
affects between 5% and 15% [19,20]. This large variation reflects, insomnia disorder. When further broken down, based on DSM-IV
in part, lack of standardized case definition and assessment proce- criteria, 3.3% of the sample met classification for primary insom-
dures across studies [18]. Of note, few epidemiological studies have nia. These results reasonably approximate those of previous epi-
implemented strict diagnostic criteria in relation to both classifica- demiological studies (eg, [9,17,18]). An important issue, however,
tion manuals (ICSD and DSM) or recorded data on whether the was the large number of individuals who, although reporting an
individual actually endorses a sleep problem/complaint. One study insomnia complaint, failed to be categorized by the classification
by Ohayon and Reynolds [12] employed both DSM-IV and ICSD-2 systems, suggesting that future refinement of criteria and measure-
criteria to assess prevalence rates in a large sample of individuals ment may be necessary. Of note, one recent epidemiological study
(25 579), aged 15 years and over, residing in seven European coun- [21], adopting putative DSM-5 criteria, reported a prevalence rate
tries. It was found that 34.5% of the sample reported at least one of 7.9% in The Norde-Trondelag region of Norway. However the
difficulty at the “symptom” level (i.e, sleep initiation and/or main- applied daytime criterion (self-report of daytime sleepiness attrib-
taining difficulties or nonrestorative sleep), and 9.8% were found to uted to poor sleep) is not particularly characteristic of those with
meet insomnia disorder at the criterion level, that is, reporting both insomnia [8]‌and thus may represent an underestimate of insom-
nighttime symptoms and daytime consequences. After excluding nia disorder prevalence. Further prevalence studies adopting strict
those not scoring “positive” for the complaint of insomnia, it was DSM-5/ICSD-3 criteria are required.

Chapter 19 insomnias: classification, evaluation, and pathophysiology 179
Table 19.2 Essential features of primary insomnia phenotypes listed of poor sleep over time. An important prospective study of good
in the International Classification of Sleep Disorders, Second Edition [2]‌ sleepers (n = 464), measured at three time-points over the course of
a 1-year period (0, 6, and 12 months), revealed that baseline assess-
Disorder Characteristic features ments of elevated depressive and anxiety symptoms, higher arous-
ability, lower extraversion and poorer mental and physical health
Psychophysiological Learned sleep-preventing associations, racing mind,
insomnia conditioned arousal were linked to the prospective onset of insomnia syndrome “inci-
dent” cases [27]. A recent small study of 54 adults with either acute
Arousal may be conceptualized in physiological,
cognitive, or emotional terms insomnia (poor sleep in response to a stressor) or normal sleep
revealed that baseline sleep architecture—namely decreased slow-
Excessive focus on sleep and consequences of sleep
loss wave sleep (SWS) and reduced latency to REM—was associated
with greater likelihood of transitioning between acute and chronic
Paradoxical insomnia Complaint of little sleep, or total sleep loss, insomnia, assessed 3 months later [28]. Once established, insomnia
that greatly exceeds objective evidence of sleep
seems to be persistent in nature, with one prospective study show-
disturbance
ing that for a group of insomnia patients assessed at baseline, nearly
Level of subjective sleep disturbance is not
50% will continue to meet insomnia disorder criteria each year for
commensurate with the reported degree of daytime
deficit
the next 3 years [29]. According to another study, sampling over
5000 participants meeting DSM-5 insomnia disorder criteria, 46%
Idiopathic insomnia Persistent complaint of insomnia typically initiating of the sample reported sleeping poorly for more than 6 years, while
during childhood or from birth, with no or few 25% reported sleeping poorly since childhood [7]‌. Important new
extended periods of sustained remission
evidence, however, looking at micro-fluctuations from month to
Inadequate sleep Insomnia associated with daily living activities that month over a 1-year period, reveals a high level of symptom fluc-
hygiene are inconsistent with good sleep quality tuation: 60% of those with insomnia syndrome and 93% of those
Practices and activities typically produce increased with insomnia symptoms reported a change in sleep status at least
arousal or directly interfere with sleep, eg, use once over the 12 monthly assessment points [30]. Such data suggest
of caffeine, nicotine, or alcohol, irregular sleep that prospective studies should be sampling more frequently than
scheduling, or engaging in non-sleep behaviors in
the typical annual assessments in order to understand the natural
the sleep environment
course of insomnia.
Adapted from Journal of Clinical Sleep Medicine, 4(5), Schutte-Rodin, S., Broch, L., Several studies have reported increased familial susceptibility
Buysse, D., Dorsey, C. & Sateia, M, Clinical guideline for the evaluation and management to developing insomnia. For example, Dauvilliers et al. [31] found
of chronic insomnia in adults, pp. 487–504, Copyright (2008), with permission from
American Academy of Sleep Medicine.
that 73% of a sample of primary insomnia patients (n = 77) had a
positive family history for familial insomnia, compared with just
24% in a normal-sleeping control group. A population-based study
Several risk factors have been associated with increased insom- similarly found that those with a past or current history of insom-
nia prevalence. Among the most strongly supported are increasing nia had a greater likelihood of a positive family history for insom-
age, being female, shift work, and comorbid medical and psychi- nia, relative to good sleepers who had never experienced insomnia
atric disorders [20,22]. Psychiatric disorders are particularly pro- before [32]. This pattern was also recently replicated in first-degree
nounced in those with insomnia, with estimates suggesting 40% relatives of adolescents meeting criteria for insomnia disorder [33].
of all patients with insomnia experience a co-occurring psychiat- Further evidence of genetic influence comes from twin studies,
ric condition [23]. In particular, depression and anxiety have been where monozygotic twins have been found to have higher rates of
found to be highly prevalent in those with an insomnia diagnosis insomnia concordance, within pairs, in comparison with dizygotic
compared with those without [24]. Moreover, those with insomnia twin pairs (heritability estimate = 57%) [34].
syndrome, compared with both good sleepers and individuals with Recent work has attempted to uncover potential genes involved
insomnia symptoms, demonstrate higher scores on questionnaire in the expression of insomnia, through both candidate gene studies
measures of depression, anxiety, neuroticism, arousal predisposi- and genomewide association studies (GWAS) [35]. Although can-
tion, and stress perception, as well as a tendency toward emotion- didate genes have not yet been reliably identified, there are several
oriented coping [25]. Those with insomnia symptoms also tend to possible targets relating to sleep homeostasis (eg, adenosine deami-
score higher than good sleepers on measures of depression, anxiety, nase), circadian timing (eg, clock genes: CLOCK, PER, BMAL,
and neuroticism, suggesting a possible linear trend with increasing CRY), and general arousal/de-arousal (eg, γ-aminobutyric acid
insomnia “severity.” (GABA) regulation) [35,36] . Such an approach may be particularly
Clinically, patients often “anchor” the onset of sleep disturbance fruitful given the high heritability of sleep EEG power spectra (δ,
to significant life events. In support of this, Bastien and colleagues θ, α, and σ bands) [37], as well as conventional polysomnographic
[26] systematically examined precipitating factors of insomnia in a (PSG) sleep parameters [38]. A study by a group in Germany [39]
sample of 345 patients presenting at a sleep disorders clinic. They revealed an association between primary insomnia and a seroto-
found that events relating to family, health, work, or school were nin transporter length polymorphism (the 5HTTLPR short allele).
most frequently associated with the onset of sleep disturbance. The association remained robust after controlling for those with a
Across all recorded events, the majority (65%) were considered to lifetime incidence of affective disorder. This finding requires rep-
be negative in nature (eg, loss of job or bereavement). Longitudinal lication but is intuitively appealing given the greater occurrence
natural history studies are also beginning to shed light on factors of this genotype within other stress-related psychiatric conditions
involved in the development of insomnia, as well as the stability (which are frequently related to insomnia) and observations of

enhanced cortisol reactivity to experimental psychosocial stress in total sleep time and overestimating time taken to fall asleep com-
healthy individuals with this genotype [40]. Finally, recent GWAS pared with PSG recordings [51,52]. This notwithstanding, insom-
data from the UK Biobank (n = 112 586) has identified several nia patients report statistically significant differences in sleep
novel genetic loci associated with insomnia symptoms, meeting parameters compared with normal sleepers, specifically reduced
genomewide significance, including near MEIS1 and TMEM132E total sleep time, lower sleep efficiency, increased latency to sleep,
[41]. These loci and related regions have been linked to restless greater number of awakenings and less time spent in SWS and
legs syndrome/limb movements during sleep and anxiety sensitiv- REM sleep [53]. Objective sleep continuity differences, however,
ity. Future work is required to replicate these observations and test are typically disproportionate to the subjective complaints of
for specific genetic associations with insomnia disorder rather than patients [54,55]. Indeed, the core defining feature of the paradoxi-
just insomnia symptoms. cal insomnia subtype (see Table 19.2) is gross sleep misperception,
when a substantial mismatch occurs between subjective report and
objective recordings (PSG or actigraphy). PSG is also an expensive
Insomnia assessment and evaluation procedure, and, given the high prevalence of insomnia disorder
Insomnia is typically diagnosed according to subjective report, in the general population, coupled with limited clinical/treatment
through clinical interview, prospective sleep diary completion, insight, overnight laboratory recording of sleep is not cost-effective.
and retrospective questionnaire assessments (see Table 19.3). However, PSG is recommended in research as a screening tool and
Assessments probe history, frequency, and severity of sleep and as an outcome measure in efficacy studies (though not as the pri-
daytime functioning symptoms, but also lifestyle factors, beliefs mary dependent variable) [56].
and attitudes about sleep, pre-sleep arousal, and applied sleep effort A recent challenge to the view that classic PSG has limited util-
[49]. Thorough work-up involves investigation of other sleep- ity in the clinical management of insomnia comes from the group
related symptoms and features (eg, snoring, leg twitches, and sleep- of Alexondros Vgontzas, who have reliably demonstrated that
walking episodes), as well as the presence of, and relationship to, reported insomnia combined with objective short sleep duration
mental and physical health comorbidities. Similarly, the potential represents the most biologically severe insomnia “phenotype,”
role of drug and substance (mis)use should also be interrogated. being strongly connected with adverse health outcomes, including
PSG, the gold standard for objectively measuring sleep, is only increased risk of cognitive impairment, hypertension, depression,
indicated in circumstances where insomnia is suspected to be diabetes, and early mortality [57]. These authors also suggest that
related to other sleep disorder pathology, such as periodic limb this phenotype would be more likely to respond to pharmacologi-
movements and sleep-related breathing disorders [50]. There are cal therapy (targeting physiological hyperarousal), while patients
at least two main reasons for this conservative use of PSG. First, it with reports of insomnia but with “normal” sleep duration may
has been known for several decades that individuals with insomnia be more responsive to cognitive–behavioral therapy (CBT). This
tend (as a group) to misperceive sleep, significantly underestimating proposition awaits empirical testing and confirmation. A related
observation from recent work is that sleep restriction therapy (part
of CBT for insomnia) is associated with marked sleep loss and vigi-
Table 19.3 Domains to probe when assessing the complaint of lance impairment during acute treatment, owing to restricted sleep
insomnia and possible investigative tools schedules that are based on self-report (i.e, large baseline objective–
subjective sleep discrepancies). This work raises the question of
Domain/sub-domain Possible assessment tool whether objective sleep recordings should be used to guide treat-
Sleep history, pattern, and Clinical interview (input from partner/carer) ment implementation [58,59].
complaint Sleep disorders screen [122]
While PSG continues to play a limited role in the clinical manage-
Insomnia severity and ment of insomnia, sleep recordings have advanced understanding
Sleep diary [123]
impact on functioning of insomnia pathophysiology. For example, increased frequency of
Actigraphy
microarousals and shifts between sleep stages has been observed in
Insomnia Severity Index [124] insomnia relative to healthy controls [54]. Moreover, EEG power-
Sleep Condition Indicator [125] spectral analysis during wake, NREM sleep, and REM sleep states
Glasgow Sleep Impact Index [8]‌ can provide information on levels of cortical arousal/excitability. A
Sleep psychology and Clinical interview number of studies (eg, [60–66]) have reported evidence for increased
lifestyle factors Dysfunctional beliefs and attitudes about power, both relative and absolute, in fast EEG rhythms (sigma, beta,
(including work pattern) sleep scale [126] or gamma frequencies) during wakefulness and NREM and REM
Pre-Sleep Arousal Scale [127] sleep, compared with normal sleepers. These alterations often occur
in the absence of conventional PSG abnormalities (when compared
Glasgow Sleep Effort Scale [128]
with controls), and are thought to account, in part, for the subjec-
Physical and mental health Clinical interview tive experience of being awake during objectively scored sleep (eg,
comorbidities, including use Psychiatric history and examination [67]). Indeed, Perlis et al. [63] observed that increased beta power
of prescription drugs and
Physical history and examination during NREM sleep was associated with greater subjective–objec-
substances
tive sleep discrepancies. Similarly, slow-wave spectral power in the
Occult sleep disorders Polysomnography delta range (0.5–4 Hz), a marker of homeostatic drive for sleep (or
(eg, sleep disordered sleep intensity), has been found to be both reduced [60,64] and
breathing, or periodic limb
increased [65] in primary insomnia patients relative to controls.
movements)
One study also revealed that treatment of insomnia through CBT

led to a more rapid decline in delta power (reflecting appropriate Table 19.4 Domains of daytime impairment reported by patients
discharge of the sleep homeostat) across the sleep period, and that with insomnia, supported by verbatim examples
the magnitude of the decline was associated with improved percep-
tion of sleep post-treatment [68]. In general, variability in methods, Domains of impairment Patient-generated examples
small sample sizes, and findings concerning sex differences [65]
Energy/motivation “feeling exhausted during the day”/”lack of
suggest that further investigations of microstructural aspects of the energy and motivation”
sleep EEG are required.
Performance at work/ “quality of work/output”/“not able to do the
school/daily activities amount of work l would like to”
Insomnia-related costs and morbidity Cognitive functioning “memory, concentration, focus”/“sharpness”
A handful of studies have estimated both direct (eg, healthcare Emotional regulation “my ability to deal with unexpected situations-I
utilization and physician consultations) and indirect costs (down- panic easily”/“feeling down”
stream consequences, eg, work productivity) of insomnia [69]. One
Health/well-being “always not feeling quite well”/“l don’t feel
of the most comprehensive studies to date on cost impact was car- healthy”
ried out by Daley and colleagues [70] in the province of Quebec,
Canada. A random sample (n = 948) of residents were classified, Social functioning “unwilling to arrange to go out to socialize at
night”/“I don’t look forward to social activities”
according to strict diagnostic criteria, into good sleepers, those
with insomnia symptoms, and those with insomnia syndrome (dis- Relationships/family “quality of time with family”/“lack of desire for
order). Assessments were made for use of healthcare services, prod- functioning physical intimacy or sex”
ucts to treat sleep disturbance, accidents, insomnia-related work Outlook “ambition”/“attitude”
absenteeism and productivity (presenteeism). Objective data were
Frustration/concern/ “worry about what the next night will bring”/
also obtained through a government register regarding recorded preoccupation with “obsession with sleep”
health-related consultations. The total estimated cost of insom- sleep loss
nia for that particular region (when extrapolated) was 6.6 billion
Appearance “eye appearance (dark circles)”/“people saying
(Canadian) dollars. In particular, insomnia-related absenteeism,
you look tired all the time”
reduced work-related productivity, and use of alcohol as a sleep aid
were the three biggest contributors. The average annual cost per Happiness “general quality of life”/“happiness”
person with insomnia syndrome was $5010, compared with $1431 Daytime sleepiness “always wanting to go to sleep”/“feeling sleepy
for those with insomnia symptoms and just $421 for good sleepers. during day at weekend”
This study underscores the economic costs associated with both Confidence “confidence”/“low self-esteem”
chronic and transient symptoms of sleep disturbance.
While insomnia manifests in the context of the sleep period, it Source data from Sleep Medicine, 14(6), Kyle, S.D., Crawford, M., Morgan, K., Spiegelhalder, K.,
is considered a 24-hour problem, affecting both sleep and daytime Clark, A., Espie, C.A, The Glasgow Sleep Impact Index (GSII): a novel patient-centred measure
for assessing sleep-related quality of life impairment in Insomnia Disorder, pp. 493–501,
periods. Indeed, it is impairment in the daytime that often prompts Copyright (2013), Elsevier.
people to seek help. Sleep-related daytime impairment can range
from irritable mood to an inability to hold down a job. As a group,
the most commonly endorsed domains of impairment reflect dif- have also now shown that switching-of-attention tasks (though
ficulties with energy and motivation, work performance, and cog- not sustained attention) are sensitive to the complaint of insomnia
nitive function, and emotion (dys)regulation (see Table 19.4 for [76,77].
verbatim patient reports). The diffuse nature and persistence of With respect to neuroimaging, two task-related functional mag-
daytime symptoms in insomnia is reflected in reduced ratings of netic resonance imaging (fMRI) studies are particularly relevant to
overall health-related quality of life [71,72]. Perhaps contrary to daytime dysfunction. Altena and colleagues [78] scanned patients
expectation, sleepiness is not a commonly reported consequence during a verbal fluency task, observing hypoactivation of medial
of insomnia [8]‌, suggesting that dysfunctional arousal or “hypera- and inferior prefrontal cortical areas, a pattern that normalized
rousal,” is present throughout the entire 24-hour period. The most post-CBT. Drummond et al. [79] compared 25 insomnia patients
comprehensive study on daytime sleepiness assessed objective sleep with 25 controls on a widely used working memory task (the
and next-day multiple sleep latency test (MSLT) performance across N-back task). They observed an abnormal pattern of neural activ-
four scheduled naps [73]. Despite sleeping more than an hour less ity in the insomnia group, with failure to engage task-appropriate
than healthy control subjects, patients with insomnia disorder took regions, including widespread areas within the frontoparietal
longer to fall asleep (by about 2 minutes, on average) during the day working memory network, motor and visual processing regions,
[73], supporting the notion of 24-hour hyperarousal. thalamus and cerebellum. They also observed reduced disengage-
Phenomenology of daytime insomnia complaints has also been ment (lower deactivation) of regions within the default mode net-
probed at the level of neurobehavioral performance and neural work (areas of the brain that are typically active when attention is
activity. Despite many historical studies failing to observe reliable not focused on the external world). Of note, both the Altena and
differences in neurobehavioral performance between insomnia Drummond studies found no evidence of behavioral impairment
patients and controls [74], a recent meta-analysis concluded that when comparing insomnia patients with controls.
patients show reliable differences of small to moderate magnitude Insomnia also appears to have general health costs. It has been
in tasks probing episodic memory, problem solving, and manipula- nearly three decades since Ford and Kamerow [23] published their
tion and retention in working memory [75]. Several large studies seminal finding that insomnia is a risk factor for the development

of subsequent psychopathology, namely, depression. This relation- stimulus dyscontrol and instrumental conditioning [103], physi-
ship has been repeatedly found across several studies, suggesting ological hyperarousal [104–106], and dysfunctional cognitive
that insomnia may be an independent risk factor for the onset of processes relating to sleep and daytime functioning (eg, [107]).
depression [80] and anxiety [81]. Mounting evidence also sup- While these accounts are well formulated, it is likely that multi-
ports a role for insomnia in the perpetuation of depression. For component perspectives are required to capture the heterogeneity
example, Pigeon and colleagues [82] showed, in a large sample of of insomnia symptoms, associated subtypes, clinical features, and
elderly individuals undergoing treatment for major depression, that insomnia development/trajectory. Although it is outwith the scope
persistent insomnia at baseline was significantly associated with of this chapter to describe each multicomponent model in detail,
poorer (depression) treatment response. Similar results have now it is worth outlining some of the main accounts, which are inclu-
been documented in the context of social anxiety disorder [83]. sive and encompassing with regard to associated characteristics of
Insomnia in addition to mood or anxiety disorder also significantly insomnia disorder.
enhances disability over and above mood or anxiety disorder in
isolation [84]. The potential causal role of poor sleep in mental ill- The 3P (predisposing, precipitating, perpetuating)
health is further supported by interventional research. Specifically, model: a general diathesis–stress framework
targeting insomnia within the context of standard treatment for The main organizing framework for most working models of insom-
depression, using both CBT [85,86] and eszopiclone [87], leads nia was laid out by Spielman et al. [108] in the 3-P model. This classic
to improvements in sleep, but also potentiates the antidepressant stress–diathesis conceptualization outlines how chronic insomnia
effect beyond monotherapy. may develop over time, proposing, as a first step, that acute sleep
Associations between insomnia and cardiovascular morbid- disturbance occurs as a consequence of the interaction between
ity have similarly been reported for some time, but possible con- predisposing factors (eg, altered neurotransmission, trait arousal,
founders have limited conclusions regarding causality [88,89]. An genetic susceptibility, and ruminative personality) and precipitat-
important study by Vgontzas et al. [90] has advanced the field in ing factors (eg, life-stressors such as occupational stress, and emo-
terms of identifying a robust link between insomnia and hyperten- tional and health problems). These precipitants push an individual
sion. Using PSG recordings (one night) in a large random popula- over a hypothetical insomnia threshold (see Fig. 19.1), engender-
tion sample (n = 1741), it was found that those meeting criteria ing insomnia symptoms. Perpetuating factors refer to maladaptive
for insomnia disorder and who also (objectively) slept less than sleep practices, which interact with experienced insomnia symp-
5 hours had a greatly increased risk of experiencing hypertension. toms and are aimed at coping with the consequences of poor sleep
This was not the case for individuals without insomnia symptoms during the day (eg, drinking coffee to improve alertness) or directly
and who also slept less than 5 hours (short sleepers). Notably, this trying to increase the probability of “achieving” sleep (eg, extending
insomnia–hypertension relationship held after controlling for sev- time in bed). After the precipitant resolves, most individuals will
eral major confounders, including depression and sleep apnea. return to the default position of normal sleep, but in those with a
Further work from the same group also revealed that insomnia and predisposition for sleep disturbance, combined with the continued
objective sleep duration were associated with incident hypertension practice of maladaptive perpetuating behaviors, sleep disturbance
over a 7.5-year period [91]. Experimental data showing attenuated may become chronic.
systolic blood pressure (SBP) (i.e, wake-to-sleep “dipping,”) and Thus a main assumption of this model is that sleep disturbance
elevated nighttime SBP in normotensive primary insomnia patients may, over time, become dislocated from the precipitating trigger
compared with normal sleepers suggests a possible mechanistic
pathway linking sleep disturbance and hypertension risk [92].
Prospective studies consistently identify insomnia as being
100
associated with new-onset physical and mental ill-health [93].
90
The mechanisms are still unclear, but experimental studies with
80
primary insomnia samples hint at putative pathways, including
Insomnia intensity
70
attenuated heart-rate “dipping” from wake to sleep [94], elevated
60 Threshold
secretion of inflammatory markers [95], lower levels of cellular
50
immunity [96], increased activity of the hypothalamic–pituitary–
40
adrenal (HPA) axis [97], and altered social–emotional processing
30
[98]. Such modifications, over time, may influence cellular ageing
20
[99] and increase vulnerability to a range of physical and mental
10
health conditions and mortality.
0
Pre-morbid Acute Early Chronic
Contemporary models of the development insomnia insomnia insomnia
and maintenance of insomnia Perpetuating factors

Precipitating factors
Several hypotheses have been proposed to explain the etiology Predisposing factors
and maintenance of insomnia disorder. For example, single-factor
Fig. 19.1 Factors contributing to the development of insomnia, according to the
accounts have tended to focus on specific sleep–wake abnormali-
“3-P” framework.
ties, psychological mechanisms, or general arousal explanations. Reproduced from Espie CA, Kyle SD, Cognitive and behavioural psychological therapies for
These include altered sleep homeostasis [100], impaired circa- chronic insomnia, in: Barkoukis TJ, Matheson JK, Ferber R, Dohramji K (Ed.), Therapy in Sleep
dian regulation of sleep [101], caudate nucleus dysfunction [102], Medicine, pp. 161–171, Copyright (2012), with permission from Elsevier.

[109]. Such a model is intuitively appealing because it suggests that psychophysiological phenotype, as a fundamental difficulty with
treatment should specifically target perpetuating factors involved the inhibition of wakefulness. While evidence exists to support
in the maintenance of insomnia. This is exactly what CBT for some aspects of the model (eg, sleep-related attention bias) [115],
insomnia attempts to do, with an emphasis on correcting maladap- further work is required to determine causal involvement of the
tive coping strategies, behaviors, and sleep-related dysfunctional aforementioned cognitive processes in the development and per-
beliefs and attitudes [49]. petuation of insomnia.
Neurocognitive model Beyond dualistic tendencies: toward an integrative

psychobiological insomnia model
Perlis and colleagues [110]extend this behavioral perspective,
acknowledging that acute insomnia is initially triggered by stress, The psychological–behavioral models that we have outlined have
and is similarly maintained by maladaptive coping strategies (eg, considerable face validity and clinical value, and have formed the
extending time in bed), but that, notably, the associated wakeful- basis of effective cognitive–behavioral intervention. In the last dec-
ness becomes classically conditioned in terms of arousal (somatic, ade, however, a new perspective has been put forward to explain
cognitive, and cortical). It is argued that increased cortical arousal insomnia across a number of different “levels”; with particular
(as measured by fast rhythms (beta/gamma) in the EEG) at sleep emphasis on underlying neurobiology. In this respect two recent
onset, and during both sleep, and middle-of-the-night awaken- contributions are noteworthy.
ings disrupts sleep initiation and maintenance through enhanced Riemann and colleagues [36] synthesize work on the hyperarousal
sensory/information processing and attenuated mesograde amnesia. concept of insomnia, focusing on empirical evidence of hypera-
These altered cognitive parameters may subsequently help explain rousal across autonomic (heart rate and heart-rate variability),
“sleep-state misperception” or “paradoxical insomnia.” A later addi- neuroendocrine (HPA axis), neuroimmunological (interleukin-6),
tion to this model also includes the possibility that sleep-related electrophysiological (event- related potentials, high- frequency
objects (bed, pillow, etc.) become conditioned stimuli for cortical EEG, and compound action potential), and neuroimaging (posi-
arousal [111] and hence contribute to the perpetuation of con- tron emission tomography data) parameters. They also draw on
tinued sleep disturbance. The implication of the neurocognitive extensive theorizing by Perlis and colleagues [116–118] in relation
account is that cortical arousal can act as the biological substrate to possible neurobiological abnormalities relevant to the features
that precipitates cognitive arousal (racing mind) in patients, rather of insomnia, as well as rodent models of stress-induced insom-
than the notion that people are simply awake and aroused because nia [119]. The development of testable hypotheses has been aided
they are engaged in worry and rumination. largely by recent understandings on the neurobiology of normal
sleep–wake regulation [120,121].
The perspective outlined is a further update of the neurocogni-
Psychobiological inhibition/attention–intention– tive account, originally set out by Perlis et al. [110]. Although at a
effort (PIM/AIE) model speculative stage regarding possible mediators of insomnia etiology
Espie and colleagues [112,113] take a starting point of normal sleep and development, it is proposed that a genetic arousal predisposi-
for their model of insomnia. They acknowledge that normal sleep tion may render certain individuals at greater risk of developing
is tightly regulated by two oscillatory processes—an endogenous insomnia via altered neurobiology and neurochemistry. Modified
oscillating circadian rhythm and an “hourglass” sleep homeostat— levels of several neurochemicals, including orexin (also known as
which operate in concert with good stimulus control, rendering hypocretin), monoamines (histamine, dopamine, norepinephrine
the (adaptive) sleep process automatic, involuntary, and, hence, (noradrenaline), and serotonin), adenosine, and the stress hormone
not under direct control. Acute stressful life events can, however, cortisol, may, during acute periods of stress, disrupt arousal-related
create both physiological and psychological “over-arousal,” which (ascending reticular activating system, ARAS) and/or sleep-
interacts negatively with normal sleep–wake regulation, leading to promoting (ventrolateral preoptic nuclei, VLPO) components of
acute sleep disturbance. For most individuals, the “plasticity” of the “flip-flop” sleep switch. Inputs to the VLPO from various lim-
the sleep system accommodates such transient disruptions, with- bic structures may also directly impact the capacity to de-arouse
out any lasting chronic modifications; remission of the stressor adequately, overcoming homeostatic sleep pressure [122]. This
heralds the return to normal sleep. However, it is argued that the would normally represent a typical adaptive response to stress.
development of acute to chronic insomnia, where the defining fea- However, the subsequent development of chronic “arousal,” post-
ture is a fundamental difficulty in inhibiting wakefulness, is pre- acute phase, which is possibly more likely in those with a genetic
cipitated by three related cognitive processes [113] (see Fig. 19.2). predisposition for arousability and/or increased stress responsiv-
Attending to sleep-related stimuli, explicitly intending to sleep, ity [123], interacts with maladaptive sleep practices, resulting in
and applying voluntary effort to the sleep onset process all repre- both circadian and homeostatic dysregulation. This dysregulation
sent an attempt to control sleep, an otherwise automatic process. may, over time, induce chronic changes in the sleep–wake system,
These attempts have the opposite effect: preventing de-arousal by reflected in cortical hyperarousal, arousal across other physiologi-
failure to reach a level of inhibitory sufficiency. Factors relevant cal parameters, and difficulties in inhibiting wakefulness. Work by
to this resultant “sleep effort syndrome” [114] include enhanced Seugnet et al. [124] in which Drosophila melanogaster were artifi-
sleep preoccupation, affect dysregulation, sleep-incompatible cially selected and bred over many generations to create insomnia-
conditioning, dysfunctional beliefs and expectations about sleep, like characteristics (sleep initiation and maintenance difficulties
and enhanced focus on the consequences of poor sleep. Rather and daytime impairment) helps one conceive of an inherited sleep
than viewing insomnia as a problem of hyperarousal or excessive system with reduced plasticity and/or an altered stress reactivity
arousal, Espie and colleagues regard insomnia, particularly the threshold [111].

Stressful life event
Selective attention Psychological and physiological

towards stressors correlates of strees
Adjustment insomnia
Arousal perpetuates Selective attention
sleep disturbance Inhibition of sleep- SHIFT
related de-arousal A1 – implicit shift
INSOMNIA toward sleep cues
SYMPOTOMS
Recovery of A2 – explicit shift
normal sleep toward sleep cues
Psychophysiological insomnia
I – explicit intention
E – sleep effort
Fig. 19.2 The attention–intention–effort pathway to psychophysiological insomnia. Insomnia occurs in a persistent fashion when there is a sufficient level of attention,
intention, and/or effort to outweigh good stimulus control and the intrinsic drives of sleep homeostatic and circadian regulation.
Reproduced from Sleep Medicine Reviews, 10(4), Espie, C.A, Broomfield, N.M., MacMahon, K.M., Macphee, L.M. & Taylor, L.M, The attention-intention-effort pathway in the development of
psychophysiological insomnia: a theoretical review, pp. 215–245, Copyright (2006), with permission from Elsevier.
Although this perspective focuses predominantly on neurobiol- systems, hypothalamic sleep–wake centers and brainstem arousal
ogy, it clearly acknowledges that insomnia is a psychobiological dis- centers. On the other hand, pharmacotherapy approaches, includ-
order, with psychological and neurobiological abnormalities likely ing sleep-promoting hypnotics, may directly modify cognitive
to be highly inter-related [117]. This seems to be a more convincing affective brain circuitry and dampen activity in arousal-promot-
integrative account of insomnia and its associated features, rather ing structures. Further empirical studies are required to test the
than a pure physiological hyperarousal perspective in isolation main tenets of this neurobiological perspective and to elaborate
[105]. Indeed, in an inclusive depiction, physiological changes are on the development/acquisition of insomnia. Similar to the pro-
paralleled with cognitive–behavioral features, which are likely to posal by Riemann et al. [36], work is required to integrate sleep–
interact at multiple levels, capturing maintenance and development wake neurobiology with psychological and behavioral constructs,
factors relevant to the original neurocognitive model, Spielman’s 3P from which the most effective treatment (CBT) modality has been
framework, and Espie’s PIM/AIE formulations. It will be important derived (see Fig. 19.3).
to investigate insomnia at each “level,” and ultimately to under-
stand how genetic, biological, and psychological factors interact to Conclusion
determine the course of sleep disturbance over time. Insomnia is highly prevalent, at both the symptom and syndro-
Buysse and colleagues [125] also outline a new framework in mal levels. The consequences of insomnia disorder range from
which to understand clinical features of insomnia, grounded in impaired day-to-day function and quality of life, through to sig-
basic sleep–wake neuroscience. The main tenet of this hypothesis nificant socioeconomic burden and enhanced vulnerability to
is that insomnia is characterized by heightened neural activity the development of physical and mental ill-health. Accumulating
in wake-promoting brain structures (limbic and parietal corti- evidence for a bidirectional and interactive relationship between
ces, thalamus, hypothalamic–brainstem arousal centers) during insomnia and health is changing how insomnia is viewed, classi-
NREM sleep (cf. [126]). This wake-like activity, co-occurring fied, and subsequently treated. Contemporary models of insom-
alongside PSG recorded sleep, may explain several clinical features nia emphasize impairments in down-regulating arousal, across
of insomnia, including (1) subjective–objective sleep discrepan-
cies and (2) why a small change in objective sleep may be asso-
ciated with large subjective sleep improvement, post-treatment.
The model, consistent with the notion that sleep and wake are not Wake
Wake
global “all-or-nothing” phenomena [127], but rather an emergent Sleep
Sleep
property of individual neurons/neuronal assemblies, draws on evi- Sleep
dence from human neuroimaging studies with insomnia patients Wake Wake Sleep
[126,128] and animal models of acute insomnia [119]. Preliminary
evidence points to the possibility of concurrent sleep-and wake- Sleep Sleep Wake
Wake
like neural activity. This abnormal pattern of neural activity may Sleep
Sleep
Wake
manifest as heightened psychophysiological arousal, across the 24-
hour period, coupled with impaired circadian rhythmicity/ampli- Wake
tude and attenuated homeostatic sleep pressure. Treatments for
insomnia may target different levels of dysfunction; that is, CBT
Fig. 19.3 “Local sleep” model of insomnia, proposing that different brain regions
may focus on homeostatic sleep pressure (sleep restriction), cir- may simultaneously show sleep-like and wake-like activity in insomnia patients.
cadian timing (strict bed and rise times, standardization of light Reproduced from Drug Discovery Today: Disease Models, 8(4), Buysse, D.J., Germain, A., Hall, M.,
exposure/activity/meals), and cognitive arousal (relaxation train- Monk, T.H., Nofzinger, E.A, A neurobiological model of insomnia, pp. 129–137, Copyright (2011),
ing), with feedback onto corticolimbic cognitive-affective neural with permission from Elsevier.

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CHAPTER 20
Pharmacological and
non-â•‰pharmacological
treatments of insomnia
Elisabeth Hertenstein, Christoph Nissen,
and Dieter Riemann
Introduction Pharmacological treatment

Persistent insomnia is a disabling disorder accompanied by a Key points
reduced health-â•‰related quality of life [1]â•„, enhanced absenteeism, There is reliable evidence for the effectiveness of benzodiazepines
and reduced job performance [2]. This has been identified as a (BZDs) and benzodiazepine receptor agonists (BZDRAs) for the
risk factor for the first onset of a major depressive episode [3]. short-â•‰term treatment of insomnia. Effects on sleep variables are
Insomnia is defined as a subjective difficulty initiating sleep or within the medium range [9]â•„. The efficacy and safety of BZDs and
maintaining sleep accompanied by subjective daytime impair- BZDRAs for short-â•‰term treatment (approximately four weeks) has
ments [4]. Frequent complaints during the day include fatigue, been demonstrated in high-â•‰quality randomized controlled trials
reduced motivation or energy, mood disturbances, impaired cog- (RCT) and meta-â•‰analyses, but data relating to the long-â•‰term effi-
nitive functioning, interpersonal difficulties, avoidance behavior, cacy and safety are sparse [9].
and a significant impact on comorbid conditions [5]. In this Low doses of sedating antidepressants are commonly prescribed
chapter, the term “insomnia” is used for both primary insom- for the treatment of chronic insomnia in clinical practice [10].
nia and comorbid insomnia associated with a somatic or mental However, research on the short-â•‰and long-â•‰term efficacy and safety
disorder. of these substances, compared with placebo and standard hypnotic
Psychological and pharmacological interventions are mainly treatment with BZs/â•‰BZRAs, is to date limited [11].
offered to patients with chronic insomnia (>4 weeks). However, Other sedating substances, including antipsychotics and mood
Morin has raised the issue whether treatment should be initi- stabilizers that are sometimes used for the treatment of insomnia,
ated earlier [6]â•„. Offering therapy to individuals who present with are suitable exclusively for patients with insomnia who present
acute (3–â•‰14 days) or transient (2–â•‰4 weeks) insomnia might have with psychiatric comorbid conditions (eg, schizophrenia or bipo-
the potential to reduce subjective distress and to prevent a chronic lar disorder). They are not recommended for patients with primary
course. insomnia, owing to the risk of severe side effects.
The first step toward successful treatment consists of a detailed Some substances that are available for insomnia treatment with-
diagnostic process, encompassing a thorough clinical evalua- out prescription, including valerian and melatonin, appear to be
tion of sleep, medical, psychiatric, and substance histories [5]â•„. relatively safe without major adverse effects, but are of limited
A patient who presents with a predominant complaint of insom- efficacy.
nia and nonrestorative sleep and with daytime fatigue should In the following section, the most relevant classes of hypnotic
always be screened for other sleep disorders that require different agents will be presented with regard to their assumed mode of
treatments (eg, restless legs syndrome, sleep apnea syndrome, or action, their effects on insomnia, and their side effects based on
narcolepsy). Consideration should also be given to the possibil- current empirical evidence.
ity that insomnia might occur as a side effect of medication (eg,
β-â•‰adrenoceptor antagonists, cortisone, or stimulating antidepres-
sants [7]) or can be explained by a behavior that is incompatible Benzodiazepines and benzodiazepine
with nighttime sleep (eg, excessive daytime naps). Insomnia is receptor agonists
often associated with somatic disorders, depression and other
mental disorders, or chronic pain [8]. In the case of comorbidi- Mode of action
ties, it is essential to recognize and treat the comorbid disorder, BZDs and a group of newer BZDRAs commonly referred to as the
because the latter might lead to the exacerbation of insomnia or z-â•‰drugs (zaleplon, zolpidem, zopiclone, and eszopiclone) are a class
vice versa. of agents that enhance the effect of γ-â•‰aminobutyric acid (GABA),

the most important inhibitory neurotransmitter in the central Table 20.1 Benzodiazepines and benzodiazepine receptor agonists
nervous system [12]. Both groups of substances act at the GABA- with half-lives and recommended dosages
A benzodiazepine receptor complex and enhance neuronal inhi-
bition. Whereas BZDs bind to different subunits of the GABA-A Drug name Half-life (h) Recommended Trade name
receptor complex, the z-substances are structurally different and dose (mg) (examples)
bind more selectively to the α1 subunit. They have been developed BZD
to overcome side effects of the BZDs such as hangover, withdrawal
syndrome, and tolerance/dependency. These z-drugs have reduced Triazolam 2–6 0.125–0.25 Halcion
muscle-relaxing and anxiolytic effects compared with BZDs. Alprazolam 5–11 1–2 Sonin
However, they still have the potential to cause tolerance, depend- Lormetazepam 8–11 1–2 Noctamid
ence, and withdrawal symptoms, and their sedating effects may also
persist into the next day. Temazepam 8–20 15–30 Remestan
Flunitrazepam 10–20 0.5–1 Rohypnol
Effects on insomnia Estazolam 8–24 1–2 Eurodin
Choice of a specific substance
Nitrazepam 25–35 5–10 Mogadan
The UK National Institute for Clinical Excellence in 2004 carried
out an investigation to determine the superiority of one BZD or Flurazepam 48–120 15–30 Dalmadorm
BZDRA drug over another [13]. The assessment group reviewed Quazepam 48–120 7.5–15 Dormalin
data from 24 RCTs comparing the effects of BZDs and z-substances BZDRA
regarding sleep quality outcomes (sleep diaries and question-
naires). The authors concluded that there is no consistent pattern Zaleplon 1 5–10 Sonata
of superiority of one drug over another. Specifically, there were no Zolpidem 1.5–2.5 10 (age < 65 yrs) Stilnox
significant differences in the rates of treatment-associated adverse 5–10 (age > 65 yrs)
events. This lack of consistency may in part be due to the limited
Zopiclone 5–6 7.5 (age < 65 yrs) Ximovan
quality of the studies.
3.75 (age > 65 yrs)
In a meta-analysis, Duendar and colleagues [14] included 24
RCTs (data of n = 3909 patients with insomnia) comparing one of Eszopiclone 5–7 2–3 (age < 65 yrs) Lunesta
the z-drugs (zaleplon, zolpidem, or zopiclone) with classical BZDs 1 (age > 65 yrs)
(diazepam, alprazolam, lorazepam, lormetazepam, nitrazepam,
BZD, benzodiazepine; BZDRA, benzodiazepine receptor agonist.
and temazepam). They found only minor differences, but increased
costs for the z-drugs. One minor difference was that zaleplon pro-
duced shorter sleep latencies than zolpidem and zopiclone.
In the absence of a clear overall superiority of one substance, BZDs (alprazolam, chlordiazepoxide, diazepam, estazolam, flu-
the choice of a specific BZD or BZDRA should be guided by the razepam, lorazepam, quazepam, temazepam, and triazolam) and
subjective complaint of the patient, the treatment goals and the zolpidem in adults with insomnia [16]. The duration of treat-
half-life of the substance. A BZD or BZDRA with a shorter half- ment was seven days on average. The authors found stable effects
life (a shorter duration of action) is suitable for patients with sleep of medium size. The combined effect sizes were 0.6 for sleep onset
onset insomnia. In contrast, substances with longer half-lives have latency (SOL), 0.7 for the number of awakenings (NOA), 0.7 for
the potential to reduce wake after sleep onset (WASO) and early total sleep time (TST), and 0.6 for subjective sleep quality.
morning awakening, but bear the risk of carry-over effects the next Holbrook et al. [17] included 45 studies (n = 2672) into their
morning. Table 20.1 provides an overview of BZDs and BZDRAs, meta-analysis and investigated the effects of short-term (average
their half-lives, and their recommended dosages (based on [15]). seven days) BZD administration (triazolam, flurazepam, temaz-
As illustrated, zaleplon is a substance with a particularly short half- epam, midazolam, nitrazepam, estazolam, lorazepam, diazepam,
life, which is recommendable for patients who mainly suffer from brotizolam, quazepam, loprazolam, and flunitrazepam) and zopi-
difficulties falling asleep. Zaleplon usually does not produce carry- clone on self-reported sleep parameters in patients with insom-
over effects on the next morning. However, it is less well suited for nia. Compared with placebo, they found a reduction in SOL of
patients who mainly suffer from difficulties maintaining sleep or 14.3 minutes and an increase in TST of 48.4 minutes.
early morning awakenings [5]‌. Eszopiclone and temazepam, on the A subsequent meta-analysis by Glass and colleagues [18] included
contrary, are well suited for patients who wish to reduce WASO. 24 studies (n = 2417) on patients aged over 60 years with insom-
Flurazepam is a substance with a very long half-life, and is most nia. The analyzed substances were BZDs (loprazolam, nitrazepam,
often not recommendable because it frequently produces hangover triazolam, chlormethiazole, quazepam, flunitrazepam, midazolam,
effects. brotizolam, flurazepam, temazepam, and lormetazepam), z-drugs
(zolpidem, zopiclone, and zaleplon), and the antihistaminic agent
Evidence diphenhydramine. The authors found only small improvements
Several large meta-analyses demonstrated that BZDs and BZDRAs in sleep compared with placebo. The effect sizes were 0.1 for sub-
have a superior effect compared with placebo in improving sleep jective sleep quality and 0.6 for NOA. TST increased by 25 min-
parameters in adults with insomnia. utes. However, in this sample of elderly individuals, adverse events
In a first meta-analysis, Nowell and colleagues summarized 22 were more common with sedating substances than with placebo.
placebo-controlled RCTs (n = 1894) investigating the effects of Adverse cognitive events were 4.8 times more common, adverse

Chapter 20 pharmacological and non-pharmacological treatments of insomnia 191
psychomotor events 2.6 times more common, and reports of day- Duration
time fatigue 3.8 times more common with medications than pla- Concerning the duration of the treatment, a sufficient data base
cebo. The authors concluded that the small positive effects do not supports the efficacy and safety of short-term treatment (up to four
outweigh the risks in older patients with insomnia. weeks) with BZDs or BZDRAs. However, research on the effects of
long-term administration remains insufficient. In 2005, the State
Side effects of the Science Conference of the American National Institutes of
Barbiturates, which have been widely used as sedatives for many dec- Health [22] pointed out that it is still unclear for which patients, if
ades, bind to the β subunit of the GABA-A receptor and act as direct any, long-term medication with BZDs and BZDRAs is useful and
agonists at the receptor. Since the late twentieth century, barbiturates sufficiently safe. However, insomnia is often chronic and thus is
have rarely been used as hypnotics owing to their side effects, most most often not satisfactorily treated with a short-term course (up
important of which is the high risk of lethal overdose arising from the to four weeks).
narrow span between the therapeutic and toxic dosages. Several newer randomized, placebo-controlled studies have
BZDs, on the contrary, are indirect GABA agonists and exert addressed the long-term efficacy and safety of the z-substances.
their modulating effect at the α subunit of the GABA-A receptor Krystal et al. [23] investigated an extended use of eszopiclone versus
exclusively in the presence of GABA. Owing to their different mode placebo for six months. They included 788 patients with primary
of action, BZDs, in contrast to barbiturates, have a low risk of lethal insomnia and reported a significantly reduced SOL (43 minutes), a
overdose. They have thus largely replaced barbiturates as hypnotic significantly reduced WASO, a significantly increased TST (76 min-
medications. utes), and improved ratings of daytime function, which were sta-
However, within the last 20 years, many publications have dem- ble over six months. They found no evidence for clinically relevant
onstrated several critical side effects of BZDs and BZDRAs (see, changes in laboratory parameters or vital signs under eszopiclone
eg, [17]). Adverse effects are primarily morning hangover (drowsi- versus placebo. The most common side effects under eszopiclone
ness and light-headedness), cognitive disturbances associated with were a bitter taste, pain, nausea, and pharyngitis. No withdrawal
performance deficits and a reduced learning and memory capac- symptoms and no rebound insomnia after discontinuation of eszo-
ity, abuse, tolerance and dependency, parasomnia (eg, sleepwalking piclone were reported. Another study by Krystal and colleagues
and nocturnal eating), nocturnal falls related to muscle relaxation, [24] investigated the effects of a retarded form of zolpidem over six
confusion, and ataxia, especially in the elderly. Besides, BZDs may months with an administration of three to seven nights per week
enhance and prolong the effects of other substances, such as alcohol. in over 1000 patients with primary insomnia. Zolpidem, compared
Kripke and colleagues [19,20] even found an elevated mortality rate with placebo, produced significant and sustained improvements in
associated with the intake of hypnotics, including zolpidem, temaz- sleep onset and maintenance, next-day concentration, and daytime
epam, eszopiclone, zaleplon, other BZDs, barbiturates, and seda- sleepiness. No signs of rebound-insomnia were found during the
tive antihistamines. Thus, patients who receive a BZD or BZDRA first 3 nights of discontinuation. The most frequent adverse events
should always be closely monitored by their health practitioner. For associated with zolpidem, compared with placebo, were head-
each individual patient, positive effects and undesired side effects ache, somnolence, and anxiety. Ancoli-Israel et al. [25] published
must be examined and weighed against each other. Especially in the results of a 12-month open-label study on the extended use of
individuals over the age of 60 years, the prescription is often not zaleplon in 260 older adults with primary insomnia. They reported
recommended in light of the small benefits and the risk of severe statistically significant improvements in SOL, NOA, and TST over
adverse events [18]. the one-year period. No rebound insomnia associated with discon-
Although the z-drugs were initially praised for generating sub- tinuation was observed.
stantially fewer adverse effects than classical BZDs, recent research BZDs and BZDRAs are not approved in Europe for the long-term
suggests that this assumption is not justified. Duendar et al. [14] treatment (longer than four weeks) of insomnia.
concluded in their meta-analysis that, regarding benefits as well Discontinuation
as adverse events, the z-substances (zaleplon, zolpidem, and zopi-
Discontinuation of a BZD or BZDRA after more than a few days
clone) do not offer convincing advantages compared with the inves-
of use is often associated with a withdrawal syndrome including
tigated BZDs, but impose elevated costs on the healthcare system.
rebound insomnia, anxiety, loss of appetite, tremor, tinnitus, hal-
Holbrook and colleagues [17] also found in their meta-analysis that
lucinations, confusion, and convulsions [26]. In order to minimize
zopiclone was not superior to BZDs on any of the investigated out-
withdrawal symptoms, guidelines recommend tapering of the fre-
comes, including adverse events.
quency and dosage in small steps until the smallest possible dosage
[5]‌. Tapering may require several weeks or even months.
Mode of administration
Frequency Melatonin and melatonin agonists
Concerning the frequency of administration, a study by Perlis et al.
[21] supports the use of an intermittent dosing strategy, which is Mode of action
often adopted in clinical practice. In this study, patients with pri- Melatonin is an endogenous hormone released by the pineal
mary insomnia were instructed to take no fewer than three and no gland that is involved in the regulation of circadian rhythms and
more than five doses of 10 mg zolpidem per week over a period of sleep. Melatonin secretion is highest during the nighttime and is
three months. The authors found significantly improved sleep com- suppressed by dawn [27]. The hormone binds to MT1 and MT2
pared with placebo, no decrease of the effect with time, no rebound receptors in the suprachiasmatic nucleus. In the USA, mela-
insomnia, and no dose escalation with time. tonin is available as an over-the-counter medication. Melatonin

receptor agonists are available on a prescription basis: ramelt- rebound insomnia or withdrawal syndrome upon discontinuation.
eon (Rozerem) in the USA and Circadin in Europe. Circadin is However, the literature concerning the long-term administration
a prolonged-release form of melatonin. The half-life of ramelteon of melatonin agonists does not yet allow for recommendations
is 1.4 hours and that of Circadin is 2.5 hours. Both thus belong concerning the optimal duration of treatment. Additional stud-
to the hypnotics with a rather short duration of effect, which are ies on the long-term efficacy and safety of these substances are
mostly recommended to patients with sleep onset, but not sleep warranted.
maintenance, difficulties.
Effects on insomnia
Antidepressants
Melatonin Mode of action
A meta-analysis of the efficacy and safety of exogenous mela- Antidepressants that are commonly used off-label for the treat-
tonin was performed by Buscemi and colleagues in 2005 [28]. ment of insomnia include trazodone, doxepine, mirtazapine, tri-
They found that melatonin decreased SOL to a clinically relevant mipramine, and amitriptyline [10]. For the treatment of persistent
degree in patients with delayed sleep phase syndrome, but not in insomnia, they are usually prescribed in low doses, below the
patients with insomnia. The weighted mean reduction of SOL was therapeutic dosages for depression. Antidepressants influence sev-
only seven minutes in patients with insomnia. The authors found eral neurotransmitter systems in the central nervous system and
no evidence of adverse effects of melatonin. They concluded that thus exert various therapeutic and side effects. Their antidepres-
short-term treatment with melatonin is not effective in patients sant effect is assigned to an inhibition of the reuptake of serotonin
with primary insomnia. and noradrenaline into the synaptic cleft and subsequent neuronal
remodeling. Their hypnotic effects, by contrast, relate to an antago-
Ramelteon nism to the H1 histamine receptor. Table 20.2 provides an overview
In a review of the literature, Sateia and colleagues [29] identified of the most relevant sedating antidepressants, their half-lives, and
eight clinical trials on the efficacy and safety of ramelteon, all of their recommended dosages for antidepressant versus hypnotic
them conducted or sponsored by the pharmaceutical company that treatment (based on [15]). The table shows that most sedating anti-
synthesizes the agent, and five of them RCTs. They concluded that depressants have relatively long half-lives and may thus produce a
ramelteon is moderately effective in reducing SOL in adults of all morning hangover.
ages with chronic insomnia, but produces negligible or no effects
on WASO and TST. The effect on SOL was comparable to standard Effects on insomnia
hypnotic agents. Safety data indicated a low side effect profile with Prescribing low-dose sedating antidepressants for the treatment
no significant impairments of next-day performance. of chronic primary and comorbid insomnia is common clinical
A meta-analysis by Liu et al. [30] included eight RCTs (n = 4055) practice in Europe and the USA [10]. Yet there is a gap between
investigating the effects of ramelteon versus placebo. They found the widespread use of this practice and a scarcity of evidence for
significant improvements with ramelteon in subjective and poly- its efficacy and safety. Buscemi et al. investigated the efficacy and
somnographic SOL, TST, and latency to REM sleep, but no effect safety of drug treatments, including antidepressants, for chronic
on the percentage of REM sleep. In this meta-analysis, the effect on insomnia in a meta-analysis [32]. The weighted mean reduction in
subjective SOL was only significant for the group of patients aged SOL measured by polysomnography after antidepressant treatment
under 65 years. With a reduction in subjective SOL by 14.3 minutes compared with placebo was 7 minutes. For SOL measured by sleep
in the younger age group and an increase in TST by 8.7 minutes, the diaries, the reduction was 12 minutes. The weighted means were
effects of ramelteon appear to be small. Ramelteon was not associ- based on four studies for SOL measured by polysomnography and
ated with relevant adverse events compared with placebo. two studies for SOL measured by sleep diaries. Based on five stud-
ies, there was an increase in sleep efficiency (polysomnography)
Side effects by 13% after antidepressant treatment versus placebo. Notably, the
To date, the literature on melatonin and ramelteon has yielded no
evidence for any severe side effects [28–30]. The most frequent
adverse events reported after the use of ramelteon were headache,
Table 20.2 Sedating antidepressants with half-lives and recommended
nasopharyngitis, and somnolence [30]. However, none of these
dosages
occurred significantly more often after ramelteon than after pla-
cebo. In contrast to BZDs and BZDRAs, melatonin agonists do
Drug name Half-life (h) Recommended dose (mg) Trade name
not carry risks of dose escalation, abuse, dependence, or rebound (examples)
insomnia upon withdrawal.
Antidepressant Hypnotic
Mode of administration
Trazodone 3–14 150–600 25–150 Thombran
The recommended dose for ramelteon is 8–16 mg, and that for
Doxepin 10–30 100–300 3–150 Aponal
Circadin is 2 mg. However, the meta-analysis by Liu et al. suggests
that for ramelteon, 16 mg is not more effective than 4 mg [30]. Mirtazapine 13–40 15–45 3.75–30 Remergil
A study by Mayer and colleagues [31] in 451 patients with chronic Trimipramine 15–40 100–300 10–150 Stangyl
primary insomnia found that ramelteon consistently reduced
Amitriptyline 5–45 100–300 25–150 Saroten,
SOL over six months of nightly administration. The authors
Equilibrin
found no carry-over effects the next morning and no signs of

increase in TST measured by polysomnography was large, at 79.4 Side effects

minutes (based on four studies), but TST measured by sleep diaries
Most antidepressants have far longer half-lives than common BZDs
decreased by 54.3 minutes (based on one study). Patients treated
and BZDRAs (see Tables 20.1 and 20.2). For this reason, they are
with antidepressants reported significantly more adverse events
often associated with morning hangover, especially in the first
than patients who had received placebo, the relative risk difference
period after treatment onset.
being 0.09 (three studies). The most commonly reported adverse
Potential side effects of sedating antidepressants in low dosages
events were somnolence, headache, dizziness, and nausea. There
have not yet been sufficiently investigated. Common side effects
were no reports of falls, injury, or death.
include sedation, anticholinergic effects such as dry mouth, consti-
A study of the effects of doxepin on polysomnographically meas-
pation, urinary retention, and glaucoma, antihistaminic effects such
ured sleep was published by Hajak et al. in 2001 [33]. Forty-seven
as weight gain, orthostatic hypotension, restless legs symptoms, and
patients with primary insomnia were randomized to either 25–50
cardiovascular side effects. In contrast to BZDs and BZDRAs, anti-
mg of doxepin or placebo for a treatment phase of four weeks.
depressants appear not to bear the risk of abuse and dependency.
Doxepin, compared with placebo, was associated with a signifi-
cantly better sleep efficiency, sleep quality, and ability to work over
the treatment phase of four weeks. Subjective improvements were Antihistaminics
small to moderate in size. Sleep returned to its baseline level after Histamine is an organic nitrogen compound that is known to be
discontinuation of doxepin. There were significantly more patients involved in local immune responses. As a neurotransmitter, hista-
with severe rebound insomnia in the doxepin group, and two mine is involved in the maintenance of wakefulness [37], with its
patients dropped out of the doxepin group due to severe side effects H1 receptor subtype being relevant for the regulation of sleep and
(increased liver enzymes, leukopenia, and thrombocytopenia). The wakefulness. Diphenhydramine, hydroxyzine, doxylamine, and
second doxepin study was published by Roth et al. in 2007 [34]. promethazine are examples of reversible antagonists of histamine
In the crossover-study, 67 patients with primary insomnia were at the H1 receptor that are available for the treatment of insomnia.
randomized to doxepin in three different low dosages (1, 3, and The efficacy and safety of antihistaminic substances for the treat-
6 mg) versus placebo for two nights with a drug-free interval of 5 ment of insomnia is not well established. In particular, studies
or 12 days. The authors found significant improvements in WASO, concerning their long-term effects are lacking. Some studies have
TST, and sleep efficiency measured by polysomnography for dox- been conducted on the short-term efficacy and safety of diphen-
epin in all dosages compared with placebo. For doxepin 6 mg, an hydramine. Glass et al. compared diphenhydramine (50 mg) with
improvement in subjective SOL was found. The safety profile of temazepam (15 mg) and placebo in a RCT in elderly patients with
doxepin for this short-term administration was comparable to pla- insomnia over a period of 14 days [38]. Diphenhydramine was
cebo, with no evidence of daytime sedation, anticholinergic effects, only effective in reducing the number of awakenings, but had no
or memory impairment. effect on sleep quality, TST, or SOL. The numbers of adverse events
Walsh and colleagues conducted a comparison of zolpidem 10 were similar in all three groups, but one person in the temazepam
mg versus trazodone 50 mg versus placebo for two weeks in 306 group suffered a fall. In another RCT, Morin et al. compared the
patients with primary insomnia [35]. After one week, an increase effects of diphenhydramine (25 mg over 14 days), a valerian–hops
in self-reported TST and a reduction in SOL were significant for combination, and placebo on sleep diary variables and polysomno-
both substances versus placebo, but zolpidem produced a greater graphically measured sleep in 184 adults with mild insomnia [39].
reduction of SOL than trazodone. After two weeks, the effects on Diphenhydramine produced significantly greater improvements
TST were nonsignificant for both substances and the effects on in sleep efficiency than placebo, but had no significant effect on
SOL were only maintained in the zolpidem group. The rates of side other sleep variables. No significant adverse events and no rebound
effects were 75% for trazodone, 76.5% for zolpidem, and 65.4% for insomnia upon discontinuation were observed for both treatments.
placebo. The most frequently reported adverse events were head- In summary, there is some evidence that diphenhydramine pro-
ache and somnolence. Both were slightly more frequent in the duces small to moderate short-term improvements in subjectively
trazodone group. reported sleep. However, various side effects have been associ-
In another study, 55 patients with primary insomnia were ran- ated with antihistaminic substances. Impaired psychomotor per-
domized to trimipramine at an average dose of 100 mg, lormetaz- formance has been reported as a side effect of diphenhydramine.
epam 1 mg, or placebo for a treatment period of 28 days [36]. Dizziness, fatigue, tinnitus, decreased appetite, nausea, vomiting,
The authors found no significant effects of trimipramine versus diarrhea, constipation, and weight gain can occur as side effects of
placebo on TST, which had been the primary outcome. However, antihistaminic substances. Clinical experience suggests a loss of
the data show increases in TST by almost 60 minutes in the tri- effect over time, indicating that antihistaminic substances are not
mipramine group and 18 minutes in the lormetazepam group, suitable for the long-term treatment of chronic insomnia.
and an almost unaltered TST in the placebo group. Thus, the lack
of significance might be due to the small sample size. An effect Antipsychotics
on sleep efficiency was significant for trimipramine versus pla-
cebo, and nonsignificant for lormetazepam versus placebo. The First-generation antipsychotics such as haloperidol are to be distin-
effects diminished after a shift from trimipramine to placebo, but guished from the so-called atypical or second-generation antipsy-
no evidence of rebound insomnia or withdrawal syndrome were chotics such as risperidone, quetiapine, olanzapine, and clozapine.
reported. No relevant adverse events were found in EEG, vital The agents of the first generation are assumed to exert their antip-
parameters, physical examination, or laboratory parameters dur- sychotic effects by blocking dopamine, mainly at its D2 receptor in
ing active treatment. the mesolimbic system. However, D2 receptors are not exclusively

located in the target regions of the brain, but also exist in other [42]. It remains to be elucidated which techniques are the active
regions such as the basal ganglia. First-generation antipsychotics do components of CBT and whether multicomponent CBT is superior
not bind selectively to the target receptors. Thus, they are associated to any single intervention [42]. One example of a treatment manual
with severe side effects such as extrapyramidal dysfunctions (dys- is the session-by-session guide by Perlis et al. [43].
kinesia, akathisia, and parkinsonism). Second-generation antip- The following section first summarizes the state of research con-
sychotics were developed in order to exert less severe side effects cerning psychological and behavioral interventions for chronic
and indeed show a lower incidence of extrapyramidal dysfunc- insomnia. Second, the most relevant interventions are illustrated.
tion. However, they can produce other side effects, such as massive
weight gain. Sedation and sleepiness are also common side effects, State of research
which probably result from antagonism of the H1 histaminic recep-
tor. Their sedating effects may suggest the suitability of some antip- Effects on insomnia
sychotics for the treatment of insomnia, but to date no controlled Five meta-analyses evaluated nonpharmacological interventions
studies of antipsychotic agents in patients with primary insomnia for insomnia in adults, two of which exclusively focused on insom-
have been conducted. Owing to their many side effects, antipsy- nia in older adults. One recent study reviewed the literature on
chotics, including the “atypical” agents, are not recommended for computerized CBT for insomnia.
the treatment of chronic primary insomnia. Their use as hypnotics The first meta-analysis was published by Morin et al. in 1994 and
should be reserved for patients presenting with severe comorbid reviewed the literature from 1974 to 1993 [44]. The review included
psychiatric conditions like schizophrenia and related disorders, 59 studies (n = 2012). Of note, this meta-analysis and most others
who might also benefit from their antipsychotic effects. on psychological and behavioral interventions calculated pre-to-
post effect sizes, whereas the meta-analyses on BZDs and BZDRAs
cited earlier in the chapter reported between-group effect sizes.
Valerian Many individual studies compared psychological and behavioral
Valerian is a herbal substance that is extracted from the roots of the interventions to a waitlist rather than a placebo group, as it is diffi-
plant Valeriana officinalis. It is sold as an over-the-counter sleep cult to realize a true placebo group in trials on psychological inter-
and anxiolytic medication. Its sedating and anxiolytic effects are ventions. Thus, the different kinds of effect sizes for psychological
assumed to relate to an activity at the GABA receptor. However, the and pharmacological interventions are of limited comparability.
mode of action of valerian is not yet fully understood. A systematic Morin et al. reported the following pre versus post effect sizes for
review by Taibi and colleagues identified 29 controlled trials and nonpharmacological interventions in a total of 2102 patients with
eight open-label studies on valerian as a sleep aid [40]. The authors primary or comorbid insomnia: 0.88 for SOL, 0.65 for WASO, 0.53
concluded that valerian has no side effects but is probably no more for NOA, and 0.42 for TST. All four effect sizes were significantly
effective than placebo for the treatment of insomnia. Many of the greater than zero. Psychological and behavioral interventions con-
reviewed studies were of insufficient methodological quality. tained five hours of therapy time on average. The most effective
A more recent meta-analysis on the efficacy of valerian for techniques were stimulus control and sleep restriction, whereas
insomnia was conducted by Fernandez-San-Martín and colleagues sleep hygiene education alone was not effective. The effects were
in 2010. They identified 18 RCTs comparing valerian preparations maintained at follow-up measures (mean follow-up duration six
to placebo [41] and found a mean difference in SOL between vale- months). Figure 20.1 illustrates the quantitative changes in sleep
rian and placebo of 0.7 minutes. The relative “risk” of sleep quality
improvement (yes/no) with valerian compared with placebo was
1.37. In view of their results, the authors suggested a shift of further
research activities to other treatments for insomnia that are more 60 Morin et al. [44] Murtagh and Greenwood [45]
promising than valerian. 50

Difference from baseline (minutes)
40
Psychological Interventions 30
Key points 20
Psychological and behavioral interventions are effective in treating 10
insomnia in the short and long term. The extant literature suggests 0
that the effects of these interventions are more sustainable than
–10
those of pharmacological treatment [9]‌. The improvements in sub-
jective sleep quality, SOL, TST, WASO, and NOA after psychologi- –20
cal and behavioral interventions are typically of medium to large –30
effect size. According to a systematic review of the literature pub-
–40
lished by a task force of the American Academy of Sleep Medicine SOL SOL WASO WASO TST TST
in 2006, relaxation training, stimulus control therapy, paradoxi- post FU post FU post FU
cal intention, sleep restriction, and cognitive–behavioral therapy
Fig. 20.1 Quantitative improvements in sleep after psychological treatment. SOL,
(CBT) are well-established treatments for patients with chronic
sleep onset latency; WASO, wake time after sleep onset (not reported by Murtagh
primary and comorbid insomnia, including older adults [42]. To and Greenwood); TST, total sleep time; post, quantitative change compared with
date, no complete dismantling studies on the effectiveness of single baseline (in minutes) directly after treatment, FU, quantitative change compared
psychological and behavioral interventions have been conducted with baseline at follow-up. All effects were significantly different from zero.

variables (in minutes) that were found in this meta-analysis and the The effects on TST (0.22), WASO (0.18), and time in bed (0.25)
following one. The figure shows that the improvements were well failed to reach statistical significance.
maintained or even increased at follow-up.
The second meta-analysis was published by Murtagh and Adherence
Greenwood [45] one year later. The authors reviewed the litera- Whereas the efficacy of nonpharmacological interventions for
ture from approximately the same time period, but only included insomnia is undisputed, patients’ adherence to the somewhat stren-
studies on patients with primary insomnia without comorbidities. uous recommendations such as restricted bed times is a challenging
Sixty-six studies (n = 1538) fulfilled the inclusion criteria and were problem in clinical practice. Matthews et al. reviewed the literature
included in the meta-analysis. The reported effect sizes for the pre on patients’ adherence to CBT for insomnia in a recent systematic
versus post comparison are similar to those found in the review by review [50]. They included 15 studies published between 1992 and
Morin et al., with 0.87 for SOL, 0.63 for NOA, and 0.49 for TST (all 2012 that investigated short-term adherence to sleep restriction,
significant). Similar to the findings of Morin et al., Murtagh and stimulus control, and sleep hygiene education using measures other
Greenwood found that the sleep improvements after psychological than study withdrawal. The authors conclude that despite the rel-
and behavioral interventions were maintained or even augmented evance of the topic, there is still a dearth of valid research devoted
during follow-up periods of six months on average. to adherence. Inconsistencies in adherence findings may be due to
The first meta-analysis that focused on adults with insomnia at an methodological weaknesses of the included studies, such as small
older age (over 60 years) was conducted by Pallesen and colleagues sample sizes, diversity of sample characteristics, and the absence of
[46]. Studies that were published between 1966 and 1998, that standardized definitions and measures of adherence. Some of the
evaluated a psychological or behavioral treatment for older adults included studies found a positive relationship between adherence
with insomnia, and that investigated quantitative sleep parameters and sleep improvements. The authors suggested that small invest-
as outcomes were included. The meta-analysis was performed on ments in the improvement of adherence might result in better out-
13 studies (n = 388). Effect sizes directly after treatment were 0.41 comes. However, the occurrence of side effects, such as sleepiness
for SOL, 0.61 for WASO, 0.25 for NOA, and 0.15 for TST. The effect and fatigue, especially at the beginning of sleep restriction therapy,
sizes at follow-up (average duration six months) were 0.61 for SOL, makes the low adherence of some patients understandable.
0.59 for WASO, 0.66 for NOA, and 0.37 for TST (all significant).
Montgomery and Dennis conducted a Cochrane Review on the Mediators
effects of cognitive–behavioral treatments for sleep problems in In a review of potential mechanisms of treatment outcomes of
the population of patients aged over 60 years [47]. They included CBT for insomnia, Schwartz and Carney [51] summarized three
only RCTs that met high methodological standards according to models of insomnia and derived different theorized mechanisms
a quality checklist. Patients with typical insomnia symptoms (eg, of action. Behavioral models emphasize that dysfunctional sleep-
difficulties initiating and maintaining sleep and impaired day- related behaviors, such as daytime napping or prolonged bedtimes,
time functioning) as well as patients with delayed or advanced weaken the homeostatic sleep drive and disrupt a consolidated
sleep phase syndrome and parasomnias were included. Six RCTs sleep–wake rhythm. These models thus propose that mechanisms
(n = 224) met the inclusion criteria. This review found a negligi- of CBT comprise a reduced time in bed, decreased daytime nap-
ble effect for SOL (−3 minutes) and modest effects for WASO (−22 ping, and a reduced variability of bedtime and rise time. Cognitive
minutes) and TST (+14.6 minutes). The authors concluded that in models, in contrast, propose that increased worry and rumination,
elderly patients with sleep problems, cognitive–behavioral inter- attentional bias toward sleep-related threats, and distorted beliefs
ventions are best suited for sleep maintenance problems. about sleep are central to the development and maintenance of
A fifth meta-analysis was published by Irwin et al. in 2006 [48]. chronic insomnia. Based on these models, suggested mechanisms
Inclusion criteria were RCTs investigating the effects of cognitive– include decreased maladaptive beliefs and attitudes about sleep,
behavioral interventions for primary insomnia with sleep param- increased experience of self-efficacy, and a shift from an external
eters as outcomes. Twenty-three trials were identified. Effect sizes to an internal locus of control about sleep. A third model is the
of acute treatment were 0.50 for SOL, 0.69 for WASO, 0.17 (nonsig- hyperarousal model, which posits that a conditioned cognitive,
nificant) for TST, 0.74 for sleep efficiency, and 0.79 for subjective somatic, and emotional hyperarousal is a central perpetuating fac-
sleep quality. The authors analyzed the type of behavioral interven- tor of insomnia, and thus that effective treatments work through a
tion as a moderating variable and found that combined CBT, relax- reduction of this arousal.
ation, and behavioral treatment alone did not significantly differ The authors found 54 studies that fulfilled their inclusion criteria
in effect sizes. The interventions were found to be equally effective (RCTs comparing CBT for adults with insomnia versus a control
for middle-aged adults and patients older than 55 years concerning condition, with sleep outcomes as dependent variables). Thirty-
sleep quality, sleep latency, and wakening after sleep onset. nine percent of these (21 studies) included the examination of
An meta-analysis by Cheng and Dizon evaluated a new trend in potential mediating variables. The reviewed studies provided some
psychotherapy: computerized CBT, a low-threshold alternative to evidence for each of the three models. The authors concluded that
face-to-face therapy [49]. The investigated interventions were sleep more research is needed to better understand whether CBT works
hygiene education, stimulus control, relaxation, sleep restriction, through its theorized mechanisms.
and cognitive restructuring, delivered through the use of a com-
puter. The authors included six RCTs in their analysis. The effect Setting
sizes of computerized CBT for insomnia compared with control In their review of the literature published between 1998 and 2004,
groups (waitlist or alternative treatment groups) were 0.41 for sleep Morin and colleagues found that psychological treatments were
quality, 0.40 for sleep efficiency, 0.45 for NOA, and 0.55 for SOL. provided over a mean period of 6.5 weeks and included 5.7 sessions

on average [42]. Bastien et al. directly compared three different soothing music or reading in front of a low-intensity light; go
treatment modalities and found no significant differences between back to bed when feeling drowsy; you can repeat these steps more
group CBT, individual CBT, and telephone consultations in a trial than once).
of 45 adults with primary insomnia [52]. In two studies, treatment u Use the bed only for sleeping (and sex), do not work, watch TV,
provided by trained primary care physicians or nurses produced eat, etc. in the bedroom.
effects that were comparable to those typically found for treatment
provided by psychologists [53,54]. CBT is most often conducted in Important, patients should be asked to stand up after approximately
group programs that include psychoeducation, sleep hygiene edu- 20 minutes; they should be instructed not to look at a clock or
cation, relaxation training, cognitive restructuring, and, as a key watch, because this would unnecessarily keep them awake.
component, behavioral interventions such as sleep restriction or
stimulus control. Sleep restriction
Similar to stimulus control, sleep restriction therapy is based on the
observation that patients with insomnia often report prolonged bed
Interventions time and daytime napping in order to compensate for poor sleep.
Stimulus control This behavior is assumed to produce a destabilization of natural
Stimulus control therapy is based on the assumption that in indi- biological sleep–wake rhythms. The rationale for sleep restriction
viduals with chronic insomnia, the bed serves as a conditioned therapy for insomnia is to increase sleep pressure in order to reduce
stimulus for wakefulness, anxiety, and arousal. Patients often report sleep latency and render sleep more restorative. The goal of the
extended bed times in order to compensate for poor sleep. Thus, therapy is thus not to help patients sleep eight hours per night, but
compared with healthy sleepers, they spend more time lying in bed to increase the restorative quality of their sleep. It is assumed that
awake, worrying about not being able to sleep and consequences of improved sleep continuity can be accomplished by compressing the
poor sleep. When lying in bed and trying hard to fall asleep without total time in bed to the actual sleep time and thus increase sleep
success, patients are assumed to experience a heightened cognitive efficiency. Besides, the individual spends less time awake in bed,
and somatic arousal and frustration about not being able to sleep. which is supposed to dissolve the conditioned connection between
As a consequence of another night with poor sleep, they might the bed as a stimulus and arousal/awakening as a response (see the
decide to spend even more time in bed in order to compensate for earlier discussion).
their sleep loss. Yet, in fact, they might be too anxious or aroused Before starting sleep restriction therapy, patients are required to
to fall asleep, they might be “trying too hard,” or they might simply keep a sleep diary for one to two weeks. The diaries are carefully
not have enough sleep pressure when going to bed early, and thus reviewed together with the therapist, and bed time is restricted to
they consolidate the learning experience that the bed is a cue for the actual total sleep time (TST). If, for example, TST is an aver-
wakefulness and arousal instead of relaxation and sleep. age five hours per night, the time in bed is restricted to five hours
Stimulus control therapy is designed to re-associate the bed with per night. However, the total time in bed should not be less than
sleep. However, it is also conceivable that the effective mechanism five hours. The patient and the therapist agree on fixed bed times
of stimulus control is not, or not exclusively, the re-association of and wake times, which should be followed for seven days a week.
the sleeping environment with deactivation and sleep. It is possible Patients are instructed not to nap during the day. Weekly sessions
that the technique works, at least in part, by sleep deprivation and for monitoring and adjustment of sleep behavior are scheduled.
a subsequent increased sleep pressure (see the later discussion of Sleep efficiency can be calculated as TST divided by time in bed,
sleep restriction therapy). multiplied by 100. If sleep efficiency is still below 85% after one
Stimulus control therapy usually starts with a psychoeduca- week, patients are instructed to decrease time in bed by another 15
tion session. Therapists might start by explaining the two-process minutes. When sleep efficiency is 85% or above, time in bed can be
model of sleep regulation (cf. [37]). Briefly summarized, sleep and increased in steps of 15–30 minutes per week.
wake behavior is regulated by two processes. The first of these is It is important to consider that sleep restriction therapy may pro-
the circadian rhythm of many biological functions, including body duce adverse effects in many patients. In contrast to pharmaceuti-
temperature, hormone levels, and a circadian component of sleep cal approaches, adverse effects of psychotherapy are often neglected
propensity. The second process is the homeostatic drive and reduc- by researchers. During sleep restriction therapy, patients may suffer
tion of sleep pressure. After a long period of wakefulness, sleep from daytime sleepiness and a reduced level of daytime function-
pressure grows and leads to faster sleep onset and an increase in ing, especially in the beginning of the sleep restriction treatment
slow-wave sleep. The same happens after a night of poor sleep. [55]. Patients should be instructed only to drive a vehicle and oper-
Thus, there will always be “good nights” following “bad nights,” ate machinery if they feel able to stay awake and concentrated. For
even if patients with insomnia sometimes feel that they do not sleep many patients, the treatment is perceived as aversive, and thus
at all. The model can be used as an introduction to the rationale of compliance is often insufficient.
stimulus control and sleep restriction therapy.
During stimulus control therapy, patients receive the following Intensive sleep retraining
instructions: Intensive sleep retraining (ISR) [56] is a brief conditioning treat-
ment. The rationale is to increase the homeostatic sleep pres-
u Go to bed only when you are sleepy.
sure by acute sleep deprivation and realize a series of rapid sleep
u If
you are not able to sleep after 20 minutes or wake up at night onsets the following night. This is supposed to dissolve the con-
and cannot return to sleep after 20 minutes, get out of bed, go ditioned insomnia response. In the night before the actual treat-
to another room, and do something relaxing (eg, listening to ment, patients are instructed to restrict their time in bed to five

hours. They attend the therapeutic setting (eg, a sleep laboratory) Cognitive interventions
the following night. The treatment is realized during a period of
The aims of cognitive therapy for insomnia are restructuring dis-
25 hours, for example from 22:00 to 23:00 the following night.
torted beliefs and attitudes and challenging unrealistic expectations
During this period, participants are provided with 50 sleep-onset-
about sleep. Dysfunctional cognitions are critically examined and
opportunities every half-hour. The opportunity for sleep onset is
replaced by more adaptive thoughts. Common distorted beliefs of
limited to 20 minutes within each trial. If patients fall asleep within
individuals with insomnia are, for example, the assumption that
this time, they are allowed to sleep for three consecutive minutes
every person needs eight hours of sleep every night to be healthy
and are then awakened. During their wake time, participants
and the concern that a night with little sleep inevitably leads to an
undertake relaxing activities such as reading or watching movies.
apparent and dramatic reduction in next-day performance.
After the intervention period, they receive detailed feedback about
Pech and O’Kearney evaluated the efficacy of problem-solving
their sleep–wake times within each trial.
therapy (PST) for primary insomnia [62]. The goal of PST is to
Potential effective components of ISR are a conditioning effect, a
reduce engagement in worry in the pre-sleep period and to enhance
discrimination training of sleep and wake states due to the detailed
the feeling of self-efficacy concerning problem solving. The treat-
feedback, and an exposure to sleep deprivation that is highly feared
ment consisted of problem-solving techniques such as setting a fixed
by many individuals with insomnia. In a recent RCT, 79 volun-
time for thinking about problems and noting down possible solu-
teers with sleep onset insomnia were randomized to IST, stimulus
tions step by step, action planning, and evaluating solutions. PST
control, a combination of both treatments, or sleep hygiene edu-
was compared with traditional cognitive therapy, as an adjunct to
cation as a control condition. All active treatments were superior
sleep hygiene education, to stimulus control therapy, and to relaxa-
to the control condition, with few differences between the active
tion. Equal effects were found in both groups. However, owing to
treatments. An advantage of ISR appears to be a faster treatment
the design of the study, it cannot be decided whether the behavio-
response [56].
ral interventions alone were responsible for the treatment effects
in both groups. Thus, the results of the study cannot be considered
Relaxation training
as evidence that PST and/or cognitive therapy are helpful. To date,
Relaxation training is assumed to work through a reduction in cognitive interventions alone are not supported by sufficient evi-
the physiological, cognitive, and emotional hyperarousal that is dence and thus are not recommended as a standalone treatment
associated with insomnia. Practitioners may also learn to focus for insomnia [42]. The extent to which the cognitive component of
their attention on muscular relaxation and thus interrupt dys- CBT plays a role in the efficacy of combined treatments remains to
functional rumination and worry. Sleep improvements have been be clarified.
demonstrated for progressive muscle relaxation (PMR) and other
forms of relaxation training such as deep breathing, hypnosis, and Paradoxical Intention
autogenic training. PMR has been developed by Edmund Jacobson
[57]. The method is based on the conscious tension and subse- The rationale of paradoxical intention therapy is to reduce the fear
quent relaxation of different muscle groups. In a second step, the of staying awake and weaken the pressure of having to fall asleep.
physical relaxation is coupled with an individual signal, such as These are in fact incompatible with falling asleep and often create a
a word or a mental image, which enables subjects to deliberately vicious circle of fear, pressure to “do it right,” and consequent failure
recall relaxation. to fall asleep in patients with chronic insomnia. In healthy sleepers,
In addition to the relaxation training itself, patients can also be in contrast, falling asleep most often happens without any deliber-
instructed not to engage in highly activating tasks before bedtime. ate effort or conscious awareness. The goal of paradoxical intention
Patients should be informed that first they will need time to learn treatment is to break this vicious circle by instructing patients to
the relaxation technique and that therefore sleep improvements stay awake as long as possible after going to bed. Two small RCTs
are not to be expected from the beginning of the training. At first, from 1979 and 1986 suggested that paradoxical intention therapy
relaxation exercises should not be performed directly before bed- can be equally effective as stimulus control and relaxation training
time, in order to prevent the experience of failure and subsequent [63,64].
frustration.
Biofeedback
Mindfulness Different kinds of biofeedback have been suggested for the treat-
Mindfulness meditation training is another intervention that is ment of insomnia. The most common is electromyography (EMG)
sometimes considered a relaxation technique. However, the aim of biofeedback. Other forms include sensorimotor rhythm (SMR)
mindfulness practice is not to achieve a state of relaxation, but to feedback and theta electroencephalography (EEG) feedback.
cultivate active awareness of body sensations, thoughts, and feel- EMG biofeedback can be considered a special form of relaxa-
ings in the present moment. Mindfulness is often taught in weekly tion training that aims at reducing somatic hyperarousal. Patients
group meetings over a period of eight weeks. Manualized mind- receive a display of their actual level of tension or relaxation
fulness trainings are Mindfulness Based Stress Reduction [58] and through sensors placed on their skin. While performing relaxation
Mindfulness Based Cognitive Therapy [59]. Jason Ong and his co- strategies, they can monitor their “success” online and adapt their
workers developed a mindfulness-based treatment for insomnia behavior to the feedback they receive.
that combines intensive mindfulness training with sleep restric- The aim of SMR feedback and theta EEG biofeedback is to
tion and stimulus control treatment. In an open-label pilot study, teach patients to deliberately induce an EEG rhythm that is typi-
the authors found first promising effects that were mainly stable at cally found in human sleep. These interventions are thus designed
12 months follow-up [60,61]. to actively induce sleep, in contrast to indirectly promoting sleep

through the reduction of arousal. Biofeedback meets the American in the study. Fourteen behavioral treatment studies (n = 250) and
Psychological Association (APA) criteria for “probably efficacious eight pharmacological studies (n = 286) were included. In this sam-
treatments” [65]. ple, the pre-to-post effect sizes averaged over all included sleep
variables (SOL, NOA, WASO, TST, sleep quality) were compara-
Sleep hygiene education ble, at 0.87 for pharmacological and 0.96 for non-pharmacological
The aim of sleep hygiene education is to eliminate behaviors that are interventions. Statistical comparisons for the individual variables
incompatible with healthy sleep. A first step is the thorough exami- showed that the weighted effect sizes were comparable for NOA,
nation of the individual sleep behavior: When does the patient go WASO, TST, and sleep quality. Behavioral interventions were supe-
to bed? When does he wake up and when does he get up? What rior to BZDs and BZDRAs concerning SOL (weighted effect sizes
does he do before bedtime? Does he drink alcohol, smoke nicotine, were 1.05 versus 0.45).
or consume any other stimulants? A systematic review by Mitchell et al. [67] analyzed trials that
According to their individual sleep-related behaviors, patients directly compared CBT for insomnia with any FDA-approved pre-
then receive information and advice. The most important sleep scription or nonprescription medication in patients with primary
hygiene rules are the following: insomnia. The levels of evidence were assessed using the GRADE
method; i.e, the strength and certainty of evidence was rated as
◆ Keep a regular sleep–wake schedule (eg, always go to bed and
high, moderate, low, or very low for each research question. Five
wake up at approximately the same time, including weekends,
RCTs that met the inclusion criteria were identified. The data were
and avoid daytime napping).
considered too small and too heterogeneous to conduct a meta-
◆ Keep to a healthy diet. analysis. The investigated medications were zolpidem, zopiclone,
◆ Regularly engage in sporting activities, but avoid sports or other temazepam, and triazolam. Evidence concerning the short-term
exciting activities before going to bed. comparison of CBT and BZDs/BZDRAs was of very low quality
and provided inconsistent results. Long-term comparisons (follow-
◆ Reduce the intake of stimulants such as coffee, cola, and black tea up periods of 6–24 months) consistently favored CBT, with low to
to a minimum, and avoid stimulating drinks after noon. moderate grade of evidence. Quality of life as an outcome was only
◆ Avoid nicotine close to bedtime, because nicotine is also a stim- included in one trial, which found no significant difference between
ulant. Additionally, the sudden withdrawal of nicotine at night patients treated with CBT versus zopiclone. The study also found no
may induce awakenings in heavy smokers. group difference in daytime fatigue as measured by reaction times.
◆ Avoid alcohol before bedtime. Alcoholic drinks shorten sleep The reporting of adverse events was too limited to draw conclusions
onset latency, but alcohol metabolizes very rapidly and thus pro- concerning the comparative safety of the two treatment types.
duces nightly awakenings as a rebound effect.
◆ Refrain from amphetamines, cocaine, and other illicit drugs that Conclusion
have sleep-disturbing effects. The current state of research on the treatment of persistent primary
◆ Avoid heavy evening meals. and comorbid insomnia in adults is that pharmacological treatment,
especially with BZDs or BZDRAs, and non-pharmacological inter-
◆ Avoid drinking a lot (including non-alcoholic beverages) in the
ventions, primarily behavior treatment, are effective for the short-term
evening.
management. However, both types of interventions bear the risk of
◆ Minimize noise and light in the bedroom and avoid a bedroom adverse effects. Most prominently, BZDs and BZDRAs are associated
that is too hot or too cold. with the risk of development of tolerance and dependency. Undesired
◆ Do not watch the clock at night, since this often leads to more outcomes of psychotherapy are often insufficiently accounted for
arousal and more pressure to finally fall asleep, and thus prevents in clinical trials. Nonpharmacological interventions are superior
one from doing so. to medication when long-term effects are considered. Whereas the
effects of psychological approaches have been found to remain stable
◆ Establish a personal bedtime ritual. after discontinuation of the treatment for follow-up periods up to two
Sleep hygiene education is not effective as a standalone treatment years, insomnia often re-occurs after the discontinuation of medica-
for patients with chronic insomnia, but is assumed to be beneficial tion. Following the present state of evidence, psychological interven-
in nonclinical cases or as an adjunct to other interventions. tions are the first-line treatment for persistent insomnia. Medication is
only recommended if psychological treatment alone fails or if patients
Comparative effects of pharmacological refuse psychological treatment. If pharmacotherapy is used, it should
be limited to a period of up to four weeks.
and nonpharmacological treatment
The comparative efficacy of pharmacological and nonpharmaco-
logical interventions has been evaluated in two systematic reviews.
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SECTION 6
Circadian rhythm
disorders

CHAPTER 21
Shift work sleep

disorder and jet lag
Vivek Pillaiâ•›† and Christopher L. Drake
Shift work sleep disorder CNS arousal [12]. Thus, the circadian alerting signal rises during
the day, in effect, opposing the homeostatic sleep pressure that
A considerable proportion of the workforce in the industrialized results from wakefulness, until eventually subsiding at night when
world engages in shift work, with schedules that are significantly homeostatic pressure peaks [13]. Desynchrony between these
aberrant from the conventional 9-â•‰to-â•‰5 work day [1]â•„. Prevalence rates precisely controlled biological rhythms and self-â•‰selected sleep–â•‰
of shift work are similar across Europe, South America, Asia, and wake schedules can trigger sleep loss and impaired wakefulness.
Africa: 22% in the UK, 25% in Greece and Finland, 24% in the Czech Shift workers must attempt to sleep during the day when the circa-
Republic, 15% in Chile, 17.5% in China, and 20% in Senegal [2,3]. dian alerting signal is strong, leading to short, fragmented sleep. The
In the US, nearly 20% of employed adults are shift workers, and 18–â•‰ resulting homeostatic sleep debt combines with blunted nighttime cir-
26% begin their shift between 2:00 pm and 6:30 am [4]. Rates of shift cadian arousal to produce excessive sleepiness during the night when
work are especially high in service occupations. Almost 50% of pro- the worker must remain awake (Fig. 21.1). However, shift workers,
tective service (eg, law enforcement and fire safety) and food prepa- including those working on the same shift, show remarkable diversity
ration/â•‰service employees, and about a quarter of transportation (eg, in their tolerance to circadian disruption [14,15]. Research suggests
train and bus drivers) and healthcare professionals are shift workers that the effects of shift work are moderated by factors such as sleep and
[4]. Though a precise, consensus-â•‰based classification system for shift circadian physiology, social and familial responsibilities, as well as the
work has yet to emerge, the US Bureau of Labor Statistics and the frequency and duration of the shift work [16]. These individual dif-
International Classification of Sleep Disorders (ICSD) recognize the ferences in the circadian and sleep-â•‰related responses elicited by shift
following categories: nightshifts, with regular start times between work have led to the recognition of shift work sleep disorder (SWD).
6:00 pm and 4:00 am; early morning shifts, which start between 4:00
am and 7:00 am; and evening/â•‰afternoon shifts, starting between 2:00
pm and 6:00 pm [5]. Finally, 2.7–â•‰4.3% of adult workers in the US are Diagnosis and prevalence
involved in rotating shifts, including both rapid shifting (eg, multi- Standard diagnostic systems such as the Diagnostic and Statistical
ples changes in work hours during a week) and slow rotations (eg, Manual of Mental Disorders Fifth Edition (DSM-â•‰5) and the ICSD-â•‰
three weeks per shift schedule) [6]. However, as most shift workers 3 highlight SWD as a specific “type” of circadian rhythm sleep dis-
return to their typical routine of nocturnal sleep during their off-â•‰ order. The cardinal feature of circadian rhythm sleep disorders is
days [7], nearly all shift workers endure rapidly shifting schedules. sleep disturbance that is the direct result of a mismatch between the
Shift work necessitates a sleep–â•‰wake schedule that conflicts endogenous circadian timing of sleep and the patient’s desired or, in
with the endogenous, physiological regulation of sleep. According the case of SWD, required sleep schedule. Specific diagnostic criteria
to the opponent–â•‰process model, sleep and wakefulness result for SWD include insomnia-â•‰like symptoms during the sleep period,
from the interaction between two central nervous system (CNS) excessive sleepiness during the wake period, or both. These symptoms
processes: a homeostatic sleep drive and a circadian alerting sys- must cause clinically significant distress or impairment in one or more
tem [8,9]. Homeostatic sleep pressure, marked physiologically areas of functioning. Finally, as we will discuss later in this chapter, it
by electroencephalographic (EEG) slow-â•‰wave activity, accumu- is important to determine whether presenting symptoms are better
lates as a function of prior wake time and dissipates with sleep. accounted for by another sleep disorder or general medical condition.
On the other hand, the suprachiasmatic nucleus (SCN), located The ubiquity of shift work and the inability of most shift work-
in the anterior hypothalamus, confers circadian rhythmicity to ers to acclimate sufficiently to circadian misalignment would sug-
the temporal profile of sleep and associated physiological func- gest a high prevalence of SWD. However, reliable epidemiological
tions, including temperature regulation and cortisol secretion data are presently unavailable owing to a number of diagnostic and
[10,11]. This intrinsic pacemaker actively facilitates wakefulness methodological challenges. A recent review of the SWD research
during the day when endogenous melatonin levels are low, and literature by an American Academy of Sleep Medicine (AASM)
promotes sleep at night when melatonin levels rise and suppress taskforce concluded that most prior studies did not apply formal
diagnostic criteria in their assessment of this disorder [17]. Further,
†â•‡
It is with regret that we report the death of Vivek Pillai during the the distinction between a normal and a pathological response to
preparation of this edition of the textbook. shift work has yet to be empirically validated. Operationalizations

204 Section 6 circadian rhythm disorders
(a) Day worker the wake period increase with age [17,20,21], and adults over the
age of 50 years are less responsive to the circadian phase-delaying
Consolidated effects of bright light (a treatment for SWD, reviewed later in the
nocturnal sleep chapter) [22]. Even fewer data are available on the association
between gender and SWD, as most prior research has involved pre-
Wakefulness
dominantly male samples. Self-report data suggest that female shift
workers report more sleep loss, sleepiness, and psychological stress
than their male counterparts [23,24]. However, the extent to which
these findings reflect gender-related differences in role obligations
Circadian drive is not clear.
for wakefulness 9:00 am 3:00 pm 9:00 pm 3:00 am 9:00 am With respect to circadian physiology, a vulnerability hypoth-
esized to moderate tolerance to shift work is circadian preference
or chronotype (morningness versus eveningness), a genetic trait
(b) Night-shift worker
related to the period of the circadian clock and a length polymor-
phism of the PER3 clock gene [25–27]. Research shows that the
Fragmented
daytime sleep morningness chronotype—these individuals prefer to go to bed
(circadian disruption)
Impaired wakefulness early and function optimally during early daytime hours—is asso-
during work hours:
circadian and ciated with reduced tolerance to shift work [27]. Note that as older
homeostatic effects
adults typically espouse morningness [28], this chronotype may
Wakefulness
also explain some of the age-related vulnerability to SWD. Finally,
certain polymorphisms in the coding region of the PER3 gene may
also explain the variance in the cognitive impairments elicited by
Circadian drive sleep loss [29], an inevitable consequence of shift work [17].
for wakefulness 9:00 am 3:00 pm 9:00 pm 3:00 am 9:00 am
Shift workers Shift workers Morbidity and mortality
required to be asleep required to be awake
A wealth of data supports the link between shift work and vari-
Fig. 21.1 Homeostatic and circadian regulation of sleep. (a) Among day workers, ous adverse health outcomes, including sleep loss, excessive sleepi-
the homeostatic and circadian systems work in tandem to promote wakefulness ness, insomnia, cardiovascular disease, metabolic disturbance,
during the environmental day and sleep during the environmental night. (b) gastrointestinal complaints, cancer, and poor quality of life [16,30].
Shift workers attempt to sleep during the day when the circadian alerting signal
Increased risk for motor vehicle accidents as a result of excessive
is strong, leading to short, fragmented sleep. The resulting homeostatic sleep
debt combines with blunted nighttime circadian arousal to promote excessive sleepiness is another noteworthy and well-documented morbid-
sleepiness during the night when the worker must remain awake. ity in this population. Shift workers, especially those engaged in
Adapted from The Journal of Family Practice, 59(1 Suppl), Drake CL, The characterization and night and early morning shift work, accrue a significant homeo-
pathology of circadian rhythm sleep disorders, pp. S12–7, Copyright (2010), Frontline Medical static sleep debt due to cumulative sleep loss over successive shifts
Communications Inc. [31–33]. While sleepiness alone can trigger driving impairments
on par with driving under the influence of alcohol [34,35], shift
workers often commute to and from work during early morning
of SWD and “cut-offs” for core symptoms such as excessive sleepi- hours when their circadian alerting signal is at its nadir [10,36]. Not
ness therefore vary across studies. In a representative commu- surprisingly, shift work greatly increases the likelihood of on-road
nity sample of over 2500 conventional day-shift, night-shift, and accidents [37–39]. Excessive sleepiness during waking hours also
rotating shift workers, 14–32% of night-shift workers and 8–26% raises other safety concerns, such as occupational accidents and
of rotating-shift workers met criteria for SWD based on DSM-IV injury. The risk of workplace accidents is nearly 60% higher among
and a standardized self-report measure of excessive sleepiness [15]. shift workers than regular day workers, and workplace and motor
However, this study was unable to establish whether reported sleep vehicle accidents attributable to shift work cost the US economy an
symptoms were attributable to shift work. A study of oil rig work- estimated $71–93 billion per year [40].
ers yielded a similar prevalence rate of SWD among shift workers However, there have been few attempts to determine whether
(23%) [18]. In light of the prevalence of shift work in the US, data the morbidity associated with shift work varies as a function of
from these studies suggest that 2–5% of the general population SWD. Drake and colleagues found significantly higher rates
likely meets SWD criteria [5]. of ulcers, sleepiness-related accidents, social and occupational
Prevalence rates of SWD may also vary as a function of demo- impairments, and depression among shift workers who met crite-
graphic characteristics and individual differences in circadian ria for SWD in comparison with both nonsymptomatic shift work-
physiology. The well-documented effects of aging on the homeo- ers and conventional day workers [15]. Further, in the majority
static and circadian sleep systems have prompted the study of age of cases in this study, morbidity indices were significantly higher
as a risk factor for SWD. Though evidence that tolerance to shift among shift workers than conventional day workers who reported
work deteriorates with age is not presently conclusive, studies have comparable sleep disturbance. With respect to mental health, a
shown variously that shift workers over the age of 40 accrue more study of radar controllers in the US Air Force revealed a signifi-
sleep loss than younger workers [19], older adults (over 50 years cantly higher risk for anxiety and depression among those with
old) show less circadian adaptation to shift work [20], reports of SWD in comparison with nonsymptomatic shift workers [41].
sleep disturbance during the sleep period and sleepiness during Preliminary data from a recent neuroimaging study also point to

Chapter 21 shift work sleep disorder and jet lag 205
significant variations in neurophysiological correlates of attention that roughly 44% of shift workers [15] and 24–33% of conventional
and memory in individuals with SWD relative to a control group day workers [53,54] score in the clinical range on the ESS.
of night shift workers [42]. Instruments such as the MSLT and the ESS can also be valua-
ble in distinguishing sleepiness from fatigue, a common present-
Clinical evaluation ing problem in SWD [55,56]. While physical or cognitive fatigue
As with other circadian rhythm disorders, the assessment of SWD may be alleviated by periods of rest or sedentary activity without
involves a careful evaluation of the degree of circadian misalign- sleeping, such inactivity will unmask sleepiness. This distinction
ment, severity and pattern of sleep disturbance, and level of distress between fatigue and sleepiness is critical because patients seldom
or functional impairment. To establish an SWD diagnosis, how- recognize that “dozing off ” during quiet periods of relative inac-
ever, this symptom complex must be attributable to the work–sleep tivity is abnormal. If fatigue is suspected, it is important to assess
schedule, and, as such, clinicians must be sure to rule out other sleep for comorbid major depressive disorder [57]. Finally, the MSLT can
disorders characterized by excessive sleepiness, including obstruc- differentiate between SWD and narcolepsy, as patients who suffer
tive sleep apnea and narcolepsy. A thorough patient history along from the latter exhibit two or more sleep-onset rapid eye movement
with the use of sleep diaries and actigraphy can greatly elucidate the (REM) periods on the MSLT despite adequate prior sleep [5]‌.
regularity, duration, and timing of sleep and wake cycles. The mini- Sleep disturbance
mal duration of sleep recording indicated for SWD is 7 days, and it Unlike sleepiness, which is considered a symptom of an under-
should include sleep and wake episodes during the offending work lying sleep or CNS condition, most diagnostic systems now rec-
shift [5]‌. When feasible, assessing markers of circadian phase such ognize insomnia as a primary disorder [5,58,59]. Describing
as salivary melatonin or core body temperature (reviewed later in insomnia as a “symptom” of SWD is hence problematic. A more
this chapter) can help quantify the degree of circadian desynchrony nuanced approach would be to characterize the insomnia-like sleep
[43–45]. Finally, in light of the morbidity and mortality associated symptoms observed in SWD, such as difficulty falling or staying
with core symptoms, such as excessive sleepiness, it is important asleep during times of circadian desynchrony, simply as “circadian
to assess the severity of these symptoms early in the evaluation sleep disturbance.” Such a framework allows for the distinction
process. between sleep disturbance that is the direct result of shift-work-
Sleepiness related circadian misalignment and those that reflect comorbid
insomnia disorder. Indeed, the association between insomnia and
The multiple sleep latency test (MSLT) [46], a measure of sleep
SWD may be more complex than current diagnostic systems sug-
latency averaged over consecutive recording intervals roughly
gest. Stress-diathesis theories such as the 3Ps model postulate that
two hours apart, is the gold standard for measuring sleepiness.
insomnia disorder results from the interaction between predispos-
The mean daytime latency on the MSLT for adults in the US is
ing, precipitating, and perpetuating factors [60]. An environmental
11.4 minutes, and latencies of 8 minutes or less indicate clinically
trigger or challenge to the sleep system can unmask a premorbid
significant or “pathological” sleepiness [5,47]. However, as these
vulnerability to produce sleep disturbance, which is then perpetu-
values derive from studies of daytime sleepiness, norms for sleepi-
ated by behavioral or conditioning mechanisms such as poor sleep
ness at other phases of the circadian cycle that are more germane
hygiene. The circadian misalignment imposed by shift work can
to SWD are currently unavailable. In two large (N = 209 [48] and
act as such a precipitant of acute sleep disturbance. Premorbid vul-
N = 216 [49]) clinical trials of night workers with an ICSD-3-based
nerabilities and behavioral factors, such as erratic sleep schedules
diagnosis of SWD, mean nighttime MSLT latencies were approxi-
across on-and off-shift days, may determine whether these sleep
mately 2 minutes. Notably, as one of the inclusion criteria for these
disturbances evolve into insomnia disorder. Support for this theory
studies was a nocturnal MSLT latency of less than 6 minutes, lev-
comes from studies that find that levels of sleep disturbance follow-
els of sleepiness in these samples may not reflect the true popu-
ing retirement are significantly higher among shift workers than in
lation average for shift workers. In a smaller sample of 10 night
regular day workers [61,62]. The possibility that shift work repre-
workers with and without SWD, symptomatic workers exhibited
sent a trigger for insomnia disorder is intriguing and begs further
a nighttime MSLT latency of 3.6 minutes whereas the asympto-
investigation.
matic group had a 6.8 minute latency [43]. Though this difference
As noted earlier, sleep disturbance in SWD may include difficulty
was statistically significant, its clinical implications are unknown.
falling asleep, difficulty staying asleep, or nonrestorative sleep. In
Together, these data highlight the need for evidence-based norms
addition to structured clinical interviews, psychometrically vali-
to accurately characterize objective sleepiness among shift workers.
dated instruments, such as the Insomnia Severity Index (ISI) [63]
It is important to note, however, that excessive levels of sleepiness
and the Pittsburgh Sleep Quality Index (PSQI) [64], can help quan-
(MSLT < 5 minutes) may still be indicative of a high risk for acci-
tify the severity of sleep disturbance and waking consequences. An
dent or injury even if consistent with the population norms for the
important caveat in the use of these measures in the SWD popula-
nocturnal phase of the circadian cycle [50].
tion, however, is that they do not discriminate between nocturnal
The high cost of the MSLT precludes routine clinical use among
and daytime sleep disturbance. Future studies should attempt to
all but narcolepsy patients. On the other hand, self-report measures
adapt and validate these instruments for the assessment of daytime
of sleepiness, such as the Epworth Sleepiness Scale (ESS) [51] or the
sleep disturbance.
Karolinska Sleepiness Scale (KSS) [52], can be easily administered
and interpreted in most clinical settings. The ESS, for instance, que- Other comorbidities
ries respondents about the likelihood of inadvertently falling asleep Shift work is associated with a wide array of mental and physi-
during routine daily activities, with scores of 10 or greater indicat- cal health problems. The increased risk for depression, cognitive
ing clinically significant sleepiness. Epidemiological data suggest deficits, cardiovascular disease, and cancer among shift workers

stress the importance of regular psychological and physical assess- Bright light therapy typically involves short or intermittent expo-
ments that are attentive to these comorbidities [30]. Evaluation of sure to a bright (2000–10 000 lux) light stimulus, scheduled 3–6
alcohol and substance use is also recommended, given that “self- hours before the expected nadir of circadian alertness [74]. Though
medication” with substances is one of the most commonly reported laboratory data support the efficacy of bright light treatment in pro-
coping strategies to contend with sleep disturbance in the general ducing large phase shifts and complete entrainment to shift work
population [65,66]. Further, prevalence rates of injurious behav- [73,75], achieving such effects in the “real world” can prove quite
iors such as alcohol use, smoking, and poor diet practices are sig- challenging. Therapeutic phase shifting relies on meticulous control
nificantly higher among shift workers than day workers [16,30,67]. over the patient’s exposure to environmental light, including bright
A battery of self- report questionnaires, called the Standard light exposure at night during the work shift and avoiding sunlight
Shiftwork Index (SSI) [68], has been used in many studies to quan- during the day using dark goggles. Further, complete circadian re-
tify these health risks. Recent research on the SSI, however, points entrainment is not only difficult (6–8 hours of bright light exposure
to certain psychometric shortcomings in some of the component at about 10 000 lux), but may be maladaptive as shift workers may
scales, stressing the need for more validation studies [69,70]. revert back to diurnal wakefulness on off-days because of social or
familial commitments. As such, recent studies have explored the
Treatment clinical utility of a stable partial/“compromise” phase delay, such
As the etiology of SWD is largely unclear, most current treatments that the nadir of circadian alertness occurs just a few hours after the
are geared toward ameliorating the extent of circadian disrup- work shift ends [75,76]. Using intermittent bright light exposure
tion and managing core symptoms. Step by step, guidelines have during the night (brief light pulses for 15 minutes each hour for
emerged in the SWD literature (Box 21.1), and cover all aspects of 5 hours) and dark goggles during the day, one simulated night-shift
patient care from circadian adaptation to behavioral and pharma- study produced a phase delay of approximately 7.5 hours among its
cological interventions for promoting sleep during rest hours and participants, a shift that was associated with better sleep and psych-
wakefulness during the work shift. omotor outcomes [76]. In summary, extant evidence supports the
efficacy of bright light treatment in conjunction with other behav-
Circadian adaptation: bright light therapy ioral interventions, such as avoiding daylight and careful schedul-
The SCN, as evidenced by consistent findings across all studied ing of sleep–wake cycles.
assays of circadian rhythm, has an average period that is slightly Circadian adaptation: other treatments
longer than the 24 hour day (about 24.2 hours) [10]. However,
Studies show that exogenous melatonin administration (0.5–3 mg)
under normal conditions of diurnal wakefulness and nocturnal
can improve circadian adaptation among shift workers, so long
sleep, the phase and period of this intrinsic pacemaker are tightly
as exposure to more potent zeitgebers such as daylight is care-
entrained to a 24-hour cycle thanks to environmental cues [71]. Of
fully monitored; poorly timed light exposure can easily counter-
these environmental zeitgebers, the Earth’s light–dark cycle is the
act any benefits of exogenous melatonin. In a laboratory study of
most influential. The transmission of photic stimuli via retinohy-
young adults, three days of melatonin administration (3 mg) led
pothalamic and retinogeniculohypothalamic pathways to the SCN
to an approximately 1.5-hour shift in circadian phase [77]. Phase-
regulates the pineal secretion of melatonin [71,72]. The central and
advance effects of 80–90 minutes were reported in another study of
peripheral abundance of melatonin receptors, in turn, facilitates
young adults who received 1, 2, or 4 mg of the melatonin agonist
photic control of hormone secretion, core body temperature, and
ramelteon 30 minutes before bedtime for a period of four days [78].
rest–wake cycles [72]. As such, carefully timed exposure to photic
Thus, as a circadian treatment, melatonin may be more suitable for
stimuli of appropriate intensity, wavelength, and duration can “shift”
other circadian rhythm disorders, such as jet lag and delayed sleep
the endogenous circadian clock (see Fig. 21.2) [73]. Among shift
phase syndrome, where even modest phase shifts can be therapeu-
workers, such shifts in endogenous rhythms can be adaptive when
tic. Note that even low doses (eg, 0.5 mg) of melatonin can pro-
they realign sleep and wake episodes with the appropriate circadian
duce performance impairments, and therefore cognitively intensive
phase [74]. These principles form the basis of bright light therapy.
tasks such as operating machinery should be avoided for several
As noted earlier, melatonin levels rise in the evening (at about
hours following administration [79]. The large-scale clinical trials
9 pm)—a phenomenon known as dim light melatonin onset
needed to establish the efficacy and safety of melatonin as a chrono-
(DLMO)—achieving a peak around mid-darkness and subse-
biotic for use in SWD have not been undertaken.
quently dropping to low daytime levels shortly before light onset.
Though physical exercise can delay circadian phase, this effect is
This temporal profile of melatonin has robust internal consistency
relatively weak and unlikely to produce therapeutic levels of circa-
per person, and is less sensitive to sleep and posture than other cir-
dian adjustment. However, the overall health benefits of exercise
cadian markers such as core body temperature. As such, plasma
may help reduce the morbidity associated with SWD, and may
or salivary melatonin assays can serve as a precise and relatively
therefore be encouraged, especially when scheduled at times when
noninvasive marker of circadian phase. A recent study investigated
light exposure is desired to shift the circadian clock [80].
the melatonin profiles of night workers with SWD and asymp-
tomatic controls during a 25-hour sleep deprivation protocol. Improving sleep
Asymptomatic workers showed a significant delay in the timing of Given that adequate circadian adaptation is challenging for many
DLMO in relation to the SWD group (Fig. 21.3), suggesting that the shift workers, behavioral and pharmacological interventions that
latter are less adept at shifting their circadian clock to match their directly address sleep disturbance are warranted. Although not all
sleep–wake schedule. The goal of bright light therapy, therefore, is shift workers may experience significant sleep onset difficulties
to reduce misalignment between endogenous and exogenous circa- during a daytime sleep episode, circadian misalignment consist-
dian schedules. ently disrupts sleep maintenance during the latter half of the sleep

Box 21.1 Guidelines for the clinical evaluation and Box 21.1 Continued

treatment of SWD
c. Encourage prophylactic nap prior to work shift.
Assessment
d. Recommend use of brief to moderate-length naps
I. Quantify degree of circadian misalignment (sleep diaries (30–60 minutes); consider pre-nap caffeine to
and or actigraphy). reduce sleep inertia.
II. Assess nature and severity of sleep disturbance both during e. Consider combined treatment strategies during
daytime and nighttime sleep periods. the work shift (alerting medications, bright light,
II. Establish level of sleepiness (ESS); pay special attention to and naps).
drowsy driving. IV. Address additional work, social, and domestic factors.
III. Determine impact on social and domestic responsibilities. A. Social/family/psychological: improve balance between
family/social, work, and sleep time; educate patient’s family
Management regarding shift workers’ need for “protected” sleep times.
I. If patient meets criteria for a diagnosis of shift work disorder, B. Health and safety: promote healthy eating habits (not
cessation of the shift work schedule should be the first option within 2–4 hours of bedtime), curtail substance use, rec-
discussed with the patient. ommend exercise at appropriate times (not within 2–4
II. Regular physicals with attention to risk for psychological hours of bedtime), stress the risks of working/driving
disorders (i.e, depression), gastrointestinal problems, car- when drowsy or at times of circadian vulnerability.
diovascular disease, and cancer.
Adapted from Drake CL, Wright Jr KP, Shift Work, Shift-Work Disorder,
A. Sleep-related comorbidity: sleep disordered breathing,
and Jet Lag. In: Kryger MH, Roth T, Dement WC, eds, Principles and
restless legs syndrome, or other sleep disorder. Practice of Sleep Medicine (Fifth Edition), pp. 784–98, Copyright (2011),
B. Other comorbidity: identify medical or psychiatric dis- with permission from Elsevier.
orders that may contribute to insomnia or excessive
sleepiness.
period [81]. Sleeping regularly for a period of about 4 hours during
III. Determine patient-specific therapeutic approach.
a particular time of day (eg, 8:00 am to 12:00 noon) on both on-
A. Circadian adaptation: and off-shift days can help anchor circadian rhythms to a particular
1. Consider individual differences (eg, age, phase sleep schedule. Such “anchor” sleep periods combined with another
preference). 3-to 4-hour sleep period taken at different times as a function of
work schedule can stabilize circadian rhythms and increase sleep
2. Consider compromise phase position (eg, partial
duration [82,83]. This strategy may also help accommodate any
phase delay using bright light during first half of night
social or familial obligations the shift worker must keep. Practicing
and increased darkness during daytime).
good sleep hygiene can further improve sleep, and involves the fol-
3. Encourage night workers to adopt a late sleep sched- lowing: air-conditioning and blackout shades/curtains to ensure
ule (bedtime: 3:00–4:00 am) on off-days. a cool, dark, and quiet sleep environment; use of earplugs and a
B. Symptom management: comfortable night mask; restricting caffeine and alcohol consump-
tion before bedtime; and educating family and flatmates about the
1. Insomnia: importance of the worker’s “protected” sleep period [16,80].
a. Improve sleep hygiene and encourage use of eye Napping prior to the night shift and for brief periods during
masks, ear plugs, and light blocking goggles dur- the night have been shown to improve alertness and performance
ing daytime sleep. among shift workers [84,85]. In a study of emergency room physi-
b. For sleep maintenance problems, consider an cians and nurses, a 40-minute nap in the middle of a 12-hour night
intermediate half-life (5–8 hours) acting hypnotic shift improved reaction time, alertness, and fatigue [86]. Notably,
or melatonin treatment (about 3 mg). alertness during the commute home following the shift was unaf-
fected. Empirical data also support the use of naps in conjunction
c. For sleep initiation problems, consider a short- with other interventions. Laboratory and field studies suggest that
acting hypnotic. the combination of an evening nap and caffeine intake (250–300
d. For sleep problems on off-days, consider fixed mg) 30 minutes before the shift can significantly improve alertness
sleep–wake schedule/anchor sleep. and performance [87]. In a study of professional drivers engaged
in shift work, two 20-minute naps followed by 10 minutes of bright
2. Excessive sleepiness (i.e, ESS > 10):
light exposure (about 5000 lux) significantly reduced PSG-verified
a. Address sleep disturbance if present. risk of falling asleep during a driving task [85]. Clinicians must,
b. Consider wake-enhancing medication prior to however, advise patients to avoid driving or operating machinery
shift (eg, modafinil, armodafinil) or off-label stim- until any post-nap sleep inertia has dissipated, as middle-of-the-
ulants (eg, amphetamine, methylphenidate). night effects of sleep inertia are more severe than those at other
times during the circadian cycle [88].

16
Maximum phase
Amplitude of melatonin (pg/mL)

Maximum phase
advance with
advance with light
eastward melatonin 12
Advance
ANW (n=10)
SWD (n=18)
Phase shift
8
4
westward
Delay
Maximum
Maximum phase 0
phase delay
delay with melatonin :00 9:00 1:00 3:00 1:00 3:00 5:00 7:00 9:00 1:00 3:00 5:00 7:00
with light 17 1 2 2 0 0 0 0 0 1 1 1 1
Time of day
14 17 20 23 2 5 8 11 14 17 20 23
Approximate clock hour for Fig. 21.3 (See colour plate section) Melatonin profiles of night-shift workers
someone with a bedtime at 24:00 hr with and without SWD. Individuals exhibit remarkable diversity in the degree of
circadian adaptation to shift work. A recent study evaluated the dim light salivary
Fig. 21.2 Phase response curves to 1 day of light exposure (green curve) and melatonin profiles of 10 asymptomatic night workers (ANW) and 18 workers with
3 days of 3–5 mg of melatonin administration (black curve) in a circadian system SWD during a 25-hour sleep deprivation protocol. Though the melatonin profile
entrained to local environment time. A phase response curve (PRC) is constructed of the SWD group was similar to that of healthy day workers (20:27 ± 5.0 h), the
by plotting the extent of phase shift (hours) in response to a particular stimulus (y- ANW group exhibited a significantly delayed DLMO (05:00 ± 3.4 h), indicating
axis) against the circadian phase at which the stimulus occurs (x-axis). Convention better circadian adaptation to night work.
dictates that phase delays to later hours be represented as negative numbers, Reproduced from Chronobiology International, 29(7), Gumenyuk V, Roth T, Drake CL,
and that phase advances be denoted by positive numbers. As can be seen , the Circadian phase, sleepiness, and light exposure assessment in night workers with and without
effects of circadian stimuli vary as a function of the time of exposure. Bright light shift work disorder, pp. 928–36, Copyright (2012), with permission from Taylor & Francis.
exposure before habitual bedtime and several hours thereafter produces the largest
(westward) phase delays, whereas the same stimulus applied just before habitual
wake time and several hours thereafter will trigger maximal (eastward) phase been shown to improve alertness and psychomotor performance
advances. At the nadir of core body temperature, which occurs about 2.5 hours over extended periods of wakefulness [94,95]. However, stimu-
before habitual bedtime in young adults (2 hours in older adults), phase delays lant use can be problematic owing to the tolerance and withdrawal
“cross over” to phase advances. Therefore, bright light exposure too close to this effects associated with caffeine [47] and the high abuse potential
crossover point can cause phase shifts in direction opposite to what is desired. In of amphetamines and methylphenidate [96]. Empirical support
contrast to light, exogenous melatonin administration in the morning causes a
for the wake-promoting effects of commercially available energy
phase delay, but results in a phase advance when given in the morning. On average,
the crossover point for exogenous melatonin occurs early in the afternoon. drinks is also limited. In a simulated shift work study, two doses of
Adapted from Drake CL, Wright Jr KP, Shift Work, Shift-Work Disorder, and Jet Lag. In: Kryger an energy drink (250 mL can; 80 mg caffeine, 1000 mg taurine, and
MH, Roth T, Dement WC, eds, Principles and Practice of Sleep Medicine (Fifth Edition), 600 mg glucoronolactone) administered at 1.30 am and 5.30 am
pp. 784–98, Copyright (2011), with permission from Elsevier. improved nocturnal wakefulness, but were associated with shorter
sleep durations and poor sleep efficiency during the subsequent
sleep episode [97].
With respect to pharmacological agents, few well-controlled
Recent clinical trials have examined the suitability of non-
clinical trials with SWD patients have been carried out. Further, it
amphetamine-based alerting agents for improving SWD-related
is difficult to generalize data from clinical trials of hypnotic medica-
nocturnal wakefulness. In a sample of SWD patients with exces-
tions for insomnia to SWD given the added complications of diur-
sive nocturnal sleepiness (MSLT < 6 minutes), taking modafinil
nal sleep and nocturnal performance concerns in the latter group.
(200 mg) for a period of 3 months was associated with significant
The AASM notes that hypnotic medications, such as triazolam and
reductions in nocturnal MSLT latencies during the first half of the
temazepam, though effective in improving diurnal sleep, have little
night (measured at 2:00 am and 4:00 am). Other correlates of alert-
impact on nocturnal alertness [17,89]. Non-benzodiazepine hyp-
ness, including psychomotor vigilance and driving (self-reported
notics, including zolpidem, can improve subjective sleep quality
accidents or near-accidents) were also significantly improved in
and achieve modest improvements in nocturnal psychomotor per-
the treatment group, and taking modafinil at the beginning of the
formance, but may trigger side-effects such as “anxious” and “irri-
night did not impair subsequent daytime sleep. Notably, despite
table” mood [90]. Exogenous melatonin at doses between 1 and 10
these improvements, levels of nocturnal alertness (mean MSLT
mg and the melatonin-receptor agonists ramelteon and tasimelt-
3.77 ± 0.5 minutes) in the treatment group did not reach average
eon, have shown efficacy in improving daytime sleep in simula-
daytime values, leaving room for further improvement. In a similar
tion studies, though data from SWD samples are rare [79,91–93].
trial, armodafinil (150 mg), an isomer of modafinil with the same
Common side effects of ramelteon include dizziness, fatigue, and
half-life (about 15 hours) but a different elimination profile (higher
nausea. Melatonin and melatonin agonists may also increase prol-
plasma concentrations about 4–6 hours following dosing) [98],
actin levels [80].
significantly improved MSLT-defined nocturnal sleepiness (2.3 ±
Improving wakefulness 1.6 minutes to 5.3 ± 5.0 minutes), as well as performance on neu-
Though prior studies have investigated the use of stimulants, such as ropsychological measures of memory and attention. Armodafinil
caffeine and amphetamine in samples of shift workers and healthy was well tolerated and did not impact daytime sleep. The US Food
volunteers, their effects on patients with SWD remain untested. and Drug Administration (FDA) has approved modafinil and
Low doses of amphetamine and repeated low doses of caffeine have armodafinil for improving nocturnal wakefulness in SWD patients;

side effects include headache, nausea, dizziness, and anxiety, with for 4–7 days following arrival. Furthermore, westward time-zone
headaches being the most common complaint [48,49]. transitions were associated with a decrease in blood pressure, while
eastward travel led to an increase in blood pressure. Other aspects of
Occupational adjustments
functioning, including decision making, driving, and general cogni-
Though disengaging entirely from shift work is seldom feasible, tive ability, may also decline owing to circadian misalignment and
certain occupational adjustments can be beneficial. First, allow- consequent sleepiness [113]. In a study of pilots flying across seven or
ing employees to choose their shift fosters a sense of agency and eight time zones in either direction, endogenous circadian rhythms
perceived control among workers, and is associated with health were out of phase not only with environmental cues in the destina-
benefits and overall improvements in quality of life [99]. Further, tion time zone, but also in relation to each other. Furthermore, fol-
this “self-selection” intervention is not associated with any appreci- lowing a 2-day layover, pilots operated the return flight during the
able increases in institutional costs. That altering the direction of nadir of circadian alertness and at peak melatonin levels, a finding
rotation can improve tolerance to shift work is another commonly that highlights the safety risks associated with jet-lag-related circa-
advocated assertion in the literature [100]. Clockwise or forward dian disruption. Behavioral and conditioning mechanisms such as
transitions in shift work i.e, from day to evening to night, are better poor sleep hygiene and self-medication with recreational substances
suited to the natural tendency of the circadian clock to delay sleep can further prolong symptoms [5,16,17]. Though the long-term
[101]. Such transitions also allow for more time between shifts and effects of chronic jet travel have not received extensive research con-
are therefore deemed preferable to backward or counterclockwise sideration, irregularities in menstrual cycles, exacerbation of psy-
transitions. However, we are only aware of one study [102] that chiatric disorders, and cognitive deficits have been reported among
documented the health benefits of clockwise versus counterclock- frequent long-distance air travelers [113–115].
wise shift rotations. Other studies show that the direction of shift There are presently no data on the prevalence of JLD, owing most
work rotations has no significant impact on the risks associated likely to the transient nature of the symptoms and insufficient clar-
with SWD [103,104]. Finally, consistent with laboratory studies, ity on the distinction between normal and pathological responses
some industrial studies suggest that switching from slow to fast to jet travel; many diagnostic systems, including DSM-V, do not
rotations, because they require workers to perform at an adverse recognize JLD. A few recent studies have examined age and gender
circadian phase for a shorter period of time, can lead to better out- as potential moderators of vulnerability to jet lag, though no clear
comes such as fewer sleep disturbances and less fatigue [105–107]. consensus has emerged owing to a lack of standardization in assess-
ment techniques, poor methodology, and contradictory findings
Jet lag [116,117]. Westward travel is typically tolerated better than east-
The rapid transmeridian travel afforded by jet planes can signifi- ward travel owing to the natural tendency of the circadian clock to
cantly derail the synchrony between endogenous circadian func- delay the onset of sleep [17,118,119]. On the other hand, the period
tions and environmental time. The slow (1–1.5 hours/day) rate of of the SCN in 20–25% of humans is slightly shorter than the 24-
resynchronization of the circadian clock to environmental zeit- hour day [120], potentially making this group more amenable to
gebers lends perspective on the burden exerted by air travel across circadian phase advances and eastward travel. Although the only
multiple zones on the sleep system [71,72]. In addition to circadian study thus far on the impact of chronotype on jet lag symptoms did
disruption, the nature of air travel itself can lead to health sequelae. not find an association, the variance in the chronotype variable in
The low cabin pressure inside jet planes can cause gases in the gas- this study was quite low: only one of the 85 participants could be
trointestinal (GI) system to expand and trigger bloating/discom- classified as an “evening” type [117]. In summary, though a num-
fort; the relative hypoxia in the cabin atmosphere can exacerbate ber of potential moderators of jet lag have been proposed based
respiratory conditions; and, finally, many travelers find it difficult to on circadian principles, few have been empirically evaluated with
sleep in a plane, thus incurring substantial sleep loss [17,108,109]. adequate methodological rigor.
The duration and intensity of these consequences of jet travel can
vary as a function of the direction (eastward/westward) of travel, Clinical assessment and management
the number of time zones crossed, the ability to sleep while trave- A thorough patient history and physical examination are needed
ling, and individual differences in circadian physiology [17]. When to establish the correspondence between presenting sleep/wake
clinically significant, the sleep and circadian disturbance elicited by symptoms and jet travel, while ruling out other sleep disorders.
jet travel warrant a diagnosis of jet lag disorder (JLD). Fatigue and other somatic complaints observed in JLD, especially
GI or urinary symptoms, may be indicative of an underlying medi-
Diagnosis, morbidity, and prevalence cal condition. Although ICSD-3 does not currently indicate objec-
ICSD-3 recognizes JLD as a circadian rhythm disorder that results tive laboratory sleep recording for diagnosing JLD [5]‌, research
from rapid air travel across multiple time zones. Core symptoms studies have demonstrated PSG-based sleep disruption as a result
include daytime sleepiness and nocturnal sleep disturbance in the of jet travel. Beaumont and colleagues measured PSG-based sleep
new time zone, in addition to travel fatigue and general malaise. GI in a sample of 27 healthy volunteers from the US Air Force Reserve
complaints are also common, and may be related to circadian vari- Unit for a period of 2 weeks following an eastward flight across
ations in glucose tolerance [110,111]. In terms of duration, jet lag seven time zones [121]. In comparison with baseline sleep, par-
is generally a temporary condition beginning a day or two follow- ticipants exhibited significantly delayed sleep onset starting on the
ing arrival in a new time zone, but can last for weeks in some cases fourth night post travel, a disturbance that did not normalize until
depending on the timing and extent of exposure to environmental the ninth night. Increased slow-wave sleep and reduced REM sleep
cues [5]‌. In a study [112] of elite athletes travelling eastward or west- were also observed on the first night in the new time zone, though
ward across six to eight time zones, training performance suffered these changes normalized within three nights.

The ephemeral nature of symptoms and the high costs of record- received phase-advancement treatment for a period of 3 days: par-
ing limit the use of PSG for assessing JLD symptoms in clini- ticipants shifted their baseline sleep–wake schedule counterclock-
cal settings. More ambulatory forms of sleep assessment such as wise by 1 hour per day and received one of three forms of light
actigraphy may serve as an efficient alternative, but have yet to be exposure for 210 minutes after waking: dim light (<60 lux), inter-
adequately validated in this population [17]. With respect to self- mittent bright light (>3000 lux; 30 minutes on, 30 minutes off), or
report, the Columbian Jet Lag Scale is the only empirically vali- continuous bright light (>3000 lux). DLMO assessment following
dated instrument currently available for the assessment of jet lag treatment revealed that continuous bright light exposure elicited a
symptoms [122]. Respondents endorse the presence and persis- significantly greater phase advance (2.1 hours) than did dim light
tence of 14 common jet lag symptoms (eg, “fatigue or tiring eas- exposure (0.6 hours), though the phase advances achieved by inter-
ily” and “decreased daytime alertness”) on a 5-point Likert-type mittent (1.5 hours) and continuous bright light did not significantly
scale (“not at all” to “extremely”); in a validation study of recent differ. Further, scores on the Columbia Jet Lag scale increased sig-
air travelers, overall scores achieved high internal consistency nificantly during the 3-day phase advancement in the dim light and
(α = 0.89–0.93). Such instruments can be easily administered in intermittent bright light groups, but did not change significantly
clinical settings and can help inform clinicians about the nature from baseline in the continuous bright light group. Thus, it may
and severity of JLD. Finally, when possible, pre-flight assays of a be possible for travelers to improve their tolerance to an eastward
patient’s underlying circadian phase, such as DLMO or core body flight by advancing their sleep–wake schedules and exposing them-
temperature recording, may not only help identify risk for JLD but selves to early morning bright light (going for a walk in the sun-
also inform treatment [123]. shine, or turning up indoor lights). Such a strategy may expedite
There are presently no FDA-approved medications for the man- post-flight environmental entrainment to the desired circadian
agement of JLD. Current interventions, derived largely from labo- rhythm and reduce the burden of jet lag [16,17,126].
ratory studies that simulate travel-related circadian disruption, aim
to improve tolerance to jet lag and expedite recovery via three basic Promoting sleep
mechanisms: improving overall circadian adaptation to the new A combination of behavioral adjustments and pharmacological
time zone; promoting sleep during the flight and during the envi- aids can help promote sleep both during the flight as well as upon
ronmental night in the new time zone; and promoting wakefulness arrival at the destination. Use of noise-canceling headphones, ear-
during the environmental day in the new time zone. plugs, and dark sunglasses can help improve sleep while in flight
and at the airport during lengthy layovers. Alcohol use, though
Circadian adaptation commonplace during jet travel, is an ineffective strategy, as the
Entraining endogenous circadian rhythms to the new time zone disruptive effects of alcohol on sleep maintenance and architecture
is the most effective means of alleviating jet lag, especially if the are well established [47]. It is generally recommended that travel-
traveler plans to spend a substantial amount of time at the destina- ers begin adapting to the new environmental sleep and wake times
tion [123]. Appropriately timed exogenous melatonin administra- immediately after arrival in the new time zone [16]. Melatonin and
tion can help shift the biological clock during travel. The melatonin its agonists, ramelteon and tasimelteon, can be effective in reduc-
phase response curve is well established in humans and is essen- ing sleep onset latency and improving total sleep duration when
tially the opposite of that for light (see Fig. 21.2). Melatonin taken taken during the biological day [79,92]. Other medications that
after waking in the morning delays circadian phase, whereas after- have been investigated for improving sleep during and following
noon or evening melatonin administration leads to a phase advance travel include zolpidem, zopiclone, and benzodiazepines, such as
[72]. A review of 10 clinical trials of melatonin and JLD concluded triazolam, temazepam, and midazolam (for a review, see [118]).
that melatonin taken at bedtime at the destination time zone sig- With few exceptions [128,129], most of these studies involved rela-
nificantly reduced jet lag symptoms, especially for eastward travel tively small samples (N = 6–33), and self-report indices of sleep
and if previous jet travel had triggered JLD symptoms [124]. The were the only endpoint in many studies. Moreover, the effects
review also noted that occasional short-term use was safe and well of hypnotic medication on daytime symptoms of jet lag have
tolerated, though most reviewed studies were unable to extricate not been adequately studied. These limitations notwithstanding,
the impact of melatonin on the circadian system from its somno- results indicate that the use of hypnotic medications to alleviate
lent effects. Bright light therapy with natural outdoor light or com- acute sleep disturbance among travelers is appropriate when care-
mercial light boxes has also been shown to improve JLD symptoms fully weighed against potential side effects [16,17,118]. Clinicians
following both eastward and westward jet travel [125,126]. Finally, must also remember to discuss the risks of drug interactions with
though the AASM recommends adjunctive treatment with mela- alcohol, because, as mentioned earlier, alcohol use is common dur-
tonin and bright light exposure for circadian rhythm disorders [5]‌, ing long-distance jet travel [17].
the efficacy of such combination treatments has not been inves-
tigated in JLD. For eastward travel, melatonin at bedtime in con- Promoting wakefulness
junction with early morning bright-light exposure can advance the Staying awake until the appropriate nocturnal bedtime in the new
circadian clock and reduce the burden of JLD symptoms. For west- time zone can improve sleep following westward travel. Brief naps
ward travel, which is better tolerated as it necessitates a phase delay, (15–20 minutes) during the flight and in the day following arrival
bright light exposure in the evening may prove beneficial [118]. can help sustain wakefulness [16,130,131]. However, long naps may
Preliminary support has also emerged for interventions aimed lead not only to greater sleep inertia, but also to blunted homeo-
at pre-flight circadian adaptation, i.e, shifting the biological clock static sleep pressure and thus impaired nocturnal sleep [88,132].
to suit the new time zone before travel [126,127]. In a labora- Taking caffeine is the most common strategy among travelers for
tory simulation study [126], a sample of 28 healthy young adults improving wakefulness. In two field studies, slow-release caffeine

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CHAPTER 22
Advanced, delayed,
free-â•‰running, and irregular
sleep–â•‰wake rhythm disorders
Guy Warman and Josephine Arendt
Introduction or from a clock that is entrained, but at a phase that is at odds with
societal norms (ASPD and DSPD).
Circadian rhythm sleep disorders (CSRDs) should be considered in The primary diagnostic tools for CRSDs are sleep diaries com-
the differential diagnosis of either hypersomnia or insomnia. While plemented by actigraphs (wrist-â•‰worn devices that record overall
the International Classification of Sleep Disorders, Third Edition movement and can be used to objectively determine sleep timing
(ICSD-â•‰3) lists a total of seven types of CRSDs (327.31 delayed sleep and quality). Measurement of more direct phase markers of the
phase type; 327.32 advanced sleep phase type; 327.33 irregular clock such as rhythms in core body temperature and endogenous
sleep–â•‰wake type; 327.34 non-â•‰entrained type; 327.35 jet-â•‰lag type; melatonin production can also be useful (particularly in diagnos-
327.36 shift work type; 327.37 due to medical condition) [1]â•„, here ing FRSD). Polysomnography (PSG), while not required for the
we focus on advanced sleep phase disorder (ASPD), delayed sleep diagnosis of CRSDs, can be beneficial in excluding other primary
phase disorder (DSPD), free-â•‰running (non-â•‰24-â•‰hour) sleep disorder or secondary insomnias [4]â•„.
(FRSD), and irregular sleep–â•‰wake rhythm disorder (ISWRD). CRSDs result from one of two different situations. The most
As has been outlined in the preceding chapters of this book, common of these is a lack of appropriately timed (or sufficiently
human sleep is controlled by the combined actions of the sleep strong) environmental light exposure. The second is a conse-
homeostat and the circadian clock in the suprachiasmatic nucleus, quence of a clock that is unable to entrain with an appropriate
which ticks with an inherently inaccurate period (on average
approximately 24.2 hours). Although food, exercise, social interac-
tion, and melatonin can adjust (or entrain) the clock, light is the
2
most important entraining agent (or zeitgeber) for the human clock,
and entrains its endogenous period to 24 hours on a daily basis.
1
Circadian photoreception is mediated exclusively by the eye and Advance
mainly by the nonvisual pigment “melanopsin” located in a sub-
0
set of intrinsically photoreceptive ganglion cells (ipRGCs) in the
Phase shift (h)
retina. –1 Delay
The human clock is affected by light differently at different times
relative to its phase (circadian times). In the biological morning (i.e, –2
the declining phase of the endogenous melatonin profile), light acts
to advance the clock to an earlier phase (phase advance), whereas in –3
the evening, light shifts it to a later phase (phase delay). These effects
(and those of orally administered melatonin) are best summarized –4
by the “phase response curve” [2,3] (Fig. 22.1). Understanding the
differential effects of light and melatonin on the clock at various 12:00 15:00 18:00 21:00 0 03:00 06:00 09:00 12:00
circadian times is crucial to understanding the theoretical basis of Afternoon Evening Night Morning
the treatment of CRSDs.
Entrainment of the clock comprises two processes. The first is Fig. 22.1â•‡ Stylized phase response curves for light (6.7 hours of 10 000 lux) (full
line) and melatonin (0.5 mg) (dashed line) in a normally entrained individual. Light
period control (adjustment of the period to 24 hours on a daily
late in the biological day (afternoon–â•‰evening) (approximately 15:00–â•‰00:00) causes
basis) and the second is phase control (adjustment of the phase of a phase delay in the circadian clock, while light in the early biological day (03:00–â•‰
the rhythm to the appropriate time of the daily light–â•‰dark cycle). In 12:00) causes a phase advance. In contrast, melatonin administered during the
this chapter, we focus on the CRSDs that result from either a lack late afternoon causes a phase advance and during the biological morning elicits a
of entrainment of the human circadian clock (FRSD and ISWRD) phase delay.

period and phase angle. The two most common environmental disorder (i.e, by minimizing evening light exposure and maxi-
situations that cause CRSDs are shift work and rapid transmerid- mizing morning exposure, the circadian clock of ASPD patients
ian air travel. From the phase response curve (Fig. 22.1), it can is perpetually being phase advanced but not phase delayed; see
be seen that in most situations the human clock can only shift a Fig. 22.1. In addition to an early sleep phase, the phase of endog-
maximum of a couple of hours per day. These maximum shifts enous melatonin secretion rhythms and core body temperature
are described as the “limits of entrainment.” Transmeridian travel are advanced in ASPD sufferers [7]‌.
beyond these limits manifests as “jet lag.” On average, without One of the underlying causes of ASPD is a clock with an inher-
interventions, the circadian clock takes a day to adapt for every ently short free-running period. This has been demonstrated in the
time zone crossed. After several days of light exposure in a new autosomal dominant “familial advanced sleep disorder” (FASPD),
time zone, the clock is able to achieve steady state entrainment at which has been shown to be a consequence of a clock with a very
an appropriate phase angle (wakening in the morning and sleep- short free-running period (23.3 hours) in at least three families
ing at night). Treatment strategies to expedite entrainment to a studied [8]‌. FASPD has been associated with a missense muta-
new time zone are clearly beneficial if the duration of stay in the tion in the circadian clock gene PER2 [9], and extreme morning
new time zone is sufficient [5].‌ preference has been associated with a number of polymorphisms,
However, for short stopovers, there is little value in attempting including a length polymorphism, in the PER3 gene [10], a silent
to entrain to the new time zone, and the best advice is to try and polymorphism in the PER1 gene [11], and a missense mutation in
work and operate (as far as is feasible) during “home” daytime. The the CSNK1D gene (encoding casein kinase 1δ) (which also predis-
rapid changes from diurnal to nocturnal sleep timing experienced poses sufferers to migraine) [12]. The pathogenesis of the disease
in shift work create the same demands on the clock as jet lag, and is, however, heterogeneous and there is currently no diagnostic
the advice about whether to try and adapt (or not) is essentially genetic marker for ASPD.
the same (although it is always more difficult to try and entrain to
a day at odds with societal norms and the light–dark cycle). Given Incidence
that an estimated 15–20% of the population in developed countries The incidence of ASPD is unknown, and it is thought to be under-
conduct “shift work,” the size of this problem is vast. reported as it causes less social/work disruption than some of the
The most common cause of CRSDs in people not shift working other CRSDs. Estimated incidence is, however, rare at less than
or conducting transmeridian travel is a lack of exposure to suf- 1% of the population. Advanced sleep phase appears to increase in
ficient entraining light (particularly in the morning). Situations in frequency with age, and onset is typically in middle age. ASPD is
which patients may present with CRSDs as a result of a low morn- reported in children, however, particularly those with autism spec-
ing light exposure include office workers in high latitudes in winter trum disorders and Smith–Magenis syndrome [13].
(which in some cases may present as seasonal affective disorder,
SAD), residents in rest homes, and patients in dimly lit hospital Presentation
settings. Prior to ascribing the diagnosis of ASPD, other causes of insomnia
In addition to the environmentally driven CRSDs, there are and early morning wakening such as major depression, mood dis-
biological causes of CRSDs in people who are exposed to the orders, and primary and secondary insomnia should be excluded
strong daily light–dark cycles that would normally be expected [14]. Patients with ASPD will present with a chronic history of
to entrain their clocks with an appropriate phase angle. The most afternoon or early evening sleepiness and early morning waken-
well characterized of these is blindness, particularly in blind ing/insomnia. If early sleep onset is not possible owing to social or
patients who have a lack of conscious light perception. Despite work commitments, patients will continue to display early morning
the fact that the primary circadian photoreceptor is nonvisual wakening accompanied by chronic sleep deprivation. If allowed to
(as above), conscious perception of light appears to provide an sleep at their “preferred” sleep times, sleep duration and architec-
acceptable surrogate to determine whether the circadian light ture are normal.
entrainment pathway is intact in blind subjects. CRSDs also occur
with psychiatric conditions, particularly with affective disorders. Assessment tools for ASPD
Chronotherapeutic treatments have been shown to be effective in
the treatment of SAD, in bipolar, and unipolar depression among 1. Patient sleep diary/sleep log for a minimum of 7 (preferably
others [6]‌. 14) days. It is important for patients to report their preferred
sleep times on “free” (i.e, non-work) days.
2. Objective monitoring of sleep–wake timing using wrist-worn
Advanced sleep phase disorder actigraphy (in conjunction with sleep diaries) for a period of at
Description least 7 days [15].
ASPD is characterized by disabling sleep times that are too early 3. ASPD sufferers are likely to score as extreme morning types in
with respect to societal norms or personal preference. Patients morningness–eveningness questionnaires such as the Munich
suffering from ASPD will have an early sleep onset (typically Chronotype Questionnaire [16] and the Horne– Östberg
between 18:00 and 21:00) and find it very difficult to stay awake Morningness–Eveningness Questionnaire [17]. However, there
past 21:00. They will habitually wake between 02:00 and 05:00 are no studies evaluating the sensitivity or specificity of these
and find it very difficult to sleep past 05:00. The nature of the questionnaires as diagnostic tools, and the AASM recommends
light exposure that these patients subject themselves to as a con- that their use be restricted to the confirmation of ASPD rather
sequence of the disease can aggravate, or even maintain their than diagnosis [4]‌.

Chapter 22 advanced, delayed, free-running, and irregular sleep–wake rhythm disorders 217
Diagnosis Recommended treatment for ASPD comprises evening bright (up to

10 000 lux) light therapy accompanied by minimization of morning
The ICSD-3 diagnostic criteria [1]‌for ASPD are as follows:
light exposure. Sleep scheduling (where practicable) may also be used
1. An advanced phase of the major sleep episode in relation to the in conjunction with bright light therapy.
desired sleep time as evidenced by a chronic/recurrent complaint.
2. Symptoms present for at least 3 months. Delayed sleep phase disorder
3. When allowed to select their preferred sleep time, patients
Description
have normal sleep duration and quality occurring at a stable
(advanced) phase with respect to societal norms. DSPD, first described in 1981 [24], is characterized by stable sleep
times that are too late with respect to societal norms or personal
4. Sleep diaries and objective sleep timing measures (actigraphy) preference. Patients suffering from DSPD will have a late sleep onset
conducted over a minimum of 7 days (preferably 14 days) show (typically between 02:00 and 06:00) and wake typically between
stable but advanced sleep timing. 10:00 and 13:00. DSPD patients present with sleep onset insomnia
5. The sleep disturbance is not explained by another current sleep, and have extreme sleep inertia when trying to conform to work
neurological, mental, medical, or substance use disorder. or social schedules [14] owing to a delay in their “wake mainte-
While not required for diagnosis, investigation of body temperature nance zone.” They will describe undisturbed sleep when sleeping at
rhythms or endogenous melatonin onset profiles (dim light mela- their (late) preferred sleep phase on free days and holidays. As with
tonin onset) can confirm the advanced phase of the clock in ASPD ASPD, the nature of the light exposure these patients receive (lit-
sufferers. PSG recordings will show “normal” sleep in patients who tle phase-advancing morning light and increased phase-delaying
are sleeping at their preferred phase and may be used to rule out evening light exposure) may aggravate or maintain their disorder.
another primary sleep disorder [4]‌. While the etiology of DSPD is unknown, possible causes include
a circadian clock with a longer than average endogenous period
Management and treatment [25,26], a hypersensitivity to evening (phase-delaying) light expo-
sure that results in more profound delays than advances in “normal”
Management of ASPD relies on the combination of timed bright
light exposure settings [27], and an abnormal phase relationship
evening light exposure and sleep–wake scheduling. Using the prin-
between the circadian clock and the sleep homeostatic process reg-
ciples of the phase response curve (Fig. 22.1), patients’ sleep time
ulating sleep and wakefulness.
can potentially be delayed to a desired phase by appropriately timed
There are reported cases of familial DSPD [28], and a number of
administration of light (and/or chronobiotics such as melatonin).
polymorphisms in circadian clock genes appear to correlate with
Evening light therapy has been reported to be effective in delay-
extreme evening-type behavior (including polymorphisms in PER3
ing wake time [18] and increasing sleep efficiency in some ASPD
[10,29–31], CLOCK [32], ARNTL2 (33), and PER1 [11]). As with
sufferers. Two evenings of bright light (4 hours of 2 500 lux) therapy
ASPD, however, none of these polymorphisms provide a diagnostic
has been reported to phase delay the clock of early waking insom-
tool for DSPD.
niacs by 2 hours, and subsequently to improve sleep parameters
A delay in the major sleep episode is usually accompanied by a
4 weeks after treatment [19]. Exposure to polychromatic blue-
delayed phase of circadian phase markers (such as melatonin and
enriched or standard fluorescent white light of approximately 370
core temperature) in DSPD patients, although recent evidence
μW/cm2 3 hours before bedtime has proven effective in delaying
suggests there may be two subtypes of DSPD patients: those with
the clock and prolonging the latency to rapid eye movement (REM)
shifted circadian phase markers and those with shifted sleep but
sleep in older subjects in the sleep laboratory [20]).
“normally” phased markers of the clock.
In contrast, a large study of 47 ASPD patients treated with 2–3
hours of “enhanced evening light” (at a relatively modest 265 lux)
Incidence
showed no benefit in altering actigraphically determined sleep
phase. Patients in this study did, however, report a subjective ben- DSPD is by far the most common of the CRSDs, representing over
efit of light therapy [21]. The long-term effects of light therapy can 80% of CRSD diagnoses, but the prevalence of DSPD in the general
dissipate once treatment ceases [22], and patient compliance in population is largely unknown, with estimates between 0.17% and
maintaining light therapy in the medium to long term can be low. 9% in the community and primary healthcare setting [34–36]. The
A second approach to the treatment of ASPD is chronotherapy/ condition is more common in adolescence (7–16%) and is reported
sleep scheduling, which has been shown to be effective in the treat- in approximately 10% of patients presenting to sleep clinics with
ment of ASPD in one case report in which a gradual advance of insomnia [1]‌. Onset is common in adolescence, with the incidence
bedtime by 3 hours every 2 days has successfully resulted in a of generally “late chronotypes” peaking in males at 21 years and
desired sleep phase at a 5-month follow-up [23]. females at 17 years [16].
The administration of low-dose oral melatonin has been reported
to be efficacious in delaying the clock when administered after Presentation
the body temperature nadir (in the early subjective morning) DSPD can present at any age, but most commonly manifests in
(Fig. 22.1). Thus, theoretically at least, it could be useful in delay- adolescence (90% of DSPD patients report the onset of their symp-
ing the clock of ASPD sufferers. There are, however, no system- toms in adolescence [37]). Onset in childhood also occurs, particu-
atic reports of its use for the treatment of ASPD [14] and the mild larly in familial cases. The incidence of DSPD is much less common
sleep-promoting effects of melatonin may negate its usefulness in at older ages. Patients present with disabling sleep onset insomnia,
the morning. great difficulty waking, and an inability to adapt to a “normal”

phase even after several days or weeks. Chronic sleep deprivation is Management and treatment
common (as evidenced by reduced total sleep time), as is associated
As with ASPD, the theory underlying the treatment of DSPD
morning sleepiness. When allowed to sleep at their preferred phase,
is based on the phase response curve (Fig. 22.1). By maximiz-
sleep quality and duration are normal. DSPD sufferers will score
ing morning (phase-advancing) light exposure and minimizing
as evening types on chronotyping questionnaires and will report
phase-delaying evening light exposure, the patient’s phase can be
being most alert in the evening. Their inability to rise in the morn-
adjusted.
ing can lead to issues maintaining work or academic careers, and in
There is good evidence to support the use of morning bright light
children and adolescents DSPD is frequently accompanied by tru-
therapy in the treatment of DSPD. A number of case reports and
ancy and academic failure. DSPD may be associated with psycho-
placebo-controlled trials have shown the efficacy of bright light
pathologies such as a mood disorders (major depression/bipolar),
therapy administered in the morning (prior to or on waking) for
severe obsessive/compulsive disorder, autism spectrum disorder,
1–2 weeks in phase-advancing sleep timing and circadian rhythms
and attention deficit hyperactivity disorder (ADHD) [1]‌.
in DSPD sufferers [25,39]. Morning light therapy has even proven
Assessment tools for DSPD to be effective when administered through closed eyelids [40].
The level of light necessary to advance sleep timing and the clock
1. Patient sleep diary/sleep log for a minimum of 7 (preferably depends on the wavelength used. As circadian photoreception is
14) days. It is important for patients to report their preferred mediated by a blue-light sensitive opsin, blue light is more effective
sleep times on “free” (i.e, non-work) days. than other wavelengths in shifting the clock [41]. However, compli-
2. Objective monitoring of sleep–wake timing using wrist-worn ance with light therapy can be problematic, particularly with long-
actigraphy (in conjunction with sleep diaries) for a period of at term therapy.
least 7 days (preferably 14 days) [15]. Oral melatonin administered during the phase advance portion
3. DSPD sufferers typically score as evening types in morningness– of the melatonin phase response curve (in the subjective evening)
eveningness questionnaires such as the Munich Chronotype (Fig. 22.1) is known to elicit phase advances of the human circadian
Questionnaire [16] and the Horne–Östberg Morningness– clock [3,42], and afternoon and evening melatonin administration
eveningness Questionnaire [17]. The Basic Language (0.3–5 mg up to 8 hours prior to sleep onset for 4 weeks) has been
Morningness Scale (BALM) is also useful in screening for used to phase advance the clock in DSPD sufferers [43,44]. Low
DSPD [38]. doses of melatonin (0.3–0.5 mg) prove to be as effective as high
doses (3–5 mg) [44], and early timing is more effective than later
As with ASPD, the measurement of circadian phase markers such [44]. Melatonin also has mild sleep-promoting effects that can
as core temperature and melatonin profiles (either analysis of be useful when administered in the subjective evening/bedtime.
dim light melatonin onsets in salivary or plasma samples or the While compliance with melatonin treatment is better than that of
rhythm of 6-sulphatoxymelatonin in urine) can be used to con- light therapy, relapse of symptoms can occur when treatment is dis-
firm the delayed phase of the clock. PSG will confirm both normal continued [45]. There are few data on the very long-term effects of
sleep architecture and duration when patients are sleeping at their melatonin treatment in adults, but there is little evidence for any
preferred phase. adverse effects to date [46].
As the phase-advancing effects of morning light therapy and
Diagnosis evening melatonin treatment are additive [47], their use together is
The ICSD-3 diagnostic criteria [1]‌for DSPD are as follows: effective in the treatment of DSPD [48–50].
Cognitive–behavioral therapy (CBT) and chronotherapy/sleep
1. A significant delay in the phase of the major sleep episode in scheduling together with bright light therapy have also been used
relation to the desired sleep/wake time. to treat DSPD in adults [51] and adolescents [52]. Adolescents
2. Symptoms present for at least 3 months. with DSPD receiving six 1-hour weekly sessions of CBT together
with an advance in daily wake time of 30 minutes, and 30–120
3. When allowed to choose their preferred sleep phase, patients
minutes of morning light therapy until their target waking time
show improved duration and quality of sleep and maintain a
of 06:00, showed improved sleep and reduced daytime impair-
delayed (but 24-hour) sleep pattern.
ments, with effects persisting at 6 months [52]. Phase-advancing
4. Sleep logs/actigraphy for a minimum of 7 (preferably 14) days chronotherapy/sleep scheduling can be particularly difficult for
show a delay in the timing of the habitual sleep period. DSPD sufferers, and an effective alternative [25] is phase-delaying
5. The sleep disturbance is not explained by another current sleep, chronotherapy (progressively delaying sleep time by 3 hours
neurological, mental, medical, or substance use disorder. every 2 days until the desired sleep time is achieved). This is, how-
ever, disruptive in patients trying to maintain a regular work and
DSPD must be distinguished from primary and secondary chronic
social life.
insomnia (in which sleep initiation and maintenance are not
improved when patients are able to sleep at their preferred phase). Recommended treatment for DSPD comprises daily morning bright
Excessive daytime sleepiness may be caused by other sleep disor- (up to 10 000 lux) light therapy (either before or on waking) accom-
ders (eg, insomnias or breathing disorders). DSPD must also be panied by minimization of evening light exposure (after 21:00) and
distinguished from “normal” delayed sleep phase (particularly in afternoon/ evening melatonin administration. Sleep scheduling/
adolescents), which does not impair functioning or work or school chronotherapy (where practicable) and CBT may be used in conjunc-
schedules. tion with these approaches.

Free-running (non-entrained Day

10
Subject 15
type/non-24-hour) sleep disorder

Description
FRSD results when the circadian clock is not properly entrained 20
to the 24-hour day and thus “free-runs” with its endogenous
period (on average longer than 24 hours). The etiology of FRSD
is unknown, but it is assumed to result either from an inability of 30
light (or other non-photic zeitgebers) to entrain the clock, or from 24 4 8 12 16 20 24 h
a clock with such an extreme free-running period that it is out of Subject 16
10
the range of entrainment of a 24-hour day. Subjectively, sufferers
will often report sleep that drifts later each day. Objectively, how-
ever, they may not show sleep–wake patterns that “free-run,” as
their work or societal demands may not allow their sleep to fol- 20
low their circadian drive. The result can be either a clearly drifting
sleep pattern or a pattern of alternating periods of “good” noctur-
nal sleep interspersed with periods of very short nocturnal sleep
30
episodes and daytime naps (when the circadian clock has drifted 24 4 8 12 16 20 24 h
out of phase with the 24-hour day and is promoting sleep during Subject 17
the day and wakefulness at night) [53] (Fig. 22.2). In the latter case, 10
it is only when a marker that faithfully represents the phase of the
circadian clock (such as melatonin or core body temperature) is
measured that the “free-running” pattern is revealed. 20
Incidence
Estimates of the prevalence of CRSDs in blind or visually impaired
populations vary, with some studies suggesting that up to 70% of 30
24 4 8 12 16 20 24 h
blind subjects suffer from a CRSD [54–58]. The severity and mag-
nitude of CRSDs in the blind appears to correlate with the degree Fig. 22.2 Three blind subjects (no perception of light) showing abnormal
of light perception of patients. As light is the primary zeitgeber sleep and melatonin rhythms. Subjectively recorded sleep is shown by the gray
that entrains the human circadian clock, FRSD is most common bars, and naps (classified as such by the subjects) are shown by the black bars.
in the blind, and particularly people with no or little conscious Melatonin was assessed as 6-sulphatoxymelatonin (aMT6s) in sequential urine
collections for 48 h weekly, and the asterisks indicate the calculated peak times
light perception. Subjective estimates of the prevalence of FRSD in
(acrophase) of the aMT6s rhythms. Note the abnormal timing of aMT6s, which
the community range from 17% to 50% in blind individuals with normally peaks between 24:00 and 06:00, and the association of naps with
no conscious light perception (NLP) or reduced light perception daytime melatonin production. Subject 17 is clearly “free-running” (i.e, showing
(RLP) and from 4% to 8% in blind individuals with light percep- endogenous periodicity), with a steady daily delay of the aMT6s rhythm. Nearly
tion (LP) [58,59]. The objectively determined incidence of FRSD all blind subjects with no eyes have shown this phenomenon. Subject 16 is
(via the measurement of 6-sulphatoxymelatonin rhythms in urine) synchronized to 24 hours, but with an abnormal phase position. Cortisol and core
is 39% in NLP and 10% LP [60]. Almost all bilaterally enucleated body temperature rhythms show abnormalities similar to those of melatonin.
These and other observations in the blind underline the importance of light for
patients show free-running rhythms [61].
synchronizing rhythms and the association of daytime endogenous melatonin
From these numbers, it is clear that FRSD does not affect all production with poor night time sleep and daytime naps.
people who have no conscious perception of light. Entrainment Reproduced from Lancet, 346(8988), Lockley S, Tabandeh H, Skene D, Buttery R, Bird A,
in these individuals may be explained by (a) intact circadian pho- Defrance R, et al, Day-time naps and melatonin in blind people, p. 1491, Copyright (1995), with
toreception (from melanopsin-containing retinal ganglion cells in permission from Elsevier.
an intact inner retina), (b) entrainment by non-photic cues (such
as social interaction, meals, or exercise), or (c) a free-running core body temperature) to determine whether their clock is truly
period that is so close to 24 hours as to be indistinguishable from “free-running.”
an entrained rhythm. Although extremely rare, free-running Patients with FRSD frequently report “drifting sleep patterns” and
sleep patterns have been reported in sighted individuals in low present with alternating periods of insomnia and excessive daytime
light environments in the laboratory, at high latitudes [62,63], in sleepiness and hypersomnia. Given that the average free-running
patients following chronotherapy for DSPD, as a result of trau- period in humans is longer than 24 hours [65], when drifting sleep
matic brain injury [1]‌, and in recovery from offshore night-shift is reported, it is usually described as drifting a little later each day.
work [64]. When sufferers’ circadian phase is aligned with the external envi-
ronment, they may be asymptomatic. As their clock drifts, patients
Presentation describe increasing sleep latency, sleep onset insomnia, and exces-
FRSD can be differentiated from DSPD (in which some patients sive daytime sleepiness. Depression and mood disorders can occur
with severe DSPD display delays in sleep onset over several days) as comorbidities. Approximately 25% of sighted individuals with
by measuring circadian phase markers (eg, melatonin and/or FRSD have related psychiatric diagnoses [1]‌.

Onset of FRSD can occur at the onset of blindness or any time 2. Symptoms persisting over the course of at least 3 months.
thereafter. In congenitally blind infants, it can be apparent early. 3. Daily sleep logs (and actigraphy) for a minimum of 14 days
FRSD has been reported in children with intellectual disabilities (preferably longer in blind patients) demonstrate a pattern that
and blindness, particularly those with optic nerve hypoplasia. typically delays each day with a period (usually) of longer than
It has also been described in children with Rett syndrome [66], 24 hours.
Angelman syndrome [67], and autism spectrum disorders. Drifting
sleep can be more readily apparent in children than adults, but is 4. The sleep disorder is not better explained by another current
frequently described by parents or caregivers as “waking too early/ sleep, neurological, mental, medical, or substance use disorder.
late” or “sleeping at abnormal times” [1]‌. As illustrated in Fig. 22.2, patients with FRSD may or may not dis-
play drifting sleep–wake patterns when analyzed by sleep diary or
Assessment tools for FRSD actigraphy. Thus, measurement of direct phase markers of the clock
1. Patient sleep diary/sleep log for a minimum of 14 days (prefer- such as melatonin [68] or core body temperature [69] may be nec-
ably longer). It is important for patients to report their preferred essary in order to diagnose FRSD.
sleep times on “free” (i.e, non-work/non-school) days.
Management and treatment
2. Objective monitoring of sleep–wake timing using wrist-worn
Given that the overwhelming majority of patients with FRSD are
actigraphs (in conjunction with sleep diaries) for a period of at
blind and are not able to entrain to photic cues, it is necessary to use
least 14 days.
non-photic entraining agents (zeitgeber) to entrain the circadian
3. Measurement of circadian phase markers (such as dim light clock of these patients to a 24-hour period.
melatonin onset (DLMO) from serially collected saliva or blood Melatonin has been shown to be particularly effective in entrain-
samples over the course of an evening, or urinary 6-sulpha- ing the clock of blind “free-runners” [70–72] (see Fig. 22.3 ). A sin-
toxymelatonin analysis for a minimum of 24 and preferably 48 gle melatonin treatment (5 mg fast-release) at the correct phase
hours) repeated at weekly intervals on ideally four occasions to can advance the clock by up to 1.5 hours (Fig. 22.1) [73]. Given
confirm “free-running” status. that the endogenous period of the clock in blind free-runners is
(on average) 24.5 hours, entrainment with melatonin is entirely
Diagnosis feasible [74]. Recent studies suggest that lower “physiological”
doses (between 0.3 and 0.5 mg) may be more effective in achieving
The ICSD-3 diagnostic criteria [1]‌for FRSD are as follows:
entrainment than higher “pharmacological” doses, but with great
1. A history of alternating periods of asymptomatic periods and individual variability. There is little evidence so far for an advantage
insomnia and/or excessive daytime sleepiness. of slow-release formulations over fast-release. In general, the lowest
(a) 0 (b)
20
40 Placebo
60 24.33 ± 0.09 h Placebo
24.35 ± 0.06 h
80
100
Study day
Melatonin
120
23.99 ± 0.19 h
140 Melatonin
160
No data
180
24.43 ±
200 Placebo 0.13 h Placebo
220 24.31 ± 0.06 h
240
24 12 24 12 24 12 24 12 24 4 8 12 16 20 24
Fig. 22.3 Entrainment of the circadian clock of a blind free-running patient with a free-running period of approximately 24.3–24.4 hours using daily melatonin. (a) Days
0–100: urinary analysis of 6-sulphatoxymelatonin (filled circles) and cortisol (open circles) rhythms shows a free-running clock with a period of 24.3 hours when the
patient is treated with placebo. Days 105–180: the rhythm is entrained to 24 hours by the daily administration of 0.5 mg oral melatonin (at 21:00). Days 185–250: the
patient free-runs again when melatonin administration is ceased and placebo is resumed. (b) The corresponding subjective sleep diary data shows cyclic appearance of
daytime naps and reduction in nighttime sleep duration in patient on placebo, which are not apparent during melatonin treatment [70].
Adapted from Journal of Biological Rhythms, 18(5), Hack LM, Lockley SW, Arendt J, Skene DJ, The Effects of Low-Dose 0.5-mg Melatonin on the Free-Running Circadian Rhythms of Blind Subjects,
pp. 420–9, Copyright (2003), with permission from SAGE Publications.

effective dose should be used. Successful entrainment is accompa- Assessment tools for ISWRD
nied by a consolidation of the nocturnal sleep episode, a decrease in
1. Patient sleep diary/sleep log for a minimum of 14 days (prefer-
daytime somnolence, and an improvement in mood.
ably longer) [80].
Increasing the structure of other non-photic cues (eg, meal tim-
ing, social interaction, and exercise) may also be helpful in entrain- 2. Objective monitoring of sleep–wake timing using wrist-worn
ing the clock of FRSD sufferers [75], although evidence in support actigraphy (in conjunction with sleep diaries) for a period of at
of this is somewhat limited. least 14 days [80]. However, compliance with wearing wrist acti-
In sighted individuals or blind individuals with light perception graphs can be low in dementia patients.
who have intact circadian photo-entrainment pathways, light may 3. Measurement of dim light melatonin onset rhythms in saliva or
be used to entrain the clock. In this case, morning (phase-advanc- plasma, or 6-sulphatoxymelatonin in urine, may show decreased
ing) light (Fig. 22.1) is effective in eliciting the required phase amplitude in ISWRD patients.
change required to entrain the clock to 24 hours.
Recommended treatment for FRSD in blind patients lacking circadian Diagnosis
photo-entrainment comprises daily evening melatonin administration The ICSD-3 diagnostic criteria [1]‌for ISWRD are as follows:
(between 0.3 and 5 mg), starting if possible during a period of good
1. The patient or caregiver reports a chronic or recurrent pattern
sleep, accompanied by increased structure of non-photic cues (meals,
of irregular sleep–wake episodes over 24 hours characterized by
social interaction, etc.). In blind patients with light perception and in
insomnia, excessive daytime sleepiness (napping), or both.
sighted individuals, morning bright light therapy can be used (with or
without evening melatonin and increased structure of non-photic cues). 2. Symptoms are present for at least 3 months.
3. Sleep diaries and actigraphy (where possible) over 7–14 days
Irregular sleep–wake rhythm disorder demonstrate no major sleep period and multiple irregular sleep
bouts (at least three per 24 hours).
Description 4. The sleep disturbance is not explained by another current sleep,
ISWRD is characterized by a lack of consolidation of the sleep–wake neurological, mental, medical, or substance use disorder.
cycle [76]. Total sleep time is essentially normal for age in ISWRD
patients, but sleep is fragmented across 24 hours and there is no PSG is not required for diagnosis, but may be used to exclude
major nocturnal sleep episode present. This disorder is common in an alternative diagnosis and when conducted over 24 hours will
people with Alzheimer’s and other dementias [77]. The etiology is show the loss of a consolidated sleep episode and normal total
unclear, but possible causes include changes in the hypothalamus sleep time.
as a result of neurological disease, a reduction in the light input to
the suprachiasmatic nucleus as a result of vision or optic tract dis- Management and treatment
orders, and/or a decreased strength of daily light–dark cycles and Increasing the amplitude of the daily light–dark signal by bright light
lack of activity associated with institutionalization in a rest-home treatment is the most effective therapeutic intervention (particu-
environment. larly in institutional settings) for ISWRD sufferers [4,81]. A num-
ber of studies have shown an improvement in rest–activity rhythms
Incidence and sleep (including consolidated nocturnal sleep, reduced noctur-
The incidence of ISWRD is unknown, but it is commonly associated nal agitation and napping, and improvement of daytime alertness)
with brain injury or mental retardation in children and with demen- in rest-home patients as a result of bright light exposure (1 500–8
tia in older adults [14]. Age per se is not a risk factor for ISWRD but 000 lux for around 2 hours) (reviewed in [4,14]). Light treatment
comorbidities in older adults such as Alzheimer’s disease and neu- has also been proven effective in treating ISWRD in some children
rological dysfunction are, particularly for those patients with even- with mental retardation who have not been responsive to CBT or
ing agitation and sun-downing [77–79]. The risk factors for ISWRD hypnotics [82].
are Alzheimer’s, Parkinson’s, and Huntington’s diseases in adults and There is little evidence for the efficacy of melatonin in the treat-
developmental disorders in children [1]‌. ISWRD has been reported ment of ISWRD. Neither fast-release nor controlled-release mela-
in children with Angelman syndrome, William syndrome, autism tonin appear to convincingly improve actigraphically determined
spectrum disorders, and Smith–Magenis syndrome [13,67]. sleep parameters in ISWRD patients [4,14,76]. Controlled-release
melatonin may, however, prove useful in improving sleep mainte-
Presentation nance in some patient populations, and the use of combined morn-
Patients with ISWRD will present with sleep maintenance insom- ing light and evening melatonin (2.5 mg) therapy has been shown
nia/nocturnal restlessness and daytime sleepiness with frequent to improve sleep duration and reduce sleep latency in Alzheimer’s
daytime naps (depending on the time of day). Sleep occurs in three patients [83]. There is also some weak evidence that melatonin may
or more short (<4 hour) intervals across 24 hours [79]. Total sleep be beneficial in treating ISWRD in children with psychomotor
time across the 24 hours is, however, normal and the longest sleep retardation [84].
period is often between 02:00 and 06:00. The fragmented nature There have been several reports of the successful use of melatonin
of the sleep in demented patients with ISWRD can make home or in treating sleep problems in children with neurodevelopmen-
family care particularly demanding, and it is cited as a driver of tal disorders (including a large UK-based randomized controlled
institutionalization of these patients. trial: the MENDS trial) [85].

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SECTION 7
Sleep neurology

CHAPTER 23
Sleep-â•‰related movement
disorders
Alessandro Gradassi and Federica Provini
Introduction the limbs, most often the lower ones. They usually consist of a
toe extension with foot dorsiflexion and despite occurring mostly
Sleep-â•‰related movement disorders are conditions characterized by while asleep (periodic limb movements during sleep, PLMS), they
simple and usually stereotyped movements. They disturb sleep’s also take place while awake (periodic limb movements of wake-
physiological occurrence and must entail (by definition) either day- fulness, PLMW). PLMS were first clinically reported by Symonds
time sleepiness or fatigue as consequence of their presence, owing in 1953, who described a patient, among five patients with dif-
to the continuous interruptions of the sleep cycle [1]â•„. The category ferent diseases, with jerks during relaxed wakefulness and sleep,
also includes other sleep-â•‰related monophasic movement disorders, and coined the term “nocturnal myoclonus” [2]â•„. Some years later,
such as sleep-â•‰related leg cramps [1]. Lugaresi and Coccagna first recorded and defined PLMS polysom-
Some movements, such as bruxism, might occur during both nographically using the term “nocturnal myoclonus” in Symonds’
wakefulness and sleep, but a clear worsening of the symptoms dur- honor [3]. Subsequently, Coleman suggested the term “periodic
ing sleep is necessary in order to include the condition among sleep-â•‰ movements in sleep” [4], which was then substituted by “periodic
related movement disorders [1]â•„. Like other movements, such as limb movements in sleep,” to emphasize the observation that arms
sleep starts (hypnic jerks), sleep-â•‰related movement disorders might may be involved as well.
occasionally be present in healthy individuals. Setting a dividing line
between normal and pathological is very difficult in such cases. Epidemiology
Once it has been determined that the patient suffers from a The prevalence of PLMS varies between 2% and 15% in the general
sleep-â•‰related movement disorder, the patient’s age and the part of population [5–â•‰7]. The simultaneous presence of PLMS and sleep
the body involved provide an idea about which movement disorder complaints (periodic limb movement disorder) [1]â•„had a preva-
might be affecting them. In some cases, following these clues, it is lence of 3.9% in a large epidemiological study [8]. PLMS are less
possible to make a clinical diagnosis, while in some others, the use common in children [9–â•‰11] and their prevalence increases with age;
of all-â•‰night polysomnography with synchronized video recording this includes patients not affected by sleep disturbances [12–â•‰17].
(video-â•‰polysomnography, VPSG) is necessary to describe properly The prevalence of PLMS reaches 80% in patients with other medi-
the neurophysiological features of the phenomenon, the time and cal and neurological diseases, the first among which is RLS, where
the stage of occurrence during the night, and the patient’s level of PLMS prevalence can reach about 95% [18,19] of RLS patients. An
consciousness in order to reach a correct diagnosis. elevated prevalence of PLMS can be found among patients with
Sleep-â•‰related movement disorders must be distinguished from other sleep disorders such as narcolepsy [20] and in elderly patients
parasomnias, such as sleepwalking or REM sleep behavior disor- with hypersomnia [12]. PLMS may be seen in obstructive sleep
der (RBD), which normally show complex muscular patterns and apnea (OSAS), and in cases of severe OSAS, PLMS may become
complex behaviors that may appear purposeful, although they may more noticeable during the continuous positive airway pressure
be unconscious too. (CPAP) treatment [21,22]. There may be an increased prevalence
This chapter describes the conditions classified as sleep-â•‰related of PLMS in patients with RBD. In a study of 40 RBD patients, 70%
movement disorders, excluding restless legs syndrome (RLS), exhibited PLMS, which were also seen during REM sleep [23].
which is dealt with in Chapter 24 of this volume. Several studies have documented PLMS in patients with various
non-â•‰sleep-â•‰related disorders (eg, essential hypertension, migraine,
Periodic limb movement disorder and end-â•‰stage renal disease), but the significance of the reported
Periodic limb movement disorder (PLMD) is characterized by data remains undetermined [6].
periodic episodes of repetitive, highly stereotyped limb movements
that occur during sleep (PLMS: see the next paragraph) and by Clinical aspects and polysomnographic features
clinical sleep disturbance that cannot be accounted for by another PLM represent a heterogeneous motor phenomenon. In their sim-
primary sleep disorder [1]â•„. plest and most common form, they consist of periodic extensions of
Periodic limb movements (PLM) are involuntary muscular con- the big toe and/â•‰or the foot. When the phenomenon becomes more
tractions that occur periodically about every 20–â•‰30 s and involve intense and diffuse, there may be knee and hip flexion. Sometimes,

228 Section 7 sleep neurology
F3-A2
C3-A2
O1-A2
Mylo.
ECG
R.Ext. Carpi
L.Ext. Carpi
R.Tib. Ant.
L.Tib.Ant.
30 sec
Fig. 23.1 Periodic limb movements during sleep (PLMS). Polygraph recording of PLMS during stage 2 NREM sleep. EMG bursts on the tibialis anterior muscles occur
with a characteristic periodicity showing different patterns of muscular contraction. Mylo.: mylohyoideus; Ext.: extensor; Tib. Ant.: tibialis anterior; R.: right; L.: left.
the forearm may also flex at the elbow. PLM may begin with one or the evident limitations of the PLMI for the description and evalu-
repeated myoclonic jerks, followed, after a short pause, by a tonic ation of PLMS, especially with regard to their presence in different
contraction, or it may consist of a single prolonged tonic contrac- neurological and medical conditions and to the response to treat-
tion (Fig. 23.1). PLM may affect only one or both legs; more often, ment, new parameters have been described. The Periodicity Index
both extremities are involved, but usually not symmetrically or (PI), a sophisticated, automatic method developed to describe the
simultaneously. Sometimes the phenomenon alternates in each leg time structure of limb movement activity [27,28]. The PI value
(Figs. 23.1 and 23.2). According to standard criteria, PLMS must ranges from 0 to 1, where 0 indicates a total absence of periodic-
occur in series of four or more consecutive movements, split by an ity, and 1 complete periodicity [29]. PI is higher in RLS patients
inter-movement interval of at least 5 seconds and a maximum of 90 and lower in patients with RBD, probably reflecting differences in
seconds (from onset to onset) [24,25]. The duration of each PLMS the mechanisms involved in the generation of these different con-
may last between 0.5 and 10 s. PLMS are polygraphically scored ditions. PLMS can also be described in terms of the time distribu-
only when the amplitude of the EMG activation exceeds 8 μV; the tion of limb movement throughout the night, which, in general, is
activation ends when the EMG amplitude falls below 2 μV. not uniform, and is also linked to the co-presence of other distur-
The number of PLMS per hour of sleep constitutes the PLMS bances [30]. PLMS, alone or associated with RLS, mostly manifest
Index (PLMSI). A PLMSI greater than 5 was formerly considered themselves after falling asleep, in the first half of the night, and then
pathological, but more recently, many authors, taking account of decrease dramatically toward the morning [31–33]. In addition,
age-related effects and night-to-night variations, have accepted a sleep stages are known to modulate PLMS frequency and periodic-
PLMSI greater than 15 as pathological in adults [1,26]. Because of ity, at least in patients with RLS, occurring mainly during stages 1
Time 23:25 01:26 03:00 04:26 06:16

W
R
N1
N2
N3
R. Tib. Ant.
L. Tib. Ant.
Fig. 23.2 PLMS. Evolution throughout the night (upper trace) of severe nocturnal myoclonus (lower traces) in a 62-year-old man. The jerks are present during relaxed
wakefulness before sleep onset and in infra-sleep wakefulness. PLMS persist during all sleep stages, affecting in particular the left leg (L. Tib. Ant.: left tibialis anterior) in the
first part of the night and then the right leg (R. Tib. Ant.: right tibialis anterior) in the last part of the night.

Chapter 23 sleep-related movement disorders 229
and 2 of NREM sleep and decreasing with deepening sleep stage dysfunction triggers PLMS or is simply coincidental. Moreover,
[34,35]. Even in subjects with only PLMS, the limb movements direct repetitive electrical stimulation [59] of the peroneal nerve
show a circadian rhythm, peaking at sleep onset, preceding the during sleep triggers a tonic contraction similar to what was pre-
evening rise in melatonin secretion [36]. viously called nocturnal myoclonus, and modifies the rhythm of
PLMS may be associated with EEG arousals or microarous- the spontaneously occurring phenomenon, suggesting that PLMS
als [35], or with pure autonomic activation alone, in the absence are in some way triggered by a sensory input [59]. Studies aimed
of an EEG arousal as defined by the ASDA criteria [37]. Spectral at finding the muscle recruitment patterns in PLMS have shown
EEG and heart rate analyses have revealed a wide variety of com- that leg muscles are most frequently involved, with no hierarchical
plex and stereotyped variations in cortical activity and heart rate order and no caudal or rostral propagation typical of propriospi-
associated with PLMS. These include increases in heart rate and in nal myoclonus, suggesting the engagement of different, independ-
alpha, theta, and delta power in the EEG [38–40]. The concomitant ent, and sometimes unsynchronized generators. Taken together, all
cerebral and autonomic responses before and during PLMS suggest these data suggest that the spinal cord hyperexcitability is induced
that these do not trigger cardiac and EEG activation but are part of by supraspinal factors, changing with sleep phases acting as trigger
the entire arousal response, which recruits several neural networks for PLMS [60,61].
from the brainstem up to the cortical level [41,42]. A pathogenetic role for the dopaminergic system is certainly
plausible, but still controversial. The results of neuroimaging stud-
Clinical relevance ies, improvement of symptoms with dopaminergic drugs, and the
It is still debated whether isolated PLMS have a clinical meaning coexistence of PLMS with conditions such as RLS and Parkinson’s
or not, and whether PLMS alone, without the complaint of non- disease where a dopaminergic dysfunction has been postulated
restorative sleep or associated daytime symptoms, in the absence would support such a theory [6]‌.
of other sleep disorders, may be an independent cause of sleep Recently PLMS, together with RLS, has been demonstrated to
disturbances [6]‌. Subjects with PLMS may or may not be aware of have a genetic risk factor based on a significant genomewide asso-
the movements, and the complaints might be referred by the bed ciation study with a common variant of BTBD9 on chromosome
partner only. Moreover, it is common experience that PLMS could 6p21.2 for PLMS in patients with or without RLS, but no such asso-
be only an incidental finding during a VPSG recording, not being ciation has been found in RLS patients without PLMS [62].
responsible for any clinical sleep–wake consequence. On the other
hand, the hypothesis of a direct pathological role of PLMS disrup- Differential diagnosis
tion is weakened by the observation that pramipexole can suppress PLMS have to be differentiated from other sleep motor manifesta-
PLMS without affecting arousals [43]. No correlation has been tions that might mimic leg movements, since the legs are mainly
found among PLMSI, arousals, and sleep structure in patients with involved in almost every sleep-related movement disorder. The
insomnia/hypersomnia [44,45], and in many cases, despite treat- characteristics of the muscular contraction, its distribution, and its
ment of PLMS, no improvement in daytime sleepiness was noted. periodic pattern make recognition of PLMS on polygraphic record-
Some authors support the view that PLMS may cause insomnia, ings quite simple. In some cases, VPSG study could be mandatory
but only when correlated with a corresponding EEG arousal, and to allow a correct diagnosis to be made. Sleep starts are physiologi-
the lack of an arousal indicates that these may be a normal sleep cal, consisting of sudden jerks of trunk and extremities occurring
characteristic [46]. Owing to autonomic activation associated with on falling asleep or during light sleep [1]‌. Propriospinal myoclonus
PLMS, especially in patients with RLS but also in controls, resulting is a type of spinal myoclonus characterized by rhythmic or arrhyth-
in increases in heart rate and blood pressure, an intimate relation- mic spontaneous contraction of the axial muscles, usually spread-
ship among RLS/PLMS on the one hand and hypertension, heart ing to limb muscles [63]. Propriospinal myoclonus may arise at
disease, stroke, and increasing mortality in patients with renal fail- sleep onset and disappear during sleep [64]. Excessive fragmentary
ure on the other has been described, but the causality is far from myoclonus is characterized by short and nonperiodic muscle poten-
established [47–54]. tials (10–100 ms), that often do not end with any distal movement
but when intensified may disrupt sleep [65]. Further differential
Pathophysiology diagnosis must include nocturnal leg cramps (see the next section)
The exact pathophysiology of PLMS is still unknown. A cortical ori- and alternating leg muscle activation (ALMA), in which a single
gin seems unlikely, in the absence of a cortical prepotential in EEG– contraction of one leg alternates with a similar contraction of the
EMG back-averaging, and the absence of a Bereitschaftspotential other leg, occurring in all sleep stages at a frequency of 0.5–3 Hz,
before PLMS indicates that PLMS are not voluntarily generated each lasting for 0.1–0.5 s in sequences of at least four ALMAs [1].
[55]. Studies with functional magnetic resonance imaging (fMRI)
indicate activation of the brainstem but not the cerebral cortex dur- Treatment
ing PLMS [56]. The fact that PLMS almost never involve the face Before describing the management of PLMS, it is necessary to reit-
suggests that the generator of PLMS is below the level of the facial erate that PLMS that do not disturb the patient’s sleep and therefore
nucleus in the brainstem. The existence of PLMS in patients with a do not represent any clinical issue are not to be treated [66]. PLMS
complete spinal cord lesion, such as during spinal anesthesia or as are treated only when the patient reports sleep complaints and
a result of spinal transection, indicates that the generator may be when other sleep disorders, likely to be responsible for them, have
in the spinal cord [57,58]. The peripheral nervous system theory been ruled out. It should be noted that several medications (eg,
has not been abandoned yet, mainly because of the presence of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepres-
small-fiber neuropathy in some RLS patients often coexisting with sants, and neuroleptics) have also been reported to worsen PLMS,
PLMS, but it is still an unresolved question whether the peripheral so a drug history must be taken before any treatment [6,67–69].

There is insufficient evidence to comment on the role of pharmaco- Muscle strain, dystonias, ischemic or neuropathic claudica-
logical therapies in isolated PLMD, because most trials have been tion, and nerve root disease might mimic leg cramps. Myopathic
open studies including small patient groups. Many of the studies in and neuropathic conditions are usually characterized by muscle
RLS patients involving dopaminergic medications (eg, pramipex- cramps, generally during the day and not just at nighttime and not
ole, ropinirole, and rotigotine) demonstrated statistically signifi- exclusively involving the legs. It is important not to confound noc-
cant decreases in PLMS. In addition, gabapentin (300–2400 mg/ turnal leg cramps with other motor disturbances that may occur
daily), pregabalin (150–600 mg/daily), and valproate (125–600 mg/ during sleep, such as PLMS and RLS, sleep starts, painful legs and
daily) have also been shown to decrease PLM indices in subjects moving toes syndrome persisting during sleep, and excessive frag-
with RLS. Oxycodone decreases both the number of PLMS and mentary myoclonus. However, the clinical features of nocturnal
arousals [66,67]; lamotrigine (100 mg/daily), melatonin (3 mg, leg cramps are distinctive, and polysomnography is rarely neces-
30 min before bedtime), and bupropion have shown a positive sary. No treatment has been proven to be both safe and effective
effect, reducing PLMS and sleep fragmentation [6,66,67]. against leg cramps. Quinine sulfate (200–325 mg) before bedtime
has shown a modest benefit, but the clinician must be aware of the
Nocturnal leg cramps serious risk of its hepatic, blood, and renal toxicity [80]. The evi-
dence of benefit from other therapies is insufficient or conflicting.
Nocturnal leg cramps are sudden and painful contractions of the Magnesium citrate, potassium, gabapentin, and botulinum toxin
calf muscles, sometimes also accompanied by contractions of the may also be effective, as may multivitamin supplementation with
intrinsic muscles of the feet. They occur during sleep or while at vitamins E and C, especially in patients with cramps during hemo-
rest, are usually unilateral, and last from a few seconds up to as dialysis. Sodium supplementation also improves the symptoms, but
many as 10 minutes [70–72]. When they occur during sleep, the there is a potential risk of hypertension. Gastrocnemius stretching
patient wakes up suddenly owing to the painful sensation felt in and deep tissue massages have long been suggested as therapies
the leg. Massage, movement, or heat usually relieves the pain, but against leg cramps, but a systematic review has found limited evi-
a residual tenderness can persist for up to half an hour. Cramps dence for the use of nonpharmacological treatment for leg muscle
can occur at any age, but tend to be more common in middle-aged cramps [81].
and older people. Between 20% and 25% of adults have experienced
leg cramps, especially those over 80 years [71,72]. Leg cramps can
be either idiopathic or secondary to systemic or focal pathologi- Sleep bruxism
cal conditions [73]. They are most commonly noted in otherwise Sleep bruxism (SB) is characterized by grinding or clenching teeth
healthy individuals after excessive physical exercise. Some authors during sleep [1]‌. It is produced by either phasic or tonic muscle
have hypothesized that the lack of repetitive leg squatting to stretch activity in jaw-closing muscles associated with tooth-grinding
the leg tendons and muscles, typical of our “civilized” lifestyle, sounds [82–84]. Series of phasic muscle contractions, termed
results in the occurrence of these cramps [74,75]. rhythmic masticatory muscle activity (RMMA), are present in
Leg cramps may be triggered by peripheral vascular diseases, about 60% of people at a frequency of about two times per hour of
prolonged standing, and varicose veins. The high prevalence of sleep without tooth grinding [85]. The exaggerated occurrence of
cramps among patients with neurological disorders, such as par- RMMA is characteristic of patients with SB (Fig. 23.3).
kinsonism and peripheral neuropathy, suggests a possible asso- In contrast to normal subjects, sleep bruxers have more episodes
ciation with nerve dysfunction or damage [76]. Leg cramps may of RMMA, more bursts per episode, and bursts of larger amplitude
arise in pregnancy and some medical conditions, including elec- and shorter duration [85]. Most people brux at some period dur-
trolyte disturbances such as uremia, diabetes, thyroid diseases, ing their lives, but most are unaware of their behavior. Bruxism
hypomagnesemia, hypocalcemia, hyperphosphatemia, hypoka- does not usually interrupt the patient’s sleep, but it can be a prob-
lemia, and hyponatremia. The cramps in these conditions may lem for the bed partner owing to the noise caused. These factors
occur predominantly or exclusively during sleep. Also, certain have led to discrepancies in the reported prevalence of bruxism,
drugs may trigger leg cramps, eg, β-agonists, calcium antagonists, namely around 8% in the healthy adult population, with a linear
potassium-sparing diuretics, thiazide-like and loop diuretics, ster- decrease with age [86]. The incidence of bruxism is thought to be
oids, lithium, and statins [77]. About 60% of patients with cirrho- highest between the second and fifth decades of life, without a gen-
sis of liver also complain of leg cramps [78]. There has also been a der dominance. Many childhood bruxers stop doing so by their
report of familial nocturnal leg cramping with an autosomal domi- teens, although self-reported bruxism appears to increase between
nant inheritance [79]. adolescence and young adulthood [87]. The repetitive nocturnal
Polysomnographic recordings are useful to clarify the nature clenching may be associated with muscle and joint pain, temporal
of leg cramps, which may occur during any sleep stage, and to headache, tooth damage, and hypersensitivity of the teeth to cold
determine whether each cramp is associated with an awakening. liquids or air.
According to the American Academy of Sleep Medicine [1]‌, the Bruxism, whether occurring during wakefulness or sleep, is clas-
diagnostic criteria for sleep-related leg cramps are as follows: (A) a sified into primary, secondary, or iatrogenic [84]. SB is classified as
painful sensation in the leg or foot is associated with sudden muscle secondary sleep bruxism if associated with medical, psychiatric, or
hardness or tightness, indicating strong muscle contraction; (B) the neurological disorders, including sleep disorders associated either
painful muscle contractions in the legs or feet occur during the with drug administration or with withdrawal from a number of
sleep period, although they may arise from either wakefulness or medications (antidopaminergic drugs, SSRIs, and calcium antag-
sleep; (C) the pain is relieved by forceful stretching of the affected onists) and recreational substances (alcohol, caffeine, cigarettes,
muscles, releasing the contraction. cocaine, and amphetamine) (Table 23.1). Anxiety and vulnerability

(a) (b)
C3-A2
O2-A1
R.EOG
L.EOG
Mylo.
R.Masseter
R.Temporal.
R.Orb.eye
R.Orb.oris
R.S.C.M.
R.Tib.ant.
Microph.
Thor.Resp.
Abdom.Resp.
ECG
3 sec.
Fig. 23.3 Rhythmic masticatory muscle activity. Polysomnographic excerpts (a and b) showing clusters of myoclonic jerks and tonic activity involving the orofacial,
masticatory and cervical muscles during REM sleep. EOG: electro-oculogram; Mylo: mylohyoideus; Temporal.: temporalis; Orb.: orbicularis; S.C.M.:sternocleidomastoideus;
Tib. Ant.: tibialis anterior; Microph.: microphone; Thor.: thoracic; Abdom.: abdominal; Resp.: respirogram; R.: right; L.: left.
to psychosomatic disorders are common findings among patients EMG episodes per hour of sleep (Brux Index) allows a good dis-
with bruxism, although the contribution of these factors has not tinction between patients with minor episodes of bruxism and
yet been fully established [84]. The real nature of the pathophysiol- complaints about pain and headaches and patients with a current
ogy of bruxism is still debated, but two main theories have been history of tooth grinding [84,88]. RMMA is often associated with
proposed: a peripheral one, based on the assumption that maloc- sleep microarousals and a shift in sympatho-vagal balance toward
clusion triggers masticatory activity, and a central theory, support- increased sympathetic activity starting some minutes preceding SB
ing a loss of cortical or basal ganglial inhibition of brainstem motor onset, in particular in subjects with moderate to severe SB [89]. The
generators as the main cause of bruxism [82]. The relationship association between respiratory sleep disturbances and bruxism is
between SB and chronic use of medications with antidopaminergic hard to establish, because of a lack of studies and the absence of
properties suggests that the CNS dopaminergic system plays a role. standard apnea–hypopnea diagnostic criteria in patients with brux-
Additionally, genetic factors appear to play an important role in the ism. It is widely known that sleep apneas evoke arousals, which may
generation of bruxism in both children and adults. facilitate bruxism. The reported prevalence of bruxism–apnea con-
The diagnosis of SB aims to demonstrate the presence of tooth comitance varies between 30% and 50%. Sleep bruxism might be
grinding, since this is the pathognomonic feature of sleep brux- misdiagnosed as different pathologies of various kinds. It is very
ism. The patient interview investigates the patient’s awareness of important to distinguish clenching (while awake) from sleep brux-
jaw clenching, the presence of pain in the jaw muscles, temporo- ism (while asleep), since these conditions probably have different
mandibular dysfunction, tooth damage or fracture, the possible pathophysiologies and etiologies. Typically, diurnal bruxism is
presence of headache on waking up in the morning, or excessive silent, whereas nocturnal bruxism may be annoying.
daytime sleepiness. Clinical examination includes examination of Sleep-related faciomandibular myoclonus (SFMM) consists of
the head and neck muscles to identify the presence of contingent sudden and brief contractions (lasting less than 0.25 s) originat-
masseter hypertrophy as an indicator of a clenching habit, rule ing from the masseter and temporalis muscles, and spreading to
out temporomandibular disorders, and estimate the jaw opening the orbicularis oris, oculi, and eventually to the sternocleidomas-
and lateral mobility, and examination of the oral mucosa to search toideus muscles. This myoclonus may be familial, never shows any
for tooth grooving or ridging on the side of the tongue and on the kind of tonic or phasic activity, and is mostly present during NREM
cheeks, suggesting a concomitant oral habit. Video-polygraphic sleep, decreasing in REM sleep. Despite the presence of tooth tap-
monitoring in bruxism demonstrates increased masseter and tem- ping sounds, SFMM is characterized by occasional bleeding of
poralis muscle activity during sleep, along with grinding sounds, the posterolateral sides of the tongue and an absence of masseter
especially during stages 1 and 2 of NREM sleep. Sleep bruxism is hypertrophy [90].
established in the presence of tooth grinding noise, associated with Since no specific cure exists, the main goal in the management of
at least three EMG events, or with a burst lasting 0.5 s or more, SB lies in the prevention or reduction of complaints related to dam-
or with one contraction lasting 2 s or more. The confirmed epi- ages to orofacial structures [84]. Of high importance is the treatment
sodes are classified by patterns into phasic events (three or more of possibly comorbid sleep disorders, and an improvement in sleep
bursts), tonic-sustained events (one episode lasting more than bruxism will improve sleep quality. Psychological therapies aiming to
2 s), or mixed events (showing both patterns). The cut-off of four decrease the psycho-emotional factors underlying sleep bruxism may

Table 23.1 Effect of drugs on sleep bruxism (SB)-related oromotor activity
Drug Dosage Effect Time of use Side effects

Diazepam 5–10 mg/night ↓ SB-related oromotor activity Short periods: 1–2 nights
Methocarbamol 1–2 g/night ↓ SB-related oromotor activity
Clonazepam 1 mg/night ↓ SB-related EMG activity by 30% in Short-term use Dizziness, somnolence and
SB patients with other sleep disorders dependence–addiction
L-dopa Two doses of ↓ SB activity by 30%
100 mg/night
Clonidine 0.3 mg/night ↓ SB by 60% Severe morning hypotension
Botulin toxin type A ↓ Jaw muscle EMG activity during sleep Further studies are needed to
in SB patients evaluate benefit/risk
Propranolol Two doses of ↓ SB activity or not effective
60 mg/night
Bromocriptine 7.5 mg Not effective
Amitriptyline 25 mg/night Failed to control SB
Selective serotonin-reuptake ↑ the risk of SB
inhibitor (SSRI) antidepressants
Source data from Kato T, Blanchet PJ, Huynh NT, Montplaisir JY, Lavigne GJ, Sleep bruxism and other disorders with orofacial activity during sleep. In: Chokroverty S, Allen RP, Walters AS,
Montagna P, [eds], Sleep and Movement Disorders, pp. 555–72, Copyright (2013), Oxford University Press.
be useful [84]. Pharmacological therapy should be used only during whole body (bodyrolling type) is moved laterally; while prone, the
periods of high emotional stress, which normally leads to exacerba- whole body rocks on the hands and knees (bodyrocking type). The
tion of sleep bruxism symptoms. Botulinum toxin A, benzodiazepines phenomenon usually lasts a few to several minutes, repeating at a
and other muscle relaxants, anticonvulsants, β-blockers, dopamin- frequency of 0.5–2 per second [1,97] (Fig. 23.4).
ergic drugs, antidepressants, and clonidine are among the available Serious injuries from RMD are rare, but bone and skull injuries
drugs used as part of an interdisciplinary approach (Table 23.1) [84]. have been reported in association with headbanging.
Orthopedic devices have not shown any medium-to long- The specific causes and physiological mechanisms underly-
term benefit in reducing muscular contraction while asleep. Thus, ing RMD remain uncertain. The absence of organic causes, in the
although they may be used to deal with and prevent tooth dam- majority of cases, has led to behavioral and psychological theories.
age or painful muscular symptoms, they are not appropriate for A recent hypothesis proposes that RMD is linked to arousal fluc-
long-term use. tuations and mediated via central motor pattern generators of the
brainstem. Rare cases of familial occurrence have been reported,
but genetic studies had never been performed [98].
Rhythmic movement disorder RMD must be distinguished from other types of sleep-related
Rhythmic movement disorder (RMD) is characterized by repeti- motor manifestations. Sleep bruxism, thumb sucking, tics, dyskine-
tive and stereotyped movements occurring immediately after sleep sias, and nocturnal seizures must be ruled out through an accurate
onset and during light sleep, although they may appear in any sleep clinical description of the episodes and a VPSG recording.
stage. It is also called jactatio capitis or corporis nocturna, head- Rhythmic foot movement (RFM, or hypnagogic foot tremor) is
banging, or headrolling, but the term RMD is a better description, characterized by asynchronous oscillations of the whole foot or toes
since many body areas are involved in the movement activity, such in both legs at about 0.3–4 Hz occurring during pre-sleep wakeful-
as axial muscles, head, neck, and trunk, and sometimes legs as well ness and light sleep; it may be considered a new kind of RMD aris-
[1]‌. RMD is usually common among normal children, as a sleeping in adults, sometimes associated with insomnia, OSAS, PLMS,
facilitating tool [91,92], with a prevalence up to 66% at the age of and RLS.
9 months and decreasing to 8% in 4-year-old children. The symp- The treatment of RMD is first of all based on reassuring the
toms of many of these patients do not cease as they grow, but may patient that the condition will resolve in most cases, but devices
persist into adulthood, although not involving any psychopathol- protecting the head might be necessary to ensure safe sleep, par-
ogy [92,93]. A late onset of RMD (in adolescence or adulthood) ticularly for children with learning disabilities. Usually, RMD does
is relatively rare and has been associated with RLS or arousal on not affect sleep quality. Pharmacological therapy should be con-
resumption of breathing after apneic or hypopnic episodes [94–96]. sidered only in patients with self-inflicted injuries and poor sleep
In some cases, RMD may persist during wakefulness, particularly quality: benzodiazepines (clonazepam 1 mg/nightly or oxazepam
in autistic or mentally retarded individuals. 10–20 mg/nightly), dopamine agonists, citalopram, and tricyclic
During a common RMD episode, normally one of the following antidepressants have shown a beneficial effect on disturbances, but
movements occurs: while supine, the head (headrolling type) or the with variable success [97].

F3-A2
C3-A2
O1-A2
R.EOG
L.EOG
Mylo.
R. Tib. Ant.
L. Tib. Ant.
ECG
Fig. 23.4 Rhythmic movement disorders. Polysomnographic excerpt of rhythmic forward and backward movements of the trunk and head arising during wakefulness
before sleep onset. Note the high-amplitude 1 Hz movement artifact on EEG leads reflecting rhythmic body movements. Upper panel: video-clips synchronous with
polysomnographic recording. EOG: electro-oculogram; Mylo.: mylohyoideus; Tib. Ant.: tibialis anterior; R.: right; L.: left (due to the courtesy of Prof. Giuseppe Plazzi).
4. Coleman RM. Periodic movements in sleep (nocturnal myoclonus)

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CHAPTER 24
Restless legs syndrome/â•‰

Willis–â•‰Ekbom disease
Luigi Ferini-â•‰Strambi and Sara Marelli
Epidemiological aspects Another study evaluated the prevalence among African American
(AA) and non-â•‰African American (NAA) racial groups [9]â•„. RLS/â•‰
Restless legs syndrome (RLS), recently renamed Willis–â•‰Ekbom dis- WED prevalence in the NAA population was approximately three
ease (WED), is a common neurological disorder characterized by times higher than in the AA group.
uncomfortable and unpleasant sensations in the legs, with an urge to A study [10] that evaluated the incidence and correlates of RLS/â•‰
move. The most common adult RLS/â•‰WED descriptors are “restless,” WED in a US population-â•‰based sample (535 participants aged
“uncomfortable,” “twitchy,” “need to stretch,” “urge to move,” and 40 years or more) found an incidence of RLS/â•‰WED of 1.7% per year.
“legs want to move on their own.” About one-â•‰third of patients express Use of estrogen and history of obstructive lung disease were associ-
their RLS/â•‰WED sensations as painful, and, it has been reported that ated with a significantly higher incidence of RLS/â•‰WED. RLS/â•‰WED,
these patients had more severe RLS/â•‰WED symptoms [1]â•„. in turn, was associated with insomnia and increased sleepiness.
The clinical spectrum of RLS/â•‰WED is broad, ranging from Two other population-â•‰based cohort prospective studies have
individuals suffering from the disease only during short peri- evaluated RLS/â•‰WED incidence in Germany: the cumulative inci-
ods in their lives up to those severely affected, with daily symp- dence was 9.1% and 7.0%, respectively, and the persistence of RLS/â•‰
toms. Considering all the clinical factors, it is the age of onset WED symptoms from baseline to follow-â•‰up was 47.4% in one study
that appears to be the unique characteristic item qualifying as an (mean follow-â•‰up 2.2 years) and 41.5% in the second (mean follow-â•‰
endophenotype [2]â•„. Two different phenotypes of RLS/â•‰WED have up 5.2 years) [11]. Another prospective Japanese study reported
been reported: (1) early-â•‰onset primary or idiopathic RLS/â•‰WED, the that RLS/â•‰WED may not be persistent in more than 50% of the
most frequent form, with a peak onset around 20–â•‰40 years of age, affected population: the frequency of RLS/â•‰WED symptoms, but not
frequent familial history, slow disease progression, and low cere- the severity, may predict the persistence of the disorder [12].
brospinal fluid (CSF) ferritin level [2,3]; (2) Late-â•‰onset RLS/â•‰WED
with a peak onset after 40 years of age, less frequent RLS/â•‰WED
familial history, rapid disease progression, and frequent association Diagnostic criteria and clinical aspects
with other diseases, including renal failure, anemia, neuropathy, In 1995, the international RLS/â•‰WED Study Group (IRLSSG) estab-
myelopathy, multiple sclerosis, and diabetes [2–â•‰4]. lished four essential criteria for the diagnosis of RLS/â•‰WED that
RLS/â•‰WED prevalence in the general population has been esti- have provided reliable diagnostic standards for clinical practice. In
mated to be approximately 5% [5]â•„, but studies conducted in Asian 2012, the IRLSSG revised the criteria by introducing a fifth crite-
countries thus far indicate a lower prevalence. In most studies, rion in order to improve the issues of differential diagnosis, stating
prevalence increases with age up to 60–â•‰70 years, except in Asian that the symptoms are not due to another medical or behavioral
populations where an age-â•‰related increase has not been found [6]. condition.
In adults over age 40, RLS/â•‰WED occurs about twice as often in No biological assay is available to make a diagnosis of RLS/â•‰WED.
women than men, but there is no gender preference in children [7] Clinical diagnosis is based on clinician interaction with the patient.
or young adults [6]. In an epidemiological survey conducted in the Concerning the first criterion, several patients will not be able to sep-
USA and five European countries [6], RLS/â•‰WED symptoms of any arate symptomatically or temporally the two components: an urge
frequency were reported by 7.2% of the general population, while to move the legs and dysesthesias. RLS/â•‰WED may also involve the
symptoms occurring at least twice a week and described as mod- arms, as well as other body parts in the severe forms of the disease
erately or severely distressing were reported by 2.7%. The authors [13]. Arm involvement is reported in up to 50% of cases [14], but
defined these latter subjects as those who probably require treat- usually the legs are affected earlier and more severely than the arms.
ment for their RLS/â•‰WED. RLS/â•‰WED typically involves symptoms in both legs, but not
Some studies have evaluated ethnic differences in prevalence. always at the same time or symmetrically [14].
A population-â•‰based study conducted among 1,754 Hispanics of Concerning the criterion that the urge to move the legs and the
Mexican descent (HMD) and 1,913 non-â•‰Hispanic whites (NHW) accompanying unpleasant sensations are partially or totally relieved
18 years of age or older [8]â•„showed that the prevalence was sig- by movement, it must be noted that patients with very severe RLS/â•‰
nificantly lower in HMD than in NHW, and significantly greater in WED may report minimal or no relief of symptoms even after a
high-â•‰acculturation HMD. prolonged period of activity such as walking or bending.

RLS/WED symptoms in the afternoon are not uncommon, No consensus has been reached in defining “clinical significance”
particularly in the case of long periods of inactivity [15]; how- in terms of the specific frequency and duration of RLS/WED.
ever the symptoms are most pronounced during the evening and However, using classical health-related quality of life (HRQoL)
night. The circadian variation in symptoms occurs independently measures, physical and mental health scores have been reported to
of activity, sleep deprivation, or sleep–wake state [16–18]. Those be lower in severe cases, and impairments are strongly associated
patients affected by very severe RLS/WED may have symptoms with RLS/WED severity [22,23]. This finding has been confirmed
persisting throughout the day and night without any clear circa- in a population-based study [24] that also showed that the impair-
dian variation. ment in activities of daily function was mediated by poor sleep
Myalgia, venous stasis, leg edema, arthritis, leg cramps, positional quality and depressive symptoms.
discomfort, and habitual foot tapping are the mimicking conditions The 2012 IRLSSG Consensus Diagnostic Criteria also reported
that must be excluded in the diagnosis of RLS/WED. It has been some patterns that can support a diagnosis, particularly when there
reported that adding differential diagnosis to the diagnostic criteria is some lack of diagnostic certainty.
in diagnostic questionnaires or scales produces a greatly improved RLS/WED has one identified sign, namely, periodic leg move-
agreement with clinical expert diagnosis exceeding 90% [19,20]. ments (PLM). PLM can occur in sleep (PLMS) or wakefulness
Patients with RLS/WED can, however, have one of these other (PLMW). A PLMS index (number of PLMS per hour of sleep)
conditions in addition to RLS/WED: the comorbidity of RLS/WED above five per hour is considered pathological: this index may be
and peripheral neuropathy is a typical example [21]. observed in almost 80% of RLS/WED patients.
In the 2012 IRLSSG Consensus Diagnostic Criteria, specifiers for It is well known that PLMS is a sensitive but not specific motor
clinical course and clinical significance have been added in order to sign of RLS/WED. However, it has been reported that the PLMS
more completely characterize RLS/WED. index shows high night-to-night variability, requiring multiple
Clinical course is generally considered an important aspect nights for its reliable estimation. This is not the case for the degree
among these patients. Some patients have sporadic episodes of of periodicity of leg movements, quantified by the periodicity index
symptoms, while others have them regularly. The latter, seen most [25]. Moreover, some other studies have documented a bimodal
frequently in clinical practice, are more likely to seek treatment. distribution of the inter-movement intervals for PLM that divide
The REST general population survey found that of all those report- into short (<10 seconds) and long (10–90 seconds) inter-movement
ing RLS/WED symptoms during the previous year, 57.5% had intervals [26], with the second interval range being representative
symptoms occurring twice a week or more; the majority (66%) also of the typical periodic activity. The PLMW of RLS/WED patients
reported the symptoms as moderate to severely disturbing [6]‌. As during the sleep period have mostly short inter-movement intervals
already mentioned, it is this latter group of RLS/WED sufferers who (<10 seconds), while the PLMS have mostly long inter-movement
are often considered to be in need of treatment. intervals (10–90 seconds) [27].
The 2012 IRLSSG Revised Criteria include the following speci- Concerning the distribution of PLMS, patients with RLS/WED
fiers for clinical course of RLS/WED: show a prevalence of movements in the first two hours of sleep and
A. Chronic-persistent RLS/WED: symptoms when not treated a progressive decrease throughout the night, in contrast to other
would occur on average at least twice weekly for the past year. disorders with PLMS, such as narcolepsy and REM sleep behavior
disorder (RBD) (Fig. 24.1).
B. Intermittent RLS/WED: symptoms when not treated would PLMS occur with significant transient changes in EEG, heart
occur on average less than twice weekly for the past year, with rate, and blood pressure [28], which have been suggested to reflect
at least five lifetime events. an increased risk of cardiovascular disease observed with RLS/
Concerning the “clinical significance” of RLS/WED, it is known WED in some but not all studies [28].
that the symptoms of RLS/WED may cause significant distress or RLS/WED has been observed to occur commonly in families,
impairment in social, occupational, and educational contexts owing indicating significant genetic or shared environmental factors for
to their impact on sleep, energy/vitality, daily activities, behavior, the syndrome. Some authors found that 20% of consecutive RLS/
cognition, or mood. WED patients in two clinical settings reported RLS/WED among
Stage
Wake
REM
1
2
3
PLM
Fig. 24.1 Hypnogram of a patient with RLS/WED.

Chapter 24 restless legs syndrome 239
their first-degree relatives [29]. Moreover, twin studies have shown Furthermore, in the “diagnostic marker” section, polysom-
high concordance for RLS/WED [30,31]. Thus, the presence of RLS/ nographic findings like an increased latency to sleep and higher
WED among first-degree relatives is supportive of the diagnosis. arousal index have been introduced. Thus, there has been an unfor-
Sleep disturbance is a common and distressing aspect of RLS/ tunate confusion in the RLS/WED diagnostic criteria created by
WED [6,32]. Epidemiological data indicate that about 75% of RLS/ three different professional physician organizations.
WED patients are likely to seek treatment for sleep disturbance
characterized by a long sleep latency or nocturnal awakenings.
Most patients report difficulty falling asleep, but some patients fall Physiopathology
asleep rapidly and wake up shortly after with unpleasant leg sensa- The physiopathology of RLS/WED is not fully established. Genetics,
tions that force them to get up and walk around. Individuals with central nervous system dopamine dysregulation, and brain iron
moderate to severe RLS/WED have chronic sleep loss with total deficiency seem to be the primary involved factors, but some data
sleep times of 4.5–6 hours a night [6,32,33], and the sleep distur- support the hypothesis that peripheral phenomena also contribute
bance correlates with RLS/WED severity [34,35]. However, indi- to the pathophysiology of RLS/WED. One study has demonstrated
viduals with moderate to severe RLS/WED usually do not report peripheral hypoxia in the legs of patients with RLS/WED [40].
a level of daytime sleepiness that would be expected for the degree According to the authors, peripheral hypoxia could be a primary
of sleep loss [36,37]. They can suffer other consequences of sleep trigger of RLS, irritating peripheral afferent nerves, or it could be a
deprivation such as fatigue, reduced concentration, and depression, secondary phenomenon resulting from deficiencies in iron metab-
but do not usually nap. In RLS/WED cases where there is excessive olism, often associated with RLS/WED.
sleepiness, a possible comorbid sleep apnea should be suspected. There is clear evidence for a genetic contribution to RLS/WED,
The recently released International Classification of Sleep considering that more than 50% of idiopathic cases report a posi-
Disorders, Third Edition (ICSD-3) [38] diagnostic criteria for tive family history [41]. Moreover, in most pedigrees, RLS/WED
RLS/WED include five essential criteria of the IRLSSG, in addi- segregates in an autosomal dominant fashion, with over 90% pen-
tion to a clinical significance criterion that is similarly worded to etrance rate [42].
the IRLSSG diagnostic specifier for clinical significance. For the However, several linkage studies of familial RLS/WED have
ICSD-3 diagnosis of RLS/WED, this clinical significance criterion identified mostly marginal associations over a wide range of chro-
“must be met.” mosomes. It must be stressed that no specific gene associated
ICSD-3 also include a part dedicated to the “associated fea- with RLS/WED has been identified in these studies. In contrast,
tures.” It has been underlined that sleep onset and maintenance genome-wide association studies (GWAS) have identified common
complaints in RLS/WED are notably higher than in controls, with susceptibility alleles of modest (OR 1.2–1.7) risk at six genomic loci
odds ratios (OR) between 1.7 and 3.5. Daytime fatigue and daytime on chromosomes 2p, 6p, 15q, and 16q [43–45].
sleepiness are also common complaints; however, the sleepiness is The increased risk of RLS/WED occurs at loci for genomic regions
not as severe as expected for the degree of sleep disruption, imply- of MEIS1, BTBD9, PTPRD, MAP2K/SKOR1, and TOX3/BC034767
ing hyperarousal in RLS/WED. Moreover, some patients with RLS/ and at an intergenic region on chromosome 2 (rs6747972). It is
WED may choose to work at night, thereby shifting quiet activities known that a MEIS1 risk variant influences iron metabolism [46]
and their sleep schedule away from the circadian peak of their RLS/ and that BTBD9 regulates brain dopamine levels and controls iron
WED symptoms. homeostasis through the iron regulatory protein-2 [47]. These find-
ICSD-3 considers that PLM, a family history of RLS/WED, and ings clearly suggest that dopaminergic neurotransmission and iron
response to dopaminergic therapy are supportive of the diagnosis. dysregulation can contribute to the pathogenesis of RLS.
In the Diagnostic and Statistical Manual of Mental Disorders, The strong positive effects of L-DOPA and dopamine agonists on
Fifth edition (DSM-5) [39], RLS/WED is elevated to a separate RLS/WED and PLMS clearly support the role of the dopaminer-
diagnostic entity, in contrast to the previous edition, based on the gic system in the physiopathology of these conditions. Moreover,
public health relevance of the condition, scientific progress made dopamine antagonists generally exacerbate RLS/WED symptoms.
by RLS/WED researchers, and the need to provide a definition of The few post-mortem studies that have been performed have
a clinically significant condition that is frequently encountered in shown no histopathological abnormalities in RLS/WED brains,
daily psychiatric practice. including the major dopaminergic areas [48,49].
In comparison with other diagnostic criteria, DSM-5 requires In general, standard MRI studies have shown no morphological
frequency (at least three times per week) and duration (at least abnormalities in RLS/WED. An MRI study with a voxel-based mor-
three months) of symptoms. While the imposition of arbitrary cut- phometric analysis showed significant regional decreases in gray
offs to restrict RLS/WED diagnosis to a more frequently occurring matter volume in the left hippocampal gyrus, both parietal lobes,
and longer-duration condition might lead to improved diagnostic medial frontal areas, and cerebellum of RLS/WED patients [50].
specificity and reliability in primary care or psychiatric practice, Also, white matter may be decreased in multiple subcortical areas
this would also minimize the potential clinical significance of the in close proximity to the primary and associated motor and soma-
intermittent subtype or recent-onset RLS/WED. tosensitive areas of RLS/WED patients [51]. Notably, the reported
Moreover, in comparison with the 2012 IRLSSG Revised Criteria, abnormal loss of myelination is consistent with that found in iron-
which define a full spectrum of RLS/WED, the DSM-5 criteria deprived animals [52].
define a narrower clinical spectrum of RLS/WED by requiring the Concerning brain functional studies on the dopaminergic sys-
RLS/WED symptoms to be “accompanied by significant distress or tem, SPECT and PET studies showed inconsistent alterations in
impairment in social, occupational, education, academic, behavio- basal ganglia postsynaptic and presynaptic D2/3 receptor binding,
ral, or other important areas of functioning.” with reports of increases, decreases, and no change [53].

However, some recent intriguing findings in RLS/WED patients decreased iron concentration in RLS/WED brains remains unclear.
suggest an overly activated dopaminergic system. PET studies in However, some authors hypothesized that the source of the brain
the striatum of patients with RLS/WED have reported a decrease in iron deficit is at the blood–brain interface [65]. They analyzed the
dopamine transport, which might be expected to increase synaptic expression of iron management proteins in the epithelial cells of
dopamine concentrations [54]. A more recent PET study showed the choroid plexus and the brain microvasculature in post-mortem
that patients with RLS/WED had lower dopamine-2 receptor bind- tissues of individuals with RLS/WED. The presence of an iron reg-
ing potentials in the putamen and caudate, but not the ventral stria- ulatory protein was demonstrated in the brain microvasculature,
tum [55]. A neuropathological study showed in RLS/WED brain and the activity of this protein was decreased in RLS/WED with the
tissue a significant decrease in D2 receptors in the putamen that consequence of insufficient iron storage in endothelial cells.
correlated with RLS severity, without any changes in D1 receptor The role of iron in dopaminergic transmission in the CNS is
or dopamine transport. Brain RLS/WED tissues showed significant noteworthy. A possible link between the iron and dopamine might
increases in tyrosine hydroxylase in the substantia nigra, but not in be represented by the additional function of iron as a cofactor of
the putamen [56]. The decreases in dopamine transport and the D2 tyrosine hydroxylase, which is the rate-limiting enzyme for dopa-
receptors are consistent with increased striatal dopamine. mine synthesis. An iron-deficient diet can induce RLS/WED-like
Moreover, CSF studies on dopamine metabolites are inconsist- sensory and motor symptoms in rodents [66]. Furthermore, iron
ent in RLS/WED, but one study showed a significant increase in deficiency is associated with increased extracellular dopamine,
3-o-methyldopa and homovanillic acid, which suggests a possible decreased DAT, and decreased D2 and D1 receptors in the striatum
increase in dopaminergic activity in severe RLS/WED patients [57]. of rats similar to the findings in RLS/WED.
It has been hypothesized that the increased presynaptic dopa-
mine state occurs with a balanced decreased postsynaptic response
[58]. This balance may not suffice at certain times in the daily vari-
Treatment
ation of dopamine. In the evening, dopaminergic activity drops In the management of RLS/WED, it is important to inform the
below a critical threshold, which triggers the RLS/WED symp- patient of the need to maintain good sleep hygiene to prevent the
toms. Administering L-DOPA or a dopamine agonist in the even- development of the insomnia that is frequently observed. Indeed,
ing would be expected to restore the pre-and postsynaptic balance, some patients go to bed later at night and remain active during
thereby reducing symptoms. hours when their symptoms make sleep difficult, and some severe
Of note, increased extracellular dopamine and decreased dopa- RLS/WED patients may even change their working schedule for that
mine transporter (DAT) and D1 and D2 receptors in the striatum purpose. Moreover, dysfunctional thinking about sleep is a central
have also been found in both animal and cell models of iron insuf- aspect in the perpetuation of primary insomnia and a target symp-
ficiency [53, 59]. tom of cognitive behavioral therapy (CBT) for insomnia. A proof-
Neuropathological, biological, and neuroimaging studies support of-concept study on CBT tailored to RLS/WED (eight group 90
the role of iron in the physiopathology of RLS/WED. Conditions minute sessions on a weekly basis) showed favorable results in both
associated with secondary RLS/WED, such as end-stage renal medicated and unmedicated RLS/WED patients [67].
disease and pregnancy, are characterized by inadequate iron. Patients should avoid alcohol, caffeine, and heavy meals in
Moreover, iron supplements have been used in several studies to the evening, since these may aggravate RLS/WED symptoms.
successfully improve symptoms of both idiopathic and secondary Improvement in RLS/ WED symptoms has been anecdotally
RLS/WED. reported when the mind has been kept alert by performing tasks
A neuropathological study showed a marked decrease in iron requiring a large amount of concentration.
and H-ferritin (the heavy-chain subunit of ferritin) staining in the There have been few studies on nonpharmacological treatments
substantia nigra, a mild decrease in transferrin receptor staining for RLS/WED. A 12-week randomized controlled trial evaluated the
on neuromelanin-containing cells, and morphological differences effectiveness of an exercise program: participants were randomized
in the cells staining for L-ferritin (the light-chain subunit of fer- to either exercise (a conditioning program of aerobic and lower-
ritin) in idiopathic RLS/WED brains compared with control brains body resistance training three days per week) or control groups. At
[48]. Another study demonstrated a decreased concentrations of the end of the 12 weeks, a significant improvement in RLS/WED
iron transport proteins (DMT1 and ferroportin) in the substantia symptoms was observed in the exercise group compared with con-
nigra of RLS/WED patients [60]. trols [68]. In another study, a six-month exercise training regime
MRI and ultrasound studies of regional brain iron content in RLS/ was as effective as six-month low-dosage dopamine agonist treat-
WED patients compared with controls have consistently shown ment in reducing RLS/WED symptoms in uremic patients [69].
reduced brain iron, particularly in the substantia nigra [61,62]. It has been also reported that pneumatic compression devices
A study performed using voxel-based MRI relaxometry showed [70], acupuncture [71], and near-infrared light treatment [72] may
that the reduction in brain iron in RLS/WED patients seems to reduce symptoms of RLS/WED, but further well-designed, large-
extend beyond the substantia nigra to other brain regions, includ- scale clinical trials are needed.
ing the cerebellum and subcortical white matter [63]. Another MRI According to the pathophysiological concept of spinal cord
study with more sensitive methods for measuring iron (a phase- hyperexcitability in idiopathic RLS/WED, a pilot study evalu-
imaging technique) found that the brain iron deficiency in RLS/ ated the effect of transcutaneous spinal direct current stimulation
WED includes other areas beside the substantia nigra and the stria- in patients compared with controls [73]: one session of cathodal,
tum, in particular the thalamus [64]. anodal, and sham stimulation of the thoracic spinal cord for
This raises the question whether RLS/WED is related to a regional 15 minutes during their symptomatic phase in the evening pro-
or a global brain iron deficiency. The mechanisms underlying the duced a reduction in RLS/WED symptoms.

On the other hand, five sessions of transcranial direct current RLS/WED and PLMS [86]. Trials of dopamine agonists have tried
stimulation with electrodes on the sensorimotor areas showed no to determine the lowest effective dose, and currently one-sixth to
significant effect in subjects with drug-naive RLS/WED [74]. one-eighth of the maximum dose used to treat Parkinson disease is
It should be noted that some common classes of drugs can exac- recommended for treatment of RLS/WED [87].
erbate RLS/WED. Dopaminergic antagonistic antiemetics or antip- Another class of drugs that has demonstrated efficacy for
sychotics may worsen RLS/WED [75–77], as may antidepressants RLS/WED and PLMS are the α2δ ligands, including gabapentin,
[75,78]. gabapentin enacarbil, and pregabalin [88] (Table 24.1). A dou-
Pharmacological treatment of RLS has undergone considerable ble-blind study has shown a greater reduction in RLS/WED
changes over the last few years. Several classes of medication have symptoms with 300 mg/day pregabalin than with pramipexole at
demonstrated efficacy, including dopaminergic agents, the α2δ a dose of either 0.25 or 0.5 mg, over periods of 12 and 52 weeks.
ligands, and opioids. According to published practice recommen- Augmentation rates were significantly lower with pregabalin
dations [79,80] pharmacological therapy should be limited to those than with 0.5 mg of pramipexole [89]. Another randomized,
patients who suffer from clinically relevant RLS/WED symptoms, double-blinded, crossover trial [90] demonstrated improvements
including intermittent RLS/WED with impaired sleep quality or in objective and subjective measures of sleep maintenance and
quality of life. sleep architecture with pregabalin (300 mg/day) compared with
Levodopa was the drug most frequently studied in earlier small placebo and pramipexole (0.5 mg/day). In particular, the effects
RLS/WED trials. The immediate response to levodopa without a of pregabalin on PLM-arousal index were comparable to those of
long titration period is really appreciated by the patient, and a posi- pramipexole.
tive response to this drug with the first dosage strongly supports the The therapeutic effects of opioids in RLS/WED have been exam-
diagnosis of RLS/WED [81]. However, a possible side effect of levo- ined in several open-label and controlled clinical trials [79]. A 12-
dopa is morning rebound, as well as augmentation. Augmentation week placebo-controlled study evaluated a fixed-dose-combination
[82] refers to the worsening of RLS/WED symptom severity from drug, oxycodone–naloxone, administered twice a day in RLS/WED
pretreatment levels following an initial therapeutic benefit for most patients who had failed previous treatments owing to lack of ben-
days of the week, associated with an earlier onset of symptoms by efit or side effects [91]. Two hundred and seventy-six patients were
at least two to four hours. A shorter latency to symptom onset with randomized to either placebo or oxycodone 5 mg–naloxone 2.5 mg
immobility, and involvement of previously unaffected limbs, can twice a day and titrated up to either benefit or a maximum dose of
also be observed. Prevalence rates of augmentation in open-label oxycodone 40 mg–naloxone 20 mg twice a day. All patients then
trials range from 18.6% to 72% [83–85]. entered a 40-week open-label extension. Oxycodone–naloxone was
In recent years, three non-ergoline derivative agonists, prami- superior to placebo, and, in the extension period, provided contin-
pexole, ropinirole, and transdermal rotigotine patches, have been ued benefit for a median of 281 days at a mean dose of oxycodone
extensively studied for RLS/WED treatment (Table 24.1). Overall, 18.1 mg and naloxone 9.1 mg. Side effects from active treatment
the dopamine agonists have been found to be effective in short- included fatigue, constipation, nausea, somnolence, and headache.
and longer-duration placebo-controlled studies for the treatment of Augmentation was not observed [91].
Table 24.1 Drugs most frequently used in RLS/WED
Drug Time to maximum Elimination half-life (h) Initial daily dose (mg) Usual dose range
blood level (h)
Dopaminergic agonists
Pramipexole 2 8–12 (increase with decreasing 0.125 0.125–1.000 mg daily approximately
glomerular filtration rate and age) 1–3 h before bedtime
Ropinirole 1–1.5 6 0.25(–0.5) 0.50–4.00 mg daily approximately
1–3 h before bedtime
Rotigotine Stable plasma levels Stable plasma levels over 24 h 1 1–3 mg daily
(transdermal patch) over 24 h (elimination half-life biphasic: 3
and 6)
α2δ ligands
Gabapentin 2 5–7 300 300–1200 mg daily; may be in split dosing
with an afternoon and bedtime dose
Gabapentin enacarbil 7–9 Relatively stable plasma levels over 600 600–1800 mg daily about 1 h before
18–24 h (elimination half-life: 6) bedtime
Pregabalin 1.5 6 25 Up to 300 mg
Opioids
Oxycodone–naloxone — 5 5 mg oxycodone–2.5 mg 10 mg oxycodone–5 mg naloxone to 20 mg
prolonged-release naloxone twice daily oxycodone–10 mg naloxone twice daily

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CHAPTER 25
An overview of sleep dysfunction

in Parkinson disease
Elisaveta Sokolov and K. Ray Chaudhuri
Introduction In two recent studies, untreated and early PD patients were com-
pared with healthy controls with respect to NMS, including sleep.
Disturbances in nocturnal sleep and their consequences dur- Mollenhauer et al. [10] studied 159 untreated PD cases with 110
ing waking in Parkinson disease (PD) were recognized by James age-â•‰matched controls and reported a significantly worse PDSS
Parkinson himself in 1817. Parkinson described sleep problems in score: 15.3 (mean 8.55, range 0–â•‰41.00) for PD versus 10.2 (6.34,
his case series as follows: “His attendants observed, that of late the 0–â•‰44.50) for healthy controls; p < 0.001. In another study, Khoo et
trembling would sometimes begin in his sleep, and increase until al. [5] studied 159 patients with early PD and 99 healthy controls
it awakened him: when he always was in a state of agitation and and reported a significantly greater number of NMS compared with
alarm” [1]â•„. Sleep disturbance in PD is complex, with a prevalence of controls: 8.4 versus 2.8. In particular daytime somnolence, dream
up to 98%, and has been shown to be a key determinant of quality re-â•‰enactment, vivid dreams, restless legs and night-â•‰time pain were
of life (QoL) These sleep disturbances are heterogeneous, ranging significantly worse in PD compared to controls. These studies con-
from insomnia to drug-â•‰induced sleep disorders, and now can be firm observations from an older study by Dhawan et al. [11], who
assessed by simple validated bedside tools such as the Parkinson’s used PDSS and polysomnography (PSG) in untreated, advanced
Disease Sleep Scale (PDSS) [2,3]. Also, sleep, contrary to previous PD, and healthy controls (Table 25.2).
perceptions, can be disordered not just in advanced PD, but also in
the pre-â•‰motor as well as the untreated states [4,5].
Sleep as a determinant of QoL and NMS
It has been shown that NMS, including sleep disturbance, are more
Epidemiology intrusive for PD patients than their motor symptoms. In an obser-
Nocturnal sleep disturbances of varying severity affect virtually all vational study, Hely and colleagues [12] evaluated PD patients
people with PD [6]â•„. Assessment of the epidemiology of sleep dis- followed for a period of 15–â•‰18 years after being recruited to a bro-
order in PD and prevalence figures are variable, based on whether mocriptine versus levodopa trial: 33% of the original cohort were
the concept includes sleep dysfunction as a whole (holistic) or assessed at 15 years. The majority had significant NMS, includ-
addresses individual aspects of sleep dysfunction in PD such as ing sleep disorders that they regarded as more bothersome than
insomnias, parasomnias (mostly REM sleep behavior disorder, their motor symptoms or levodopa-â•‰induced dyskinesias. A study
RBD), excessive daytime sleepiness (EDS), sleep apnea, or drug-â•‰ by Politis et al. [13] surveyed early and late PD patients, who were
induced sleep disorders (Tables 25.1 and 25.2). asked to rate their most bothersome symptoms. In both groups,
sleep dysfunction was self-â•‰rated as one of the most bothersome
Controlled studies symptoms by patients. A recent study by Kurtis et al. [14] investi-
The validation study of the non-â•‰motor symptoms (NMS) question- gated 388 PD patients in a cross-â•‰sectional, multicenter study and
naire (NMSQuest) compared 123 PD patients with 96 age-â•‰matched reported that fatigue, depression, and urinary, cardiovascular, and
controls and reported that sleep-â•‰related complaints such as insom- thermoregulatory dysfunctions were significant contributors to the
nia (41%), intense/â•‰vivid dreams (31%), acting out during dreams SCOPA sleep scale nighttime (SCOPA-â•‰NS) score (variance 23%),
(33%), restless legs (37%), and daytime sleepiness (28%) are sig- while cognitive impairment, urinary, cardiovascular, and pupillo-
nificantly more prevalent in PD [7]â•„. In another community-â•‰based motor disorders influenced the SCOPA-â•‰daytime score less (vari-
study, Tandberg et al. [8] reported that 60% of patients with PD ance 14%) . However, fragmentation of sleep occurred much more
(144 of 239) had a range of sleep problems, compared with 33% of frequently in PD patients and the impact on their QoL was con-
healthy controls (33 of 100) with similar age and sex distribution. A sidered greater. In addition, a community-â•‰based study involving
multicenter assessment of NMS and their impact on quality of life 239 PD patients reported that 60% experienced sleep disturbance,
in PD was carried out, demonstrating that in over 1000 PD patients compared with 33% of healthy controls with the same demograph-
studied, sleep disturbances (64%) were the second most reported ics [15]. The NMSQuest study in 2006 [7]â•„has enabled delineation
symptom after psychiatric symptoms (67%). The prevalence of sleep of NMS in PD. By using the validated NMSQuest, it was found
disturbance in untreated subjects was approximately 40%, which that symptoms such as nocturia (67%) are common in controls,
increased to approximately 82% in more advanced disease [9]. whereas other sleep-â•‰related complaints, such as insomnia (41%),

Table 25.1 Epidemiological studies of sleep studies with healthy controls
Authors [reference] Year Study type Methodology Numbers Overall results

Dhawan et al. [11] 2006 Comparative study PDSS and PSG DNPD: 25 DNPD: 105.72 ± 21.5
APD: 34 APD: 86.95 ± 20.78
HC: 131 Nocturia, nighttime cramps, dystonia,
tremor, and daytime somnolence related
to nocturnal disabilities in DNPD
Chaudhuri et al. [7]‌ 2006 NMSQuest Questionnaire PD: 123 Nocturia (67%) was common in controls.
HC: 96 Insomnia (41%), vivid dreams (31%),
acting out during dreams (33%), restless
legs (37%), and daytime sleepiness (28%)
were more prevalent in PD
Tandberg et al. [15] 1999 Community Clinical PD: 239 15.5% of patients experienced EDS
HC: 100 compared with only 1% of controls
Van Hilten et al. [72] 1994 Holistic Clinical Compared with controls, patients with
PD had a raised nocturnal activity level
and raised duration of movement,
indicative of a more disturbed sleep.
Fragmentation of sleep was more
frequent in PD patients, and impact
on QoL was considered greater than in
controls
QoL: quality of life; PSG: polysomnography; EDS: excessive daytime sleepiness; DNPD: drug-naive PD; APD: advanced PD; HC: healthy controls.
Table 25.2 Published sleep studies reporting varying outcomes
Authors [reference] Year Type of sleep Type of study Outcomes

dysfunction
Wetter et al. [73] 2000 PLM Clinical and PSG Sleep disruption and increased motor activity during REM and NREM sleep
were a frequent finding in PD. 50% showed REM sleep features
Chaudhuri et al. [3]‌ 2002 Holistic PDSS validation The mean difference between controls and patients with early/
moderate PD was 18%. Mean difference between controls and patients
with advanced PD was 35%. PDSS discriminated well between sleep
problems of patients with advanced PD and those of patients with
early PD
Fabbrini et al [85]. 2002 EDS Clinical and PSG EDS was significantly higher in treated PD than untreated PD or controls
Stiasny-Kolster et al. [43] 2005 RBD and olfactory Clinical and Imaging 97% of the RBD patients had a pathologically increased olfactory threshold.
dysfunction RBD patients had profound impairments of olfactory function
Hely et al. [12] 2005 Holistic Questionnaire The majority had significant NMS, including sleep disorders that they
regarded as more bothersome than their motor symptoms or levodopa-
induced dyskinesias
Gjerstaad et al. [23] 2006 EDS Questionnaire 8-year prevalence of 54.2%. EDS was a persistent feature in the majority
of patients. EDS was related to age, gender, and use of dopamine
agonists
Barone et al. [9]‌ 2009 Holistic Questionnaire Sleep disturbances were present in 64% of cohort. Sleep disturbance in
untreated subjects was 40%, Sleep disturbance in advanced disease was 82%
Dusek et al. [66] 2010 Daytime REM Clinical RPR demonstrated an improvement in sleep scale scores compared with
RIR. 43% reported disappearance of sleep attacks on RPR
Bliwise et al. [30] 2013 Daytime REM MWT Sizeable proportion of PD patients demonstrated REM sleep and daytime
sleep tendency during daytime nap testing. These data confirmed
similarities in REM intrusions between PD and narcolepsy
PSG: polysomnography; PDSS: Parkinson’s Disease Sleep Scale; EDS: excessive daytime sleepiness; REM: rapid eye movement; RPR: ropinirole prolonged-release; RIR: ropinirole immediate-
release; MWT: maintenance of wakefulness testing.

Chapter 25 an overview of sleep dysfunction in parkinson disease 247
intense/vivid dreams (31%), acting out during dreams (33%), rest- Table 25.3 Classification of sleep problems in PD
less legs (37%), and daytime sleepiness (28%), are more prevalent
in PD. This was observed in 123 PD patients and 96 age-matched Category Subtype
controls in an international multicenter setting (Table 25.1). The
Insomnia Sleep onset
overall prevalence figures vary because of the non-homogenous
Sleep maintenance
methodology of ascertainment and range from 25% to 98%.
Mixed
Classification of sleep problems Parasomnias Mainly during non-REM sleep (NREM parasomnias)
Commonly observed:
and their impact in PD
Confusional arousals
Sleep disturbances in PD can be categorized as follows: insomnia, Sleep terrors
parasomnias, EDS, motor symptom-related sleep disturbances, and
Nightmares
sleep disordered breathing (Table 25.3). There are some unifying
Sleep-talking
features in terms of sleep architecture in PD patients, including
reduced total sleep time, multiple sleep arousals, sleep efficiency, Rare:
and fragmentation of sleep [16–18]. We suggest a sleep classifica- Catathrenia
tion as described in the following subsections. During REM sleep (REM parasomnias)
RBD
Excessive daytime sleepiness REM loss of atonia
This can be defined as the desire and the necessity to sleep dur-
EDS Generalized somnolence
ing the daytime to such a degree that it interferes with normal
function. EDS may be experienced by patients as feeling sleepy or Episodes of sudden onset of sleep
feeling fatigued; however, it is different from fatigue. This phenom- Secondary narcolepsy without cataplexy
enon may be so severe that activities such as driving have to be Postprandial hypotension
discontinued [19]. The somnolence can be generalized, or present RLS type symptoms Typical RLS
as sudden onset of sleep or as secondary narcolepsy without cata- Akathisia
plexy, the last of these in particular being precipitated by dopamine RLS-L (recently reported)
agonists such as pramipexole and ropinirole, possibly through a
PLM
D3 receptor-mediated action [20]. Tests such as the Multiple Sleep
Latency test can be carried out in order to delineate and subtype Sleep disordered OSA
EDS in PD [21]. breathing
Drug-induced EDS
Generalized somnolence
SooS
EDS is an important aspect of sleep-related morbidity in PD and
may be caused by underlying dopaminergic denervation or may be Insomnia
due to poor nocturnal sleep. It is prevalent in up to 50% of those Night-eating and impulse control disorder
with a PD diagnosis, it has been related to age and gender, and it Nocturia
is thought to be a progressive problem [21–23]. The pathophysiol-
REM: rapid eye movement; RBD: REM behavior disorder; EDS: excessive daytime sleepiness;
ogy of EDS is unclear. and both disease-related and drug-related RLS: restless legs syndrome; RLS-L: restless legs syndrome-like; PLM: periodic limb
factors play a part. Rye et al. [24] and others have argued the case movements; SooS: sudden onset of sleepiness.
for sleep dysfunction in PD being a manifestation of the dopamine-
denervated state, an argument supported by MPTP studies in mon-
key models. The role of drugs and somnolence in PD is discussed as a complication of dopamine agonist therapies as well as a sub-
later in this chapter. Fatigue could be a confounder of sleep and type of PD being particularly prone to sleep attacks. The events can
EDS in PD. One study by Valko and colleagues [22] demonstrated occur without any pre-warning (similar to narcolepsy), though in
that fatigued patients were almost twice as likely to suffer from EDS some patients sleepiness typically occurs prior to attacks [26,28].
than non-fatigued patients (60% versus 31%). Of these patients, Narcolepsy without cataplexy
50% were taking a combination of levodopa and a dopamine ago- Narcolepsy is a chronic, disabling condition that is recognized by
nist, 38% were just taking levodopa, and 10% were just receiving a tetrad of symptoms comprising EDS, cataplexy, sleep paralysis,
a dopamine agonist. Dopaminergic treatment had a greater effect and hypnagogic hallucinations. Approximately 25% of narcoleptics
on EDS than on fatigue. In addition, EDS was more common and do not have cataplexy. Of these, the majority have normal levels of
severe with prolonged disease course, but the same pattern was not hypocretin in their cerebrospinal fluid (CSF), unlike those present-
observed when it came to fatigue. The pathophysiology may involve ing with narcolepsy with cataplexy (Figs. 25.1 and 25.2).
a denervation of the wakefulness flip–flop switch and may also be Narcolepsy without cataplexy can be caused by a partial loss
exacerbated by dopaminergic therapies [25,26]. of hypocretin cells [29]. Hypocretin-1 and -2 (also called orexin
Sudden onset of sleepiness A and B) are neuropeptides produced from prepro-hypocretin.
In the 1990s, it was reported that some patients with PD may fall Hypocretin-containing cells are found within the lateral hypo-
asleep suddenly while driving when taking dopamine agonists [27]. thalamus, with widespread projections to the whole neuraxis. It
This became known as sudden onset of sleep and is now recognized has been demonstrated that with advancing motor PD, there is a

50 µm
50 µm
Fig. 25.1 (See colour plate section) Example of hypocretin neurons (DAB staining: dark) that contain a Lewy body (alpha-synuclein, AP-body) in PD patients. Several
hypocretin neurons that do not show this colocalization are also present. “F” indicates the fornix.
Reproduced from Brain, 130(6), Hegeman I, van Pelt J, van Duinen S, Jan Lammers G and Swaab DF, Fronczek R, Overeem S, Lee S, Hypocretin (orexin) loss in Parkinson’s disease, pp. 1577–1585,
Copyright (2007), with permission from Oxford University Press.
progressive loss of hypocretin neurons. Many PD patients have inconclusive. Some studies have reported particularly low levels
daytime sleep attacks that present similarly to narcoleptic sleep from ventricular CSF sampling, and others have reported nor-
attacks, and those may be increased with the use of dopamin- mal values. A recent PET imaging study utilizing the serotonin
ergic agonists, but can also arise independently of these drugs receptor-active ligand DASB suggest that there may be seroton-
[26]. A recent study by Bliwise et al. [30] showed that a large ergic dysfunction in the raphe area of the brain underpinning
proportion of PD patients studied demonstrated REM sleep EDS in PD [25] (Table 25.4).
and daytime sleep tendency during daytime nap testing. The
authors concluded that there were similarities in REM intrusions Dopamine agonists, sleep attacks, and somnolence
between narcolepsy and PD, and a parallel neurodegeneration Korner et al. found that in their cohort of 6620 PD patients, 42.9%
of hypocretin deficiency was suggested. The loss of hypocretin had sudden onset of sleepiness (SooS), and 10% of these arose with-
neurons may be a cause of the narcolepsy-type symptoms of PD, out warning. Notably, the risk of SooS was significantly increased
and it has been postulated, but not confirmed, that symptoms with monotherapy using non-ergot derivatives compared with
may be improved by therapies to reverse the hypocretin defi- ergot derivatives or the combination of non-ergot derivatives with
ciency [31]. CSF has been studied in terms of hypocretin level; L-DOPA in patients younger than 70 years. These findings were
however, analysis of hypocretins in these PD patients has been independent of duration of drug intake [31]. Dopamine agonists
(a) (b)
600
60 000
Total number of hcrt-1 IR cell bodies
50 000
hcrt-1 pg/mL in CSF
500
40 000
P = 0.02 P = 0.01
30 000
20 000 400
10 000
Controls Parkinson disease Controls Parkinson disease
Fig. 25.2 Boxplots showing the median, 25th–75th percentiles and range of (a) the number of hypocretin neurons and (b) the hypocretin-1 (hcrt-1) concentration in
post-mortem ventricular cerebrospinal fluid in PD patients and controls. Open circles represent controls and filled triangles represent PD patients.
Reproduced from Brain, 130(6), Hegeman I, van Pelt J, van Duinen S, Jan Lammers G and Swaab DF, Fronczek R, Overeem S, Lee S, Hypocretin (orexin) loss in Parkinson’s disease, pp. 1577–1585,
Copyright (2007), with permission from Oxford University Press.

Table 25.4 Studies reporting orexin/hypocretin measurements in PD
Authors [reference] Year Type of study Outcomes

Thannickal et al. [29] 2009 Post-mortem human brain/ PD characterized by massive hypocretin cell loss, with greater loss with
immunohistochemistry disease progression and severity
Fronczek et al. [74] 2007 Post-mortem/immunoassay Significant decrease between PD patients and controls in the
number of hypocretin neurons (40% lower in prefrontal cortex
and 25% lower in CSF)
Compta et al. [75] 2009 Clinical CSF studies CSF hypocretin-1 levels were unrelated to either Epworth sleepiness
scale. Excessive daytime sleepiness was more frequent in
PD patients with dementia than PD patients without dementia, but
lumbar CSF hypocretin-1 levels were normal and unrelated to severity of
sleepiness or the cognitive status
Weinecke et al. [76] 2012 Clinical Progressive loss of hypocretin cells over the course of PD
Bridoux et al. [77] 2013 Clinical (ventriculography High levels of hypocretin-1 in PD may be associated with loss of REM
during DBS) muscle atonia
CSF: cerebrospinal fluid; REM: rapid eye movement; DBS: deep brain stimulation.
are known to have a variable effect on sleep. They impact sleep at least 50–60% of patients with advanced PD, and an association
architecture, causing EDS or SooS in susceptible patients. Onset between vivid dreams and PD psychosis has been shown in some
insomnia and maintenance insomnia may be an effect. During cases [46–48]. Arnulf et al. [49] found that REM periods during
NREM sleep, night-eating syndromes have been reported, possibly wakefulness were present in patients with PD and psychosis. A pro-
as part of impulse control disorder, as well as hallucinations and spective two-year study showed that patients with RBD and halluci-
night terrors [32]. nations tended to be older, with a greater extent of loss of executive
function than those who did not experience hallucinations [50].
REM sleep behavior disorder
Daytime REM intrusion
This is a parasomnia that involves abnormal behavior during the
The interruption of REM sleep into the daytime is a feature of
sleep phase with rapid eye movements. It was first described in
narcolepsy. The importance of these interruptions is, however,
1986 by Schenk et al. [33]. RBD is characterized by loss of skel-
yet to be determined. Some PD patients demonstrated REM
etal muscle atonia with prominent motor activity and dream-
sleep and daytime sleepiness during daily nap assessments. This
ing [34]. There is a loss of motor inhibition that triggers various
verifies similarities between REM interruptions in narcolepsy and
behaviors during sleep, ranging from limb twitches to more com-
PD. This could implicate a similar hypocretin deficiency in both
plex movements such as kicking, boxing, and other purposeful
conditions [30].
movements. This is often associated with frightening dreams or
nightmares [35] during which the patient will shout out or act
Sleep disordered breathing
out their thoughts [36–39]. The REM Sleep Behavior Disorder
Screening Questionnaire (RBD-SQ), and REM-Sleep-B ehavior Sleep disordered breathing is increasingly recognized in PD.
Disorder Severity Scale (RBD-SS) are available for bedside screen- Obstructive sleep apnea (OSA) is thought to be prevalent in
ing [40,41]. Diagnosis of definite RBD requires PSG and is usually 50% of PD patients [51], resulting in daytime tiredness or sleepi-
made using the criteria established by Schenck and colleagues and ness. Upper airway dysfunction in PD may promote OSA, lead-
the International Classification of Sleep Disorders, Second Edition ing yo symptoms such as daytime fatigue and somnolence, as
(ICSD-2) [42]. well as loud and/or irregular snoring accompanied by intermit-
tent gasping. However, unlike non-PD subjects with OSA, PD
RBD in pre-motor PD patients do not have a large body habitus or a thick neck circum-
RBD is a strong predictor of development of synucleinopathy [43], ference. OSA may coexist with restless legs syndrome (RLS),
and studies suggest that it could be a robust pre-motor marker of RBD, or periodic limb movements (PLM). However, some stud-
PD, with up to 82% of older men diagnosed with RBD going on ies have found the link between OSA and PD to be tenuous
to develop parkinsonism or dementia [44]. The sublaterodorsal [52]. Formal PSG will identify sleep apnea in the majority of
nucleus (SLD) inhibits locomotor generators and spinal interneu- patients [53].
rons throughout REM sleep. It is therefore possible that muscle ato-
nia may be due to degeneration of these nuclei [45]. The pathological Nocturia
basis of RBD is unknown; however, the key structures potentially Nocturia is a common cause of sleep disruption in PD and was
implicated in RBD pathology include the locus coeruleus, lateral shown to affect 43% of patients in one study [54], with an esti-
pontine tegmentum, pedunculopontine nucleus, ventrolateral pre- mated prevalence of 30–80% [10,55–57]. Studies using bedside
optic (VLPO) nucleus, and SLD. Psychosis can be experienced by scales such as the Non-Motor Symptoms Scale (NMSS) and the

Table 25.5 Animal models of PD demonstrating sleep disturbance
Authors [reference] Study title Animal model Symptoms studied

Jenner et al. [78] Animal models of Parkinson’s disease: a source of novel 6-OHDA-lesioned rodents. Sleep/wakefulness, circadian
treatments and clues to the cause of the disease rhythms, RBD
Chesselet et al. [79] Progressive mouse model of parkinson’s disease: Alpha-synuclein over-expressor Circadian rhythm, insomnia
the Thy1-aSyn (Line 61) mice (ASO = Thy1-aSYN) mice
Jenner et al. [78] Animal models of Parkinson’s disease: a source of novel MPTP-treated primates Sleep–wake cycle.
treatments and clues to the cause of the disease REM sleep/RBD
Taylor et al. [69] Non-motor symptoms of Parkinson’s disease revealed in an VMAT2-deficient mice Altered sleep latency
animal model with reduced monoamine storage capacity
6-OHDA: 6-hydroxydopamine; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; VMAT2: vesicular monoamine transporter 2; REM: rapid eye movement; RBD: REM sleep behavior
disorder.
PDSS have consistently identified nocturia as one of the most patterns by reducing slow-wave and REM sleep. Dopaminergic
prevalent symptoms in PD, becoming more intrusive to sleep as medications in low doses increases sleep duration at night and
the disease advances [58]. More than 50% of PD patients have induce somnolence. Several studies, such as the RECOVER study
severe bladder symptoms, commonly symptoms of overactive suggest that sustained overnight dopaminergic stimulation can
bladder [59]. Furthermore, in patients with comparable levels of reduce nocturnal akinesia, RLS, and PLM and thereby improve
nocturia, poorer sleep as defined on PSG is regarded as more both- sleep quality and quantity [62]. Drugs, including amantadine,
ersome [60]. In terms of causation, one theory is that the micturi- selegiline, and anticholinergics aggravate sleep initiation and
tion reflex is normally inhibited by the basal ganglia. Degeneration may induce insomnia, while selective serotonin reuptake inhibi-
then occurs, leading to a loss of this D1-mediated inhibition and tors (SSRIs) may need to be avoided in the evening as they pro-
subsequent detrusor overactivity [56]. Uchiyama et al. [61] found mote wakefulness [64]. Insomnia may also be caused by giving
that the effects of apomorphine on bladder function in rats are inhibitors of monoamine oxidase B (MAO-B) inhibitors such
both time-and dose-dependent. At low doses, it decreased void- as selegiline late at night; in the case of selegiline, this is likely
ing frequency and increased micturition volume (which reflected due to it having an amphetamine metabolite [65]. Evidence sug-
an increase in bladder capacity). At medium and high doses of gests that dopamine agonists such as short-acting ropinirole and
apomorphine, there was an initial increase and then a subsequent pramipexole may potentiate SooS, with levodopa doing so to a
decrease in frequency and an initial decrease and a subsequent lesser extent [66].
increase in volume. The pharmacodynamics of dopamine recep-
tor agonists on nocturia and urgency are clearly more complicated
than anticipated. This fresh perspective may be useful in under-
Pathophysiology
standing the often conflicting data on the effects of dopamine Animal models
receptor agonists on NMS in PD. Rotigotine, for instance, has been Studies in both cats and rats have demonstrated important struc-
shown to be effective for nocturia in open-label studies, while the tures involved in the condition [67]. It has been suggested that
RECOVER study (randomized and placebo-controlled) failed to degeneration of brainstem nuclei such as the locus coeruleus,
confirm this observation [62]. pedunculopontine nucleus, and sublaterodorsal nucleus may be
important in the pathophysiology of RBD. These nuclei have been
Insomnias shown to be closely interconnected, either activating or inhibiting
The ICSD describes insomnia as “difficulty in initiating and/or one another. Muscle atonia and enactment during REM sleep may
maintaining sleep.” Broadly insomnia is of two types: sleep initia- be due to disturbances in the sublaterodorsal nucleus, which has
tion insomnia (SII) and sleep maintenance insomnia (SMI). The inhibitory effects on locomotor generators and spinal interneu-
latter is reported to be one of the five most bothersome symp- rons [68]. Thus, animal studies have shown a close relation-
toms of advanced PD [20]. Patients with PD have problems with ship between dopamine and sleep (Table 25.5). Degeneration of
sleep fragmentation and early awakening compared with controls, central sleep regulatory neurons and related thalamocortical
whereas sleep initiation problems are equally frequent among pathways is implicated in the sleep disturbance evident in PD
patients and healthy elderly people [13]. SMI may be due to fre- [69–70]. This essentially arises as an indirect effect of dopamin-
quent waking at night as a result of nocturnal akinesia and off ergic cell depletion in the brainstem. The ventral tegmental area
periods [63]. and the pars compacta of the substantia nigra both display con-
nections to areas related to sleep regulation. Stimulation of D1-like
Sleep disturbance secondary to anti-parkinsonian receptors is wake-related, whereas stimulation of D2-like receptors
medications is biphasic. Stimulation occurs at low doses, and sleep-inducing
Dopaminergic therapy can affect the sleep–w ake cycle and effects precipitate at higher doses. In addition, D3 agonists pro-
in high dose induces wakefulness and disrupts typical sleep mote sleep [71].

Table 25.6 Validated scales for the assessment of sleep in PD Table 25.7 Treatment of sleep disturbance in PD
Reference Scale Insomnia-related Pharmacological Short-acting benzodiazepines

symptoms: strategies Non-benzodiazepine
[80] Parkinson’s Disease Sleep Scale (PDSS) Versions 1 and 2 fragmented sleep hypnotics: zopiclone
[81] Pittsburgh Sleep Quality Index (PSQI) with problems in
Tricyclic antidepressants:
sleep onset and
[82] Scales for Outcomes in Parkinson’s Disease (SCOPA) amitriptyline
maintenance
Sleep Scale
Nonpharmacological Avoid alcohol at night, caffeine,
[83] Epworth Sleepiness Scale (ESS) measures tobacco
[84] Inappropriate Sleep Composite Score (ISCS) Daytime exercise and exposure
[84] Stanford Sleepiness Scale (SSS) to sunshine
Relaxation and cognitive
therapies
Motor symptoms: Pharmacological Trial of sustained dopaminergic
Diagnostic tools for sleep disorders in PD fidgeting, cramps, strategies stimulation (nighttime
posturing, tremor, dosing of):
Clinical tools
akinesia levodopa + COMT inhibitor;
The systematic use of a sleep questionnaire is recommended long-acting dopamine agonists
in order to accurately recognize these NMS in PD, and the (rotigotine patch therapy has
Movement Disorders Society (MDS) task force has reviewed and level 1 evidence to support
recommended a number of PD validated scales for use in the nighttime use)
clinic and at the bedside. Table 25.6 illustrates scales fulfilling Nocturnal apomorphine
the criteria outlined by the MDS that are recommended for use. infusion (only in specialized
In addition to assessment of the PD patient using one of these centers)
scales, measurement of sleep and wake is indicated in patients Nonpharmacological Use of satin bed sheets and
with potential sleep apnea or parasomnias. For a brief screen in measures bed straps to help movement
the clinic, the patient-completed NMSQuest, which has a sleep in bed
domain, can be used.
RBD Pharmacological Clonazepam
strategies Melatonin
Treatment Pramipexole + clonazepam
The nature of sleep disturbance in PD is multifactorial and, as Donepezil, levodopa (have
such, treatment has to be tailored to individual cases and etiology. been tried)
The evidence base in most cases remains poor and recently both Urinary symptoms: Pharmacological Low-dose amitriptyline
the American Academy of Neurology (AAN) and the MDS have nocturia strategies Consider transdermal
issued guidance on evidence-based management of NMS of PD rotigotine patch.
that includes sleep disorders. Recommended treatments from these If detrusor
guidelines are shown in Table 25.7. instability: oxybutynin,
tolterodine
Conclusions If morning
hypotension: desmopressin
Overall, sleep dysfunction is a key NMS of PD and a major deter-
nasal spray; do not use evening
minant of QoL of patients as well as caregivers. Sleep dysfunction diuretics, antihypertensives, or
in PD is multifactorial and complex and can be present from the vasodilators
pre-motor to the palliative stage. It is essential that sleep dysfunc-
Nonpharmacological Decrease evening fluid intake
tion be correctly identified and treated by healthcare professionals.
strategies Empty bladder prior to bed
Exciting new developments suggest that aspects of sleep problems
could function as possible clinical biomarkers for PD and also Catheters/bedside commode
subtypes of PD. Several validated clinical sleep scales for bed- If associated with postural
side use are available and serve to refine accurate management of hypotension, head-up tilt of
aspects of sleep dysfunction in PD and subsequent improvement in bed
patients’ QoL. Sleep apnea NIV, CPAP, MRS, soft palate
implants
Acknowledgements EDS Modafinil, caffeine tablets
This chapter presents independent research funded by the National RLS/PLM Dopamine agonist, gabapentin
Institute for Health Research (NIHR) Mental Health Biomedical
COMT: catechol O-methyltransferase; RBD: REM sleep behavior disorder; CPAP: continuous
Research Centre and Dementia Unit at South London and Maudsley positive airway pressure; NIV: noninvasive ventilation; MRS: mandibular responding splint;
NHS Foundation Trust and King’s College London. EDS: excessive daytime sleepiness; RLS: restless legs syndrome; PLM: periodic limb movements.

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CHAPTER 26
Sleep disorders in
neurodegenerative diseases
other than Parkinson disease
and multiple system atrophy
Raffaele Manni and Michele Terzaghi
Introduction main systems involved in sleep regulation: the homeostatic system,

which determines sleep, including its duration and structure; the
The twenty-â•‰first century will witness an unprecedented increase in circadian system, which regulates sleep propensity in relation to
the aging of the population [1]â•„. Between 2000 and 2050, the pro- the time of day/â•‰night; and the ultradian system, which regulates
portion of the world’s population aged over 60 years will double, NREM/â•‰REM alternation.
rising from about 11% to about 22%. Since there is a strong link
between aging and the likelihood of developing neurodegenerative Age-â•‰related changes in sleep
diseases, the number of people suffering from these conditions is Age-â•‰related changes in homeostatic as well as circadian processes
expected to rise. Thus, the assessment and management of neuro- may account for the sleep fragmentation, difficulty in falling asleep,
degenerative diseases is set to play an increasingly prominent role and decreased slow-â•‰wave sleep (SWS) typically observed in the
in clinical practice in the coming decades. elderly [12–â•‰14,18]. Objective sleep changes occurring in this popu-
Patients affected by neurodegenerative diseases frequently report lation include a lower density of phasic events (i.e, a decrease in
sleep–â•‰wake disturbances of various kinds [2–â•‰4]. There is grow- K-â•‰complexes and sleep spindles), more frequent stage shifts, lower
ing evidence that sleep alterations are associated with a higher sleep efficiency, and lower percentages of SWS and REM sleep
incidence of cognitive and neuropsychiatric problems, leading to [18,19]. Sleep efficiency, in particular, continues to decrease with
a reduced quality of life [5–â•‰7]. Furthermore, sleep alterations re- increasing age (Table 26.1).
sult in an increased caregiver burden [8,9] and can ultimately be a The modifications in sleep architecture and schedule that are
factor leading to the institutionalization of affected patients [10,11]. induced by alterations in the circadian modulation of sleep occur-
Yet, in spite of these considerations, there are no large-â•‰scale sys- ring with advancing age potentially contribute to a variety of
tematic studies of sleep in neurodegenerative diseases other than age-â•‰related disorders [13,14]. Moreover, the prevalence of sleep
Alzheimer disease (AD) and other dementias. disorders such as sleep-â•‰related breathing disorder (SRBDs), restless
Changes in sleep patterns, in particular greater nocturnal sleep legs syndrome (RLS), and periodic limb movements (PLM) in sleep
fragmentation and the development of a tendency to nap during increases with age [18].
the day, are part of the normal aging process [12–â•‰14]. In this set- In neurodegenerative disorders, however, the prominence of
ting, neurodegeneration, in affected patients, causes further disrup- sleep alterations is much greater than that which can be attributed
tion of sleep patterns [15]. Accumulating evidence indicates that to aging per se [4]â•„. Furthermore, comorbid conditions (cardiovas-
sleep disturbances in neurodegenerative diseases should not be cular, metabolic, osteomuscular, respiratory, gastrointestinal, nyc-
considered merely ancillary symptoms, but rather that their pres- turia, etc.) or the effects of the medications for these comorbidities
ence is directly related to the neurodegenerative process. Although further contribute to the sleep disruption [19–â•‰23].
the mechanisms underlying sleep alterations in neurodegenerative
conditions are still to be fully clarified, it is possible that they can
be attributed both to direct structural alterations to the networks Alzheimer disease
orchestrating sleep generation and to a variety of indirect mecha- Sleep disturbances in AD patients frequently occur in association
nisms acting against them [16]. with behavioral and psychiatric symptoms of dementia [24–â•‰26]; for
The neuronal degeneration leading to the central nervous this reason, they tend to be overlooked, especially in the early stages
system-â•‰related manifestations typically characterizing neurode- of the disease.
generative diseases affects multiple neurotransmitter pathways However, recent studies report sleep disorders among the core
[17]. The resulting dysfunctions are likely to impact on the three non-â•‰cognitive symptoms in mild cognitive impairment (MCI) [27],

Table 26.1 PSG findings in normal aging and neurodegenerative diseases
Sleep macrostructure Aging Alzheimer disease Dementia with Lewy bodies Progressive supranuclear palsy Huntingtondisease
Reduced sleep efficiency x x x x x
Long sleep latency x x
Long REM sleep latency x
Lower percentages of SWS x x x x
Lower percentages of REM sleep x x x x x
Diminished total sleep time x x
Increased arousal index x
Lower density of phasic events x
Increased frequency of stage shifts x
x: present.
and, globally, 45–50% of patients with AD report sleep complaints delirious state; these symptoms peak in the evening and can con-
such as early morning or recurrent nocturnal awakenings and day- tinue into the night.
time sleepiness [28–31]. Sleep disruption in AD patients is report- Actigraphic investigations have revealed disruption of circadian
edly the main reason for their institutionalization [12,32]. rhythms in about half of AD patients [45]. Neuropathological stud-
Polysomnographic (PSG) studies in patients with AD (Table ies have indicated that deterioration of the suprachiasmatic nucleus
26.1) indicate that their sleep is characterized by longer and more (SCN) in the hypothalamus can be documented in AD patients, as
frequent awakenings, decreased SWS and REM sleep, and more can alterations in the 24-hour melatonin secretion profile [46,47].
daytime napping [30,33–35]. Sleep disordered breathing (SDB), in Furthermore, retinal abnormalities have been documented in AD
the form of sleep apnea, may be present with a prevalence ranging patients, potentially affecting the transmission of light stimuli to
from 33% to 53% of patients with probable AD. The prevalence of the SCN [48]. The SCN is considered to be the main biological
obstructive sleep apnea (OSA) increases with aging, but it seems clock regulating circadian rhythms.
that patients with AD are at an even higher risk, with 40–70% of The neurodegeneration per se, however, is likely to be only a
patients experiencing five or more apneas/hypopneas per hour of part of the overall determinants of sleep disorders in AD. A role
sleep [36–38]. of genetic susceptibility as well as environmental factors, namely,
No studies have specifically assessed the prevalence of PLM in sleep hygiene and light exposure within the 24-hour cycle, can
dementia, and it should be noted that the effective role of PLM in be postulated [49]. A greater deterioration of sleep parameters
sleep fragmentation needs to be clarified: a higher PLM index was in apolipoprotein E (APOE) ε4-negative AD patients has been
found to be associated with longer sleep latency, but assessment of reported [50], although this finding awaits further confirmation,
the effective correlates of PLM is difficult, as it has been reported and particular forms of the monoamine A oxidase (MAOA) poly-
that PLM (in sleep) may occur in subjects without any sleep com- morphism may influence the occurrence of sleep disturbances
plaints and are more frequent with aging [39,40]. RLS is reported in [51]. Some variables—such as poor sleep hygiene, unfavorable en-
up to 24% of demented subjects [41]. vironmental conditions, and medications—seem to be responsible
Abnormal nocturnal behaviors during sleep are significantly for the sleep architecture alterations and for the predisposition to
more frequent and appear earlier in dementia with Lewy bodies sundowning in AD patients. Disrupted sleep cycles and nighttime
(DLB) than in AD [42]. Furthermore, as far as REM parasomnias wakefulness may underlie this phenomenon. In particular, dysreg-
are concerned, it should be remembered that a substantial burden ulation of circadian mechanisms has been suggested to play a role
of coexisting Lewy body pathology was found to be present in a in the pathophysiology of delirium, and various possible relation-
majority of patients affected by REM sleep behavior disorder (RBD) ships have been hypothesized. Indeed, a vicious cycle involving de-
plus dementia submitted to post-mortem analysis [43]. Thus, clini- lirium and circadian integrity has been conjectured: it is suggested
cians should be aware that careful differential diagnosis is always that the cognitive and psychiatric disturbances of delirium affect
warranted in the presence of suspected or video-PSG-documented circadian integrity by interfering with external cues entraining
RBD in demented subjects. This should focus, in particular, on any the circadian rhythms (zeitgebers); circadian alterations, in turn,
features indicative or reminiscent of parkinsonism. impairing wakefulness, result in a worsening of the delirium [52].
The presence of agitation in the later hours of the day is reported Several papers in the literature have explored the role of interven-
in only a minority of nursing home residents with dementia, and tions of various kinds (light exposure, melatonin administration,
is a less frequent occurrence in AD than in DLB subjects. This agi- educational interventions, etc.) intended to stabilize rest–activity
tation, together with other time-of-day-related behavioral abnor- rhythms and prevent sundowning [13,14,53]. In extreme cases, the
malities, constitutes a phenomenon known as sundowning [44]. circadian sleep rhythms are disrupted to such a degree that the sub-
Occurring in subjects with dementia, sundowning is a set of symp- ject displays a complete day–night reversal of sleep patterns, with
toms (including sleep–wake disruption) that can build up into a the main sleep period occurring during daytime.

Chapter 26 sleep disorders in neurodegenerative diseases 257
The question of whether sleep disorders contribute to the cog- throughout the 24-hour cycle. Actigraphy is useful in patients with
nitive deterioration processes occurring in neurodegenerative AD both for initial evaluations of sleep patterns and for assessing
diseases is debated in the literature. However, there is preliminary the effects of interventions. In patients with dementia, the degree of
evidence suggesting that disordered sleep may worsen cognitive de- correlation with PSG findings has been reported to be fairly good
terioration (memory and executive functioning) in the MCI stage [45]. However, even though actigraphy has been shown to be a
of these diseases [49,54]. Furthermore, negative effects of sleep dis- suitable method for the assessment of sleep patterns in the elderly,
orders on cognitive functions have been reported in patients with video-PSG continues to be the gold standard under certain circum-
dementia as well as in non-demented elderly subjects [55,56]. On stances. Although video-PSG can introduce an important bias in
the basis of this evidence, treating sleep disorders and preserving the evaluation of sleep structure (due to the well-known first-night
good sleep quality for as long as possible may be hypothesized to effect), it offers the possibility of evaluating polygraphic and video
delay cognitive and functional decline. traces in a synchronized way, which is essential when investigating
The decrease in REM sleep documented in AD has been found to sleep movement disorders, parasomnias, and SDB. Furthermore,
correlate with dementia severity [30,31,57–59]. Dementia severity ambulatory video-PSG will increasingly allow patients to be
has also been suggested to correlate with the severity of RBD, while recorded outside the sleep laboratory, for instance in the ward or
an association between APOE4 genotype, sleep apnea, and cogni- at home. Furthermore, 24-hour ambulatory PSG recordings allow
tive impairment has been hypothesized [49,50]. There is a grow- the evaluation of nighttime sleep as well as daytime functioning,
ing interest in the potential interaction between sleep apnea and including napping and daytime somnolence.
AD [23,38,60]. Several studies have reported the occurrence of de-
lirium associated with OSA and central sleep apnea (CSA), and its
resolution with continuous positive airway pressure (CPAP) treat- Dementia with Lewy bodies
ment [61–67]. A prospective study systematically using validated DLB, the second most common cause of dementia in the elderly
screening tools for delirium and OSA showed OSA to be a pre- [75], is frequently associated with changes in sleep patterns [76,77].
dictive risk factor for the occurrence of delirium in elderly surgical Questionnaire-based surveys indicate that patients with DLB have
subjects [68]. a wide range of sleep disorders, including impaired sleep quality or
A possible association of RLS with cognitive impairment has reduced sleep efficiency, vivid dreams and confusion on awakening,
been reported in the literature [69,70]. Sleep reduction/fragmen- and abnormal motor control during sleep in the form of probable
tation due to RLS might worsen cognitive symptoms or even accel- RLS and probable PLM during sleep [76,77]. PSG data show that a
erate neurocognitive degeneration. high percentage of DLB subjects display a mixture of different sleep
pathologies ranging from unstable and fragmented sleep to SDB
Clinical/instrumental assessment of sleep disorders and various motor-behavioral abnormalities. Objective PSG data
Sleep disturbances should be evaluated in AD patients in the early (Table 26.1) show that DLB patients have poor sleep continuity,
stages of the disease. In MCI and dementia, studies based on sub- long sleep latency, long REM sleep latency, reduced REM sleep, and
jective reports of sleep often mingle the direct experiences of bed a significant number of arousals not accounted for by a movement
partners with the reports of caregivers/nurses, who might over-or or breathing disorder [78,79]. The observation that sleep comor-
underestimate the frequency and severity of the sleep disorders. bidities do not seem to fully explain the sleep instability in DLB
In AD patients, the diagnosis of sleep disturbances should be [78] highlights the possibility that a complex pathophysiology, po-
based primarily on a detailed and targeted medical history, and tentially linked to neurodegenerative changes, underlies the sleep
corroborated whenever possible by data collected using question- fragmentation in these patients. DLB subjects who show a more
naires [71]. Unfortunately, the questionnaires and scales used to severe cognitive impairment and an early onset of visual hallucina-
investigate sleep in the general population have not been formally tions are more likely to display the simultaneous presence of dis-
validated in individuals with cognitive decline. Nevertheless, tinctive elements of wakefulness, NREM sleep, and REM sleep in
evidence-based recommendations for the assessment of sleep dis- the absence of identifiable conventional sleep stages (dissociated
orders in older people can be applied to individuals with MCI or sleep), which represents an extreme form of disorganization of
dementia within the same age range. The use of a rapidly and easily sleep architecture [79].
administered sleep questionnaire able to identify sleep patterns po- RBD is the most prominent sleep disorder in DLB, reported in
tentially associated with clinical and functional disease variables in 50–80% of patients. Indeed, the presence of RBD supports a diag-
AD appears to be suitable for the early identification and longitu- nosis of DLB, potentially heralding its onset by years [80], and the
dinal monitoring of AD subjects [72]. A scale investigating sleep inclusion of RBD in the DLB diagnostic criteria was found to im-
fragmentation was recently constructed and found to correlate prove the classification accuracy in autopsy-confirmed DLB cases
significantly with variables considered indexes of cognitive and [81]. Numerous cases of RBD have been reported in association
functional deterioration in AD: Mini Mental State Examination with clinically diagnosed DLB.
(MMSE), Activities of Daily Living (ADL), and Clinical Dementia Furthermore, nocturnal motor-behavioral episodes in DLB are
Rating (CDR) scores [73]. more complex than generally assumed, since they include not only
Actigraphy, shown to be an appropriate and reliable method in RBD, but also confusional arousals with or without hallucinations
clinical practice, is an interesting support tool for the study of sleep and other arousal-related episodes during NREM or REM sleep
in AD [74]. It allows long-term evaluation (over periods ranging and reported as RBD-like at clinical interview [67,82]. Nocturnal
from days to several weeks) of sleep–wake cycles in a patient- sleep enactment behaviors have been found to occur even more fre-
friendly environment (the patient’s own home). The patient is quently in patients with DLB than in those with Parkinson disease
therefore free to follow his or her habitual sleep–wake schedule (PD); these episodes consisted of isolated RBD in about one-third

of the cases, whereas in the majority they took the form of ab- of OSA, which was mild (AHI values between 5 and 15) in 8.6%,
normal arousal-related motor-behavioral episodes. moderate (AHI between 16 and 30) in 17.4%, and severe (AHI >30)
Clinicians evaluating patients with DLB should be aware of the in 8.6% of the subjects. The frequency of sleep apnea in our patient
complex disordered sleep patterns these individuals may present series (mean age 75.4 ± 5.1 years) was in line with that reported
and thus of the possibility of misleading symptoms, and the risk in the literature in elderly patients (30.5% of >65-year-olds having
of overlooking sleep comorbidities. Accordingly, they should con- an AHI of 5 or higher, versus 33.3% of 70-year-olds and 39.5% of
sider performing PSG sleep investigations; nocturnal video-PSG, 80-year-olds) [88,89] and in PD patients unselected for sleep com-
overcoming the limits of questionnaire-based investigations and plaints [90]. Moderate to severe sleep apnea (AHI > 15) was found
yielding an objective analysis of sleep patterns, should allow them in 26.1% of DLB subjects.
to make a correct diagnosis and achieve optimal treatment of dis-
rupted sleep in DLB. In particular, video-PSG should be used to Progressive supranuclear palsy
examine disruptive sleep behaviors suggesting dream enactment,
since RBD is only one of the possible causes of these behaviors. Progressive supranuclear palsy (PSP) is a neurodegenerative dis-
The question of whether and how sleep disorders may contribute ease characterized by gaze dysfunction, extrapyramidal symptoms,
to cognitive decline in DLB is a complex one. Literature data [42] and cognitive dysfunction. Sleep disturbances are present in most
show that altered sleep patterns are not associated with a more pro- cases of PSP [34,91]. Sleep studies (Table 26.1) in patients with PSP
nounced cognitive decline in DLB, as measured by MMSE, or with showed increased awakenings, diminished total sleep time, and
substantial deficits in specific cognitive domains. reduced REM sleep. Marked insomnia, characterized by increased
Limited evidence indicates that DLB subjects reporting a sleep- sleep latency and increased awakenings, was the most common
related disturbance as the presenting symptom, particularly those complaint [34]. Insomnia severity was related to overall disease se-
whose onset symptom was RBD, obtain higher MMSE scores and verity, the number of awakenings increasing with greater motor im-
perform better on tests of logic and executive functions than those pairment, and total sleep time declining with progressing dementia.
with other symptoms at onset [67]. Starting from these data, and Insomnia has been found to be worse in PSP than in AD or PD.
assuming that the evolution of clinical features reflects the topog- Nocturnal motor-behavioral events, in the form of RBD, have been
raphy of the degeneration over time, it can be suggested that different reported to occur in PSP [92]. REM sleep without atonia (RSWA)
patterns of neurodegeneration could occur in DLB [83–85], reflect- is found in up to 27% of patients with PSP [93]. Standardized sleep
ing different neuronal susceptibility to degeneration. This pattern questionnaires have identified possible RLS in more than half of
of progression may explain the presence of less severe cognitive im- PSP patients, and the condition has also been associated with sig-
pairment and slower progression of dementia in those with RBD as nificantly increased PLM in sleep [94].
the presenting symptom. In this context, it is possible to hypothesize
a “bottom-up” (ascending) and patchy progression of neurodegen- Corticobasal degeneration
eration [83,84], wherein more resilient neuronal groups in networks The most common sleep disorder in corticobasal degeneration is
implicated in cognition are affected later than those responsible for insomnia, although PLM and RBD can also be present [94]. It has
the critical expression of RBD. The presence of a sleep disturbance been shown that focal dystonia, and “alien limb” phenomenon,
(eg, RBD) as the prodromal symptom of DLB was found to indicate can potentially persist unchanged throughout wakefulness, NREM
a different disease phenotype, characterized by earlier appearance of sleep (all stages), and even REM sleep. In an anecdotal case report,
parkinsonism, visual hallucinations, and delayed emergence of de- the occurrence of dystonia was not found to be triggered by EEG
mentia [86], supporting the “bottom-up” hypothesis of progression arousal, which instead tended to follow the dystonic manifesta-
of neurodegeneration from the brainstem to the cortex. tions, and indeed appeared to be evoked by them [95].
A “top-down” (descending) progression [83,84,87] from the neo-
cortex/limbic system to the brainstem networks may explain the
occurrence early in the disease course of cognitive impairment that Huntington disease
is not associated with RBD, which would not appear until a later In Huntington disease (HD), as in PD, there is a growing awareness
stage of neurodegeneration. Neuropathological studies are needed that, alongside the motor symptoms, sleep and circadian abnor-
to determine whether neuronal loss and Lewy body-related neuro- malities are important non-motor features of the disease. Although
degeneration in the brainstem nuclei and corticolimbic areas are the long-term impact of sleep disruption in HD is unknown, sleep
different in subjects with RBD as opposed to those without RBD. alterations are deemed to contribute to the progressive evolution
Respiratory patterns during sleep in DLB subjects have been of the condition [96]. Sleep disturbances in HD are likely to be
poorly investigated; only two papers have reported PSG-based find- underdiagnosed, because of underreporting by patients, who might
ings [78,79]. The Mayo Clinic group reported retrospective data on lack the insight necessary to provide information about their sleep
78 patients diagnosed with possible or probable DLB, submitted to pattern in relation to their psychiatric features [97]. Nevertheless,
video-PSG to evaluate the presence of suspected comorbid sleep up to 90% of patients may complain of sleep problems, which
disorders. On video-PSG, 60% of the sample had evidence of SDB have a moderate to severe impact on their overall health [98].
(respiratory disorder index RDI > 5); 36% of the patients had an RDI HD patients report insomnia and have a tendency to experience
≥ 10. The mean RDI was 11.9±15.8. No data were presented about increased daytime somnolence [98,99]. The few PSG studies (Table
the distribution according to SDB severity. Our group, conducting 26.1) available show multiple sleep pattern alterations: reductions
a study on this topic, evaluated 29 consecutive subjects diagnosed of REM sleep and of SWS, increased sleep latency, impaired sleep
with probable DLB according to agreed consensus criteria for DLB continuity, reduced sleep efficiency, reduced total sleep time, and
[67]. Video-PSG revealed SDB in 34.8% subjects, mainly consisting increased wakefulness after sleep onset [96].

Genetic neurodegenerative Table 26.2 Principles of treatment

disorders—spinocerebellar ataxias Global approach Screening for sleep comorbidities—medical
Patients affected by other neurodegenerative disorders of genetic or psychiatric illness—undesired side effects
origin may present several sleep disturbances. The spinocerebel- Insomnia Nonpharmacological interventions:
lar ataxias (SCAs) are a large group of heterogeneous disorders in Sleep hygiene—cognitive–behavioral
which sleep disorders can be frequent. Different SCA subtypes are therapy—daytime bright light exposure—
characterized by different patterns of sleep disturbances [100]. sleep restriction
SCA1, SCA2, SCA3, SCA4, and SCA6 patients can exhibit RLS Pharmacological interventions:
and PLM in sleep; the highest prevalence of RLS is found in SCA3 Z-drugs—short-life benzodiazepines—
[101,102]. melatonin—trazodone—neuroleptics
SCA2 is characterized by good subjective sleep quality, paral- (quetiapine)—antidepressants
leled by reduced REM sleep, reduced REM density, the presence
REM sleep behavior Clonazepam—melatonin—melatoninergic
of RSWA and PLM. REM sleep alterations and PLM are related disorder agents—quetiapine
to SCA2 severity; in particular, REM alterations are related to
increases in ataxia scores, whereas RSWA is related to the number Confusional spells/ ACh inhibitors—second-generation
hallucinations neuroleptics (quetiapine)
of cytosine–adenine–guanine repeats. More advanced SCA2 can
be associated with disappearance of REM sleep and an increase of Excessive daytime Modafinil—caffeine—activating
SWS [103]. sleepiness antidepressants
SCA3 is characterized by impaired sleep efficiency and decreased Restless legs syndrome/ Dopaminergic agonists—clonazepam—
REM sleep. Subjects with SCA3 may also complain of RLS, PLM, periodic limb movement gabapentin—pregabalin—opioids
vocal cord paralysis and RBD [104–106]. disorder
SCA6 is characterized by only minor sleep abnormalities in the
form of RLS and PLM [107].
particularly in institutionalized subjects [13,14,52]. It is important
Status dissociatus to be aware that many drugs, such as diuretics, beta-blockers, bron-
chodilators, corticosteroids, cardiovascular drugs, and H2 blockers,
In subjects with the most advanced and severe neurodegenera- can cause or exacerbate insomnia. Alcohol and caffeine should be
tive diseases, as well as in patients affected by some prion diseases consumed in minimal quantities, especially during the evening and
like fatal familial insomnia, an extreme form of sleep alteration just before going to sleep.
can occur [108]. The term status dissociatus refers to the simul- The sleep environment should be favorable to sleep onset and
taneous coexistence of three different states of being: wakefulness, maintenance; at night, noise and ambient light should be reduced
NREM sleep, and REM sleep. When the clear-cut distinctions be- to a minimum. External interventions (by caregivers or nurses)
tween these states are lacking, they may inappropriately overlap, potentially triggering arousal from sleep should also be kept to a
leading to an intermediate state of being that is characterized by minimum.
a wide range of clinical phenomena [109]. In particular, patients Reinforcement of the distinction between night and day may
affected by status dissociatus show subcontinuous behavioral mani- strengthen the circadian rhythm, and external cues entraining cir-
festations of vivid dreams and oneirism, persisting throughout the cadian rhythms should also be reinforced by avoiding or limiting
24-hour sleep–wake cycle. daytime napping, maintaining regular meal times, eating a light
meal in the evening, doing regular physical activity, and ensuring
Key points for the treatment of disrupted regular exposure to bright light in the morning [53,110–112].
The pharmacological management of disrupted sleep in subjects
sleep in neurodegenerative disorders with neurodegenerative disorders, and particularly in those at risk
In view of the multiple and complex mechanisms potentially of experiencing delirium, usually culminates in the use of atypical
underlying disrupted sleep in neurodegenerative disorders, evalu- antipsychotics. It should be remembered that sedative drugs should
ation of sleep patterns should include a comprehensive workup, a be chosen paying careful consideration to their side effects, their
full assessment of sleep hygiene, and a careful evaluation of pri- interactions with other drugs, and the risk of excessive sedation,
mary and other sleep comorbidities (eg, SDB, movement disorders which could worsen neuropsychological deficits.
during sleep, parasomnias, and comorbid medical, psychiatric, or Every drug treatment should be started and conducted at the
iatrogenic conditions). Table 26.2 outlines principles of treatment. minimum effective doses, and reduction or suspension of treat-
Inappropriate sleep habits and environmental conditions (es- ment considered whenever possible.
pecially inadequate exposure to natural light) should be corrected
whenever found. Once a correct diagnosis has been established, sleep
comorbidities should be properly treated. In particular, associated
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CHAPTER 27
Sleep and stroke
Mark Eric Dyken, Kyoung Bin Im,
George B. Richerson, and Deborah C. Lin-â•‰Dyken
Stroke and sleep: background adult population), were first considered “less well-â•‰documented or
potentially modifiable risk factors” for stroke, suggesting a poten-
Stroke and sleep disorders are both common individually. Stroke is the tial cause-â•‰and-â•‰effect relationship between OSA and stroke [5,6].
second major cause of death and the leading cause of long-â•‰term disa-
bility worldwide. It is responsible for half of all acute neurological hos- An association
pital admissions in the USA, with a prevalence of 6.5 million among In 1962, reports suggested that sleep apnea could be caused by
adults aged 20 years and older and a yearly incidence of 795 000 [1–â•‰2]. central nervous system (CNS) injury [7]â•„. Automatic respiration
The National Sleep Foundation’s “Sleep in America” poll from 2002 (i.e, that which occurs in the absence of any conscious effort,
reported that 93% of people with fair or poor health had sleep prob- such as during sleep) is generated by a network of interconnected
lems (55% complaining that sleepiness interfered with daily activities) neurons within the medulla and pons, including the ventrolat-
[3]â•„. Given the large numbers of patients with stroke, treating concomi- eral portion of the nucleus of the solitary tract (corresponding
tant sleep problems can improve quality of life, potentially reducing approximately to the dorsal respiratory group (DRG), which is
morbidity and mortality in many cases. Major sleep disorders are not defined anatomically, but as a region containing neurons
defined in the International Classification of Sleep Disorders, Third that fire bursts in phase with respiratory output), the Bötzinger
Edition (ICSD-â•‰3) under sleep-â•‰related breathing disorders (SRBDs), complex, pre-â•‰Bötzinger complex, nucleus ambiguus, nucleus
insomnia, hypersomnias of central origin, circadian rhythm sleep dis- para-â•‰ambigualis, and nucleus retroambigualis (together forming
orders, parasomnias, and sleep-â•‰related movement disorders [4]. a column corresponding approximately to the ventral respiratory
group (VRG), also defined functionally, not anatomically) (Figs.
Stroke and SRBDs 27.1 and 27.2) [8,9]. Neurons in the medulla that generate the
In 2006, SRBDs, including obstructive sleep apnea (OSA, a problem respiratory output are stimulated by peripheral chemoreceptors
with a prevalence up to 24% in men and 9% in women in the general that detect a decrease in blood PO2 and/â•‰or an increase in blood
Cerebral cortex
Hypothalamus
Pons
Cerebellum
Medullary respiratory center
Ventral respiratory group Dorsal respiratory group
Pharynx Nucleus tractus solitarius CN IX

Larynx CN X CN X
Primary inspiratory neurons
CO2
Inspiratory neurons
Expiratory neurons
Accessory muscles
Intercostal muscles
Diaphragm
Fig. 27.1â•‡ Afferent and efferent connections of the medullary respiratory network.

Reproduced from Dyken et al, Stroke in Sleep. In: Chokroverty S, Sahota P, [eds], Acute and Emergent Events in Sleep Disorders, Copyright (2011), with permission from Oxford University Press.

(a) (b)
Pons
Pons
Vagus
Medulla nerve
Ventral respiratory group
(VRG)
Dorsal respiratory group
(DRG)
N. ambiguus, N. para-ambiguus, N. retroambigualis

(c) Nucleus tractus solitarius Bötzinger complex, pre-Bötzinger complex
(DRG) (VRG)
Vagus nerve
Accessory muscles
Spinal motor neurons

Intercostal muscles
Branchiomeric muscle
of pharynx and larynx
Diaphragm
Fig. 27.2 Neuroanatomy of the medullary respiratory network: the brainstem showing in a parasagittal section (a) the location of the dorsal and ventral respiratory
groups (DRG and VRG) and their projection to the spinal cord; in a basal brain view (b) the vagus nerve rootlets exiting the lateral surface of the medulla, and in a
transverse section of the medulla (c) projections from the DRG to VRG, and the output from both groups to respiratory muscles.
Reproduced from Dyken et al, Stroke in Sleep. In: Chokroverty S, Sahota P, [eds], Acute and Emergent Events in Sleep Disorders, Copyright (2011), with permission from Oxford University Press.
PCO2, as well as central respiratory chemoreceptors (CRCs) that Snoring

respond to an increase in PCO2, but not to hypoxia. Neurons In 1989, Palomake et al. studied 167 men with stroke (36% dur-
in the raphe nuclei, the retrotrapezoid nucleus, the locus coer- ing sleep) [16]. Snoring, using stepwise multiple logistic regression
uleus, and the nucleus of the solitary tract all have been proposed analysis, was the only potential risk factor significantly related to
to be CRCs [10–11], but the relative importance of each group stroke in sleep [16]. In 1991, Palomake found that the odds ratio
is unknown. Of these candidates, there is greatest support for (OR) of snoring as a risk factor for ischemic stroke increased when
Phox2b-expressing neurons of the retrotrapezoid nucleus [12] obesity and sleepiness (classical OSA signs and symptoms) were
and for serotonin neurons of the raphe nuclei [13], both in the also present [17].
medulla. Central sleep apnea (CSA) has been reported follow-
ing stroke of the nucleus of the solitary tract, and OSA has been PSG studies
observed after stroke of the nucleus ambiguus, with dysfunc- Case reports
tional vagal motor innervation to the larynx and pharynx [14]. In 1982, Chaudhary et al. reported a man with right lateral med-
Case reports suggest that diffuse CNS injury can also affect these ullary stroke, an apnea index (average number of apneas/hour of
areas, causing apnea [10,15]. sleep) of 18, and an oxygen saturation (SaO2) low of 60% [18].

Chapter 27 sleep and stroke 265
stroke, as 15% of strokes are preceded by TIAs (90-day risk up to

17.3%) [3,26–27].
Cohort studies
Table 27.1 shows the results of incidence studies for OSA and
stroke risk.
Population-based studies
In 2001, Shahar et al. studied the cross-sectional association
between SRBDs and self-reported cardiovascular disease in 6424
subjects using home polysomnography (PSG) [28]. The relative
odds of prevalent stroke (upper versus lower AHI quartile) was 1.58
(95% confidence interval, CI, 1.02–22.46).
In 2005, Arzt et al., utilizing logistic regression (using 12 years of data
from a stratified random sample), performed a cross-sectional analy-
sis of 1475 subjects (30–60 years) [29]. A baseline AHI ≥ 20 indepen-
dently increased the OR for stroke (3.83; 95% CI 1.17–12.56; p = 0.03)
compared with a reference group with an AHI < 5, after adjusting for
sex, age, body mass index (BMI: weight in kilograms/square of height
in meters), alcohol, smoking, diabetes, and hypertension.
A longitudinal analysis of 1189 individuals tested whether SRBD
was associated with increased incident stroke at 4-year intervals.
Fig. 27.3 This brain CT without contrast was performed in a 34-year-old man
A baseline AHI ≥ 20 had significantly higher OR for incident stroke
who awoke with stroke, after which he was diagnosed with obstructive sleep
apnea. This study reveals a hemorrhage, with a surrounding area, greater than 1 cm compared with the reference group (4.48; 95% CI 1.31–15.33;
in diameter, of low density, consistent with edema, involving the putamen and p = 0.02), when controlling for sex and age.
posterior limb of the right internal capsule. Clinic-based studies
Reproduced from Dyken ME, Cerebrovascular disease and sleep apnea. In: Bradley DT,
Floras JS, [eds], Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease
In 2005, Yaggi et al. examined an observational cohort of 1022
(Lung Biology in Health and Disease), pp. 285–306, Copyright (2000), with permission from subjects with suspected SRBD and compared the risk of develop-
Informa Healthcare. ing stroke, TIA, or death from any cause in 697 subjects with OSA
(AHI ≥ 5) with the risk in individuals with an AHI < 5 [30]. Many
with SRBD were treated (diet, upper-airway surgery, and positive
Hypothetically, nucleus ambiguus injury caused this OSA; neverthe- airway pressure (PAP) therapies).
less, pre-stroke weight gain, snoring, and sleepiness suggested that Over 3.3–3.4 years, the OSA group had 22 incident strokes and/
OSA was present prior to stroke. In 1985, Tikare et al. diagnosed or TIAs and 50 deaths (the comparison group had 2 strokes and/or
OSA in a patient with recent stroke (brain computerized tomogra- TIAs and 14 deaths). OSA was associated with significant risk for
phy (CT) showed paraventricular low attenuation), and suggested composite stroke, TIA, or death (hazard ratio (HR) 1.97; 95% CI
that OSA-induced hypoxia and cardiac arrhythmia caused the stroke 1.12–3.48; p = 0.01), after adjusting for sex, age, race, smoking, BMI,
[19]. In 1991, Dyken et al. diagnosed OSA in a sleepy, sonorous, diabetes, hyperlipidemia, atrial fibrillation, and hypertension. Trend
obese 34-year-old man, after he awoke with left hemiparesis (brain analysis found that increased OSA severity was associated with
CT suggested a hypertensive hemorrhagic stroke: Fig. 27.3) [20,21]. increased risk of stroke, TIA, or death from any cause (p = 0.005).
Hemodynamic studies reporting elevated blood pressures following In 2006, Munoz et al. studied a non-institutionalized, elderly pop-
sleep-related respiratory obstructions supported the hypothesis that ulation (range 70–100 years, median 77.28), drawn from a random
OSA precipitated this hypertensive bleed [22,23]. one-stage cluster sampling stratified by sex, age, and census area [31].
After adjusting for sex, a baseline AHI ≥ 30 was a risk factor for inci-
Case-controlled studies dent ischemic stroke or TIA (HR 2.52; 95% CI 1.04–6.1; p = 0.04).
In 1992, Dyken et al. published preliminary data of a 4-year follow- In 2008, Valham et al. studied a population (≤70 years), with
up study of 24 consecutively encountered inpatients admitted for angina and coronary artery disease (verified by angiography and
stroke, along with 27 healthy gender-and age-matched controls left ventriculography) [32]. Initial PSGs (without electroencepha-
[24,25]. OSA was diagnosed in 71% of strokes: 10 of 13 males (77%) lography (EEG), using a pressure sensitive bed to monitor respira-
and 7 of 11 females (64%). However, it was diagnosed in only 3 tion) of 392 randomly selected subjects showed sleep apnea (AHI
of 13 males without stroke (23%) (p = 0.169) and in only 2 of 14 ≥ 5) in 54%. A 10-year follow-up, during which 9 apneics received
females without stroke (14%) (p = 0.0168). OSA therapy, showed that 47 subjects (12%) suffered strokes. Sleep
apnea was associated with an increased stroke risk; HR of 2.89
A risk factor (95% CI 1.37–6.09, p = 0.005), independent of treatment, previ-
Transient ischemic attacks ous stroke or TIA, sex, age, BMI, smoking, diabetes, hyperten-
Reports of patients with transient ischemic attacks (TIAs, or “min- sion, left-ventricular function, hypertension, and atrial fibrillation.
istrokes,” that is to say, focal neurological deficits resolving within Compared with individuals without apnea, subjects with an AHI > 5
24 hours) during sleep, subsequently diagnosed with OSA and but < 15, and subjects with an AHI > 15, respectively, had 2.44 (59%
whose treatment for OSA was followed by long-term resolution CI 1.08–5.52, p = 0.011) and 3.56 (95% CI 1.56–8.16, p = 0.011)
of TIA, suggest a cause-and-effect relationship between OSA and times increased risk of stroke, independent of confounders.

Table 27.1 OSA and stroke risk: incidence studies
Incidence Subjects studied Population AHI used to SDB AHI used Mean follow- Group outcome: Risk estimate
studies size define SDB prevalence to define up period total number of SDB as risk factor
group comparison (years) of subjects in a for outcome
group given group with (95% CI)
outcome
Authors/year
Arzt et al. Population- † 1475 ≥20 7% <5 Three Stroke *OR = 4.48
2005 based †† 1189 (N = 99) intervals of SDB = 4 (1.31–15.33; p = 0.02)
General adult 4 years Comparison = 9
30–60 years
Yaggi et al. Clinic-based 1022 ≥5 68% <5 3.4 SDB Stroke, TIA, **HR = 1.97
2005 Referred for (N = 697) 3.3 CG or death (1.12–3.48; p = 0.01)
suspected SDB SDB = 72
≥50 years Comparison = 16
Munoz et al. Clinic-based: 394 ≥30 25% <30 4.5 TIA or ***HR = 2.52
2006 Random sample, (N = 98) ischemic stroke (1.04–6.1; p = 0.04)
non-institutional SDB = 9
elderly Comparison = 11
70–100 years
Valham et al. Clinic based 392 ≥5 54% <5 10.0 Stroke ****HR = 2.89
2008 Symptomatic SDB = 38 (1.37–6.09; p = 0.005)
angina and CAD Comparison = 9
Redline et al. Community- 5,422 >15 Male <4.1 8.7 Ischemic stroke Male: *****HR = 2.86
2010 based 44% Male (1.1–7.4)
≥40 years (N = 1095) SDB = 54 Female: ****** A 2%
Female Female increase in HR
24% SDB = 37 (0–5) after threshold
OAHI of 25
(N = 720)
AHI, apnea/hypopnea index = the average number of apneas and hypopneas per hour of sleep; SDB, sleep-disordered breathing; CG, comparison group; CI, confidence interval;
P, probability; OR, odds ratio; HR, hazard ratio; CAD, coronary artery disease; OAHI, obstructive apnea hypopnea index.
† Original population providing original cross-sectional prevalence data.
†† Population used for longitudinal analysis of incident stroke.
* In a model adjusted for age and sex.
** In a model adjusted for age, sex, race, smoking, BMI, diabetes mellitus, hyperlipidemia, atrial fibrillation and hypertension.
*** In a model adjusted for sex.
**** In a model adjusted for age, BMI, left ventricular function, diabetes, sex, intervention, hypertension, atrial fibrillation, previous stroke or TIA.
***** In a model for male subjects comparing the risk for ischemic stroke and the OAHI in the top quartile (quartile IV; OAHI > 19) to the lowest quartile (quartile I; OAHI < 4.1) of the
overall population studied.
****** In a model using non-linear, covariate adjusted associations between OAHI and the female sex.
Adapted from Chest, 136(6), Dyken MD, Im KB, Obstructive sleep apnea and stroke, pp. 1668–1677, Copyright (2009), with permission from American College of Chest Physicians.
In 2010, Redline et al. followed 5422 subjects, without stroke for a had OSA (n = 5; one used continuous positive airway pressure
median of 8.7 years, during which 193 ischemic strokes occurred [33]. (CPAP), dying from urosepsis) [27,28]. Only one male control, an
Men with an obstructive AHI (OAHI) > 19.1 (the top quartile) had individual without OSA, died (prostatic carcinoma). Respectively,
an adjusted HR for stroke of 2.86 (95% CI 1.1–7.4), compared with stroke subjects dead versus alive at 4 years had original diagnostic
men with an OAHI < 4.1 (quartile I). Stroke risk did not associate with mean AHIs of 41.3 and 22.1, suggesting that the diagnosis and
OAHI quartile or oxygen desaturation in women. Nevertheless, using severity of OSA in stroke was associated with worse long-term
nonlinear covariate-adjusted associations with the OSA exposures mortality.
and interactions with gender, there was a 2% increase (95% CI 0–5) in A 1990, prospective, treatment versus non-treatment study by
stroke HR with each unit increment in OAHI above a threshold of 25. Partinen et al. suggested a cause-and-effect relationship between
OSA and stroke [34,35]. Seven years after treating 198 OSA sub-
Treatment versus no treatment jects with weight loss (n = 127) or tracheostomy (n = 71), 5.2% of
Morbidity and mortality the weight loss group had stroke (17.3% died, 11% from vascular
In 1996, a 4-year follow-up by Dyken et al. of a 1992 prevalence etiologies), whereas only 1.2% with tracheostomy suffered stroke
study of OSA and stroke showed that all stroke subjects who died (2.8% died).

CPAP thickening, resulting in painful vaso-occlusion. In 1988, a case

In 2005, Martinez-Garcia et al. showed that of 51 patients with recent report described a 6.5-year-old with SCD and multiple ischemic
stroke and minimum AHI of 20, only 15 (29.4%) tolerated CPAP strokes, in whom PSG diagnosed severe OSA from adenotonsil-
after 1 month [36]. Those not tolerating CPAP had a fivefold (OR lar enlargement [42]. The authors suggested that apnea-associated
5.09) increase in the probability of suffering a new vascular event. hypoxemia contributed to these strokes. A 1989 study reported that
In 2006, Palombini et al. showed that only 22% of 32 patients 13 of 21 children with OSA and SCD had resolution of symptoms
with recent stroke tolerated CPAP for 8 weeks owing to difficul- and improvement in hypoventilation after tonsillectomy/adenoid-
ties from facial weakness, motor impairment, and discomfort [37]. ectomy (T&A) [43]. A French group reported that two boys, ages
Brown et al. found that patients with stroke took longer putting on 5 and 6 years, with SCD and snoring, had elevated middle cerebral
and taking off (p < 0.01) traditional CPAP headgear compared with artery blood flow velocities (≥ 200 cm/s), as determined by transcra-
one-piece systems [38]. Palombini et al. stated, “Better education nial Doppler (TCD), that normalized (<170 cm/se) after T&A [44].
and support of patients and families, and special training session A retrospective study evaluated children ≤17 years with SCD,
in rehabilitation services, will be needed to improve compliance” who underwent T&A, matched to patients without T&A [45]. T&A
[42]. Disler et al. showed that, with better “support,” patients with was associated with a significantly reduced rate of hospital visits
moderately severe motor and cognitive functional independence in subjects with OSA and cerebrovascular ischemia (stroke and
measurement scores tolerated CPAP [39]. TIAs). PSG was used in a cross-sectional study to assess the preva-
lence of SDB in children with SCD [46]. Sixty-four subjects, aged
Positional therapy 2–14 years, were evaluated with the Pediatric Sleep Questionnaire,
Positional OSA (worse supine, from gravitational effect) is com- and PSG was performed in those with snoring. The prevalence of
mon in acute stroke [40]. In 2008, Dziewas et al. diagnosed OSA in SDB was 23.7%, but no association was found between elevated
78% of 55 subjects within 72 hours of stroke (65% positional) [45]. TCD velocity and SDB. Finally, a review article, not limited to SCD,
After 6 months, only 49% had OSA (33% positional). The authors concluded that there is strong evidence for an association between
stated that “positional sleep apnea is a predominant feature in acute SDB and cardiovascular morbidity in children and that treatment
stroke and its incidence decreases significantly during the follow- of SDB results in improvements in blood pressure, cardiovascular
ing months. These findings may have implications for sleep apnea control, and inflammation and endothelial function [47].
treatment in patients with acute stroke.” They suggested that serial
PSG studies may permit modifying, reducing, and eventually with- Potential mechanisms for OSA-induced stroke
drawing OSA treatment. Metabolic syndrome
Medications The odds of having the metabolic syndrome is increased up to nine-
Brunner evaluated mirtazapine as an alternative treatment in eld- fold in individuals with OSA (53% of newly diagnosed apneics)
erly stroke patients with sleep apnea in an open trial [41]. Ten [48–49]. A cross-sectional case–control study found the metabolic
subjects, all of whom refused CPAP, underwent PSG before and syndrome more often in apneics than controls (men 49.5% versus
after a course of mirtazapine. Four individuals showed worsening 22.0%, p < 0.01; women 32.0% versus 6.7%, p < 0.01) [50].
of apnea, and although six had significantly reduced apnea, some OSA is independently associated with obesity, hypertension, and
experts hypothesize that this improvement may be related to the insulin resistance/diabetes (stroke risk factors of the metabolic syn-
natural progression of the disorder over time after stroke, as sug- drome) [3,51–52]. Elevation of the BMI by one standard deviation
gested by Dziewas et al. [45]. increases the OR for SRBD (AHI ≥ 5) by 4.17 [7]‌. A prospective
population-based study showed that after 4 years, the OR for devel-
Other therapeutic considerations oping hypertension of subjects with AHI between 5.0 and 14.9,
The evaluation and treatment in acute stroke must be tailored, be- and those with AHI ≥ 15.0 was respectively two versus three times
cause critical illness in an intensive care setting may require portable greater compared with non-apneics [53]. A community-based
PSG with end-tidal CO2 monitoring, complemented with arterial cross-sectional study of 69 non-diabetics showed that those indi-
blood gases when hypoventilation, CO2 retention, and underlying viduals with mild and moderately severe OSA had reduced insulin
lung or neuromuscular compromise are suspected. Although pos- sensitivity when compared with non-apneics (AHI < 5), independ-
itional therapy should be considered, even simple head-of-bed ele- ent of sex, race, age, and body fat percentage [54].
vation may be contraindicated because of perfusion pressure issues;
as such, the utilization of positional devices preventing supine sleep Autonomic activity
might be preferable. Various PAP therapies (including CPAP, bi- Microneurography (a direct measure of efferent sympathetic neural
level PAP (BPAP), and noninvasive positive pressure ventilatory activity, SNA), supports the hypothesis that OSA-induced hyper-
units such as auto-adjusting BPAP, which includes adaptive servo- tensive events, from elevated SNA (secondary to reflex effects of
ventilation for CSA, and volume-assured pressure support for severe hypoxia, hypercapnia, and decreased input from thoracic stretch
hypoventilation) may need to be presented in a supportive educa- receptors), can cause stroke (Figs. 27.4 and 27.5) [24]. In 1995,
tional manner with close follow-up for adherence. Initially, severe Somers et al. studied 10 subjects with OSA and found that SNA
cases may require intubation and tracheostomy. increased by 246% during the last 10 s of apnea, with a mean blood
pressure increase from 92 mmHg waking to 127 mmHg in rapid
Pediatric stroke and OSA eye movement (REM, stage R) sleep [55]. Persistently elevated wak-
There is a relative paucity of information about the relationship ing sympathetic tone in apneics suggested that OSA might induce
between stroke and sleep apnea in the pediatric population. The chronic changes predisposing to stroke.
majority of reports involve sickle cell disease (SCD), an inher- Autonomic effects could contribute to cardiac arrhythmias in
ited hemoglobinopathy where hypoxemia leads to red blood cell up to 48% of apneics [56–57]. In 1992, Somers et al. showed that

Fig. 27.4 A PSG tracing (paper speed 10 mm/s) has been reduced to correspond to the temporally related microneurographic tracing shown in Fig. 27.5 (paper speed
5 mm/s). Arrows indicate a prolonged mixed apnea of approximately 26 s duration occurring during REM sleep, associated with severe oxygen desaturation. LOC: left outer
canthus; ROC: right outer canthus; T: temporal; C: central; ET: ears tied; O: occipital; EMG: electromyogram; N: nasal airflow; OA: oral airflow; TM: thoracic movement.
Adapted from Dyken ME, Cerebrovascular disease and sleep apnea. In: Bradley DT, Floras JS, [eds], Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease (Lung Biology in Health
and Disease), pp. 285–306, Copyright (2000), with permission from Informa Healthcare.
Fig. 27.5 The arrows in this microneurographic tracing recorded from the peroneal nerve indicate a gradual elevation of efferent nerve activity during a mixed apnea.
The activity peak is immediately followed by cessation of the apnea, with a subsequent marked elevation of arterial blood pressure to 215/130 mmHg from a baseline of
135/80 mmHg. MSNA: muscle sympathetic nerve activity; PNEU: chest excursion; FINAPRESS; fingertip blood pressure.
Adapted from Dyken ME, Cerebrovascular disease and sleep apnea. In: Bradley DT, Floras JS, [eds], Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease (Lung Biology in Health
and Disease), pp. 285–306, Copyright (2000), with permission from Informa Healthcare.

obstructive apneas (inspiration against a closed glottis with hyp- Studies suggest that obstructions induce arousals from NREM
oxemia) could cause excessive parasympathetic response with epi- sleep after inspiratory effort reaches a variable arousal threshold
sodic sinus arrest and dramatic blood pressure reductions (180/ [71]. One study hypothesized that impaired arousal led to prolonged
100 mmHg prior to obstructions, to systolic pressures < 50 mmHg apneas, EEG flattening, and generalized tonic spasms, “cerebral an-
during obstructions) [58]. oxic attacks” [72]. Dyken et al. described cases involving critically
ill patients with OSA, where elevated arousal thresholds led to pro-
Cardiogenic
longed obstructions, resulting in diffuse cerebral hypoxemic EEG
The diagnosis of atrial fibrillation also carries with it a 49% risk for patterns, clinical encephalopathy, and death (Figs. 27.6–27.8) [11,73].
OSA, and CPAP non-compliance is associated with greater recur- White et al. showed that sleep deprivation can increase the
rence after cardioversion [59,60]. Atrial fibrillation might contrib- arousal threshold to hypoxia and hypercapnia [74]. As sleep de-
ute to stroke in some patients with OSA, as it is a strong risk factor privation is common in acutely ill patients, they “speculate—as to
for stroke [3]‌. the clinical significance of these findings as they apply to the patient
A patent foramen ovale (PFO) is a well-known stroke risk factor with a precarious respiratory status.” OSA, a “precarious respiratory
found in approximately 30% of patients with ischemic stroke [61]. status,” can also increase the arousal threshold, possibly as a result
OSA is associated with increased right heart pressure, and during of sleep fragmentation and hypoxemia.
obstructive events a PFO can result in right-to-left shunting. Beelke
et al. observed right-to-left shunting in 9 of 10 subjects with PFO Mechanisms of arousal during OSA
and OSA [62]. The number of microembolic signals during apneas An apnea often resolves with an arousal or “micro-arousal” (of which
positively correlated with the number during waking Valsalva the patient is usually not aware) [75]. This protective reflex allows
maneuvers. In one patient, Pinet and Orehek showed resolution of obstruction relief, with an increase in tidal volume and respiratory
apnea-associated shunting after 1 week of CPAP [63]. frequency, and without the arousal the apnea might not terminate.
During apnea, several stimuli induce arousal, including hypercapnia,
Circadian rhythms hypoxia, and increased airway resistance/respiratory effort.
Dyken et al. hypothesized that if stroke has an equal probability Increasing partial pressure of carbon dioxide (PCO2) in arterial
of occurring at anytime during a 24-hour time period, 33% of blood is a powerful stimulus for arousal. Healthy sleeping humans
all strokes should occur during an 8-hour period of sleep [28]. exposed to 8% CO2 in ambient air will usually awaken within 60
Nevertheless, stroke tends to occur during early morning, and their s [76]. As described above, an increase in blood PCO2 is detected
prospective prevalence study showed that a higher than expected by serotonin neurons in the medulla that stimulate breathing.
percentage of subjects with OSA had strokes during sleep (54%; Serotonin neurons in the midbrain also respond to an increase in
p = 0.0304) [28,64]. blood PCO2 and they cause arousal from sleep. Both groups of sero-
REM sleep tonin neurons are found in close association with large branches
Prolonged REM sleep occurs in early morning (coinciding with of the basilar artery [77,78]. They sense variations in arterial CO2,
greatest stroke risk). Normal REM sleep physiological phenomena responding indirectly to brain pH changes by increasing their ex-
negatively affect OSA: hypotonia (worsens obstructions), elevated citatory drive to other neurons (possibly thalamic, cortical, and
SNA and blood pressure (reaching waking levels with surges during parabrachial) that mediate arousal [16,79]. Transgenic mice with
muscle twitches of phasic REM), and increased cerebral blood flow selective deletion of the transcription factor Lmxlb in serotonin
(apneas increase intracranial pressure and reduce cerebral perfu- neuron precursors fail to develop virtually all brain serotonin neu-
sion pressure) [65–66]. rons [80]. These mice do not awaken from sleep in response to an
Early morning is associated with low fibrinolytic activity and increase in ambient CO2 to as high as 10% [81].
high levels of catecholamines, blood viscosity, and platelet aggrega- Hypoxic air alone can induce arousal without hypercapnia
bility, when REM SNA activation might potentiate platelet aggrega- [82]. Arterial PO2 reductions are sensed by peripheral arterial
tion and plaque development [67]. Effects of OSA on this otherwise chemoreceptors in the carotid and aortic bodies. Central mecha-
normal hematological milieu might include further elevations in nisms, although not clear, do not involve serotonergic neurons,
catecholamines and platelet activation, increasing thrombus and but may include raphe and solitary tract nuclei [91,83]. Although
embolus formation and stroke risk [76 –68]. upper airway obstruction can induce arousal by increasing work
Elevated platelet activation proteins, soluble CD40 ligand of breathing, prolonged apneas imply that the concomitant devel-
(sCD40L) and soluble P-selectin (sP-selectin), have been linked to opment of hypoxia and hypercapnia is critical in the arousal phe-
silent brain infarctions (SBIs) [69]. Using magnetic resonance imag- nomena associated with OSA [84].
ing (MRI) Minoguchi et al. showed SBIs in 25% of patients with
moderate to severe OSA but in only 6.7% of controls, with higher Stroke and insomnia
serum levels of sCD40L and sP-selectin that reduced significantly
Insomnia—“repeated difficulty with sleep initiation, duration,
after CPAP [79].
consolidation, or quality that occurs despite adequate time and
Arousal opportunity for sleep and results in some form of daytime impair-
Definition ment”—resulting from stroke is formally referred to as “insomnia
PSG arousal from non-REM (NREM) sleep is defined as an abrupt due to medical condition” [6]‌. Stroke patients have a high inci-
shift of EEG including alpha, theta, and/or frequencies > 16 Hz dence of insomnia [85]. In a study of 277 subjects, 18.7% had in-
(not including sleep spindles) lasting ≥ 3 s, with ≥ 10 s of stable somnia acutely and 56.7% developed insomnia within 3–4 months
sleep preceding the change [70]. An arousal from REM sleep also of stroke [86].
requires an increase in submental electromyographic (EMG) ac- Contributing factors include initial shock, adjustments to
tivity, lasting ≥ 1 s [80]. physical and cognitive limitations, post-stroke depression, and

Fig. 27.6 This patient suffered a prolonged obstructive apnea, which eventually resulted in a sudden EEG change from a classic REM sawtooth pattern (arrows) to a
poorly organized, diffuse delta slow-wave pattern (black circle), followed by a general flattening of all activity (black square) that led to attempts to arouse the patient
(as evidenced by diffuse movement artifact: black diamond). Nevertheless, persistent obstruction (black triangle) necessitated emergency rescue breathing maneuvers.
Persistent EEG flattening followed by slowing and eventual recovery of normal waking patterns was appreciated in subsequent epochs. L: left; R: right; T: temporal;
C: central; O: occipital; CHIN: mentalis EMG; L LEG: left anterior tibialis EMG; R LEG: right anterior tibialis EMG; SNORE: snoring microphone; ABDOMEN: abdominal
effort; SaO2: oxygen saturation.
Adapted from Neurology, 62(3), Dyken ME, Yamada T, Glenn CL, et al, Obstructive sleep apnea associated with cerebral hypoxemia and death, pp. 491–93, Copyright (2004), with permission from
Wolters Kluwer Health, Inc.
medication effects. Damage to the CNS “sleep switch” (nuclei in the may improve insomnia in stroke, and a recent sham-controlled
preoptic area of the hypothalamus) can also contribute to insomnia randomized trial in patients hospitalized with acute stroke
(Fig. 27.9) [87,88]. A study of 336 elderly stroke patients showed experiencing insomnia for ≥ three days found acupuncture to
insomnia to be most prevalent with hemorrhage and with lesions in be therapeutic [93,94]. Cognitive–b ehavioral therapy (CBT)
the brainstem, frontal lobe, and basal ganglion [95]. has been supported in the treatment of insomnia in geriatric
The sleep switch uses γ-aminobutyric acid (GABA) in recipro- populations; however no study has focused specifically on post-
cal inhibitory relays with variable waking centers of the reticular stroke patients [103,95].
activating system (Fig. 27.9) [97,98]. Benzodiazepine receptor
agonists include those with nonselective affinity for the GABA
receptor complex (eszopiclone) and others with selective affin- Stroke and hypersomnia
ity for the GABAA receptor (zolpidem and zaleplon) [89,90]. Hypersomnia due to a medical condition is diagnosed when stroke
Although various benzodiazepine and non-b enzodiazepine directly causes sleepiness [6]‌. The ascending reticular activating
hypnotics and antidepressants have been used to treat insom- system promotes wakefulness through monoaminergic and cho-
nia in stroke, many have CNS depressant effects that could linergic neurotransmitter systems (Fig. 27.10) [98]. Stroke affect-
exacerbate OSA [91,92]. Reducing dopaminergic stimulation ing the hypothalamus (the orexin/hypocretin-containing lateral

LOA-A1
ROA-A1
50 uv
T3-CZ
CZ-T4
C3-A2
T3-O1
CHIN-EMG
ECG
LL EMG
RL EMG
OFF
SNORE
SENSOR
NA
CE
AE
OFF
SAO2
3 SEC
Fig. 27.8 After the patient in Fig. 27.7 (upon whom no heroic therapeutic

Fig. 27.7 An 80-year -old man with multiple medical problems, who was admitted
interventions were allowed) had a final series of apneic events, no discernible
with exacerbation of pulmonary and cardiac disease under a do-not-resuscitate/do-
EEG activity was captured while utilizing a recording sensitivity or 1.0 µV/mm.
not-intubate status (for whom signed consent had been given for PSG as part of an
A prolonged period of asystole (see arrow) was followed by cardiac arrest, at
IRB-approved study) had a 30 s obstruction that was associated with an SaO2 low
which time the patient was declared dead (black circle). LOC: left outer canthus;
of 12%. At that time, the EEG showed progressive development of a disorganized
A1: left ear reference; A2: right ear reference; T: temporal; C: central; O: occipital;
slow-wave pattern over a 2.5-minute period, followed by electrocerebral silence
LL: left leg; RL: right leg; NA: nasal airflow; CE: chest effort; AD: abdominal effort;
(using a recording sensitivity of 1.0 µV/mm). A1: left ear reference; A2: right ear
SaO2: oxygen saturation.
reference; T: temporal; C: central; O: occipital; LL: left leg; RL: right leg; NA: nasal
Adapted from Neurology, 62(3), Dyken ME, Yamada T, Glenn CL, et al, Obstructive sleep apnea
airflow; CE: chest effort; AD: abdominal effort; SaO2: oxygen saturation.
associated with cerebral hypoxemia and death, pp. 491–93, Copyright (2004), with permission
Reproduced from Dyken et al, Stroke in Sleep. In: Chokroverty S, Sahota P, [eds], Acute
from Wolters Kluwer Health, Inc.
and Emergent Events in Sleep Disorders, Copyright (2011), with permission from Oxford
University Press.
nucleus and the histaminergic tuberomammillary nucleus), the Reductions in hypersomnolence have been reported following
brainstem (the noradrenergic locus coeruleus and the “REM sleep- bilateral mesodiencephalic paramedian infarction using 200 mg
on” cholinergic cells of the pedunculopontine/laterodorsal nuclear of modafinil, and during stroke rehabilitation using methylphen-
complex), and cholinergic and GABAergic cells in the basal fore- idate (5–30 mg/day) and levodopa (100 mg/day) [100–101].
brain could result in hypersomnolence. Bromocriptine 20–40 mg/day may improve hypersomnolence, ap-
Hypersomnia can follow lesions of pontine tegmental reticular athy, and behaviors counterproductive to good sleep [102].
formation and the paramedian nuclei of the thalamus. In a pro-
spective observational study of 100 consecutively hospitalized Stroke and circadian rhythm
patients, the prevalence of CNS hypersomnia in acute ischemic
stroke patients was estimated as 22% [96]. sleep disorders
Hypersomnia can be a side effect of a medical regimen. A 52-year- A circadian rhythm disorder (CRSD) is a persistent or recurrent
old woman with an ischemic infarction in the upper brainstem teg- pattern of sleep disturbance due to alterations of the circadian
mentum from subarachnoid hemorrhage developed sleep attacks timekeeping system or misalignment between the endogenous
and cataplectic-like events on valproic acid and diphenylhydantoin circadian rhythm and exogenous factors that affect the timing or
seizure prophylaxis [97]. Her sleep symptoms resolved imme- duration of sleep and lead to insomnia or excessive daytime sleepi-
diately after discontinuing anticonvulsants. Neurotransmitters ness and impairment of functioning [6]‌. Multi-infarct dementia,
associated with CNS waking centers rationalize pharmacological the second leading dementia type in the USA, may cause greater
treatments that include modafinil, methylphenidate, levodopa and circadian sleep disruption than Alzheimer disease [103,104].
antidepressants with stimulant effects [98]. Modafinil may be use- Circadian rhythms are maintained by the suprachiasmatic
ful in hypersomnolence associated with anticonvulsant treatment nucleus of the anterior hypothalamus, and lesions result in asyn-
of post-stroke seizures [99]. chrony of circadian rhythms of sleep and wakefulness, possibly

LATERAL HYPOTHALAMUS
(Orexin/Hypocretin)
Thalamus
PREOPTIC NUCLEI
(GABA/Galanin)
VENTRAL PERIAQUEDUCTAL GREY

(Dopamine)
LATERAL DORSAL TEGMENTAL NUCLEUS

(Cholinergic)
PEDUNCULOPONTINE TEGMENTAL NUCLEUS

Hypothalamus (Cholinergic)
LOCUS COERULEUS
(Norepinephrine)
TUBEROMAMMILLARY NUCLEUS
(Histamine)
RAPHE NUCLEI
(Serotonin) Pons
Fig. 27.9 Basic sleep onset systems. Diagrammatic representation of the brainstem in the parasagittal plane showing the proposed structures and mechanism involved
in sleep onset. Excited nuclei in the preoptic nuclei of the hypothalamus (the ventrolateral and median preoptic nuclei) use inhibitory neurotransmitters (GABA and
galanin) in reciprocal inhibitory relays with waking centers, and in direct thalamic projections. In addition, gradual inhibition of REM-off cells that function in part
through cholinergic cells of the pedunculopontine tegmental nucleus and lateral dorsal tegmental nucleus complex leads to disinhibition of GABAergic reticular
thalamic nuclei that assist in the generation of NREM sleep through intrathalamic connections to limbic forebrain structures that include the orbitofrontal cortex. Sleep
is also facilitated by the solitary tract nucleus, utilizing unknown neurotransmitters, through direct connections with the hypothalamus, amygdala, and other forebrain
structures. Serotonergic neurons in the midline (raphe) of the medulla, pons, and mesencephalon of the brainstem help modulate sleep. The black circle and lines
indicate inhibitory nuclei and tracts during sleep onset; green circles indicate wakefulness nuclei.
Reproduced from Chest, 141(2), Dyken et al, Sleep-Related Problems in Neurologic Diseases, pp. 528–544, Copyright (2012), with permission from American College of Chest Physicians.
Cerebral cortex
Waking EEG Thalamus
VENTRAL PERIAQUEDUCTAL GREY

(Dopamine)
BASAL FOREBRAIN
(Cholinergic)
LATERAL DORSAL TEGMENTAL NUCLEUS

(Cholinergic)
Hypothalamus
PEDUNCULOPONTINE TEGMENTAL NUCLEUS
(Cholinergic)
(Orexin/Hypocretin) LOCUS COERULEUS
(Norepinephrine)
TUBEROMAMMILLARY NUCLEUS
(Histamine)
Pons
RAPHE NUCLEI
(Serotonin)
Fig. 27.10 Basic wake systems. This diagrammatic representation of the brain/brainstem in the parasagittal plane shows the very basic structures and mechanism
hypothesized to be involved in the generation of wakefulness in humans. There are two ascending independent waking pathways that travel through the
pontomesencephalic junction that eventually lead to diffuse cortical projections: (1) the neuronal tracts and nuclear areas in dark green define a ventral system through
the hypothalamus (involving hypothalamic nuclei in the tuberomammillary nucleus and the lateral hypothalamus, LH), which relays to cholinergic basal forebrain
(BF) cells and the cerebral cortex; and (2) the neuronal tracts and nuclear areas in light green define a dorsal thalamic route that leads to stimulation of thalamic relay,
nonspecific midline and intralaminar nuclei (while inhibiting the reticular nucleus of the thalamus). The orexin/hypocretin neurons in the LH reinforce the waking
activity of all these nuclei and directly innervate the BF (the nucleus basalis, diagonal band of Broca, and medial septal nuclei), and the cerebral cortex. In the BF, there are
cholinergic cells that excite cortical pyramidal neurons and GABAergic cells that inhibit cortical inhibitory neurons (thus disinhibiting the cortex). Both groups are active
during wakefulness and REM sleep, but relatively inactive (or at least less active) during NREM sleep.

THALAMUS
PREOPTIC NUCLEI
SUPRACHIASMATIC NUCLEUS PINEAL GLAND
OPTIC CHIASM
PITUITARY GLAND
PONS
PREOPTIC NUCLEI VENTRAL
(”Sleep switch’’) SUBPARAVENTRICULAR ZONE
(”Wakefulness center’’) CEREBELLUM
PARAVENTRICULAR
NUCLEUS
DORSOMEDIAL
SUPRACHIASMATIC NUCLEUS
NUCLEUS
(”Biological clock’’)
VENTRAL SUBPARAVENTRICULAR ZONE DORSOMEDIAL NUCLEUS
Fig. 27.11 Diagrammatic representation of the brainstem in the parasagittal plane showing the close proximity of the suprachiasmatic nucleus (the “biological clock”)
to the waking and sleep centers of the hypothalamus. The major neuronal pathway mediating the SCN-generated circadian rhythm of sleep and wakefulness is through
a projection to the ventral subparaventricular zone (vSPZ), followed by second-order projection from the vSPZ to the dorsomedial nucleus (DMN). The DMN sends
primarily GABA projections to the preoptic nuclei (the “sleep switch”) and glutamatergic projections to the lateral hypothalamus (the “wakefulness center”). Open
circle: facilitatory.
related to damage to vasopressin-and neurotensin-containing neu- nevertheless, studies suggest that melatonin may promote vasocon-
rons (Fig. 27.11) [98,105]. Stroke affecting these mechanisms can striction [110,111].
disrupt the sleep–wake cycle, classically evidenced as “sundown- Psychoactive medications (thioridazine 25–50 mg or haloperidol
ing”—nocturnal exacerbation of delirium (agitation and confu- 1–2 mg at bedtime) have been used for sundowning, but often cause
sion), often associated with daytime sleepiness [6]‌. orthostasis and extrapyramidal side effects, while benzodiazepines
When addressing dementia, sundowning, and stroke, OSA often exacerbate agitation. Agonists such as zolpidem and zaleplon
should always be considered. A randomized double- blind that preferentially bind to GABAA sleep-promoting receptors in the
placebo-controlled trial utilizing CPAP in 52 men and women frontal cortex may be more effective, with fewer side effects than
with dementia showed significantly improved neuropsychological traditional hypnotics [112].
scores after 3 weeks [106]. Medical problems such as renal and A multicenter double-blind placebo-controlled trial of atypical
hepatic disease, systemic infection, hypovolemia, acid–base and antipsychotics (olanzapine, quetiapine, and risperidone), involv-
electrolyte imbalances, and hypovitaminosis should also be cor- ing 421 subjects with dementia psychosis, aggression, or agitation,
rected. Restricting naps, and incorporating cognitive–behavioral found no significant difference between drug and placebo in out-
strategies emphasizing good sleep hygiene (comfortable, quiet, comes measured by the Clinical Global Impression of Change, but
dark sleep environment), can reduce nighttime behavioral there was a significant increase in adverse events with every anti-
disturbances [107]. psychotic compared with placebo [113]. In addition, risperidone
Light is a powerful zeitgeber (external cue synchronizing the may increase cerebrovascular disease risk in older patients [114].
sleep–wake cycle). Sundowning tends to be worse when daytime
illumination is low. Exposure to bright light may help optimize the
sleep–wake cycle (the best time has not been defined). Increasing Stroke and parasomnia
activities with outdoor sunlight exposure is valuable. A 14-week REM sleep behavior disorder (RBD) generally occurs in older men,
intervention trial showed benefits of daytime physical activity when with violent behaviors from REM sleep, followed by arousals where
combined with improved nighttime sleep hygiene practices [108]. the patient describes dreams paralleling observed behaviors (iso-
Anecdotes report successful sundowning treatment with pro- morphism), with up to 77.1% reporting dream-related injuries [6]‌.
pranolol, trazodone, and clonidine, but general avoidance of nar- Normally, REM sleep is associated with relative paralysis prevent-
cotics, sedative–hypnotics, H2 receptor blockers, anti-parkinsonian ing dream enactment. This is due to activated pontine “REM sleep-
medications, and anticholinergics is recommended, as all have been on” cells that project caudally to stimulate medullary centers in the
associated with delirium [109]. A majority of 30 stroke patients brainstem that subsequently inhibit alpha motor neurons in the
with sleep rhythm disorders had “good results” with melatonin; spinal cord (Fig. 27.12) [98].

Cerebral Cortex
REM EEG Thalamus
LATERAL NUCLEUS
(Orexin/Hypocretin)
Hypothalamus REM-on cells

(Glutamatergic)
PRECOERULEUS REGION
MEDIAL PARABRACHIAL NUCLEUS
SUBCOERULEUS AREA
BASAL FOREBRAIN
(Cholinergic and GABAergic)
REM-off cells PROPOSED

(GABAergic) RBD LESION SITE
VENTRAL PERIAQUEDUCTAL GRAY (Glutamatergic)
LATERAL POTINE TEGMENTUM SUBCOERULEUS AREA
NUCLEUS GIGANTOCELLULARIS
ANTHERIOR HORN CELLS
Fig. 27.12 This parasagittal section of the brain and brainstem shows the suspected pathology explaining RBD, based upon the recently proposed “flip-flop” model
of sleep state transitions by Saper et al. [115]. In normal REM sleep, glutamatergic REM-on cells in what would be considered the subcoeruleus area (SCA) in cats
and the sublaterodorsal nucleus (SLD) in rats (an area presently not well defined in humans), directly and indirectly (through the nucleus gigantocellularis, one of the
ventromedial groups of reticular nuclei in the medulla oblongata) cause hyperpolarization of anterior horn cells in the spinal cord, resulting in atonia. From animal studies,
it has been hypothesized that in RBD, degeneration of the SCA disrupts descending tracts that would normally lead to atonia/paresis, thus allowing violent behaviors
during REM (dreaming/paralyzed) sleep. Black circles and lines nuclei and neuronal tracts normally inhibited during REM sleep; green circles and lines indicate nuclei and
neuronal tracts normally activated during REM sleep; the rectangle indicates the proposed lesion site in RBD.
Atonia of REM sleep is dependent upon two brainstem systems: a inhibitory motor systems), as REM without atonia (a classic PSG
motor-inhibitory system (activated in REM sleep) and a motor- finding in RBD) tends to persist after successful clonazepam treat-
excitatory system (inhibited in REM sleep) [115,116]. Experiments ment. Therapy also includes providing a safe sleeping environment
suggest that the motor-inhibitory system uses midbrain atonic (mattress on the floor, etc.) [119].
regions to control caudal brainstem areas. A stroke affecting these
atonic regions anywhere from the mesencephalon to their point of Stroke and sleep-related movement
colocalization with the excitatory motor system (the subcoeruleus
area) could lead to RBD (reported with stroke affecting the pontine disorders
tegmentum bilaterally and in unilateral right paramedian pontine Restless legs syndrome (RLS), defined by the acronym “URGE”—
tegmental infarction) [116,117]. Urge to move (usually legs), worse Resting, relieved by Going
Clonazepam successfully treats up to 90% of idiopathic RBD, and (moving limbs), and most disturbing in the Evening—can lead to
its recommended use in RBD with neurodegenerative disorders problems with insomnia, sleepiness, concentration, memory, mo-
such as Parkinson disease has been without significant tolerance tivation, anxiety, and depression [6]‌. PSG-defined periodic limb
or abuse [6,118]. Although significant improvements are usually movements during sleep (PLMS) are found in up to 90% of RLS
noticed within a week using 0.5–1.0 mg, it could precipitate sun- patients. If they cause insomnia and sleepiness, periodic limb
downing or exacerbate OSA. Taking clonazepam 2 hours prior to movement disorder (PLMD) is diagnosed.
sleep may also address insomnia, restless legs syndrome, and/or Walters and Rye suggest that sympathetic hyperactivity asso-
periodic limb movements in sleep, and reduce the risk of morning ciated with RLS/PLMS may lead to hypertension, heart disease,
hangover effects. and stroke [120]. Case reports document RLS/PLMS with basal
Clonazepam’s benefits in RBD may be from a “serotonergic ganglia infarctions involving the lenticulostriatum [121]. Sechi
effect.” Lesions in the raphe nucleus (which is the source of brain et al. hypothesized that a “lesion in this area (nuclear complex
serotonin) increases REM sleep phasic motor activity [119]. The or fiber systems) may exert both an ascending disinhibition on
serotonin effect is suspected to be inhibition of a specific excita- sensorimotor cortex, and a disinhibition of descending inhibi-
tory motor system for RBD (rather than a general excitation of tory pathways, resulting in a facilitation of RLS and PLM.” This

OBSTRUCTIVE
SLEEP APNEA
Hypercapnia Parasympathetic
Hypoxia
thoracic stretch activity
HR
BP
Sinus arrest
SNA HR
BP
Atrial fibrillation
Insulin resistance Diabetes mellitus
AROUSAL
STROKE
Blunted dipping Chronic

of BP hypertension
Platelet activation Thrombus

and aggregation embolus
Fig. 27.13 This over-simplistic diagram highlights some of the major suspected factors linking OSA, arousal, and stroke. OSA can lead to autonomic instability.
Inspiration against a closed airway with hypoxemia can increase parasympathetic activity, potentially leading to bradycardia, sinus arrest, and hypotensive events.
Increased sympathetic neural activity (SNA) from the reflex effects of hypoxia, hypercapnia, and decreased input from thoracic stretch receptors can lead to tachycardia,
blood pressure surges, and potentially to arrhythmias such as atrial fibrillation. While an acute arousal can be protective in preventing untoward effects of a single
prolonged apnea, chronic concomitant SNA elevations have been hypothesized to help explain the known associations with a variety of stroke risk factors, including the
development of thrombus/emboli, diabetes mellitus, and chronic hypertension.
Reproduced from Dyken ME, Richerson GB, Im KB, Sleep apnea, stroke risk factors, and the arousal response. In: Culebras A, [ed], Sleep, Stroke, and Cardiovascular Disease, Copyright (2013), with
permission from Cambridge University Press.
is consistent with evidence relating RLS/PLMS to dopamine cause-and-effect relationships exists between OSA and stroke, the
deficiency/dysfunction. The ventral striatum receives its major known pathophysiology of untreated OSA mandates therapeutic
dopaminergic innervation via mesolimbic pathways from mesen- intervention whenever reasonably possible (Fig. 27.13). Symptoms
cephalic A10 cells of the ventral tegmentum. Correction of the of OSA often suggest other primary sleep disorders. If OSA is ruled
deficiency/dysfunction may explain successful treatment of post- out, good sleep hygiene practices through the implementation of
stroke RLS/PLMS with dopamine agonists [122]. Levodopa is cognitive–behavioral techniques should be considered, as stroke
associated with augmentation (chronic therapy worsening RLS), patients may be prone to the adverse effects of many medications
whereas agonists specific for the D2 family of dopamine receptors otherwise routinely used to treat sleep-related problems.
may reduce augmentation [123].
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CHAPTER 28
Sleep and epilepsy

Lino Nobili, Paola Proserpio,
Steve Gibbs, and Giuseppe Plazzi
Introduction Indeed, during NREM sleep, the discharges may spread ipsilat-
erally and contralaterally from the primary focus, whereas during
The relationship between sleep and epilepsy has intrigued research- REM sleep, the discharges seem to focalize maximally (Fig. 28.2),
ers and thinkers since antiquity. Descriptions of episodes of epi- especially in temporal lobe epilepsy [8]â•„.
leptic seizures occurring during sleep can be found in the extant From a physiological point of view, NREM sleep seems to act as a
writings of both Aristotle and Hippocrates. Yet, a precise account of proconvulsant because this state is characterized by diffuse cortical
seizure occurrence in relation to the sleep–â•‰wake cycle was revealed synchronization mediated by the thalamocortical input, which can
only at the end of the nineteenth century when pioneer studies favor an already hyperexcitable cortex to generate seizures. On the
derived from clinical observations revealed that seizure occurrence other hand, during the transition to REM sleep, inputs from activat-
did not follow a random distribution over the 24 hours but rather ing cholinergic pontine REM-â•‰on cells lead to a relative depolariza-
clustered at certain times of the day [1–â•‰3]. Following these pivotal tion of the thalamocortical cells, thus blocking the thalamocortical
observations, further advances in the field were brought about by oscillations in both the spindle and the delta range and giving rise
the development and wider use of the EEG. In 1947, in a landmark to a low-â•‰amplitude desynchronized EEG pattern (slow α and θ
paper [4]â•„, Gibbs and Gibbs reported that sleep could activate epi- frequencies) [10]. Such a desynchronized state reduces the spread
leptiform discharges on the EEG. of EA, thereby reducing its visibility on the scalp EEG, as well as
In recent years, the combination of clinical and EEG observa- reducing seizure occurrence. This also explains the attenuation of
tions along with advanced brain imaging and signal analysis meth- bilaterally synchronous epileptiform discharges during REM sleep.
ods has confirmed and helped to further understand the complex The descending brainstem pathways responsible for lower motor
and reciprocal interactions between sleep and epilepsy. neuron inhibition during REM sleep also appear to protect against
In this chapter, an overview of the relationships between sleep generalized motor seizures during REM sleep [11]. As for gener-
and epilepsy will be presented, focusing on the strong link between alized epilepsy, REM sleep has been considered the most potent
the physiology of the sleep state and the pathological mechanisms antiepileptic state in the sleep–â•‰wake cycle. Notably, Cohen et al.
of epileptic seizures. found a lowered convulsive threshold during REM deprivation in
cats [12]. REM deprivation may thus exacerbate epilepsy.
Interrelationship between sleep and Furthermore, Busek et al. found a negative correlation between
the occurrence of rapid eye movements during REM sleep and EA
epilepsy: physiological mechanisms on the scalp [13], suggesting that the desynchronizing effect of this
Neuronal synchronization and interactions between neurons and stage of sleep seems to be accentuated during phasic REM sleep
neuronal populations are the basic features of brain function. events, probably as a consequence of a further cholinergic activity
Alterations of synchronization and neuronal hyperexcitability are increase caused by phasic disinhibition of cholinergic neurons of
also central factors in epilepsy that may transform an interictal state the pontomesencephalic tegmentum.
to an ictal one [5]â•„. Factors enhancing synchronization are condu- Different clinical studies have revealed that in the majority of
cive to active ictal precipitation in susceptible individuals. These focal and generalized epilepsies, during NREM sleep, interictal
factors include nonspecific influences, such as sleep and sleep EAs are more likely to occur and propagate to other brain regions.
deprivation. However there are considerable controversies surrounding the
Sleep consists of repetitive cycles where NREM and REM sleep issue of whether light NREM or deep NREM sleep exerts a stronger
alternate with a periodicity of about 90–â•‰100 minutes. These two facilitating effect on spiking. Data from the literature suggest that
neurophysiological conditions (NREM and REM) generally exert this may depend on the type of epilepsy syndrome being studied.
opposite effects on interictal and ictal epileptic activity (EA). Indeed, it has been observed that in a range of focal childhood epi-
Indeed, many studies show that NREM sleep can enhance visuali- leptic syndromes characterized by a marked activation of interictal
zation of interictal epileptiform discharges (IEDs) on the scalp EEG spikes during NREM sleep (benign rolandic epilepsy, Landau–â•‰
in both partial and generalized seizures, while REM sleep reduces Kleffner syndrome, and electrical status epilepticus during sleep),
the production and spread of EA (Fig. 28.1) [6–â•‰9]. interictal EA seems to be modulated mainly by spindle oscillatory

Wakefulness NREM sleep REM sleep
Fig. 28.1 Scalp EEG during the sleep–wake cycle in an epileptic child. In this example, no clear epileptiform discharges are visualized during wakefulness and REM sleep.
On the contrary, NREM sleep is a known enhancer of interictal epileptiform discharges (IEDs) on scalp EEGs. Bursts of IEDs are visible (and more diffuse) during NREM
sleep. EEG recorded according to the 10–20 international nomenclature. EOG, electro-oculogram; MILO, chin electromyography; TIB SX, left tibialis electromyography;
TIB DX, right tibialis electromyography.
Wakefulness NREM sleep NREM sleep REM sleep
1 Fp1-F7
2 F7-T3
3 T3-T5
4 T5-O1
5 Fp2-F8
6 F8-T4
7 T4-T6
8 T6-O2
9 Fp1-F3
10 F3-C3
11 C3-P3
12 P3-O1
13 Fp2-F4
14 F4-C4
15 C4-P4
16 P4-O2
17 Fz-Cz
18 Cz-Pz
31 Eaa
32 Milo
Fig. 28.2 Scalp video-EEG monitoring during the sleep–wake cycle of a patient with pharmacoresistant focal epilepsy. In this example, the scalp EEG during wakefulness
is within normal limits. During NREM sleep, IEDs are clearly evident, but appear asynchronously in the right and the left frontotemporal regions (and are therefore
nonlocalizing). During REM sleep, the IEDs are more circumscribed and located in the right temporal region, localizing to the known MRI lesion. The inset at lower left is
a brain MRI coronal section showing a hypersignal in the right fronto-operculo-insular region compatible with a focal cortical dysplasia. EEG recorded according to the
10–20 international nomenclature. Eog, electro-oculography; Milo, chin electromyography.

Chapter 28 sleep and epilepsy 281
(a) of synchronization as expressed by the CAP [19,20] . Intracerebral

100 5 recordings of this phenomenon show that during these intervals of
the sleep–wake cycle, brain activity is in a transitional unbalanced
Sigma activity (µv2/Hz)

4
Number of spikes
75 state, showing important fluctuations in the level of synchroniza-

3 tion, both spatially and temporally, with the possible coexistence of
50 sleep-like and wake-like electrophysiological activity [21,22]. These
2
features seem to constitute the electrophysiological substrate favor-
25 ing the occurrence of seizures during sleep [23].
1
Video-EEG studies have shown that the distribution of focal-
0 0
0 20 40 60 80 100 120 onset seizures throughout the sleep–wake cycle is influenced mainly
by the location of the epileptogenic zone: frontal lobe seizures are
Time (minutes from sleep onset) Spikes (TS)
Sigma activity more likely to occur during sleep, whereas patients affected by tem-
poral lobe epilepsy or with a posterior epilepsy (originating from
(b)
Rem
the occipital or parietal lobes) have a reduced probability of sleep-
S4 related seizures [18]. On the other hand, temporal lobe seizures
S3 tend to generalize more frequently during sleep.
S2
S1 Specific histopathology has also been linked to sleep-related sei-
W
zures, more precisely to sleep-related hypermotor seizures. Case
(c) series of patients with pharmacoresistant seizures have associated
100 400 a common epileptogenic lesion, namely, type II focal cortical dys-
plasia (FCD) or Taylor type, with a significant increase in sleep-
75 300 related seizures—much more so than for other histopathological
Number of spikes
SWA (µv2/Hz)
substrates, regardless of its location inside the brain [24].

50 200 Since many MRI-negative cases of pharmacoresistant patients
with sleep-related seizures submitted to surgical intervention are
25 100 associated with type II FCD after histopathological analysis, it has
been suggested that the propensity of some type II FCDs to mani-
0 0 fest during sleep might be partly related to their size [25]. Indeed,
0 20 40 60 80 100 120
a small type II FCD might not be able to recruit sufficient non-
Time (minutes from sleep onset) Spikes (TS) dysplastic cortex for seizure propagation during wakefulness owing
SWA to a low critical mass of neurons, and therefore hijacks the sleep
Fig. 28.3 Spectral analysis of the scalp EEG signal during the first two sleep cycles oscillatory mechanisms during the night in order to manifest itself
of the night in a patient with Landau–Kleffner syndrome. (a) Temporal series [25,26].
of the number of spikes/min plotted against sigma activity (SA, bold line). On
scalp EEG, interictal spikes follow the SA distribution from sleep onset, suggesting
modulation of the interictal spikes by the spindle oscillatory mechanisms.
Clinical features
(b) Representative hypnogram during the first two sleep cycles of the night. Sleep has a well-documented and strong association with syn-
(c) Temporal series of spikes/min plotted against slow-wave activity (SWA, dromic and nonsyndromic epilepsies (Table 28.1). The current
bold line). Note the discrepancy in the distribution of spikes in relation to SWA ILAE classification highlights the fact that specific epileptic syn-
compared with the SA in (a).
dromes have a particular tendency for seizures to present exclu-
Adapted from Epilepsia, 41, Nobili L, Baglietto MG, Beelke M, De Carli F, De Negri E,
Tortorelli S, Ferrillo F, Spindles-inducing mechanism modulates sleep activation of interictal
sively or predominantly during sleep or upon wakening. Here we
epileptiform discharges in the Landau-Kleffner syndrome, pp. 201–206, Copyright (2000), discuss their electroclinical features.
with permission from John Wiley and Sons.
Grand mal seizures on awakening
Awakening epilepsy [27] is an age-related syndrome of idiopathic
mechanisms (mostly evident in the N2 stage of sleep; Fig. 28.3) generalized epilepsy characterized by generalized tonic–clonic
[14–16]; conversely, in adult focal epilepsies, interictal EA is gener- seizures (GTCS) occurring predominantly on awakening (inde-
ally modulated by ultraslow arousal fluctuations (expressed by the pendently of the time of day). The EEG is characterized by frequent
so-called cyclic alternating pattern, CAP; Fig. 28.4) and follow the generalized spike waves, rare focal abnormalities, and increased
intra-night dynamics of EEG delta activity (Fig. 28.5) [17]. photosensitivity. The common denominator among external influ-
It is frequently stated that it is the increase in neuronal syn- ences precipitating seizures is lack of sleep. With regard to sleep
chronization by the thalamocortical system that favors seizure habit, patients with awakening epilepsy can roughly be described
occurrence during NREM sleep. However, clinical studies clearly as late sleepers and late risers, which may predispose them to a
show that sleep-related seizures occurring during NREM sleep chronic sleep deficit. Polygraphic studies have shown the presence
occur predominantly in stage N2 (61–68%) and not during N3 or of a disturbance in sleep stability in these patients.
slow-wave sleep, where the maximum level of synchronization is
achieved (9–14%) [18]. Independently of NREM sleep stage, elec- Juvenile myoclonic epilepsy
troclinical studies have shown that seizures occur mostly during Juvenile myoclonic epilepsy (JME) is a prototype of idiopathic
transitional unstable states, when the EEG shows fluctuating levels generalized epilepsy, commonly presenting with myoclonic jerks

A B A
Fig. 28.4 (See colour plate section) Intracerebral EEG recording during NREM sleep in an adult patient with pharmacoresistant mesial temporal lobe epilepsy. During the
A phase of CAP (dotted boxes) IEDs in the mesial temporal lobe (lower MRI image) are more numerous and spread to the orbital region (upper MRI image). During the
B phase of CAP, IEDs are reduced and circumscribed to the temporal lobe.
8 during adolescence, and is characterized by a strong genetic pre-

Delta power
(0.5-4.0 Hz)
Spikes/minute disposition [28]. Generalized tonic–clonic seizures can occur inde-
12 pendently or precede the myoclonus. Seizures tend to occur in the
Delta power (arbitrary values)
6 early morning hours shortly after awakening, with a second peak

of occurrence in some patients in the early evening. Myoclonic
Spikes/minute
8
seizures can be subtle and overlooked for many years as simple
4 clumsiness. These patients also have daytime absence seizures with
staring spells, which can mimic daytime sleep attacks. Patients
may be exceedingly sensitive to sleep deprivation and alcohol con-
2
4 sumption. Using transcranial magnetic stimulation, it has been
shown that cortical excitability is increased early in the morning in
patients with idiopathic generalized epilepsy, particularly in JME,
but not in subjects with focal epilepsy or controls without epilepsy
0 60 120 180 240 300 360 420 [29]. This finding may explain the increased seizure susceptibil-
Time (minutes) ity in these patients at this time of the day. Interictal discharges
in these patients are prominent at sleep onset and on awakening.
Fig. 28.5 Spectral analysis of the scalp EEG signal during the whole night in During NREM sleep, EA is facilitated by arousal fluctuations [30],
a patient with temporal lobe epilepsy. IEDs (dotted line) follow the temporal
and conversely it may promote sleep instability which will foster
distribution of delta power (full line) and its known decay during the night.
further EA, and conceivably seizures.

Table 28.1 Sleep-related epilepsies Benign epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes is the most common
Generalized epilepsies and syndromes
partial epilepsy syndrome in the pediatric age group, with an onset
Grand mal seizures on awakening between ages 3 and 13 years and with remission in adolescence
Juvenile myoclonic epilepsy [37]. The clinical seizures are characterized by focal clonic facial
seizures, often preceded by perioral numbness. In many cases,
Lennox–Gastaut syndrome
patients have generalized tonic–clonic seizures that appear to be
West syndrome a secondary generalization. On occasion, there is speech arrest.
Focal epileptic syndromes Consciousness is preserved. The seizures are mostly nocturnal,
with 55–59% of patients having seizures exclusively during sleep.
Benign epilepsy with centrotemporal spikes
The EEG shows centrotemporal or rolandic spikes or sharp waves
Childhood epilepsy with occipital paroxysms with the typical morphology of a triphasic sharp wave of high
Nocturnal frontal lobe epilepsy* amplitude localized to the centrotemporal region but sometimes
spreading to the contralateral hemisphere. The activation of inter-
Undetermined (focal or generalized) epileptic syndromes
ictal epileptic discharges (IEDs) by NREM sleep is a well-known
Epileptic encephalopathy with continuous spikes and slow waves during slow feature of benign epilepsy of childhood with rolandic spikes [38].
sleep (CSWS/ESES) The discharge rate is increased during drowsiness and light sleep
Landau–Kleffner syndrome when compared with the waking record, with no change in spike
morphology. Despite the increased frequency of seizures and inter-
* Sleep-related complex motor attacks can also have an extrafrontal origin.
ictal EA during sleep, the sleep architecture is not affected and no
sleep disruption is seen in these children [39]. The response to
medication is excellent and the epilepsy prognosis is universally
Lennox–Gastaut syndrome
benign. However, mild neuropsychological deficits may be seen
In Lennox–Gastaut syndrome, the clinical features consist of when interictal EA during sleep is high [40].
multiple primary generalized seizure types, including prominent
nocturnal tonic, astatic/atonic, atypical absence, myoclonic, and Childhood epilepsy with occipital paroxysms
generalized tonic–clonic seizures with accompanying psycho- Panayiotopoulos syndrome is an interesting benign epilepsy syn-
motor and cognitive maldevelopment [31]. Tonic seizures, typi- drome seen in children aged 2–6 years and is approximately half
cally activated by sleep, are much more frequent during NREM as common as rolandic epilepsy [41] Autonomic seizures and
sleep than during wakefulness, and are never seen during REM autonomic status epilepticus are the main clinical manifestations.
sleep. They may only be characterized by subtle and frequently Seizures are characterized by autonomic instability (thermoregula-
undetected brief apneas, but are often very frequent, being asso- tory alterations, tachycardia, hyperpnea, high blood pressure, and
ciated with characteristic paroxysmal fast activity on EEG; such pallor), frequently accompanied by nausea and emesis. Seizures
sleep-related tonic seizures are seen in over 90% of patients with mostly start in sleep, with the child waking up or found confused
Lennox–Gastaut syndrome. EEG typically demonstrates slow or unconscious [42]. The same child may have seizures both during
spike-and-wave complexes at 1.5–2.5 Hz, multifocal epileptiform sleep and during wake. Impairment of consciousness is typically
abnormalities, and generalized background slowing [32]. In sleep, followed by prolonged periods of eye deviation, which can last from
the spike-and-wave discharges characteristically increase in NREM minutes to hours in the case of status epilepticus. Interictal EEG
sleep and may be intermixed with trains of fast spikes of 10–25 Hz shows a predominance of interictal multifocal spikes with a pref-
lasting 2–10 seconds (so-called grand mal discharges) as interictal erence for occipital paroxysms (more than 50%). Electrographic
abnormalities [33]. seizures also seem to emanate from the occipital region during
these events. Sleep typically accentuates the spike abnormalities.
West syndrome (infantile spasms) Panayiotopoulos syndrome has a very benign course, with com-
In West syndrome, spasms consist of brisk myoclonic-like muscle plete spontaneous remission within a few years. The majority of
contractions, in flexion or extension, that usually start between patients do not require any antiepileptic treatment, which is best
3 and 7 months of age [34]. They are usually repeated in clusters reserved for more severe and distressing cases [42,43].
and are usually observed in relation to arousal from sleep or before
going to sleep. The characteristic high-amplitude “hypsarrhythmic” Epileptic encephalopathy with continuous spikes
interictal EEG pattern is seen most prominently in NREM sleep, and waves during slow sleep
particularly at onset, which therefore constitutes the best period in Epileptic encephalopathy with continuous spikes and waves during
which to perform a diagnostic EEG [35]. Less than 3% of spasms slow sleep (CSWS), formerly known as electrical status epilepticus
occur during sleep [34]. However, clusters of subclinical ictal EEG during sleep (ESES), is a disease of childhood characterized by a
discharges not associated with motor spasms may occur during triad of epilepsy, cognitive or behavioral impairment, and continu-
REM sleep and may become associated with clinical spasms if the ous spike-and-wave EEG discharges during slow-wave sleep [44].
patient awakens from REM sleep during the cluster [36]. Response All-night PSG study is necessary for diagnosis. In this syndrome,
to treatment is variable, and a majority of patients continue to have it is the dramatic decline of the neuropsychological state that is the
seizures at follow-up, sometimes evolving into Lennox–Gastaut most disturbing and problematic clinical feature. The regression of
syndrome, and with a poor developmental outcome. skills is usually of insidious onset and progressive.

Most diagnosed patients have a prior history of epilepsy. The quickly recognized as a genetically heterogeneous disorder, since
characteristic EEG finding consists of 2.0–2.5 Hz generalized spike- most of the described families did not show mutations in CHRNA4,
and-wave discharges seen during at least 85% of NREM sleep and and new loci and genes were reported in the following years. In
greatly reduced during REM sleep. Occasional bursts of spike-and- particular, another linkage site was later reported at chromosome
wave discharges or focal frontal spikes are seen during REM sleep. 15q24, and mutations were found in CHRNB2, the gene encod-
There are a few bursts of generalized spike-and-wave discharges ing for the B2 subunit of the ACh neural receptor and localized
seen in the EEG during wakefulness. These EEG discharges disrupt on chromosome 1. Another linkage locus at chromosome 8p12.3–
the stages of NREM sleep. In particular, the vertex sharp waves, K 8q12.3 and a missense mutation in the gene CHRNA2 encoding
complexes, and spindles are usually difficult to recognize. However, the neural ACh receptor A2 subunit have been reported in familial
a normal cyclic pattern of REM–NREM persists. Generally, no seizures characterized by complex ictal behavior resembling epilep-
sleep disturbances are observed, but some children have difficulty tic nocturnal wanderings, as well as mutations in the corticotropin-
awakening in the morning [45]. releasing hormone gene (for a review, see [54]).
CSWS is now considered an epileptic encephalopathy of child- The findings of genetic alterations of the cholinergic system may
hood. The EEG findings of continuous epileptic discharges gener- give some insight into the relationships among genes, epileptogen-
ally disappear within three years of appearance. Focal abnormalities esis, and arousal-regulating processes. Indeed, the nAChR are ex-
in the EEG may persist, however. It is not clear whether CSWS is a tensively distributed in the brain and contribute to the regulation
focal epilepsy or a generalized epilepsy with heterogeneous presen- of sleep and arousal oscillations, at both the cortical and subcor-
tation, and hence it is classified under the category of undetermined tical levels. Experimental studies have shown that a mutation of the
epileptic syndromes. Seizures show a benign course and respond nicotinic receptors may facilitate the occurrence of an unbalanced
well to antiepileptic medications, with disappearance of seizures by excitation/inhibition circuitry within GABAergic reticular thal-
the mid-teens. The psychological impairment, however, persists. amic neurons, thus generating seizures through the synchronizing
effect of spontaneous oscillations in thalamocortical connections
Landau–Kleffner syndrome [55]. Conversely, other experimental investigations have shown a
Landau–Kleffner syndrome (LKS) is an acquired disorder with epi- physiological involvement of nAChR in the regulation of NREM
leptic aphasia in which children, usually 3–8 years of age, who have and REM stability, notably in the regulation of transient events
developed age-appropriate speech experience language regres- such as microarousals [56]. Thus, it seems that a genetic alteration
sion with verbal auditory agnosia, abnormal epileptiform activity, observed in NFLE might facilitate both the epileptogenesis and the
behavioral disturbances, and sometimes overt seizures [46]. There occurrence of arousal instability. With these assumptions, the high
are several similarities between ESES and LKS. In both conditions, prevalence of parasomnias in the personal and family histories of
a normal EEG background during wakefulness, with generalized individuals with NFLE [57] might rely on a common alteration of
spike-wave discharges or focal epileptiform activity, can be found. the arousal-regulating system. However, ADNFLE is related not
However, in ESES, discharges during sleep are generalized, while in only to mutations in the cholinergic system. Since 2005, other
LKS, spike waves tend to be more localized in the temporal deri- genes, not belonging to the nACh receptor subunit family, have
vations. Compared with ESES, patients with LKS also have fewer been identified (the corticotropin-releasing hormone gene, a gene
seizures, as well as more focal cognitive impairment and less psy- encoding the sodium-activated potassium channel subunit 1, and
chological impairment. Consequently, overall prognosis is usually the DEPDC5 gene) [51,58,59].
better in LKS [47]. From a clinical point of view, given the high intra-familial vari-
ability and overlapping features of the clinical manifestations,
Nocturnal frontal lobe epilepsy ADNFLE patients do not show a clear distinction from sporadic
Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heteroge- NFLE cases, except for certain ADNFLE mutations frequently
neous etiology, with genetic, lesional, and cryptogenetic forms hav- associated with specific additional neurological or psychiatric
ing been described [48–50]. NFLE is usually considered a benign symptoms. In the great majority of NFLE patients, seizures begin
clinical epileptic syndrome because seizures occur almost exclu- before the age of 20 years, with a peak during childhood, although
sively during sleep, and in the majority of patients pharmacological onset during adulthood has been also reported. Seizure frequency
treatment is effective; however, severe and drug-resistant forms, oc- is usually high, and patients generally experience many seizures
casionally associated with mental retardation, have been described a night, although the frequency may diminish during adult-
[51]. Although heterogeneous, NFLE is a syndrome that has been hood. Of note, occasional seizures during wakefulness can occur.
extensively studied and characterized during recent decades. Subjective seizure manifestations, uncommon during the night,
In the 1990s, the occurrence of sleep-related motor attacks in have been reported by patients during these diurnal events; how-
numerous individuals belonging to the same family was observed, ever, frontal auras generally have poor localizing and lateralizing
and the definition of autosomal dominant nocturnal frontal lobe values [48,49,54].
epilepsy (ADNFLE) was introduced for the first time [52]. The NFLE patients may show different sleep-related motor events
genetic origin of the disease was confirmed by a linkage study in of increasing complexity and duration, even during a single night.
Australian kindred. More specifically, a locus was identified at chro- These include (1) short-lasting (2–4 seconds) stereotyped move-
mosome 20q13.2–q13.3, and two different mutations were detected ments involving the limbs, the axial musculature, and/or the head
in the gene (CHRNA4) encoding the α4 subunit of the neuronal [60,61]; (2) paroxysmal arousals (PAs), characterized by sudden
nicotinic acetylcholine receptor (nAChR) [53]. Three de novo or and brief arousals (5–10 seconds in duration) sometimes accom-
inherited CHRNA4 mutations, occasionally associated with mild panied by stereotyped movements, vocalization, frightened ex-
to moderate mental retardation, were later reported. ADNFLE was pression, and fear [62]; (3) major attacks, lasting 20–30 seconds,

characterized by asymmetric tonic or dystonic posturing, or 3 Hz, alternating with short bursts of fast discharges interrupted by
complex movements such as pelvic thrusting, pedaling, choreo- suppression of activity. These bursts of fast discharges are relatively
athetoid, and ballistic movements of the limbs [49]; (4) epileptic rare and sporadic during wakefulness, but become numerous dur-
nocturnal wandering, consisting of ictal deambulatory behaviors ing slow-wave sleep, when they tend to recur pseudoperiodically
often associated with a frightened expression and fear [63]. The and often spread over surrounding nonlesional areas and develop
increasing complexity of NFLE ictal motor behaviors, from minor into a seizure.
to major events, reflects different durations and propagations of With regard to the pharmacological treatment of NFLE, the first-
the discharge within the frontal lobe [62]. Owing to the recurrence choice drug is carbamazepine, which can be administered before
of nocturnal motor events, some NFLE patients may complain of sleep, resulting in satisfactory seizure control in this population.
nonrestorative sleep and of daytime sleepiness. Other drugs have shown efficacy in the treatment of NFLE, but
Studies with intracerebral electrodes (stereo-EEG) conducted in usually as a second choice: topiramate, oxcarbazepine (OXC), and
drug-resistant patients with NFLE have shown that seizure onset levetiracetam (LEV). It has been shown that surgery can also pro-
in patients with asymmetric tonic or dystonic posturing is gen- vide excellent results in drug-resistant NFLE patients, with 76% of
erally localized in the posterior portion of the frontal cingulated cases being completely seizure-free [64].
gyrus and in the posterior mesial frontal cortex with a primary Many of the differences between NFLE and non-epileptic sleep-
involvement of the supplementary motor area [64]. In patients related events have now been clarified, and a number of clinical
with seizures characterized by hyperkinetic automatisms and com- features have been categorized to help physicians in the differen-
plex motor behaviors, the region of seizure onset may involve the tial diagnosis (Table 28.2). However, considering the similarities
dorsolateral and anterior frontal regions (frontopolar and frontal and the possible coexistence of parasomnias in people with NFLE,
anteromesial regions). Seizures characterized by the association of the diagnostic process may be complicated, especially if it is based
fear and nocturnal wandering seem to involve a cerebral network only on anamnestic investigations. Efforts to obtain a systematic
including the anterior cingulate, orbitopolar, and temporal regions. assessment of the diagnostic reliability of clinical history have led to
Some of these clinical manifestations have been interpreted as a re- two instruments: the Frontal Lobe Epilepsy and Parasomnias Scale
lease of inhibition (provoked by the seizure) of innate behavioral (FLEPS) [72] and the Structured Interview for NFLE [73]. Despite
automatisms and survival behaviors, programmed in cortical and their clinical usefulness, these tools are limited by contradictory
subcortical central pattern generators [65]. diagnostic accuracy.
Often, interictal and ictal scalp EEG features of NFLE patients are Sleep V-PSG is unanimously considered the “gold-standard”
uninformative, owing to the inaccessibility of much of the frontal diagnostic test, but it is expensive, with limited availability, and
lobes to surface electrodes and to the presence of movement arti- does not always capture the event in a single-night recording.
facts related to seizures [49,64]. Moreover, the reduced contribu- Moreover, even when the nocturnal episode has been recorded,
tion of scalp EEG is accompanied by a low incidence of significant the diagnosis can remain doubtful because ictal scalp EEG often
MRI findings, even in symptomatic cases. fails to disclose epileptiform abnormalities or because the episode
In recent years, it has been shown that sleep-related complex captured is a minor motor event for which the diagnosis is not re-
motor attacks, similar to those occurring in NFLE patients, may liable, even among experts. To make video analysis of nocturnal
also originate from the temporal lobe [66,67], the insular–opercular paroxysmal events more reliable, a diagnostic algorithm focusing
region [68], and the posterior cerebral regions [69] rendering the on the semiological features of the arousal parasomnias and NFLE
term NFLE somewhat misleading. To address this issue and the has been proposed [74]. Despite the limits of V-PSG, the possibility
fact that seizures are not “nocturnal” per se but rather facilitated of analyzing a video of the nocturnal attack remains an important
by NREM sleep, a recent consensus conference has proposed that diagnostic tool, making home video recording a useful adjunct
NFLE be renamed “sleep-related hypermotor epilepsy” (SHE), a when episodes are infrequent, even if the onset of the episode is
term deemed to better represent this heterogeneous syndrome [70]. missed [75].
To identify an extrafrontal onset in NFLE patients, a careful ana-
lysis of aura features may be particularly useful in the differential Comorbidities: epilepsy and sleep disorders
diagnosis of NFLE. Indeed, these patients may report subjective
manifestations that could suggest an origin of seizure outside the Patients suffering from nocturnal epilepsy, and from epilepsy in
frontal lobe, such as epigastric and acoustic sensations, and/or déjà general, can have sleep disorders [76]. These can manifest inde-
vu in temporal lobe onset; laryngeal and throat sensations, dys- pendently from the epileptic events, but can also negatively influ-
arthria, hypersalivation, and diffuse or bilateral cutaneous pares- ence the epilepsy itself; conversely, the expression of sleep disorders
thesias of unpleasant or electrical character in opercular and/or can be negatively influenced by the epileptic condition in a bidir-
insular onset; and visual hallucinations in occipital seizures. ectional influenced system [77]. The possible occurrence of comor-
As stated earlier, studies conducted in patients with drug- bidities also brings about the problem of differential diagnosis, as
resistant epilepsy have shown that type II focal cortical dysplasia previously discussed, because of the potential difficulty in distin-
(type II FCD; Taylor-type cortical dysplasia) is the most frequent guishing referred non-epileptic nocturnal events from epileptic
etiological substrate of NFLE. Regardless of its anatomical localiza- attacks, which in the majority of cases need individualized thera-
tion, frontal or extrafrontal, type II FCD increases the risk of sleep- peutic approaches.
related epilepsy, in particular type IIb [24,71]. During wakefulness,
type IIb FCD shows a peculiar pattern of interictal activity that is Parasomnias
characterized by the occurrence of rhythmic and subcontinuous Parasomnias and epileptic seizures may occur in a subject either
spike and polyspike waves with a frequency usually between 1 and simultaneously or at different times in his or her life, the clinical

Table 28.2 Clinical features useful in the differential diagnosis between unrelated to the epileptic process, possible pathophysiological
nocturnal frontal lobe epilepsy (NFLE) and NREM parasomnia interactions can explain, to a certain extent, the coexistence of the
two pathologies in a non-negligible portion of epileptic patients.
NFLE NREM parasomnia OSA has been seen in up to 10.2% of an unselected group of
patients with epilepsy with no other sleep or cerebral disorder
Age at onset Any age (usually before 3–8 years
the age of 20 years) [81]. In patients with refractory epilepsy, OSA might be even more
frequent, and has been reported in one-third of patients investi-
Family history of Possible Frequently present gated for epilepsy surgery. OSA has also been seen in up to 20%
parasomnias
of children with epilepsy undergoing polysomnography because
Time of occurrence Any time Usually during the of complaints about sleep disturbance [82]. Predisposing factors
during the night first third for OSA in epileptic subjects are male gender, obesity, nocturnal
Sleep-stage onset NREM sleep NREM sleep seizures, and a later age of seizure onset. In general, OSA in epi-
of episodes (usually N2) (usually N3) leptic patients is reported to be mild or moderate. OSA can be
Frequency during one Several episodes/ Usually one episode/ facilitated by weight gain (a well-known risk factor for OSA), as a
night night night consequence of reduced physical activity and of antiepileptic drug
(AED) therapy, for example with valproate (VPA) or carbamaze-
Frequency in a month Almost every night Sporadic
pine (CBZ). Women taking VPA show a significantly increased
Duration Seconds–3 minutes 1-10 minutes risk of polycystic ovarian syndrome, which in turn is associated
Evolution Stable, increased Tend to disappear with obesity and so indirectly can lead to sleep apneas. Some
frequency, AEDs, such as phenobarbital (PB), benzodiazepines (BDZs), and
rare remission possibly phenytoin (PHT), can cause upper airway tone reduc-
Triggering factors Rare Frequent (sleep
tion, thus facilitating sleep apneas. Nonpharmacological treatment
deprivation, febrile of epilepsy with vagus nerve stimulation has also been shown to
illness) worsen OSA. On the other hand, remission of OSA as well as of
seizures has been seen anecdotally in a patient following frontal
Stereotypic motor pattern Yes No
lobe resection [83].
Consciousness if awakened Usually preserved Usually impaired Conversely, OSA can negatively influence epilepsy, because sleep
Recall of the episode on Variable No fragmentation induced by snoring and apneas produces sleep in-
awakening stability (a high CAP index), thus promoting seizure occurrence.
An improvement in seizure control after treatment of OSA with
continuous positive airway pressure (CPAP) has been described
along with a parallel improvement in sleep architecture [84].
pattern of this comorbidity varying according to the patient’s age Therefore, identifying and treating a coexisting breathing disorder
and epileptic syndrome [57,76,78]. in an epileptic patient allows better management of the epileptic
NREM arousal parasomnias have been reported to be com- disease and can direct the neurologist toward a more appropriate
mon in sporadic as well as in familial forms of NFLE. A system- pharmacological choice among the available AEDs.
atic investigation of the presence of NREM arousal parasomnias in
the personal and family histories of subjects with NFLE found this Excessive daytime sleepiness
comorbidity to be present in up to 34% and 39%, respectively [57]. Epileptic patients frequently complain of excessive daytime sleepi-
As previously stated in the discussion of NFLE, it can be hypoth- ness (EDS). This is found in about 30–50% of people with epilepsy
esized that these two disorders, even if etiologically different, could [85] and may result from clinical seizures, particularly nocturnal
share a common, possibly genetically determined, pathophysio- seizures and ictal or interictal EEG epileptiform discharges; comor-
logical substrate involving a defective arousal system favoring the bid conditions; and effects of antiepileptic medication. The AEDs
occurrence of both disorders [79]. Although not yet identified, the most commonly associated with EDS are PHT, BDZs, and gabap-
cholinergic system and related pathways could represent a model entin (GBP). Frequently used AEDs that are less sedating are CBZ,
unifying the pathogenesis of both disorders. It has been further VPA, topiramate (TPM), and lamotrigine (LTG).
speculated that the clinical manifestations of NFLE and NREM Independently of drug therapy, it has been shown that sleep
arousal parasomnias may arise from the activation of innate motor architecture is abnormal in many epileptic patients, and this can
behaviors underlain by central pattern generators, via different pro- lead to EDS. Some studies have described an increased number of
cesses in which arousal is a triggering mechanism [65]. arousals, awakenings and stage shifts, and reduced total sleep time,
Lastly, REM parasomnias, in particular REM sleep behavior dis- slow-wave sleep, REM sleep, and sleep efficiency. These alterations
order (RBD), may coexist with SRE and can lead to diagnostic dif- are seen even in the absence of nocturnal seizures in both gener-
ficulties or misdiagnosis as well, especially in elderly people, where alized and focal epilepsies. Subjective sleepiness is also frequently
RBD is more frequent [80]. reported in patients with refractory seizures undergoing investiga-
tions for epilepsy surgery, with improvement after surgery [86].
Obstructive sleep apnea Other contributing factors for EDS in epileptic patients are coexist-
Obstructive sleep apnea (OSA) is a very common sleep disorder ence of OSA, restless legs syndrome. or inadequate sleep hygiene,
and is likely to be diagnosed in an epileptic patient, given the high which should all be sought out during patient consultation and
prevalence of the two diseases in the general population. Although follow-up [87,88].

Therapeutic approach and pharmacological The BZD group of drugs is generally used for status epilepticus
(eg, lorazepam, diazepam, and midazolam), but sometimes clon-
implications azepam and clobazam are used in some drug-resistant seizures
When a sleep disorder and epilepsy coexist, the best strategy is to and certain types of seizures (eg, myoclonic seizures and Lennox–
use a single drug to treat the two pathologies. CBZ taken at night Gastaut syndrome). These drugs generally cause decreased sleep
for NFLE can sometimes be efficacious in the treatment of NREM efficiency, sleep onset latency, stage 1 NREM, slow-wave sleep, and
and REM parasomnias, for which the mainstay treatment is usually arousals.
clonazepam (CNZ). On the other hand, the chronic use of CNZ Ethosuximide can reduce slow-wave sleep and increase stage 1
and other sedative AEDs, such as PB, should be avoided in NFLE and REM sleep, as well as increasing the tendency to wake after
patients because, by increasing light NREM sleep and arousals, they sleep onset (WASO).
can exacerbate seizures. If an epileptic patient presents with symp- Several newer AEDs have come onto the market to treat patients
toms of restless legs syndrome, then an AED such as CNZ (but also with seizure disorders; most of these have been approved as add-
CBZ, OXC, GBP, or VPA) can be effective in the treatment of both on therapy, but some are now being used as primary AEDs. These
disorders [89]. Finally, some patients with epilepsy may complain drugs have not been studied extensively to determine their effects
of insomnia related to sleep fragmentation and repeated arousals on sleep architecture.
as a result of nocturnal seizures and interictal EEG epileptiform Vigabatrin does not seem to affect sleep structure. GBP increases
discharges, AED side effects, depression, anxiety, or withdrawal REM sleep and slow-wave sleep, reducing stage 1 and arousals and
or tapering of AEDs. Indeed, some AEDs are known to cause in- awakenings, contributing to sleep consolidation, and allowing,
somnia. Sadler reported a 6.4% incidence of dose-dependent lamo- above all if taken only at night, a improvement in daytime alert-
trigine-related insomnia [90]. In contrast, Foldvary et al. failed to ness. It seems to act on sleep through a serotonergic mechanism.
observe any effect of lamotrigine on sleep efficiency, sleep latency, Lamotrigine has minimal effects on sleep in general. It may cause
or total sleep time in a PSG study of seven subjects with epilepsy increased REM sleep and decreased slow-wave sleep [92]. TPM
[91]. The other AED that has been found to have stimulant-like does not seem to modify sleep architecture. Tiagabine can increase
effects in patients with epilepsy is felbamate; however, because of slow-wave sleep and sleep efficiency. LEV in healthy volunteers
serious toxicity, this has largely been withdrawn from the market increases total sleep time, sleep efficiency and stage 2 and slow-
and is rarely used nowadays to treat epilepsy. wave sleep, while reducing stage shifts and WASO, without affect-
AEDs have variable effects on nocturnal sleep and daytime vigi- ing daytime vigilance [93]. Hypersomnia after LEV treatment in
lance (for reviews, see [85,87,92]. The effects of AEDs on sleep can epileptic patients has been described [94,95]. Studies of the effects
be divided into general effects consisting of reduction of REM and of OXC and zonisamide on human sleep are lacking.
slow-wave sleep, reduction of sleep latency, and increased per- Finally, it should also be mentioned that conflicting reports have
centage of NREM stages 1 and 2, and specific effects depending on been published on the effects of melatonin on seizure control.
the individual AED (Table 28.3). Definitive data supporting its recommendation in the absence of
Studies suggest that the short-and long-term effects of CBZ on a circadian sleep disorder are still lacking. Vagus nerve stimulation
sleep differ. CBZ in acute administration leads to a reduction in
REM sleep, with REM fragmentation and increased sleep stage
shifts, as well as an increase in daytime somnolence. These effects Table 28.3 Effects of antiepileptic drugs (AEDs) on sleep architecture
are not observed during chronic CBZ use, where sleep consolida-
tion with reduced awakenings and increased slow-wave sleep and AED Sleep Sleep N1 N2 N3 REM
sleep efficiency have been observed. Whether these effects vary sig- efficiency latency
nificantly between different populations is still unknown. Carbamazepine I D – – I D
VPA in general has minimal effects on sleep architecture in
Valproate – – ? D I D
patients with epilepsy. At higher doses, it can cause an increase in
slow-wave sleep and a decrease in REM sleep. However, different Phenobarbital D D I I – D
VPA-related effects have been described: difficulty initiating sleep, Primidone ? D ? ? I D
daytime sleepiness, and an increase in stage 1 and a decrease in
Phenytoin D D I I D –
stage 2 sleep. Furthermore, an absence of sleep structure modifica-
tion and even a stabilizing effect have also been described. Benzodiazepines D D D I D ?
The acute administration of PB usually shortens sleep latency, Ethosuximide D I I – D I
increases stage 2 sleep, reduces REM sleep, and decreases arousals,
Vigabatrin ? – ? ? ? ?
but the chronic use of PB can increase sleep fragmentation.
Primidone (PRM) in chronic use produces shortened sleep la- Gabapentin I D D – I I
tency and a reduction in REM density, but not REM percentage. Lamotrigine – – – – D I
PHT in acute administration causes reduced sleep latency, a re-
Tiagabine I – – – I –
duction in stage 1 and 2 sleep, and an increase in slow-wave sleep
but also of arousals, with no change in REM sleep and no relation- Topiramate – – – – – –
ship with serum drug levels. The long-term effects consist mostly Levetiracetam I – – I I –
of a reversal of the observed short-term effects, together with an
Oxcarbazepine ? ? ? ? ? ?
increase in NREM sleep stages 1 and 2 and a decrease in slow-wave
sleep. REM sleep remains unaltered. I, increase; D, decrease; -, no change; ?, unknown.

(VNS) therapy, frequently used for refractory epilepsy, can affect 9. Ferrillo F, Beelke M, Nobili L. Sleep EEG synchronization mechanisms
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CHAPTER 29
Autonomic dysfunction
and sleep disorders
Giovanna Calandra-â•‰Buonaura and Pietro Cortelli
Introduction that receive and integrate humoral, viscerosensory, and environ-

mental inputs to generate specific autonomic, endocrine, and
There is a close relationship between the autonomic nervous system somatomotor responses, and two efferent pathways, the sympa-
(ANS) and sleep, which are interdependent on each other by virtue thetic and parasympathetic nervous system. Each efferent pathway
of their common controls, neurobiological substrates, and func- is composed of a two-â•‰neuron system consisting of preganglionic
tions. Sleep induces profound changes in the activity of the ANS, neurons located in the brainstem and spinal cord connected with
and disorders of the ANS adversely affect vital functions during ganglionic neurons, which in turn make synapses with the target
sleep. As a consequence of this intimate interconnection between organ. The preganglionic neurons of both systems act through the
the ANS and sleep, several neurological and general medical disor- neurotransmitter acetylcholine (Ach), which is also released by the
ders present both autonomic dysfunctions and sleep disturbances. postganglionic neurons of the parasympathetic nervous system.
This chapter focuses on the description of autonomic dysfunc- Norepinephrine (noradrenaline) (NE) is the primary postgangli-
tions associated with sleep disorders [1]â•„. This association may onic sympathetic neurotransmitter in all organs (except the sweat
result from a common pathogenetic mechanism that affects both glands) receiving Ach. The sympathetic action is also amplified by
the autonomic and sleep functions, as in fatal familial insomnia, the neurohormone epinephrine (adrenaline) (EPI), released by
or from a prevalent expression of a primary disorder of autonomic the adrenal medulla. Other neurochemical transmitters involved
regulation during sleep, as in congenital central hypoventilation in ANS control include adenosine triphosphate, nitric oxide, and
syndrome. Alternatively, the autonomic dysfunction may be mainly vasoactive intestinal polypeptide. The effects of each system in the
caused by the sleep disorder, as observed in obstructive sleep apnea regulation of visceral functions are listed in Table 29.1.
syndrome (OSAS), or the causal mechanism resulting in an associ- As dysfunction of the autonomic control of the cardiovascu-
ation between autonomic dysfunction and a sleep disorder has not lar system is frequently associated with sleep disorders leading to
yet been defined with certainty, as in narcolepsy with cataplexy and harmful consequences, it is important to bear in mind the main
REM sleep behavior disorder. Autonomic dysfunction may results mechanism by which blood pressure (BP) is regulated in humans.
in an overactivity or a failure of ANS functions. In both cases, it has BP is determined by cardiac output and total peripheral resistance.
been demonstrated that the autonomic disorder, particularly when Cardiac output depends on venous return to the heart, cardiac con-
this involves cardiovascular or respiratory control, not only impairs tractility, and heart rate (HR). The moment-â•‰to-â•‰moment control of
the patient’s quality of life, but also has a significant negative impact the arterial BP is exerted through a complex integration between
on the prognosis of the associated sleep disorder and may repre- cardiovascular reflexes and central autonomic influences. The baro-
sent a risk factor for the development of other chronic diseases or receptor reflex, or baroreflex, is the most important mechanism
for life-â•‰threatening events. Therefore, prompt recognition of auto- involved in this physiological task. The arterial baroreceptors are
nomic disturbances is of crucial importance to achieve the correct mechanoreceptors mainly located in the carotid sinuses and aortic
diagnosis, choose the most proper therapeutic approach, and treat arch, innervated by the glossopharyngeal and vagus nerves, respec-
the risk factors that could severely influence prognosis. tively, which respond to changes in carotid or aortic stretch elic-
ited by rise or fall in arterial BP. Activation of the baroreceptors in
The autonomic nervous system response to an increase in BP elicits a decrease in sympathetic activ-
The ANS regulates visceral functions (circulation, respiration, ther- ity and an increase in parasympathetic control of the heart, which
moregulation, neuroendocrine secretion, and gastrointestinal and cause a decrease in total peripheral resistance and HR and a sub-
genitourinary functions) and integrated processes that control vital sequent reduction of venous return and cardiac output. Opposite
functions in response to internal and external demands with the consequences, tachycardia and vasoconstriction, are evoked by a
final aim to maintain the homeostasis [2]â•„. The ANS comprises the decrease in arterial BP. The baroreflex also inhibits the release of
central autonomic network (CAN), which includes several inter- vasopressin by magnocellular neurons of the supraoptic and para-
connected areas distributed throughout the central nervous system ventricular nuclei of the hypothalamus; vasopressin is involved in
(CNS) (insular cortex, anterior cingulate cortex, amygdala, hypo- the long-â•‰term modification of BP. Primary baroreceptor afferents
thalamus, periaqueductal gray, parabrachial nucleus, nucleus of the provide excitatory input to the nucleus of the solitary tract. This
solitary tract, ventrolateral reticular formation, and raphe nuclei) nucleus through its connections with the ventrolateral medulla,

Table 29.1 Main effects of the sympathetic and parasympathetic neuronal populations that participate in the transition from wake
branches of the autonomic nervous system on visceral functions to sleep and in the subsequent development of different sleep stages
are localized nearby several areas of the CAN and also act through
Organ Sympathetic branch Parasympathetic branch the same neurotransmitter. As a consequence the modulation of
the ANS on vital functions changes according to behavioral state
Pupil Dilation Constriction
(wakefulness, NREM sleep, and REM sleep). A sympathetic preva-
Blood Vessel Constriction None lence is observed during wakefulness, while the parasympathetic
(arterioles) tone is dominant during most of the sleep period, with variations
Lungs Bronchodilation Bronchodilation during different sleep stages. Sympathetic activity is lower during
Heart Increase rate Decrease rate NREM sleep compared with wakefulness and parasympathetic
activity prevails, while during REM sleep, sympathetic activity is
Increase myocardial Decrease myocardial
contractility contractility enhanced to levels comparable to those during wakefulness [9]‌. As
a consequence, during NREM sleep, progressive decreases in arte-
Gastrointestinal Decrease motility Increase motility rial BP and HR, which become more pronounced from stage 1 to
tract
stage 3 NREM, are observed. Healthy normotensive persons show
Kidney Decrease output None a BP decline during sleep of 10–20% compared with mean day-
Bladder Relax detrusor Relax sphincter time values, a phenomenon generally referred to as “dipping” [10].
Contract sphincter Contract detrusor Similarly, sympathetic nerve activity, recorded in skeletal muscle
and skin nerves, is decreased by more than half from wakefulness
Penis Ejaculation Erection to deep NREM sleep [11]. The baroreflex function is differently
Sweat glands Secretion Palmar sweating modulated by central influences during the different sleep phases;
Piloerection Increase none in particular, during NREM sleep, the baroreflex maintains a slow
HR despite a decrease in BP.
Lacrimal gland Slight secretion Secretion REM sleep is characterized by consistent variations in cardiovas-
Parotid gland Slight secretion Secretion cular parameters and also in baroreflex activity. During tonic REM
Submandibular Slight secretion Secretion sleep, a marked bradycardia and decreased peripheral resistance
gland are observed, resulting in a BP decrease below the levels reached in
NREM sleep. This BP decrease is interrupted during bursts of rapid
eye movements and muscle twitches by large transient increases in
BP and HR, which are consequences of phasic inhibition of para-
is responsible for the sympatho-inhibitory effect described above sympathetic and phasic increase of sympathetic activity.
and, with a direct input to vagal preganglionic neurons in the Changes in ventilation also occur during sleep, as breathing
nucleus ambiguus, elicit increased parasympathetic modulation of control is different during wake, NREM, and REM sleep. In the
the heart. The activity of the baroreflex is continuously modulated transition from wakefulness to sleep, a progressive inactivation of
in relation to prevailing behavioral and physiological conditions, voluntary control of ventilation occurs, and during NREM sleep,
by reciprocal connections of the CAN with the hypothalamus, ventilation is only automatically driven by chemical feedback
contributing to both short-and long-term control of BP, including related to arterial CO2 and O2 levels. Sleep onset is characterized
the circadian changes in BP between daytime activities and night- by oscillations in breathing amplitude and sporadic central apneas,
time sleep [3,4]. Finally, the arterial chemoreceptors, which are while during steady NREM sleep, breathing becomes progressively
located within the carotid bodies and the aortic arch and primarily regular. In this stage, a reduction in minute ventilation is observed
monitor blood oxygen variations, participate in the regulation of due to a decrease in tidal volume and respiratory frequency. REM
cardiovascular parameters. Their stimulation induced by hypoxia sleep is characterized by breathing variability, which seems to be of
may lead to sympathetically mediated vasoconstriction with sub- central origin and is characterized by sudden changes in breathing
sequent increase in BP and vagally mediated decrease in HR. This amplitude and frequency concurrently with REM bursts.
respiratory–cardiovascular interaction may be involved in the During the entire sleep period, oscillations of EEG activity, sys-
pathophysiology of harmful cardiovascular consequences of sleep temic arterial BP, HR, and ventilation occur periodically, every
disordered breathing, such as sympathetic overactivity and hyper- 20–30 seconds [12,13] or transiently as part of the physiological
tension in OSAS [5–7]. response to an arousing stimulus [14].
Finally, body temperature decreases during NREM sleep,
Modulation of autonomic control during sleep together with decreases in metabolic activity, glucose consump-
The sleep–wake cycle may be viewed as a rhythmic alternation tion, and cerebral blood flow. The regulation of body temperature
between two contrasting systems, the arousal and anti-arousal sys- is controlled by the ANS, which uses many sources of informa-
tem, which act as a kind of flip–flop switch allowing the transition tion to generate specific thermoregulatory responses (eg, sweating,
from wake to sleep states and vice versa, with stability in any one of shivering, and skin vasomotor adjustments). These mechanisms
these states of vigilance allowed by the action of neurotransmitters, are still active during NREM sleep, whereas they are mostly sus-
such as the orexin system [8]‌. pended during REM sleep, characterized by an abolition of the
The anti-arousal system, which promotes sleep, originates from thermoregulatory responses to environmental heating and cooling
the ventrolateral preoptic hypothalamic nucleus and inhibits the [15]. However, sleep and temperature are more widely interrelated,
dorsal and ventral arousal systems at the level of their nuclei. The and thermoregulation also plays important role in initiating sleep,

Chapter 29 autonomic dysfunction and sleep disorders 293
whose onset typically occurs on the declining portion of the circa- Table 29.2 Main clinical manifestations of autonomic dysfunction
dian body temperature curve, when body heat loss is maximal [16].
Pupil Abnormal miosis
Assessment of autonomic functions Abnormal mydriasis
Autonomic disorders may result from an overactivity or a failure
Cardiovascular Orthostatic hypotension
of ANS functions and may present with a wide variety of symp-
toms and signs (Table 29.2). Their diagnosis may be arduous Supine hypertension
because of the overlap with other conditions and because mild Paroxysmal hypertension
symptoms might be concealed for years because of compensatory
Bradycardia
mechanisms. For these reasons, a carefully taken history and a
detailed examination, including the detection of BP response to Tachycardia
upright posture, are necessary when an autonomic dysfunction Urinary Frequency
is suspected. The majority of ANS functions cannot be directly
Nocturia
evaluated; therefore, the assessment of ANS integrity frequently
relies on indirect methods, which measure the reflex responses Urgency
of the target organs to physiological and pathological stimuli. Incomplete bladder emptying
Laboratory investigations are performed with the aims of detect-
ing the presence of the autonomic dysfunction and its severity, Incontinence
determining whether the dysfunction is due to an impairment Sexual Erectile failure
of the ANS or is secondary to other causes like drugs, assessing Priapism
which branch of the ANS is mostly impaired, and locating the site
of the lesion [17]. Retrograde ejaculation
For example, the cardiovascular reflex tests (head-up tilt test Ejaculatory failure
(HUTT), Valsalva maneuver, handgrip, deep breathing and cold Sudomotor Hypohidrosis
face) assess HR and BP changes in response to specific maneuvers
and allow to reveal dysfunctions of the autonomic control of the Anhidrosis
cardiovascular system and to separately examin the integrity of Hyperhidrosis
the parasympathetic and sympathetic branches and the barore- Heat intolerance
ceptor reflex. These tests are easy to perform, reproducible, sensi-
tive, and specific, and are therefore suitable as first-line methods Hyperpyrexia
for both diagnosis and longitudinal evaluations. Blood samples
can also be collected during the tests to quantify catecholamine
levels, which provide measures of adrenal medullary and sympa- is still debated, the LF/HF ratio is widely used as a reliable indi-
thetic neural activity. When an impairment of the physiological cator of sympathetic and parasympathetic outflow balance [19].
circadian variation of the autonomic parameters is suspected or Finally, pharmacological probes (eg, growth hormone release in
the autonomic disturbances are manifested mainly during sleep, response to arginine or clonidine) [17] or imaging studies with
24-hour or nocturnal polygraphic recordings may be performed radioactive tracers may distinguish the central or postganglionic
to evaluate these parameters (eg, BP, HR, respiratory rate, oxygen site of the autonomic lesion. For example, cardiac 123-meta-iodo-
saturation (SaO2), temperature, and sudomotor activity) in rela- benzylguanidine (MIBG) scintigraphy is used to assess cardiac
tion to different physiological states (wakefulness, NREM sleep, sympathetic innervation which is impaired in postganglionic
and REM sleep) or degree of alertness (eg, autonomic arousal autonomic disorders [20]. As these tests are not available in all
response). Several indirect techniques have also been applied to centers and are more invasive and expensive, they should be per-
estimate baroreflex function. In particular, the slope of the HR formed only as a second-line approach to better define an auto-
changes in response to BP changes evoked by these methods is nomic dysfunction that has not yet been ascertained.
commonly referred to as baroreflex sensitivity (BRS, measured
in ms/mmHg) [18]. BRS has a prognostic value in cardiovascu-
lar diseases like myocardial infarction and heart failure, and is Fatal familial insomnia
impaired in pathological conditions, including sleep disorders Fatal familial insomnia (FFI) is a rare prion disease whose clini-
like OSAS [4]‌. Spectral analysis of HR variability (HRV) calcu- cal hallmark is agrypnia excitata syndrome, which is characterized
lated from the interval between two consecutive R-waves of QRS by a progressive and untreatable sleep loss associated with motor
complexes (RR interval) in the ECG trace is also used to esti- and autonomic sympathetic overactivation persisting night and
mate sympathetic or parasympathetic modulation in autonomic day and with a peculiar oneiric behavior (oneiric stupor) [21,22].
cardiac control. The power spectrum of HRV comprises high- Somatomotor abnormalities also occur with variable latency and
frequency components (HF: 0.15–0.4 Hz), reflecting parasympa- degree during the disease course [21,23]. The disease arises at a
thetic outflow and breathing activity, low-frequency components mean age of 50–51 years and is uniformly fatal, leading to death
(LF: 0.04–0.15 Hz), mediated mainly by sympathetic activity, and after either a short (<12 months) or a long (12–72 months) course
very low-frequency components (VLF: 0–0.04 Hz) whose physio- following onset of insomnia. FFI is transmitted as an autosomal
logical correlates are not fully understood. Even if the interpreta- dominant trait and is linked to a missense mutation at codon 178
tion of the LF component as a pure marker of sympathetic activity (D178N) of the prion protein gene located on chromosome 20

co-segregating with methionine at codon 129, the site of a com- All these data point toward an imbalanced autonomic control in
mon methionine–valine polymorphism [24,25]. Methionine- FFI characterized by normal parasympathetic activity and a higher
homozygous patients at codon 129 have on average shorter disease background and stimulated sympathetic activity. Sympathetic
duration and a clinical phenotype slightly different to that of het- overactivity in these patients is also supported by the follow-
erozygotes, who usually display fewer sleep and autonomic distur- ing observations: (1) an elevated norepinephrine plasma level at
bances at onset but earlier and more severe motor abnormalities rest, increasing further under orthostatic stress; (2) an exagger-
[26]. A sporadic form of fatal insomnia has also been described, ated BP increase in response to physiological stimuli (HUTT,
sharing clinical and neuropathological features with FFI but lack- Valsalva maneuver, or isometric handgrip); (3) absent BP rise after
ing the D178N mutation [27]. From a clinical point of view, at
disease onset, patients usually complain of progressive inability
to initiate and maintain sleep. They also appear taciturn and apa- Temperature
thetic and may look drowsy owing to sleep deprivation. An early
38
progressive impairment of attention and vigilance is observed,
whereas intellectual function remains substantially intact until 37
C
the advanced stages of the disease. Autonomic signs accompany
insomnia, such as a tendency to perspire, salivate, and lacrimate, 36
tachycardia, hypertension, urgency, impotence, and slight evening
Heart rate
pyrexia. Fluctuating diplopia is also a common early manifesta-
Beats per minute

110
tion. Worsening of sleep and autonomic disturbance are associated
with episodes of oneiric stupor, a peculiar hallucinatory behavior 80
during which patients lose contact with the environment and dis-
play motor gestures mimicking daily life activities that they link 50
to the content of a dream. These episodes initially last only a few
Mean arterial pressure
seconds, but with disease progression patients become more con-
fused, alternating between wakefulness and oneiric confusional 140
states. Patients then develop disturbances of gait, spontaneous
and evoked myoclonus, dysarthria, dysphagia, and pyramidal mm Hg 100
signs (hyper-reflexia and Babinski’s sign), and finally progress
60
into incomprehensible speech, inability to stand and walk, recur-
rent spasms, and occasional convulsive seizures. Death occurs Norepinephrine
from sudden cardiorespiratory failure or ensuing infections [21]. 750
Longitudinal 24-hour polysomnographic studies document a pro-
gressive wake–sleep cycle derangement characterized by a dras-
pg/ml
tic reduction in total sleep time, with loss of physiological sleep 400
structures (sleep spindles, K-complexes, and delta waves). The
dominant EEG pattern is characterized by stage 1 NREM sleep
50
interspersed with short episodes of REM sleep with or without
atonia, which can arise directly from wake [28]. Motor activity Cortisol
is markedly increased, with loss of physiological circadian motor 225
rhythmicity [29]. Heart and breathing rate, BP, and core body
150
temperature are higher in FFI patients compared with controls in
ng/L
24-hour polysomnographic recordings. The circadian rhythms of 75

HR and BP show a dominant 24-hour rhythm, with a progressive
reduction in amplitude and a shift in phase. An early loss of the 0
physiological nocturnal fall in BP with maintenance of nocturnal
bradycardia, which is due mainly to parasympathetic activation, Melatonin
90
is also observed [30]. The rhythmic components of HR and BP,
despite reductions in amplitude, persist even after the total dis- 60
appearance of sleep, and only in the pre-terminal stage of FFI
ng/L
all the 24-hour variations are abolished. Further serial 24-hour 30

monitoring of hormonal and catecholamine levels reveals a persis-
tently increased plasma concentration of cortisol, which is known 0
to modulate the vascular response to catecholamines and to act
1600 2000 0000 0400 0800 1200 1600
centrally to increase sympathetic activity, in contrast to a normal
adrenocorticotropin level in the early stage of the disease. This pat- FFI Control
tern is followed by the appearance of a pathological nocturnal peak
Fig. 29.1 The 24-hour circadian rhythms of body core temperature, heart rate,
of cortisol and adrenocorticotropin, and then by a norepineph- mean arterial pressure, norepinephrine, cortisol, and melatonin in a FFI 129 Met/
rine and epinephrine elevation. In contrast, melatonin secretion is Val patient compared with a normal sex-and age-matched control. The dark bar
reduced and it lacks the physiological nocturnal peak (Fig. 29.1). represents the dark period.

norepinephrine infusion due to down regulation of adrenoceptors; for the diagnosis of CCHS, and different mutations aid in pre-
(4) abnormal HR increase after atropine infusion; (5) diminished dicting different phenotypes, including severity of the ventilatory
depressor and sedative effects of clonidine, which usually inhibits control disorder and the autonomic dysfunction, risk of associated
central sympathetic activity; (6) increased mean level of resting disorders, and adverse consequences like sudden cardiac death
awake muscle sympathetic nerve activity measured by microneu- [35]. The disease usually manifests in the newborn period in other-
rography [23,31,32]. Both sleep and autonomic disturbances in wise healthy infants who do not breathe spontaneously or breathe
FFI are thought to be related to damage to the medial thalamus, only shallowly or erratically or experience episodes of hypoventila-
which is severely affected in the disease. Neuropathological stud- tion or apnea, frequently requiring mechanical ventilation immedi-
ies disclosed severe neuronal loss and reactive astrogliosis in the ately after birth. Occasionally, patients may present in the first few
thalamus, especially the anterior ventral and mediodorsal nuclei, months of life with acute life-threatening events (cyanosis, respira-
and PET studies showed a severe thalamic hypometabolism at the tory arrest, or hypoxic neurologic damage) or in childhood with
onset of insomnia and dysautonomia [23]. These nuclei belong to signs of end-organ damage from chronic hypoxemia and hypercar-
the circuits that connect the limbic prefrontal cortex to the hypo- bia (cor pulmonale, seizures, or developmental delay). Later-onset
thalamus and brainstem. In particular, the mediodorsal nucleus is presentation has also been described and may be related to variable
deeply interconnected with several areas involved in autonomic penetration of the PHOX2B mutations, to the possibility that envi-
control (anterior cingulate, insula, amygdala, and hypothalamus). ronmental cofactors are needed to elicit the phenotype, or as a con-
The interruption of these circuits, disconnecting the limbic cortical sequence of a delayed diagnosis due to unrecognized mild disease
areas that control instinctive behavior and the structures responsi- manifestations at an early age [35].
ble for sleep and autonomic control, results in sleep loss associated During sleep, the pattern of breathing in CCHS patients is char-
with a persistent generalized activation syndrome [21,28]. acterized by hypoventilation with decreased tidal volume and res-
piratory rate, which is more severe during NREM than REM sleep.
Congenital central alveolar Central apnea may also occur, particularly at sleep onset [40,41].
Ventilation is generally adequate during wakefulness, but more
hypoventilation syndrome severely affected children hypoventilate also during wakefulness.
The term “congenital central alveolar hypoventilation syndrome” Previous studies showed that children with CCHS lack ventila-
(CCHS) defines a syndrome characterized by failure of automatic tory responsiveness to hypercapnia and hypoxemia, suggesting an
central control of breathing, resulting in hypoventilation during abnormality of both central and peripheral chemoreceptor func-
sleep and to a lesser degree during wakefulness, usually presenting tion. However it has also been demonstrated that during sleep, the
in the newborn period. The diagnosis is made in the absence of other arousal response to hypercapnia is not impaired in CCHS patients.
causes of hypoventilation, such as primary lung, cardiac, or neuro- This suggests as an alternative hypothesis that chemoreceptors are
muscular diseases, other sleep or neurological disorders, brainstem functionally intact, while the abnormality in CCHS may be located
lesions, or medication use. In the International Classification of in areas of the brain involved in integration of chemoreceptor affer-
Sleep Disorders (ICSD-3), CCHS is included under the category ent pathways for ventilation [42,43].
“Sleep-related hyperventilation disorders” [1]‌; however, this condi- A diffuse autonomic modulation impairment of both the sym-
tion, despite long being considered a unique disorder of respiratory pathetic and parasympathetic branches of the ANS is observed in
control, has recently been more correctly recognized as a disorder CCHS and includes abnormalities of pupillary response to light,
of autonomic regulation, owing to the coexistence of autonomic esophageal dysmotility, swallowing dysfunction, decreased basal
dysfunctions in other systems. Central hypoventilation is therefore body temperature, poor heat tolerance and sporadic profuse sweat-
the most severe manifestation of a generalized ANS dysfunction ing, elevated HR and reduced HR variability at rest, blunted BP
[33–36]. CCHS is also associated with neural crest tumors (neu- response to actively standing, reduced BRS, reduced respiratory
roblastoma, ganglioneuroblastoma, and ganglioneuroma) and with sinus arrhythmia, and abrupt asystole [34,44,45]. This diffuse auto-
Hirschsprung disease (congenital absence of ganglion cells in the nomic modulation impairment supports the hypothesis of signifi-
myenteric plexus causing bowel obstruction) [35,37]. cant functional alterations of brain areas involved in autonomic
A genetic basis of the disease has been recognized with the control. Macey and co-workers [46] used functional magnetic
discovery of mutations of the paired-like homeobox gene 2B resonance imaging (fMRI) techniques to examine signal responses
(PHOX2B) on chromosome 4p12 [38,39], which encodes a tran- in the brains of CCHS patients compared with controls while per-
scription factor that plays a role in the regulation of neural crest cell forming a voluntary Valsalva maneuver, which elicits a sequence
migration and embryologic development of the ANS. Nearly 90% of sympathetic and parasympathetic actions. Increased signals
of CCHS patients are heterozygous for PHOX2B mutations causing emerged in control over CCHS patients in the cingulate, right pari-
expansion of the 20-residue polyalanine region of this transcription etal cortex, cerebellar cortex, fastigial nucleus, and basal ganglia,
factor (polyalanine repeat mutations, PARMs), adding 4–13 cop- whereas anterior cerebellar cortical sites and deep nuclei, dorsal
ies and producing genotypes 20/24 to 20/33. The remaining 10% midbrain, and dorsal pons showed increased signals in the patient
are heterozygous for nonpolyalanine repeat mutations (NPARMs), group. The dorsal and ventral medulla showed delayed responses in
including missense, nonsense, and frameshift mutations of the CCHS patients. The authors suggested that the delayed responses
PHOX2B gene. Most mutations occur de novo in CCHS, but 5–10% in medullary sensory and output regions and the aberrant reac-
are inherited from a mosaic typically unaffected parents. The inher- tions in cerebellar and pontine sensorimotor coordination areas
itance of the PHOX2B mutation from CCHS cases and from mosaic may be implicated in the rapid cardiorespiratory integration defi-
parents is autosomal dominant. A PHOX2B mutation is required cits in CCHS.

A further fMRI study, assessing neural response patterns to In OSAS patients, still normotensive during the day, a reduced
Valsalva maneuver in 9 CCHS patients and 25 controls, demon- BRS and a hyperactive chemoreflex function were demonstrated
strated abnormal responses in limbic areas such as the amygdala in the awake state. This peculiar combination of reduced barore-
and hippocampus, and muted responses across other multiple flex and hyperactive chemoreflex function suggested that a central
brain areas, in particular in the insulae and ventral cerebellum in remodeling of autonomic cardiovascular control may precede the
patients compared with controls [47]. development of daytime hypertension [4,51]. It has been hypothe-
Patients with CCHS require lifetime mechanically assisted venti- sized that sympathetic activation, which occurs as an acute effect of
lation during sleep to ensure adequate ventilation and oxygenation, OSAS, when repeated over a long period of time in predisposed sub-
and to prevent acute and long-term consequences. Some patients jects, may change the afferent regulation of the barosensitive neu-
(from 6% to 33%) require ventilatory support during both wake- rons located in the nucleus of the solitary tract. This could attenuate
fulness and sleep. Positive-pressure ventilators via tracheostomy, their inhibitory effect on the sympatho-excitatory neurons, which
bilevel positive airway pressure, negative-pressure ventilators, and could in turn be responsible for the sustained chronic peripheral
diaphragm pacing can all be used in these patients. The mortality sympathetic overactivation and its cardiovascular consequence [4]‌.
rate varies from 8% to 38% among studies and has been reduced The alteration of cardiac autonomic modulation and risk of
with modern techniques for home ventilation [35,43]. developing cardiovascular diseases, in particular hypertension,
have also been correlated with presence of excessive daytime sleepi-
Obstructive sleep apnea syndrome ness in OSAS patients. In fact, patients with both OSAS and exces-
sive daytime sleepiness, when compared with patients without,
Obstructive sleep apnea syndrome (OSAS) is characterized by re- had significantly lower BRS and significantly higher LF/HF ratio
petitive episodes of complete (apnea) or partial (hypopnea) upper during the different stages of sleep [55]. In addition the association
airway obstruction occurring during sleep, which usually result between sleep disordered breathing and hypertension is stronger
in blood oxygen desaturation and often terminate by brief arousal in patients who report daytime sleepiness than in those who do
[1]‌. The apneic episodes are associated with peculiar fluctuations not [56]. Lombardi and co-workers hypothesized that the com-
in HR characterized by an HR decrease at onset of apnea, followed mon mechanism causing excessive daytime sleepiness and cardiac
by abrupt tachycardia on resumption of breathing generally accom- autonomic dysfunction may lie in the occurrence of apnea-related
panied by an arousal [48]. In addition, hyperactivity of the sym- autonomic arousals from sleep, resulting in further sympathetic
pathetic nervous system, recorded through muscle sympathetic overactivation [55].
nerve activity, has been documented in relation to these respiratory Finally, findings from cross-sectional studies suggest a high
events [5–7] and confirmed also by spectral analysis of HRV, which prevalence of cardiac arrhythmias in patients with OSAS and
demonstrated increased LF and LF/HF ratio during sleep apnea a high prevalence of OSAS in those with cardiac arrhythmias.
episodes [49]. Bradycardia, sinus pauses, second-degree heart block, atrial fibril-
Chemoreflex stimulation induce by repeated hypoxia is the main lation, ventricular repolarization disturbances, ventricular prema-
mechanism implicated in enhanced sympathetic activity during ture complexes, and ventricular tachycardia have been associated
sleep apnea [7]‌. However, a depression of spontaneous BRS, which with OSAS. Further, OSAS-related arrhythmogenesis has also been
has been demonstrated in severe OSAS patients, may also con- implicated in sudden cardiac death [57–60].
tribute to a further increase in sympathetic activity [50]. Several mechanisms have been involved in the genesis of dys-
OSAS is associated with an impaired autonomic control of car- rhythmias in OSAS, including (1) intermittent hypoxia associated
diovascular parameters and an enhanced sympathetic tone not only with both ANS activation and increased oxidative stress, which
during sleep but also during wakefulness. Cortelli and co-workers could in turn lead to cardiac cellular damage and alteration in
[51] demonstrated that normotensive OSAS patients have higher myocardial excitability; (2) recurrent arousals from sleep, causing
HR and norepinephrine plasma levels at rest during wakefulness further sympathetic activation; (3) increased negative intrathoracic
and a higher BP response to HUTT compared with controls, sug- pressure, which may mechanically stretch the myocardial walls and
gesting sympathetic overactivity. thus promote acute changes in myocardial excitability as well as
Analysis of the circadian rhythm of HRV confirmed an enhanced structural remodeling of the myocardium [59].
sympathetic modulation from morning to noon (lower mean HF Treatment of OSAS with continuous positive-airway pressure
value and higher mean LF/HF ratio) in OSAS patients compared has been demonstrated to significantly improve cardiovascular
with controls [52]. Finally, elevated levels of plasma and urinary autonomic modulation, reducing sympathetic overactivity and the
catecholamines have been demonstrated in these patients while risk of development of cardiovascular diseases like hypertension.
awake [53]. The main consequence of the described alterations of Preliminary evidence from uncontrolled interventional studies
autonomic control of the cardiovascular system in OSAS patients suggests also that treatment of OSAS may prevent cardiac arrhyth-
is an increased risk of developing cardiovascular and cerebrovas- mias. However randomized studies are still needed to address this
cular diseases (hypertension, myocardial infarction, arrhythmias, important issue [53,54,59].
heart failure, and stroke). There are now several epidemiological
studies supporting a direct contribution of sleep apnea to hyper-
tension, and many hypotheses have been advanced to explain the Narcolepsy with cataplexy
causal relationship between the two conditions [53,54]. However, Narcolepsy with cataplexy (NC) is a sleep disorder characterized by
the sympathetic overactivity demonstrated in OSAS patients dur- excessive daytime sleepiness and cataplexy (sudden loss of bilateral
ing both wakefulness and sleep seems to have the prominent role in muscle tone provoked by emotions) and usually associated with
the etiology of OSAS-related hypertension [53]. sleep paralysis, hypnagogic hallucinations, and nocturnal sleep

disruption [1]‌. Loss of orexin neurons of the lateral and posterior 90

HR
hypothalamus has been demonstrated in NC. These neurons are
connected with cerebral areas involved in central autonomic con- 80
trol (prefrontal cortex, hypothalamus, limbic structures, and brain-
bpm
stem autonomic nuclei). Orexins, also known as hypocretin 1 and 70
2, are neuropeptides implicated in several physiological functions
60
(arousal, energy homeostasis, feeding, thermoregulation, and neu-
roendocrine and cardiovascular control), which are mediated by
50
changes in the ANS [61]. Autonomic dysfunctions in NC patients
have been observed [62], including abnormal pupillometry func- SBP
tion [63–65], erectile dysfunction [66], impaired autonomic control
of the cardiovascular system during sleep [67,68], and wakefulness 135
[69]. Furthermore, increased body mass index and increased risk
125
mmHg
of type 2 diabetes have been frequently reported in NC patients.
Although association could reflect a disturbance in food intake and
energy metabolism related to orexin deficiency, both the pathophys- 115
iological mechanism and the relationship between orexin deficit and
metabolic syndrome remain unclear [70–73]. Particular interest has 105
recently been directed at dysfunctions of the autonomic control of DBP
the cardiovascular system in NC patients owing to their possible
contribution to an increased cardiovascular risk in this population. 80
The effect of orexins on the cardiovascular system is controversial.
mmHg
The initial animal studies indicated that the orexin system triggered
sympathetic activation, as intracerebroventricular or brain tissue 70
microinjections of orexin in rats caused increases in HR, BP, and
body temperature. Further orexin-knockout or orexin-neuron-
depleted mice showed an attenuated sympatho-excitatory response 60
8:00
12:00
16:00
20:00
0:00
4:00
8:00
to stress. However, opposite results were found in these models of
orexin-deficient mice during sleep, as they demonstrated a blunted Time C (n = 12)
decrease in BP on passing from wakefulness to NREM sleep and an NC subjects (n = 10)
enhanced increase in BP on passing from NREM to REM sleep com-
pared with controls. Similarly, recent studies suggested that orexin Fig. 29.2 Mean ± standard error (SE) values of heart rate (HR), systolic blood
deficit in humans is not unequivocally associated with reduced pressure (SBP), and diastolic blood pressure (DBP) during 24 hours in control
subjects (C) and patients with narcolepsy with cataplexy (NC). The dark bar
sympathetic tone but may be associated with sympathetic cardio- represents the dark period. SE has been reported in one direction for clarity.
vascular activation, parasympathetic withdrawal, or both. Grimaldi
and colleagues [67] demonstrated in drug-free NC patients com-
pared with controls significantly higher systolic BP values dur-
ing nighttime REM sleep and a blunted decrease in nocturnal BP
(non-dipping pattern) (Fig. 29.2). These data were confirmed by a REM sleep behavior disorder (RBD) is a sleep parasomnia charac-
further study, which found a high percentage of NC patients show- terized by dream-enacting behaviors, often violent and injurious,
ing a non-dipper profile [68], suggesting an increase in sympathetic occurring during REM sleep and associated with loss of the physi-
modulation during sleep. However, an attenuated HR response to ological REM muscle atonia [1]‌. This condition may be either idio-
leg movements [74] and arousal [75] during sleep pointing toward a pathic (iRBD) or associated with another neurologic disorder [78].
decrease sympathetic tone was also observed. RBD has been frequently observed in the α-synucleinopathies, neu-
Three studies carried out spectral analyses of HRV in NC patients rodegenerative disorders characterized by the presence of intracel-
and obtained different results. Fronczek and colleagues found a lular inclusions containing α-synuclein, namely, Parkinson disease
higher power in all frequency bands in the supine awake condition, (PD), Lewy body dementia (LBD), and multiple system atrophy
associated with a similar LF/HF ratio, and hypothesized a reduced (MSA), which can also present dysfunctions of the ANS. The onset
sympathetic tone in NC patients [76]. In contrast, an increase LF/ of RBD can precede, by years, the onset of these diseases [79–82].
HF ratio (increased sympathetic modulation) during wakefulness For this reason, several studies have tried to disclose signs predic-
preceding sleep [69] and an enhanced sympathetic activity at rest tive of the future development of a neurodegenerative disease in
[77] were observed in NC patients compared with controls. patients with iRBD by means of clinical, neuropsychological, elec-
In conclusion, impaired autonomic control of the cardiovascular trophysiological, and neuroradiological modalities. Impairment of
system in NC patients has been observed, and despite the fact that autonomic functions, in particular a dysfunction in the autonomic
the direction of the cardiovascular autonomic changes is not une- control of the cardiovascular system, has been observed in iRBD.
quivocally ascertained, the clinical importance of these findings, Mahowald and Schenck first reported a lack of HR increase in
particularly if it is confirmed that an overactivity of the sympathetic association with the vigorous behaviors during REM sleep shown
branch exists in NC, may be relevant due to a possible increased by these patients [83]. Three subsequent studies demonstrated a
cardiovascular risk in this population. blunted HR response associated with sleep-related movements in

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CHAPTER 30
Neuromuscular
disorders and sleep
Katerina Sajgalikova, Erik K. St. Louis, and Peter Gay
Introduction result in marked orthopnea due to markedly decreased supine VC.

Maximum expiratory and inspiratory flow–â•‰volume curves show
This chapter examines the range of sleep disturbances seen in a decline in inspiratory flow, and reduced peak expiratory flow at
patients with neuromuscular disorders, particularly emphasiz- higher volumes, correlating with the reduction in FVC, with blunt-
ing sleep-â•‰related breathing disorders, which may be a presenting ing of the expiratory curve contour and abrupt expiratory flow
manifestation of neuromuscular disorders, and which significantly cessation immediately prior to reaching RV. Maximum voluntary
contribute to morbidity and mortality in this patient population. It ventilation is also proportionately reduced to lost respiratory mus-
provides an overview of physiological and pathological alterations cle function [4]. Diffusing capacity is usually normal in neuro-
in neuromuscular breathing mechanisms and control during sleep. muscular patients unless an additional parenchymal or infiltrative
The symptoms and forms of sleep disordered breathing (SDB) pulmonary process is also present.
seen in specific neuromuscular disorders such as amyotrophic lat- During sleep, particularly rapid eye movement (REM) sleep,
eral sclerosis (ALS), myopathies, and disorders of neuromuscular upper airway resistance increases, while chemosensitivity and skel-
junction transmission are reviewed. The chapter concludes with a etal muscle tone decrease, with the exception of the diaphragm and
discussion of management strategies for neuromuscular disorder extraocular muscles, resulting in suppressed ventilation. Breathing
patients with SDB, which is common in such patients, requiring is more rapid, superficial, and irregular and sleep is fragmented;
generalists, neurologists, and sleep physicians to work together total sleep time is shorter, accompanied by frequent breathing-â•‰
toward prompt diagnosis and optimal treatment approaches. related arousals [5,6]. While these changes in ventilation are not
prominent in healthy patients, these alterations are accentuated in
Neuromuscular contributions patients with respiratory muscle weakness and may lead to hyper-
capnic respiratory insufficiency and failure. Hypercapnia becomes
to sleep-â•‰related breathing particularly likely when respiratory muscle strength is less than 30%
Patients afflicted by neuromuscular disorders may develop res- of normal and when vital capacity is less than 55% of the predicted
piratory muscle weakness causing impairment of pulmonary gas value [4]â•„. Significant hypercapnia is therefore usually a late mani-
exchange, which may in turn lead to sleep-â•‰related breathing disor- festation of respiratory muscle failure. Patients suffering from neu-
ders. SDB often manifests earlier than daytime respiratory symp- romuscular disorders may present with impairment at the levels of
toms and may be the presenting manifestation in patients with the upper motor neuron (in the case of amyotrophic lateral sclero-
neuromuscular disorders. Hence, unrecognized and untreated SDB sis, ALS), lower motor neuron, neuromuscular junction, or muscle,
may result in chronic or acute respiratory failure, which is the most including weakness of respiratory muscles that may result in SDB.
common cause of morbidity and mortality in up to 80% of patients Nocturnal symptoms of SDB include shorter total sleep time, sleep
with neuromuscular diseases [1]â•„. fragmentation due to frequent respiratory-â•‰related arousals, inter-
Pulmonary function abnormalities in neuromuscular patients mittent snoring or suppressed breathing, insomnia, and oxyhemo-
most often include reduced vital capacity (VC), which is particu- globin desaturation, which in turn may lead to daytime symptoms
larly useful for following disease progression, treatment response, of impaired functioning and quality of life in patients with neu-
or evaluation in the acute setting, since VC measurement assesses romuscular diseases. Daytime symptoms resulting from sleep
both inspiration and expiration. Inspiratory muscle weakness fragmentation include fatigue and tiredness, sleepiness, morning
demonstrates restrictive physiology with decreased VC, total lung headaches, and waking with breathlessness. However, patients
capacity (TLC), functional residual capacity (FRC), and normal with neuromuscular disorders may have isolated SDB with relative
FEV1/â•‰FVC (forced vital capacity) ratio. Residual volume (RV) pro- preservation of daytime respiratory function. SDB is more likely
gressively increases as expiratory muscle weakness progresses [2]â•„ to occur in patients with rib-â•‰cage and spinal deformities, obesity,
(Fig. 30.1). VC generally remains normal (or minimally reduced) and craniofacial abnormalities. Secondary restrictive lung disease
until respiratory muscle strength pressures are under 50% of pre- due to atelectasis, recurrent pneumonia, and pulmonary fibrosis
dicted values [3]. As respiratory muscle weakness progresses, VC may occur in addition to respiratory muscle weakness. Pneumonia
falls in a curvilinear fashion [3]. Diaphragmatic paralysis may occurs following repeated aspiration and retention of secretions

12 0 levels while awake (according to the International Classification of

FET
Pred Mayo Sleep Disorders, ICSD). Sleep-related hypoxemia is defined as oxy-
Control
10
12.5
2
hemoglobin saturation less than 90% not related to discrete obstruc-
tive or central apneas or hypopneas for 5 or more consecutive
Maximal inspiratory flow, L/s

Maximal expiratory flow, L/s
minutes. Sleep-related hypoventilation in adults increases PaCO2

8 4 by 10 mmHg or more compared with waking levels. Features indi-
cating sleep-related hypoventilation such as abdominal paradox in
6 6 the supine position, daytime hypercapnia with PaCO2 > 45 mmHg,
impairment of pulmonary function tests (FVC < 50%, maximal
4
inspiratory pressure < 40 cmH2O), awake oxyhemoglobin satura-
8
tion < 91%, or SpO2 saturation < 88% for 5 minutes or more on
nocturnal pulse oximetry suggest that a polysomnography (PSG)
2 10 study should be performed, and that ventilatory support should
be introduced. Evidence to guide when supportive noninvasive
0 12 positive pressure ventilation (NIV) should be initiated remains
0 1 2 3 4 5 6 7 8
Expired volume, (L) weak given the absence of randomized controlled trial evidence;
however, expert consensus has established guideline thresholds
Fig. 30.1 Impaired flow–volume curve in neuromuscular disease. This was for the initiation of NIV in patients having chronic respiratory
obtained during pulmonary function tests in a 58-year-old man with bilateral insufficiency associated with restrictive thoracic disorders, with
isolated phrenic neuropathies resulting in hypercapnic respiratory failure. Note the Centers for Medicare and Medicaid generally following these
the severe limitation of expiratory flow and the reduction in expired volume.
recommended thresholds for coverage determination, as shown in
Table 30.1 [9,10].
due to a weak cough reflex. With chronic hypoventilation, hypox-

emia and hypercapnia develop, which may be complicated by sub- Sleep-related breathing in specific
sequent heart failure and autonomic dysfunction. neuromuscular disorders
The respiratory muscles include the diaphragm, intercostal, and
abdominal muscles, in addition to accessory respiratory muscles Amyotrophic lateral sclerosis
of the sternocleidomastoid and neck strap muscles. Upper airway ALS, also called motor neuron disease or Lou Gehrig’s disease, is
patency depends on adequate muscle tone and strength of the a degenerative disorder based on progressive premature death of
tongue, pharyngeal wall, hypopharynx, and larynx. The diaphragm upper and lower motor neurons in the motor cortex of the brain,
is the most important muscle for inspiration during wakefulness brainstem, and spinal cord. ALS is characterized by progressive
or sleep, and the severity of hypoventilation parallels the degree muscle weakness and atrophy, fasciculations, hyperreflexia, spastic-
of diaphragmatic weakness. According to the severity of respira- ity, dysarthria, dysphagia, and dyspnea. The major cause of morbid-
tory muscle weakness, REM sleep may further reduce respiratory ity and mortality in ALS is progressive respiratory muscle weakness
muscle function, which can lead to life-threatening hypoxemia and and ultimately respiratory failure. The sporadic form of the disease
hypercapnia. is most common, with the average age of onset being in the sixth
The most common forms of SDB in neuromuscular diseases are and seventh decades. Familial ALS comprises only 5–10% of cases,
nocturnal hypoventilation, obstructive sleep apnea (OSA), and and onset may be at a younger age. Weakness in ALS often begins
central sleep apnea (CSA). Alveolar hypoventilation in patients focally in a specific muscle group or body region. Three types of
with neuromuscular diseases typically appears during REM sleep. disease onset in ALS can be distinguished: limb (60%), bulbar
Respiration during REM sleep depends on metabolic control, (30%), and respiratory (2%).
while voluntary control diminishes. Chemosensitivity may, how- Sleep in ALS patients is disturbed by dyspnea and hypoxemia.
ever, accustom to the changes in blood gases, potentially lead- Patients often experience frequent nocturnal awakenings, and sleep
ing to longer periods of hypoxia during REM sleep. Prolonged quality is unrefreshing, often with daytime sleepiness and morning
hypoventilation stimulates bicarbonate retention and additional headaches. The main cause of hypoxemia is REM sleep hypoventi-
decrease in respiratory drive, leading to more marked REM sleep lation, which is most often induced by phrenic nerve dysfunction
hypoventilation. As a neuromuscular disease advances, hypoventi- and resultant diaphragmatic weakness. Pulmonary function tests
lation may also be observed in non-REM (NREM) sleep and during are prognostically valuable in monitoring the progression and sur-
the daytime [7]‌. Hence, daytime respiratory function most often vival of ALS patients [11,12]. Significant respiratory insufficiency
occurs later in the course of advancing neuromuscular weakness during sleep should be treated with NIV, initially for in-home care
and accordingly has markedly greater prognostic value for immi- with bilevel positive airway pressure (BPAP). Bulbar symptoms and
nent respiratory demise than earlier-presenting nighttime signs. frontotemporal dementia may partially account for intolerance of
In patients with neuromuscular disorders, sleep is fragmented by NIV [9]‌. When considering initiation of NIV, the measurements
frequent arousals, which may disturb sleep, with arousal serving of nocturnal gas exchange, muscle strength, and symptomatic
as a protective mechanism to blunt deleterious changes in blood complaints must be taken into consideration. FVC < 50%, possibly
gases [8]. even earlier to achieve better survival, maximal inspiratory pres-
Nocturnal hypoventilation is defined as an increase in PaCO2 sure (MIP) < −60 cmH2O, supine vital capacity nasal inspiratory
greater than 45 mmHg, or disproportionately increased relative to pressure (SNIP) < 40 cmH2O, oxygen saturation of 88% or less for

Chapter 30 neuromuscular disorders and sleep 303
Table 30.1 Recommended guidelines for initiation of noninvasive PSG to identifying SDB in DMD patients increases when PaCO2
positive pressure ventilatory devices in chronic respiratory insufficiency exceeds 45 mmHg and the patient develops apparent daytime
associated with restrictive thoracic disorders symptoms such as excessive sleepiness, morning headaches, and
fatigue caused by sleep fragmentation and REM sleep deprivation.
Consensus Guidelines 1. Symptoms of hypoventilation (one or more In patients suffering from sleep-related hypoventilation and
‌(1999) [9] needed): daytime symptoms, NIV should be considered. This can improve
Daytime sleepiness the patient’s quality of life by decreasing daytime sleepiness, as
Fatigue well as improving oxygenation and increasing survival. Significant
Morning headache nocturnal and later daytime respiratory insufficiency and inef-
2. Physiological criteria (one or more needed): fective coughing occur as muscular weakness progresses, leading
PaCO2 ≥ 45 mmHg to complications such as aspiration pneumonia and atelectasis,
Oxyhemoglobin saturation < 88% for and patients may need to receive 24-hour ventilatory support.
≥ 5 minutes Tracheostomy is indicated in patients with recurrent respiratory
MIP < −60 cm infections when direct airway suctioning is necessary, and in DMD
patients with severely compromised chest wall compliance [18,19].
FVC < 50% predicted
Since nocturnal hypoxemia is caused by hypoventilation, oxygen
CMS Criteria [10]: all 1. Requires both Consensus Guideline should not be utilized alone without ventilatory support, since patients
Consensus Guidelines Categories above with chronic hypercapnia are dependent upon hypoxemic breathing
criteria above, plus: 2. COPD does not contribute significantly drive, and oxygen alone could result in a further blunted breathing
3. Both PaCO2 and nocturnal oximetry are on drive with resultant severe hypercapnia and respiratory failure.
patient’s usual FiO2 Scoliosis is associated with increased arousals and decreased
sleep efficiency and REM sleep time. DMD patients with scoliosis
are usually treated with steroids, which can decelerate the progres-
at least 5 consecutive minutes, and PaCO2 > 45 mmHg are sug- sion of scoliosis and delay spinal corrective surgery. Correction of
gested thresholds for NIV initiation [9,13–15]. NIV improves noc- scoliosis does not improve vital capacity or ameliorate sleep distur-
turnal breathing and often improves sleep quality, energy, speech bances or diurnal consequences, although corrective surgery plays
clarity, quality of life, and survival time. NIV increases oxygena- a significant role in improving DMD patients’ quality of life and
tion, but has no significant effect on objective sleep efficiency or nursing care [18].
arousal index [16]. Oronasal masks are often poorly tolerated by
ALS patients with severe sialorrhea and jaw closure weakness. Myotonic dystrophy
Excessive salivation can be reduced by tricyclic antidepressants or Myotonic dystrophy (dystrophia myotonica, DM) is an autosomal
a scopolamine patch, or ultrasound-guided submandibular injec- dominant multisystem disease. Two subtypes of this disorder have
tion of botulinum toxin [9]. Diaphragmatic pacing stimulation been identified, according to the chromosomal location and type of
to induce phrenic nerve function may delay chronic mechanical intron defect. Both are caused by untranslated repeat expansions of
ventilation up to 24 months [17]. ALS patients ultimately face the RNA, forming a pathological change of a chloride channel protein.
decision concerning whether to choose life-prolonging long-term Myotonic dystrophy subtype 1 (Steinert disease, DM1) is the result
mechanical ventilation by tracheostomy, which is postponed to the of a CTG trinucleotide repeat expansion (ranging from 50 to thou-
late stages of the disease to reduce consequences of immobility and sands of repeats), resulting in mutation in the gene for myotonin
limited communication. Dyspnea in terminal stages can be palli- protein kinase (DMPK) [19,20]. The greater the number of repeats,
ated with morphine. the more severe is the manifestation of the disease [21], leading to
the phenomenon of genetic anticipation, with progressively more
Duchenne muscular dystrophy severe phenotypes in successive generations given a progressively
Duchenne muscular dystrophy (DMD) is a hereditary X-linked lengthened number of repeats. DM1 is characterized by a variety
muscle disease in the gene encoding the synthesis or expression of different severity of phenotypes, which vary according to tem-
of the protein dystrophin. Afflicted boys are born without initial poral onset through the lifespan, including congenital-type DM1.
disability, but clinical manifestations develop later between 3 and A defect in the zinc finger protein 9 (ZNF9) gene characterizes
5 years of age with progressive muscular weakness involving res- myotonic dystrophy type 2 (DM2, also previously known as proxi-
piratory muscles, ultimately causing respiratory failure, the most mal myotonic myopathy, or PROM). In most patients, symptoms
common cause of death in DMD by the third decade of life. In the of DM2 typically appear during the third decade. DM2 is usually
first decade, SDB, including OSA, occurs with the gradual progres- a milder disease than DM1, but may involve a different spectrum
sion of muscle weakness to relative atonia, affecting particularly of sleep disturbances, including prominent restless legs syndrome
the upper airway dilator muscles and deforming the rib cage. As (RLS) [22]. DM affects skeletal and cardiac muscles, respira-
DMD advances in the second decade, patients suffer from alveolar tory, endocrine and central nervous systems, the gastrointestinal
hypoventilation mainly during REM sleep, marked by hypercapnia tract, and lens, and is associated with a variety of sleep disorders.
and oxyhemoglobin desaturation despite normal waking respira- Interestingly, DM also impacts the central nervous system; in the
tory function. Therefore, the severity of SDB must be evaluated by brain, DM appears to predominantly involve the white matter,
PSG and CO2 evaluation, since daytime pulmonary function tests especially in the callosal body and the limbic system [20].
may not reveal the full impact of functional impact and resultant Sleep disorders are very common in both DM subtypes and, com-
hypoxia and hypercapnia during sleep [18,19]. The contribution of pared with other neuromuscular diseases, show great variability.

Sleep disturbances in DM may include SDB, central hypersom- in the plasma of most patients with MG. Antibodies cause recep-
nia resembling narcolepsy or idiopathic hypersomnia, prominent tor degeneration or blockade resulting in reduction of functional
fatigue, insomnia, RLS, and periodic limb movement disorder postsynaptic acetylcholine receptors (AChR). Even though the
[20–26]. SDB is the most common sleep manifestation in DM1, proper amount of acetylcholine is released from the presynaptic
with a spectrum of disordered breathing including OSA or CSA neuron, there is decreased muscle contraction, given compromise
and sleep-related hypoventilation. In some patients with congeni- of the postsynaptic AChR function by anti-AChR antibodies. IgG-
tal DM1, mixed obstructive and central apneas develop. Owing to positive MG is associated with thymoma or thymic hyperplasia.
severe diaphragmatic, intercostal, upper airway, and tongue muscle The autoimmune process in MG is thought to be initiated by reac-
weakness, patients may demonstrate significant alveolar hypoven- tion of thymic B cells with thymic cells that have similar antigenic
tilation with hypoxemia and hypercapnia, especially during REM characteristics to skeletal muscle cells. Muscle-specific tyrosine
sleep. Patients with DM tend to have a high BMI, so the degree kinase antibodies (MuSK) are found in the blood of a subset of
of nocturnal desaturation is greater than in other neuromuscu- patients with MG.
lar patients with similar degrees of muscle weakness. SDB in DM MG is characterized by fatigable muscle weakness due to
may lead to early respiratory failure, and pulmonary function tests reduced muscle contraction. The majority of MG patients present
and arterial blood gases while awake often may underestimate the with abnormalities of eye movements or eye opening, with diplo-
degree of sleep-related respiratory function compromise. CSA may pia and ptosis. Other manifestations are limb muscle weakness,
be due to direct involvement of the brainstem and diencephalon by dysarthria, and dysphagia. MG symptoms typically worsen as the
DM pathology [24]. PSG shows different patterns of SDB, including day progresses, especially following repeated activity, and are clas-
obstructive, central, or mixed apneas and hypopneas, respiratory- sically worse in the evening hours and better in the morning. With
effort-related arousals, shallow and periodic breathing, and non- progressive disease, particularly during subacute periods of wors-
apneic sustained sleep-related hypoxemia due to hypoventilation. ening known as myasthenic crisis, respiratory muscle weakness
Other PSG features seen frequently in DM include frequent spon- is present. Myasthenic or iatrogenic cholinergic crisis (the latter
taneous arousals (which may be associated with muscle pain and resulting from excessive doses of pyridostigmine) may lead to pro-
stiffness, especially in DM2), decreased sleep efficiency, and fre- nounced SDB, respiratory insufficiency, and eventual respiratory
quent periodic leg movements of sleep with movement arousals. failure.
SDB and excessive daytime sleepiness (EDS) can be the presenting Respiratory and sleep disturbances can be detected by subjective
symptoms heralding a DM diagnosis [23–26]. symptoms such as morning headache, fatigue, nocturnal breathless-
EDS is present in DM1 patients and has also been described, al- ness, daytime somnolence, and cognitive dysfunction, or by objec-
though less frequently, in the DM2 subtype [26,27]. Sleepiness in tive testing demonstrating oxygen desaturation or hypercapnia.
DM may be attributed to sleep disturbances caused by respiratory SDB is especially prominent during REM sleep given the
muscle weakness or sleep apnea, but also results from dysfunction dependence of effective ventilation on diaphragmatic function dur-
of sleep–wakefulness control. Hypersomnia often persists after ing REM, making patients with diaphragmatic weakness particu-
SDB has been effectively treated by continuous positive airway larly vulnerable to severe desaturations. SDB in MG may involve
pressure (CPAP) as a result of central hypersomnia caused by DM obstructive, central, or mixed sleep apnea. CSA has been associated
brain pathology [24,25]. The central hypersomnia disorder of DM with the presence of AChR-antibodies in cerebrospinal fluid. OSA
is thought to result from a decrease in serotonergic raphe and su- in MG patients occurs mainly as a result of oropharyngeal weak-
perior central nucleus neurons, reduction of medullary reticular ness, and OSA frequency may be up to 15–20% higher in MG than
catecholaminergic neurons, as well as dysfunction of hypothalamic in the normal population, although evidence has been conflicting
hypocretinergic function proven by reduced cerebrospinal fluid and further studies are needed [29,30]. Daytime pulmonary func-
hypocretin levels [28]. tion tests are usually normal when MG is in clinical remission, or if
Early PSG to evaluate for SDB may help prevent early respira- there are no risk factors for respiratory compromise such as older
tory failure. Positive PSG results inform the implementation of ei- age or obesity, steroid-induced myopathy of the oropharyngeal
ther CPAP or NIV with BPAP during sleep. In patients with EDS muscles, or decreased TLC [31,32].
resulting from OSA, CPAP is preferred. In those presenting with MG treatment only rarely induces complete remission.
daytime hypercapnia or sustained non-apneic hypoxemia due to Treatments for MG include cholinesterase inhibitors, thymectomy
sleep-related hypoventilation, BPAP is necessary to provide NIV. in anti-AChR antibody-positive cases, corticosteroids, immuno-
If the sleep study is normal, or symptoms of EDS remain in spite suppressive drugs, and plasmapheresis or IVIG during myasthenic
of otherwise effective therapy for SDB, then evaluation for central crisis. Most MG symptoms respond at least transiently to sympto-
hypersomnia and stimulant medications (eg, modafinil, methyl- matic therapy with slow-release cholinesterase inhibitors such as
phenidate, or dexamphetamine) can be considered. pyridostigmine. Thymectomy is helpful in reducing disease sever-
ity and frequently induces remission in anti-AcChR antibody-
Neuromuscular junction disorders positive MG cases, and has been reported to reduce the frequency
Neuromuscular junction disorders include myasthenia gravis, of sleep apnea episodes, nocturnal hypoxia, and weakness of the
Lambert-Eaton myasthenic syndrome, congenital myasthenic syn- oropharyngeal muscles [7,33]. Corticosteroids can induce weight
drome, and botulism. gain that may in turn increase OSA severity, and steroid therapy
often induces severe and brittle insomnia [32]. SDB can be sympto-
Myasthenia gravis matically treated by introduction of nasal CPAP or NIV. Nocturnal
Myasthenia gravis (MG) is an autoimmune disorder. IgG anti- hypoventilation and sleep apnea may be severe and occasionally
bodies against the postsynaptic acetylcholine receptor are found require assisted ventilation.

Lambert–Eaton myasthenic syndrome, botulism, Limb-girdle muscular dystrophy

and congenital myasthenic syndrome LGMD is a rare autosomal dominant muscle disorder with clini-
SDB has also been described in Lambert–Eaton myasthenic syn- cal similarities to Duchenne and Becker muscular dystrophies. The
drome (LEMS), botulism, and congenital myasthenic syndrome age of onset ranges from the first to third decades of life. Earlier
(CMS), and although it is thought to be less frequent than in MG disease onset correlates with more severe symptoms and more
[7]‌, it may be underdiagnosed [34]. Significant muscle weakness rapid progression. As LGMD progresses, respiratory muscle func-
can lead to severe respiratory impairment that may require assisted tion decreases, resulting in sleep disruption. Sleep abnormalities
ventilation. Regular screening of muscle strength is indicated; clini- are similar to those in DMD. SDB appears owing to both CSA on
cal examination of the bulbar muscles, as well as cervical flexion account of failure of respiratory control and OSA due to upper air-
and extension, can help identify segmental weakness that may way muscular weakness [39]. LGMD patients with SDB should be
assist in portending diaphragmatic weakness and the need for NIV adequately treated with nocturnal NIV or, if needed, by tracheos-
or mechanical ventilation. tomy and mechanical ventilation.
Other myopathies Metabolic myopathies

Metabolic myopathies are rare hereditary disorders characterized
Other less common myopathies that may manifest sleep disorders
by impairment of biochemical metabolism of muscle tissue, with
are facioscapulohumeral muscular dystrophy (FSHD), congeni-
defects in a wide variety of proteins. The most important meta-
tal muscular dystrophies (CMDs), metabolic, mitochondrial, and
bolic myopathy that significantly affects respiratory muscle func-
inflammatory myopathies, and limb-girdle muscular dystrophy
tion and results in SDB is acid maltase deficiency (AMD), also
(LGMD).
known as Pompe disease. AMD is a glycogen storage disorder
Facioscapulohumeral muscular dystrophy resulting in muscle tissue function failure. AMD may manifest in
FSHD is the third most common hereditary muscular dystrophy. both childhood and adulthood forms and, given slow progression,
Most cases of FSHD are inherited in an autosomal dominant fash- survival time is long. The most frequent cause of death is respira-
ion, while the remainder is due to sporadic mutations. FSHD is a tory muscle failure. Diaphragmatic insufficiency is frequent and
slowly progressive myopathy resulting from chromosomal dele- may manifest earlier than other muscle group weakness in AMD
tion of 4q35. The onset of FSHD is usually in the second dec- [40]. The failure of diaphragmatic muscle function is most pro-
ade, but it may also manifest in early childhood. The greater the nounced during REM sleep, resulting in SDB characterized by
chromosomal impairment or mutation, the more severe are the profound and long-duration periods of sleep-related hypoventila-
manifestations of FSHD. FSHD is characterized by craniocau- tion, apneas, substantial oxyhemoglobin desaturation, and hyper-
dal spreading of muscle weakness, usually sparing respiratory capnia. SDB and sleep-related hypoventilation may be predicted
muscles. by diurnal pulmonary function tests [9,39]. In order to improve
Poor sleep quality results particularly from reduced nocturnal quality of life and prevent early respiratory failure, NIV should be
mobility correlating with weakness severity. Body movement is administered [40].
essential to obviate peripheral nerve compressions and subsequent
pain and paresthesias [35]. OSA is a frequent cause of sleep dis- Mitochondrial myopathies
turbance in FSHD patients owing to pharyngeal muscle weakness. Mitochondrial myopathies are characterized by respiratory chain
Kyphoscoliosis resulting from asymmetrical FSHD involvement impairment, and are also known as oxidative phosphorylation dis-
of the trunk and scapular muscles may also induce sleep-related orders. These disorders result in reduced energy metabolism affect-
hypoventilation. PSG shows longer sleep latency, frequent spon- ing the most energy-demanding tissues, the muscles and brain,
taneous arousals, reduced overall sleep time, and shortened REM earliest and primarily. Therefore, these disorders are also called
sleep time [36–37]. mitochondrial encephalomyopathies. Prominent fatigue is typical,
Congenital muscular dystrophies and respiratory compromise has been reported [41].
CMDs are a genetically heterogeneous group of autosomal reces- Inflammatory myopathies
sive, slowly progressive muscle disorders. Clinical manifestations
Inflammatory myopathies, including dermatomyositis (DM), poly-
depend on mutations in specific genes encoding proteins such as
myositis (PM), and sporadic inclusion-body myositis (sIBM), are
laminin. Muscle weakness is obvious at birth or during the first
rare systemic connective tissue diseases that may lead to mobility
months of life. Examples of CMDs are laminin-α2-deficient CMD,
impairment and loss of muscle tone. Weakness of respiratory mus-
Ullrich CMD, and muscle–eye–brain disease. Sleep is disrupted by
cles, particularly the oropharyngeal muscles, may result in OSA
CSA due to a central ventilatory control disorder, or by OSA result-
and respiratory compromise [42].
ing from upper airway muscle weakness [38]. Mixed apnea/hypo-
pnea may also occur. Accessory respiratory and intercostal muscle
Isolated phrenic neuropathy
atonia during REM sleep may cause nocturnal oxyhemoglobin
desaturation and hypercapnia, fragmented sleep with frequent Isolated phrenic neuropathy (IPN) is a rare cause of acute or suba-
arousals, and reduced REM and total sleep times [38]. Clinical cute unexplained dyspnea and orthopnea, and can lead to hyper-
examination and diurnal respiratory function tests are in most capnic respiratory failure when bilateral involvement of the phrenic
cases normal, but it is important to identify SDB in asymptomatic nerves occurs (Fig. 30.1). Acute diaphragmatic palsy can develop
CMD patients early enough to prevent respiratory failure. PSG is in association with a variety of disorders, such as Parsonage–
therefore an important part of screening, and, if needed, ventilatory Turner syndrome, immune brachial plexus neuropathy, diabetic
support should be introduced. polyneuropathy, Guillain–Barré syndrome, motor neuron disease,

large artery vasculitis, and von Recklinghausen disease. Unilateral activity of intercostal and respiratory accessory muscles, especially
phrenic neuropathy is most often asymptomatic, and is a relatively during REM sleep, and the ventilatory function of the diaphragm
frequent incidentally detected finding as hemidiaphragmatic ele- may be altered during NREM sleep. CSA may appear after high
vation on chest radiography. Bilateral IPN (BIPN) usually has an cervical spinal cord injury, especially when the injury also extends
acute, painless onset, without an antecedent trigger. To distinguish to brainstem respiratory centers. Other possible causes of CSA are
diaphragmatic weakness from other causes of dyspnea such as syringomyelia and syringobulbia. A recent study found that the
pulmonary embolism or cardiac failure, the examiner should lay mode of administration of intrathecal baclofen also impacted the
the patient supine, which results in worsened dyspnea, and often severity of SDB, with bolus administration leading to more fre-
accessory muscle (sternocleidomastoid and neck strap muscles) use quent and severe respiratory events (especially central apneas) than
and abdominal paradox may be seen. There may be an up to 50% continuous infusion [47]. Treatment of SDB and central hypoven-
decrease in vital capacity when transferring between the upright tilation syndrome includes both symptomatic measures such as
and supine positions when upright and supine pulmonary func- avoiding the supine position and respiratory suppressant drugs,
tions are formally measured [7]‌. Chest X-rays show bilateral dia- as well as the use of NIV, tracheostomy, and diaphragmatic pacing
phragmatic elevation, electrophysiological testing demonstrates [17,48].
reduced or absent phrenic nerve conductions and active diaphrag- Postpoliomyelitis syndrome
matic denervation, and diaphragmatic ultrasound and fluoroscopy
PPS occurs in approximately 25% of patients with a remote history
show reduced diaphragmatic movement [44].
of acute poliomyelitis caused by poliovirus. The onset of PPS ranges
Patients with bilateral or severe unilateral IPN are at significant
from two to five decades after the primary disease. In the acute
risk of SDB. Severe nocturnal hypoventilation and desaturation
poliomyelitis infection, poliovirus destroys spinal cord anterior
during REM sleep can occur. Unlike many other neuromuscular
horn motor neurons, thus denervating skeletal muscles acutely.
disorders, SDB often occurs independently of BMI. Patients suf-
However, chronically during recovery, reinnervation of muscle
fer from fragmented sleep and consequently from fatigue, morning
fibers occurs by axonal sprouting from surviving motor neurons.
headaches, and hypersomnia. To evaluate disordered sleep, PSG is
PPS usually occurs in patients who had the paralytic form of polio-
indicated. The phrenic nerve may take years to regenerate, and in
myelitis, and mainly affects previously involved muscles, although
some cases may never fully recover. During this time, patients re-
it may also affect muscles that appeared to have been spared dur-
quire NIV to improve quality of life and prevent respiratory failure,
ing the earlier acute attack of poliovirus. PPS is thought to develop
and NIV often reduces sleeping problems and the ability to rest in
owing to normal loss of motor neurons consequent to aging, and
a recumbent position [43,44]. Diaphragmatic plication can also
possibly also to overuse of the affected muscles. In PPS, the process
be considered for patients who suffer permanent diaphragmatic
of ongoing chronic denervation due to motor neuron loss related
paralysis.
to aging exceeds the capacity for reinnervation of the muscle by
healthy motor neurons. In patients who previously had the bulbar
Spinal cord disorders
form of poliomyelitis, PPS patients may develop impaired respir-
Spinal cord disorders manifesting sleep impairment are primarily ation and swallowing. Capacity for recovery depends on the ability
spinal cord injuries, postpoliomyelitis syndrome (PPS), and spinal of the surviving motor neurons to successfully reinnerrvate the
muscular atrophy (SMA). affected muscles.
Sleep disorders in PPS are usually due to underlying impaired
Spinal cord injury
respiratory function in patients experiencing worsening of ventila-
The severity and manifestations of sleep disorders in patients with
tory function, mostly affecting patients whose respiratory muscles
spinal cord injury depends on the location of the lesion. If spinal
were involved during their primary illness with acute poliomyel-
cord injury extends to the brainstem and alters reticular formation
itis. PSG demonstrates nocturnal hypoventilation, hypopneas,
(RF) function, altered sleep–wake regulation may occur, so the more
apneas, hypoxemia, delayed REM sleep latency and reduced REM
rostral the spinal cord damage, the poorer the sleep quality may
time, recurrent arousals, and sleep fragmentation [49]. Morning
be. Concomitant closed head injury often accompanies spinal cord
headaches, EDS, or frank respiratory insufficiency may appear.
injury, which may also impact sleep–wake regulation, cause cen-
Most apneas are obstructive or mixed. Musculoskeletal deformities
tral posttraumatic hypersomnia, and impact melatonin secretion.
such as kyphoscoliosis may induce restrictive ventilatory impair-
Melatonin plays important roles in circadian rhythms and sleep
ment associated with respiratory accessory muscle weakness [7]‌.
promotion. Consequences of low plasma melatonin concentra-
Therapeutic options for respiratory disorders in PSS are introduc-
tion include shortened total sleep duration, repeated arousals, long
tion of NIV and, rarely, tracheostomy with mechanical ventilation.
wakefulness periods, and shortened REM latency and decreased
REM percentage [45]. Defective melatonin secretion can be treated Spinal muscular atrophy
with replacement by 2–6 mg of exogenous melatonin dosed before SMA describes a heterogeneous group of hereditary autosomal
bedtime. Insomnia and daytime sleepiness resulting from head recessive disorders characterized by deterioration of spinal cord
injuries can be treated with prescribed hypnotics and modafinil or anterior horn motor neurons and, in some cases, nuclei of caudal
other psychostimulant medications [45,46]. Pain, spasms, immo- cranial nerves ranging from the trigeminal to hypoglossal nerves. In
bilization, supine position, and bladder distension each may influ- SMA, four subtypes may occur, according to age of onset. Patients
ence sleep as well, so optimal treatment of these complications is may have intercostal and diaphragmatic muscle weakness and dif-
also important to optimize sleep in this patient population. ferent degrees of bulbar symptoms, leading to respiratory dysfunc-
The most common type of SDB in patients with spinal cord injury tion and SDB. Also, chest wall deformities and scoliosis may worsen
is OSA. Sleep-related hypoventilation may occur, given reduced the extent of SDB, which can eventually lead to respiratory failure,

especially in childhood-onset forms I and II. SDB is characterized Supine vital capacity nasal inspiratory pressure (SNIP) is able
by OSA, hypercapnia, and oxyhemoglobin desaturation during to measure the function of inspiratory muscle strength, predomi-
REM sleep. Sleep is disrupted by frequent arousals and sweating, nantly the diaphragm. SNIP > 70 cmH2O (in an adult male) and
morning headaches and nausea, daytime sleepiness, and school SNIP > 60 cmH2O (in an adult female) exclude the presence of
performance difficulties in children and adolescents [50]. NIV can clinically significant respiratory muscle weakness. SNIP has been
improve subjective and objective symptoms of SDB. shown to be a very good predictor of nighttime desaturation and
respiratory failure in ALS [15]. NIV should be considered when
Diagnostic assessment and approach to SNIP decreases to less than 40 cmH2O [51,52].
Mouth pressures (maximum inspiratory and expiratory pres-
the patient with neuromuscular disease sures, MIP and MEP, also known as bugle pressures) character-
and sleep-related breathing disorders ize global inspiratory and expiratory muscle strength. Inspiratory
Patients with chronic neuromuscular disease should be routinely muscle strength includes assessment of the diaphragm, respira-
assessed for sleep complaints. The presence of symptoms is the tory accessory, and intercostal muscles, while expiratory muscle
primary consideration to initiate evaluation for OSA, CSA, or strength encompasses expiratory muscles through evaluation of
hypoventilation. However, some patients may have SDB without cough strength. Mouth pressures should be measured at the time of
any evident symptoms. Therefore, evaluation by a sleep specialist diagnosis and follow-up to aid identification of deterioration, and
and screening for SDB should be considered, with at least an ini- may also be used in acute situations to decide whether mechanical
tial unattended in-home study such as portable overnight oxime- ventilation is needed. In patients with facial muscle weakness, the
try. No single test is completely accurate for detecting the presence mouth pressure is inaccurate because of insufficient mouth sealing.
of nocturnal desaturation or respiratory failure. Therefore, several Arterial blood gas (ABG) values remain in the normal range
different means of evaluation should be used in concert to assess during wakefulness until the underlying neuromuscular disor-
for possible SDB and hypoventilation, beginning with a thorough der becomes chronic and involves signs of respiratory failure, or
clinical history and examination. Patients should be carefully ques- in cases of acute respiratory insufficiency. Abnormal ABG val-
tioned about past and present sleep history, including whether they ues correlate with significant weakness of respiratory muscles.
have a history of loud disruptive snoring, whether snoring varies by Respiratory failure in neuromuscular patients is characterized by
sleep position, whether snort or gasp arousal or witnessed pauses a chronic, compensated respiratory acidosis, with findings on ABG
in breathing have been noted, and whether symptoms of morning of elevated PaCO2 and bicarbonate, accompanied by normal or
predominant headache, dry mouth, or sore throat are regularly slightly reduced pH. Nocturnal hypoventilation is diagnosed by
present. Inquiring about restless legs symptoms (an uncomfort- nighttime oxyhemoglobin desaturation (SpO2 < 88%) for five or
able urge to move the legs, with rest onset and worsening, relief more consecutive minutes, together with a morning ABG demon-
by movement or getting up to walk, and evening predominance of strating daytime hypercapnia (PaCO2 > 45 mmHg) with raised pH
symptoms) is also important, especially in patients with myotonic and bicarbonate values [5,7]. Findings consistent with nocturnal
dystrophy. Taking a thorough family history and drug, alcohol, and hypoventilation can support an indication for NIV initiation.
medication use history is also important. Psychiatric history may Portable overnight oximetry is useful to screen for sustained
also play an important role in further diagnostic assessment. oxyhemoglobin desaturation associated with nocturnal hypoven-
Pulmonary function tests (PFT) help to evaluate the likelihood tilation and for frequent oscillatory desaturation events associated
of sleep-related hypoventilation, evaluate the ventilatory con- with OSA or CSA. When patients develop diaphragm dysfunction,
trol system, and exclude intrinsic bronchopulmonary disease, they may show characteristic oximetry patterns heralding impend-
and may have prognostic value [11]. PFT include vital capacity, ing progressive respiratory muscle dysfunction as shown in Fig.
forced expiratory volume, total lung volume, minimal residual 30.2. As diaphragmatic failure becomes more advanced, the oxi-
volume, and gas distribution and transfer measurements [7–9] metry findings become more profound and show the characteristic
Vital capacity (VC) is a global respiratory function test using clustered periodic deep episodic desaturations dependent on REM
both inspiratory and expiratory muscles. VC can be measured stage sleep. Again, this is because of the superimposed influence of
in both upright and supine positions. VC in the supine position normal REM sleep stage muscle atonia upon preexisting diaphrag-
sensitively differentiates the origin of respiratory impairment. If matic weakness that further compromises respiratory function,
VC values fall within the normal range, then respiratory mus- given that the diaphragm is the sole muscle supporting respiratory
cle weakness is probably not responsible for ventilation prob- function in the REM sleep state. Overnight oximetry is recom-
lems. PFT findings consistent with diaphragmatic weakness and mended when relevant symptoms suggestive of SDB are observed,
probable nocturnal hypoventilation include a fall in FVC values including daytime sleepiness, loud disruptive snoring, morning
between the sitting to supine positions of 15–20%, or when sitting headaches, and repeated arousals and restlessness during sleep.
FVC is less than 80%. FVC less than 50%, along with recurrent Portable screening devices are not very sensitive and are able to
respiratory tract infections, is typical of patients with neuromus- detect only moderate to severe OSA; therefore, if typical symptoms
cular disease with nocturnal hypoventilation disorders. Owing to of SDB are present, PSG should still be considered to detect mild
fluctuation of muscle weakness in myasthenia gravis, assessment OSA or the upper airway resistance syndrome.
of FVC must be done carefully. Sleep hypoventilation is very In-lab PSG is the most sensitive assessment of sleep in patients
likely to be seen when FVC is less than 50% of predicted value, or with neuromuscular disorders, and provides polygraphic data con-
if a greater than 20% decrement is seen between the upright and cerning respiratory function, movement, and sleep architecture.
supine positions. In this case, a PSG should be performed, and PSG is indicated in patients with symptoms of SDB, unexplained
NIV should be considered. cor pulmonale, inspiratory VC < 50% of predicted value, and

Saturation
100 175
90 150
88
Heart Rate (beats/min)

O2 Saturation (%)
80 125
70 100
60 75
50 50
Heart Rate
40 25
21:00 22:00 23:00 0:00 1:00 2:00 3:00 4:00
Time (Hr:Min)
Fig. 30.2 Portable overnight oximetry in a patient with progressive neuromuscular disease. Oximetry shows features of both recurrent oscillatory desaturation typical of
obstructive sleep disordered breathing, in addition to sustained hypoxemia representing hypoventilation from diaphragmatic weakness. Note the periodic worsening of sustained
hypoxemia, especially in the first third of the night, which was verified during polysomnography to correspond to periods of worsened hypoxemia during REM sleep stage.
reduced peak inspiratory pressure < 2.5 kPa. The absence of REM The latter is often better tolerated by neuromuscular patients and is
sleep appears to correlate with a poor prognosis in neuromuscular more effective for nocturnal ventilation. CPAP should be initiated
disorders, and suggests impending respiratory failure. Other typi- only in neuromuscular patients with normal nocturnal ventilation,
cal findings include reduced total sleep time, an increased numbers since it may increase the burden on weak respiratory muscles. NIV
of arousals, sleep fragmentation and disorganization, obstructive, can be applied via mouthpiece, nasal mask, nasal pillows, or a full
central and mixed sleep apneas, oxyhemoglobin desaturation, or face mask interface.
delayed initial sleep latency and prolonged wake after sleep onset Since SDB and respiratory impairment are first detected during
time consistent with initial and sleep-maintenance insomnia. REM sleep, patients usually need initial ventilatory support only dur-
Addition of transcutaneous or end-tidal CO2 monitoring can be ing nighttime, allowing them to breathe on their own during the day.
very helpful to more directly assess hypoventilation, and can help When daytime hypercapnia evolves, nocturnal ventilation should be
guide NIV treatment [7,53]. introduced. The level of nocturnal ventilation must be determined
in the sleep laboratory or at the hospital bedside with careful moni-
Management of sleep-related breathing toring [54]. Contraindications for NIV include bulbar involvement,
swallowing impairment, inability to clear secretions, and lack of
disorders in neuromuscular diseases patient cooperation with inability to tolerate a mask interface.
Timely recognition and treatment of sleep disorders in patients NIV ventilatory support may prevent decline in lung function
with neuromuscular disorders can significantly improve quality of and improve sleep quality, quality of life, and survival [11,55,56].
life. SDB is often the first indicator of impaired respiratory func- Initiation of NIV is recommended when patients become sympto-
tions in neuromuscular patients, and can be detected earlier than matic with EDS, loud disruptive snoring, orthopnea, and morning
other ventilatory problems that may ultimately lead to respiratory headaches, or when they reach an FVC < 50% of predicted value,
failure, the chief cause of morbidity and mortality in these patients. SNIP < 40 cmH2O, PaCO2 > 45 mmHg, or oxyhemoglobin satura-
tion < 88% [9,51,52]. In stable chronic hypoventilation syndromes,
Chronic management considerations NIV should be initiated with inspiratory and expiratory PAP (IPAP
The aims of long-term treatment are to prolong survival and and EPAP) set at 8 cmH2O and 4 cmH2O, respectively, with titra-
improve quality of life. General options applicable to all neuromus- tion as necessary to adequately support hypoxemia toward the
cular patients include lifestyle changes (loss of weight if obese), suf- maximum IPAP and EPAP of 30 cmH2O and 20 cmH2O, respec-
ficient nutrition, proper sleep hygiene with regular sleep schedule, tively. Use of NIV is dependent on patient compliance, interface
and avoidance of caffeine, alcohol, or sedative drugs that may dis- fit and seal (avoiding air leakage), and tolerability of NIV, as well
turb sleep or suppress breathing. If possible, exercise and rehabilita- as severity of scoliosis [51]. The earlier the initiation and patient’s
tion of respiratory muscles should also be introduced. successful adoption of NIV, the better the tolerance that may be
achieved [55]. NIV becomes ineffective when ability to clear secre-
Positive airway pressure and noninvasive positive tions decreases or the primary disease progresses, especially when
pressure ventilation
bulbar symptoms become more severe.
Noninvasive positive pressure ventilation (NIV) is the preferred ini-
tial treatment for SDB, as well as daytime ventilatory support when Invasive mechanical ventilation
necessary. There are two types of delivery: continuous positive air- Tracheostomy is usually considered when NIV becomes ineffec-
way pressure (CPAP) and bilevel positive airway pressure (BPAP). tive, when severity of bulbar impairment progresses or scoliosis

undergoes marked deterioration, for increasing patient safety when MIP > −30 cmH2O, or MEP < 40 cmH2O are predictors of impend-
unable to clear secretions, for avoiding cognitive impairment, and ing respiratory failure and an indication for invasive ventilation in
for prolonging survival [53–54,56]. The benefits of mechanical Guillain–Barré syndrome, and similar values are generally favored
ventilation are complete control of gas volumes, ability to admin- in neurocritical care settings for other acutely deteriorating neuro-
ister higher ventilatory pressures, permitting direct airway suc- muscular patients in the consideration of intubation and mechani-
tioning of secretions, and treatment of acute respiratory failure. cal ventilation [58]. Tracheostomy does not have to be considered
However, many complications can occur such as hemorrhage, immediately, nor is it necessarily a permanent solution when the
tracheal necrosis or stenosis, tracheoesophageal fistulae, bacterial patient is expected to recover from an acute bout of neuromuscular
colonization, increased secretions and risk of aspiration, and swal- weakness, but should be considered after 7–10 days of mechanical
lowing problems. Tracheostomy impairs communication, so is usu- ventilation through an endotracheal tube to prevent tracheal ero-
ally considered by patients as the last resort for treatment of SDB sion or superinfection [59].
and respiratory impairment and should be carefully discussed with NIV is used acutely during some episodes of ventilatory insuf-
them. Another major secondary result is that the performance of a ficiency (PaCO2 ≥ 45 mmHg, pH ≤ 7.35) and to treat respiratory
tracheostomy commonly results in other major life-altering deci- failure when invasive ventilation is considered inappropriate, or
sions, such as displacement to a skilled nursing facility and separa- when avoiding endotracheal intubation is desirable. NIV should
tion from family members. be initiated when patients with chronic neuromuscular respira-
tory insufficiency develop daytime symptoms of sleepiness, fatigue,
Oxygen therapy
or morning headache, or when hypercapnia is found, and acutely
Oxygen therapy may improve hypoxemia, but at the risk of mask- during respiratory infection to prevent respiratory failure, in pal-
ing underlying hypoventilation or atelectasis. Oxygen therapy may liative care settings, and as supportive ventilation in stabilized
lead to deterioration in central respiratory drive by blunting the patients after tracheostomy is no longer needed. Oxygen therapy
hypoxic drive to breathe in the context of chronic hypercapnia, should be reserved for acute infections, such as pneumonia, to
and may lead to acute respiratory failure. Therefore, oxygen may improve hypoxemia, and should be accompanied by other venti-
be dangerous to use alone, and should be delivered as a supplemen- latory support and not used alone, to avoid blunting hypoxemic
tary adjunct to NIV or assisted cough therapy. Specific indications breathing drive.
for oxygen administration may include infection with pneumonia.
Monitoring of PaCO2 should be considered during oxygen treat-
ment to ensure there is no evolving hypercapnia. Conclusions
Diaphragm pacing stimulation SDB is common in patients with neuromuscular disorders, and is
Diaphragm pacing stimulation (DPS) may replace long-term a significant contributor to morbidity and mortality in this patient
mechanical ventilation in patients with failure of brainstem res- population. SDB often manifests earlier than daytime respiratory
piratory control centers or malfunction of upper motor neurons symptoms and may be the presenting manifestation of a neuro-
subserving the diaphragm. DPS provides direct electrical phrenic muscular disorder. The most common forms of SDB in patients
nerve stimulation to drive diaphragmatic movement. Possible can- with neuromuscular disorders are nocturnal hypoventilation,
didates for DPS include patients with spinal cord injury above the OSA, and CSA. During REM sleep in particular, altered upper air-
C3 level and those with ALS. DPS may delay institution of trache- way resistance and chemosensitivity impair sleep-related breath-
ostomy and mechanical ventilation by up to 24 months [17,48]. ing, and effective respiration depends upon diaphragmatic effort
Prior to DPS, laparoscopic diaphragm mapping is required to due to generalized muscle atonia, so that REM-related hypopneas,
identify the best contractible motor point and to evaluate for apneas, and hypoventilation are common early in the course of
diaphragmatic atrophy [17,48,57]. Before weaning patients from neuromuscular bellows failure. Typical early symptoms of SDB
ventilatory support, the diaphragm’s fast fatigable anaerobic-type in neuromuscular patients include daytime symptoms resulting
muscle fibers must be conditioned during daily 15–30 minute ses- from sleep fragmentation, such as fatigue and tiredness, sleepi-
sions to enable conversion to slow-conducting aerobic oxidative ness, morning headaches, and orthopnea. PSG should be consid-
fibers [17,48,57]. ered early in the course of neuromuscular disorders when clinical
features of sleep-related hypoventilation such as supine abdomi-
Acute, urgent, and emergent management nal paradox, daytime hypercapnia with PaCO 2 > 45 mmHg,
considerations or impaired pulmonary function tests (FVC < 50%, MEP < 40
Respiratory failure can manifest as an acute situation emerging cmH2O) are seen, as NIV is likely necessary. Timely application of
from an otherwise healthy and stable-appearing state in Guillain– NIV reduces morbidity and may delay mortality in patients with a
Barré syndrome or high-level spinal cord injury, or during acute variety of neuromuscular problems, including ALS, the myotonic
respiratory decompensation in chronic neuromuscular disorders dystrophies and other myopathies, myasthenia gravis, isolated
such as myasthenia gravis, ALS, or DMD. phrenic neuropathies, or spinal cord injury. Oxygen therapy alone
For acutely deteriorating unstable neuromuscular patients, inva- should be avoided in neuromuscular patients, since it may further
sive mechanical ventilation should be initiated in an intensive care blunt the hypoxic drive to breathe in the setting of chronic hyper-
unit to avoid respiratory arrest. Endotracheal intubation with posi- capnia. In most cases, NIV satisfactorily ameliorates hypoxemia
tive pressure ventilation is the preferred initial approach. Prior to and improves related symptoms of SDB. A team approach involv-
invasive ventilation, comorbidities, quality of life after extubation, ing generalists, neurologists, and sleep physicians is necessary to
and respect for the patient’s wishes must be considered. Rapid pro- promptly diagnose and effectively treat SDB problems in neuro-
gression of muscle weakness, bulbar symptoms, VC < 20 mL/kg, muscular patients.

18. Polat M, Sakinci O, Ersoy B, Sezer RG, Yilmaz H. Assessment of

Acknowledgements sleep-related breathing disorders in patients with duchenne muscular
The work described here was supported in part by the European dystrophy. J Clin Med Res 2012;4(5):332–7.
Regional Development Fund—Project FNUSA-ICRC (No. CZ.1.05/ 19. Prendergast P, Magalhaes S, Campbell C. Congenital myotonic dystro-
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Czech Republic, and the National Center for Research Resources
dystrophy 1 and 2: evidence for a predominant white matter disease.
and the National Center for Advancing Translational Sciences, Brain 2011;134(Pt 12):3530–46.
National Institutes of Health, through Grant Number 1 UL1 21. Savić Pavićević D, Miladinović J, Brkušanin M, et al. Molecular
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CHAPTER 31
Sleep in other neurological

disorders—â•‰headache
Pradeep Sahota and Niranjan N. Singh
Introduction Snoring and headache have also been examined in various stud-
ies. According to a Swedish study, morning headaches were present
Headache and sleep disorder are among the most commonly in 18% of snorers versus 5% of controls [16]. Headache frequency
reported problems in clinical practice and often coexist in the same in sleep apnea varies from 15% to 50% and occurs more frequently
patient. The two are related in several ways, though the relationship than in insomniacs [16]. Hence, headaches in sleep or related to
is very complex and still not very well understood [1–â•‰8]. sleep are common (see Boxes 31.1 and 31.2).
In 1873, Living published the very first observation on the rela-
tionship between sleep and headache [1]â•„. However, he did not offer
any explanation. In 1929, Hans Berger recorded the first EEG and Relationship between headache and sleep
demonstrated the difference in electrical activity between awake This relationship can be divided into two aspects:
and sleep [9], with subsequent development of polysomnography
1. Headache may affect sleep.
(PSG). In 1945, Bing described headaches on awakening [2]. In
1970, Dexter and Weitzman described a relationship between head- 2. Sleep may affect headache.
ache and sleep stages [6]. Relationship between chronic paroxysmal
hemicrania and REM sleep was described in 1978. A relationship Headache may affect sleep
between dreams and headache has been also reported [10]. In 1990, Headache may or may not be associated with sleep disruption.
Sahota and Dexter published a review describing the spectrum of Kayed et al. reported 17/â•‰18 attacks of paroxysmal hemicrania dur-
this relationship between headache and sleep [11]. ing REM sleep [17]. Headaches disrupted the sleep architecture,
PSG has become more widely available in the last 30 years, and leading to decreased total sleep time, diminished REM sleep, and
there is now increased access to trained physicians who treat sleep an eightfold increase in awakenings during REM sleep.
disorders, headaches or both with better understanding of the rela- Wolff reported that “in two-â•‰thirds of the patients with cluster
tionship between sleep and headache. We will review the spectrum headache, the headache always began during sleep and the pain is
of this relationship between these two entities and then focus on so severe that the patient frequently jumps out of the bed before he
treatment of headaches related to sleep. is fully awake” [18]. Dexter and Weitzman reported four patients
with cluster headache, when they noticed significant decrease in
Epidemiology total REM sleep along with increases in stage III and IV sleep [6]â•„.
Headache may be intrinsically related to sleep (migraine with and There is also experimental data to suggest a common anatomi-
without aura, cluster headaches, hypnic headaches, and paroxysmal cal and physiological substrate for headache and sleep. Recent
hemicrania). It can also cause chronic sleep disturbance (chronic advancement in functional imaging and biochemistry suggest a
migraine, chronic tension-â•‰type headache, and medication-â•‰overuse potential central generator regulating both headaches and sleep
headache) or may be the manifestation of a sleep disorder (eg, sleep [19–â•‰21].
apnea-â•‰related headache). Headache and sleep disorder may be a
common manifestation of systemic illness like infection, anemia, Sleep may affect headache
hypoxia, or any metabolic disturbance. Headache may occur during sleep, after sleep, and in relation to
According to a population-â•‰based study from the United States, different stages of sleep [2,6–â•‰8,11,14]. Headache may be triggered
the 1-â•‰year prevalence of migraine in the general population is by sleep dysregulation. Lack of sleep and excessive sleep are both
11.7% (17.1% for females and 5.6% for males) [12]. Cluster head- considered among the most common triggers for migraine head-
ache is relatively rare, with a prevalence of 0.1–â•‰0.3%, and more ache [22].
common in males [13]. Headaches on awakening or nocturnal According to a large migraine and sleep study in over 1283
headaches were reported in 17% of patients attending a headache migraineurs, sleep disturbance and oversleeping were recognized as
clinic [14]. According to Rasmussen, 24% of migraineurs and 12% headache triggers in 50% and 37% patients, respectively, while 85%
of tension-â•‰type headache patients have headaches during sleep or of patients reported sleep as a deactivator. More than two-â•‰thirds of
upon awakening [15]. these patients reported early morning headaches. Less than 6 hours

Box 31.1 Extent of relationship between sleep and headache Box 31.2 Interrelationship between headache and sleep
(sleep and headache are known to be related in several ways)
◆ Headache is a symptom of a primary sleep disturbance
Sleep-related headaches (during and after sleep)
◆ Sleep disturbance is a symptom of a primary headache disorder
◆ Migraine with and without aura
◆ Sleep disturbance and headache are symptoms of an unrelated
◆ Paroxysmal hemicrania (PH)
medical disorder
◆ Cluster headache (CH)
◆ Sleep disturbance and headache are both manifestations of a
◆ Hypnic headache (HH) similar underlying pathogenesis
Source data from Headache, 5(10), Paiva T, Batista A, Martins P, Martins A,
Sleep-phase-related headaches The relationship between headaches and sleep disturbances, pp. 590–6,
Copyright (1995), John Wiley and Sons.
With stage N3 and REM sleep
◆ Migraine with and without aura
headaches were common in patients with sleep disorder: 34% ver-
With REM sleep
sus 7% in controls. Twenty-five percent of patients reported morn-
◆ Episodic cluster headache ing headache versus 3% of controls [24].
◆ Migraine with and without aura A variety of sleep disorders were associated with headache,
including obstructive sleep apnea (OSA) syndrome (OSAS),
◆ Paroxysmal hemicrania insomnia, restless legs syndrome (RLS), hypersomnia, and paras-
◆ Hypnic headache omnias [24]. Compared with insomniacs, morning headaches are
more common in OSA: 74% versus 40% in controls [25].
Length of sleep and headaches (excessive deep sleep,
lack of sleep, and sleep disruption) Sleep–headache relationship: anatomical
◆ Migraine with and without aura and physiological basis
◆ Tension-type headache (TTH) While the relationship between headache and sleep is complex
and is still not well understood, there are some common neural
Sleep relieves headaches substrates. Sleep and trigeminal pain processing share several com-
◆ Migraine with and without aura mon pathways with respect to neurotransmission and function of
distinct brain areas. The central structure involving both headache
Sleep disorders and headaches and sleep include the hypothalamus (especially orexinergic neu-
rons) and periaqueductal gray areas (PAG) [26].
◆ Obstructive sleep apnea syndrome (OSAS) and headaches The transition from wake to sleep and vice versa is thought to be
◆ Somnambulism and headaches mediated via a flip-flop switch [27]. The anatomical basis of this
◆ Other parasomnias and headaches flip-flop mechanism is an interconnection between the arousal-
generating centers and sleep-regulatory centers in the brain. The
Effect of headaches on sleep (minimal to significant arousal-associated network consists of the orexinergic perifornical
sleep disruption) hypothalamus, tuberomammillary nucleus, locus coeruleus, and dor-
sal median raphe, which are inhibited by the sleep-regulatory ventro-
◆ Migraine with and without aura lateral preoptic nucleus of the hypothalamus via γ-aminobutyric acid
◆ Cluster headache (GABA) and galanin. A circadian mechanism also exists to regulate
◆ Hypnic
sleep in a 24-hour cycle. The ventrolateral portion of the periaque-
headache
ductal gray matter (vlPAG) is a region that regulates both sleep and
pain. Stimulation of this region may lead to REM sleep and antino-
Dreams and Headaches
ciception [28]. Involvement of the hypothalamus ia also suggested
◆ Migraine with and without aura by clinical aspects of headache—such as the autonomic activation,
Adapted from Headache, 30(2), Sahota PK, Dexter JD, Sleep and headache yawning, and sleepiness associated with migraine [29].
syndromes: a clinical review, pp. 80–4, Copyright (1990), with permission Neurophysiological and positron emission tomography (PET)
from John Wiley and Sons. imaging studies have shown hypothalamic activation in cluster
headache and brainstem activation in migraine headaches [30].
There is evidence that dysfunctional hypothalamic activity contrib-
sleep was noticed in 38% of patients [22]. In another study of 289 utes to both altered sleep–wake function and headache via orexin-
headaches, the prevalence of insomnia was reported to be 60% [23]. ergic neurons, which are exclusively localized in the perifornical
Goder et al. reviewed association between sleep and headache in hypothalamus and synthesize two neuropeptides (orexins A and B)
432 patients who underwent PSG and 30 controls without any sleep that bind to receptors found throughout the neuraxis, including the
problem and reported that combined nocturnal and early morning brainstem [31].

Chapter 31 sleep in other neurological disorders—headache 315
Melatonin also has an important role to play in sleep and head- Simple questionnaires can provide key information. The headache
ache. It is synthesized from serotonin by the pineal gland. The con- and sleep diaries are important tools which can help to characterize
trol of melatonin secretion involves the suprachiasmatic nucleus, the headache and its relationship to sleep. In the following sections,
which integrates light-independent activity of the retinal hypo- we will give a brief overview of sleep-related headaches, followed by
thalamic pathway. Cluster headache shows a decrease in peak and a discussion of their management.
median melatonin secretion [32].
The brainstem and hypothalamic nuclei are hypothesized to
regulate both sleep and headache. The hypothalamus has a role in
Sleep-related headaches and their
descending control of pain perception, with connections to the per- management
iaqueductal gray, the locus coeruleus, and the median raphe nuclei. Cluster headache
The hypothalamus and interconnected brainstem areas likely rep-
Cluster headache is a trigeminal autonomic cephalalgia that pre-
resent the neural sites responsible for the chronobiological features
sents as episodes of severe excruciating unilateral retro-orbital pain
of some headaches, in particular the sleep-related attacks typical
with profound autonomic features of Horner syndrome including
of trigeminal autonomic cephalalgia (TAC), migraines, and hypnic
miosis, anhydrosis, ptosis, rhinorrhea, lacrimation, nasal conges-
headaches [33].
tion, and redness of eye. A single episode may last 15–180 minutes.
Functional imaging studies using H215O-PET and functional
The episodes may happen in a cluster of one to nine attacks in one
magnetic resonance imaging (fMRI) have shown activation of the
day, clustered over months, or throughout the year [38].
hypothalamus during cluster headache, short-lasting unilateral
Russell found a preponderance of attacks beginning during sleep,
neuralgiform headache with conjunctival injection and tearing
with the majority of daytime attacks happening when the patient
(SUNCT syndrome), and hemicrania continua [34,35]. PET scans
was physically relaxed [39]. Cluster headache has been reported
have already demonstrated brainstem activation in spontaneous
to occur during REM sleep [6,40]. Dexter and Weitzman recorded
migraine attacks [36].
nine cluster headache episodes in three patients, of which seven
The locus coeruleus and dorsal raphe nuclei are repositories of nor-
episodes occurred during REM sleep within 9 minutes of REM
epinephrine (noradrenaline) and serotonin (5-hydoxytryptamine,
onset [6]‌.
5-HT). The serotonergic system has an inherent rhythm, under
The majority of the headaches occur between 9 pm and 10 am
the control of the suprachiasmatic nucleus. The role of 5-HT in
[41]. It has also been reported in several studies that patients with
migraine is well established. Intravenous 5-HT can abort migraine
cluster headache have a high incidence of OSA [40,41] There
attacks, by supplementing the depletion that induces migraine
is an 8-to 24-fold increase in the incidence of OSA in cluster
attacks [37]. This has led to the development of serotonin receptor
headache [41].
agonists (triptans), which are the mainstay of treatment of acute
Nocturnal hypoxia related to OSA could be a trigger for cluster
migraines. Serotonin depletion is also observed during REM sleep,
headache [42].
which may account for a relationship between REM and migraine.
Hypothalamic involvement has also been implicated, as there is a
The trigeminovascular system is involved in migraine headache.
correlation between improvement of headache and sleep architec-
There is overwhelming evidence that cluster headaches and hyp-
ture with deep brain stimulation [43].
nic headaches are chronobiological disorders with a strong asso-
ciation with sleep and hypothalamus. Cluster headache shows a
remarkable periodicity (circannual and circadian), suggesting a Hypnic headache
linkage to the circadian rhythm. In cluster headache, pain is located Raskin in 1988 described six elderly patients with headaches occur-
peri-orbitally in the trigeminal nerve distribution, with ipsilateral ring exclusively during sleep. [44]. This is a rare headache syn-
parasympathetic (rhinorrhea and lacrimation) and sympathetic drome, with only 174 cases reported in the literature by 2011 and
(Horner syndrome) manifestations and with periodicity and clus- with a prevalence of less than 0.1% in the headache clinic [45].
tering (hypothalamic dysfunction and suprachiasmatic nuclei). The Hypnic headache is also called alarm clock headache. It is char-
regulatory role of the suprachiasmatic nucleus on the sleep–wake acterized by dull headache occurring exclusively during waking up
cycle and circadian rhythm provides strong evidence of an inherent from sleep at a constant time, usually between 1 am and 3 am, and
relationship between sleep and headache. lasting for an hour, with an average frequency of one per week to
six per night. It is more common in elderly females. It is distinct
from cluster headache, being less severe, with a lack of unilater-
Differential diagnosis of headache alism and an absence of cranial autonomic symptoms [44,46,47].
during sleep A meta-analysis of data pulled from 71 published cases of hypnic
Headache in relationship to sleep has a wide differential diagnosis. headache revealed a duration of 67 ± 44 minutes with a frequency
Important differential considerations include sleep apnea-related of 1.2 ± 0.9 per 24 hours [46].
headache, hypnic headache, cluster headache, exploding head The relationship between hypnic headache and sleep stages
syndrome, episodic and chronic migraine headaches, and tension- is complex and controversial. In the initial description, Raskin
type headaches. A diagnosis of these primary headache disorders hypothesized that hypnic headache is related to REM sleep [44].
is based on the recurring pattern of the headache with normal There have been anecdotal reports of association between hypnic
interval examination. Secondary causes of the headache should be headache, OSA, and REM sleep [47]. Recently, this hypothesis was
excluded by a careful history, examination, and appropriate diag- challenged by Holle et al., who reported that 73% of hypnic head-
nostic testing including neuroimaging and other tests as required. ache attacks occur during non-REM (NREM) sleep [48].

Migraine early morning awakening, and daytime fatigue when compared

with the individual without headache [60].
The relationship between migraine and sleep is very complex. Sleep
In population-based study from Hong Kong, in Chinese women
is a known deactivator for a migraine, but patients can wake up
with different headache diagnoses, early waking up was noted in
with a migraine attack as well. Migraine can emerge during noc-
29% of patients, difficulty in staying asleep in 28%, and difficulty in
turnal sleep, or following a brief period of nap, or in relation to a
falling asleep in 24.4% [61].
change in sleep duration (either over-or under-sleeping). Patients
In another population-based study from Sweden, difficulty in
with migraine without aura have much higher prevalence of sleep
initiating sleep, a high degree of sleepiness when waking up, and
abnormalities [49]. Various sleep abnormalities, including insom-
daytime sleepiness were more common in patients with migraine
nia, parasomnia, RLS, narcolepsy, excessive daytime sleepiness
than in those without [62]. Insomnia was not common in patients
(EDS), and feeling sleepy when waking up, have been found to be
with migraine in this study.
associated with episodic and chronic migraine. The exact patho-
physiology remains unclear. In the following subsections, impor- Migraine and excessive daytime sleepiness
tant sleep disturbances with migraine will be described. A high prevalence of EDS has been reported in patients with
Migraine with and without aura is an episodic throbbing head- migraine. Peres et al. reported EDS in migraine patients with an
ache of moderate to severe intensity lasting between 4 and 72 hours. Epworth Sleepiness Scale (ESS) score of more than 10 in 37% [63].
It can be unilateral or bilateral in location. The headache may be EDS was more frequent in migraineurs than in controls [64].
preceded by a visual or other somatosensory aura. The patient In a recent population-based study from Sweden addressing the
becomes sensitive to light, sound, movement, and smell in various relationship between headache and sleep, among 297 participants
combinations. Approximately 15–20% of patients may experience (77 headache-free subjects, 135 diagnosed with tension-type head-
reversible focal neurological deficits lasting less than 60 minutes, ache, 51 with migraine, and 34 with other headaches, including
the most common being visual symptoms. hangover headache, caffeine withdrawal headache, headache attrib-
As early as 1970, Dexter and Weitzman studied three migraine uted to systemic viral infection, medication-overuse headache, and
patients and reported eight arousals. Six of these were during REM possible migraine with tension-type headache), ESS over 10 was
sleep, within 3–9 minutes [6]‌. Another study by Dexter revealed more common in those with migraine than in those without [62].
a consistent relationship between morning headache and arousals
during nights with larger amounts of stage III and IV and REM Migraine and other sleep disturbances
sleep [7]. In a recent, larger study of over 3 years, involving 1698 An increased prevalence of parasomnias, including bruxism, sleep-
migraine patients (3582 migraine attacks), the chance of waking talking and sleepwalking, and night terrors, has been reported in
up with a migraine attack per hour was more than twice between children with migraine [65].
4 am and 9 am (254 attacks/hour) compared with any other hour Chronic migraine and sleep
(115 attacks/hour). This trend associates the later parts (REM pre-
The relationship between chronic migraine and sleep is differ-
dominant) of the sleep cycle with the occurrence of migraine [50].
ent from that between episodic migraine and sleep. Patients with
However, these data were not confirmed by Goder et al., who found
chronic migraine present with headache of more than 15 days
no association between sleep stages and migraine headache [24].
in a month, each episode lasting more than 4 hours for at least
Migraine is associated with a variety of known sleep disorders,
3 months. These headaches arise from episodic migraine. There
some of which will be described here.
is often a component of medication-overuse headache defined as
Migraine and restless legs syndrome use of pain medications more than 15 days in a month or triptans
The frequency of RLS in migraine patients in the pediatric age group more than 10 days in a month on a regular basis. There are often
is significantly higher than in adults (22% versus 5%) [51]. A strong associated psychiatric comorbidities including insomnia. The
association between migraine and RLS is reported in women [52]. Nord-Trondelag Health Study revealed that subjects with chronic
Rhode et al., in a case–control study of patients with migraine, migraine had a 17 times higher risk of severe sleep disturbance [62]
found a significant higher lifetime prevalence of RLS than the con- than those without chronic migraine.
trol group [53]. Similar correlation has been reported by d’Onofrio
et al. [54] and by Chen et al. [55].The underlying pathophysiology Sleep apnea headache
has been linked to the dysfunction of dopaminergic metabolism in According to the International Classification of Sleep Disorders,
migraine [53,56]. Third Edition (ICSD-3), sleep apnea headache is classified as a sec-
Migraine and narcolepsy ondary headache attributed to disorders of homeostasis. A typical
sleep apnea-related headache is a bilateral pressing quality pain
The association between migraine and narcolepsy is controversial.
occurring more than 15 days in a month—without nausea, photo-
Dahmen et al. reported a two-to fourfold increase in migraine
phobia, phonophobia, or vomiting, the headache improves within
prevalence in patients with narcolepsy [57, 8]. On the contrary, in a
30 minutes of waking up, with complete resolution within 72 hours
multicenter case–control study of 96 patients with narcolepsy, there
of effective treatment of sleep apnea. Prevalence of sleep apnea
was no significant association with migraine [59].The patients with
headaches is variable. According to Aldrich et al., the frequency of
narcolepsy showed nonspecific headache due to sleep disturbance,
morning headaches was 18% in patients with OSA versus 21–38%
not fulfilling the diagnostic criteria for migraine.
in patients with other sleep disorders [66]. Morning headaches have
Migraine and insomnia been reported in habitual snorers as well as in their bed partners [67].
In a survey by Lateef et al., adults with migraine reported more In a recent population based cross-sectional study from Norway,
frequent difficulty in initiating sleep, difficulty with staying asleep, sleep apnea headache was reported in 11.8% of patients with OSA

versus 4.6% of participants without sleep apnea. The prevalence of hemorrhage, and meningitis. Headaches on awakening or early
headache was also related to the severity of sleep apnea, with higher morning headaches can be observed in patients with sleep apnea,
prevalence in severe sleep apnea with apnea–hypopnea index depression, anxiety, chronic TTH, substance abuse, and medication-
AHI > 30 [68]. Similarly, in a Turkish study, morning headache was overuse headache. Red flags in the history and examination include
reported in 33.6% of patients with OSA with AHI > 5. These head- first and worst headache, progressive worsening of headache,
aches resolved with effective treatment of sleep apnea using positive intractable vomiting, fever, signs of encephalopathy, stiff neck, and
pressure [69]. In a large telephone survey of 18 980 participants weakness, and these necessitate careful workup, including a neuro-
from Europe, the prevalence of chronic morning headache was logical consultation along with neuroimaging and lumbar puncture,
found to be 7.6%. The headache was more common in patients with depending upon the headache characteristics. A careful sleep history
depression, insomnia, and sleep-related breathing disorders [70]. along with a sleep diary should be obtained in the context of 24-hour
It is still unclear whether hypoxia or degree of oxygen desatura- sleep–wake cycle. A combined sleep–wake and headache diary is
tion is the underlying pathophysiology for morning headache. most helpful in delineating the occurrence of headache in relation-
ship to sleep. The Berlin Sleep Questionnaire has a positive predictive
Exploding head syndrome value of 89% for sleep apnea [28]. An insomnia calendar is helpful for
First described by Armstrong-Jones in 1920, this is unique and a the patient with significant insomnia and headache, inquiring about
rare syndrome of sudden loud painless explosive sound in the head bedroom environment, sleep schedule, daytime naps, whether caf-
without any actual headache. The condition may be frightening, feine and medication promote insomnia, and whether nicotine leads
awakening the patient from sleep [71]. to emotional and cognitive arousals [28].
In a polysomnographic evaluation of nine patients with exploding PSG may be required for better assessment of sleep factors,
head syndrome, the episode occurred during nocturnal awakening including sleep apnea, parasomnia, and other sleep disorders.
when the subject was relaxed but temporarily awake. In ICSD-3,
exploding head syndrome is listed among the parasomnias [72]. Treatment of different headache syndromes
Tension-type headache Migraine with and without aura, chronic migraine,
Various sleep abnormalities, including insufficient sleep and over- and medication-overuse headache
sleeping, have been associated with tension-type headache (TTH). The treatment of headache can divided into pharmacological and
In a study by Karly et al., 12.9% of the patients with TTH reported nonpharmacological options.
oversleeping as a precipitating factor [73]. Insufficient sleep has
been noted as an aggravating factor for TTH [74,75]. Nonpharmacological management
Results from the third Nord–Trøndelag Health Survey indicated There should be an individualized approach, depending upon the
that subjects with chronic headache were 17 times more likely to patient’s comorbid conditions. The following are some general
have severe sleep disturbances, with the association being some- guidelines:
what stronger for chronic migraine than for chronic TTH [62]. 1. Maintenance of the biorhythms with regular sleep schedule, reg-
In a recent study using actigraphy and computerized ecological ular meals, aerobic exercises, and avoiding triggers.
momentary assessment, a longer total sleep time along with poor
2. Diet has an important role in the management of migraine head-
sleep quality was associated with TTH [76]. In a cross-sectional
aches, with avoidance of high carbohydrate food and caffeine
study from Norway, sleep apnea did not have any association with
being very important.
TTH in the general population [77].
3. Patients with medication overuse will require detoxification,
Paroxysmal hemicranias limiting pain medication to fewer than 10 days in a month.
Attacks with characteristics of pain and associated symptoms and Naproxen has been shown to be effective during the weaning
signs similar to those of cluster headache have been described in period [78].
paroxysmal hemicranias, but they are shorter-lasting, more fre- 4. Smoking cessation and maintaining an appropriate weight are
quent than in cluster headache, occur more commonly in women very important.
than men, and respond very well to indomethacin. Each attack
consists of severe unilateral, hemicranial headache with ipsilateral 5. Appropriate screening for sleep disorders in patients with a
cranial autonomic features (miosis, ptosis, lacrimation, and rhi- headache, including detailed history and PSG if needed, cannot
norrhea) lasting from 2 to 45 minutes, and occurs more frequently be overemphasized.
within a 24-hour period. 6. Patients with insomnia or poor sleep hygiene should be encour-
Paroxysmal hemicrania has been called “REM-locked” headache. aged to undergo behavioral sleep modification. Referral for more
Kayed et al. reported 17 out of 18 attacks during REM sleep [17]. intensive behavioral insomnia treatment may be needed.
The headaches also disrupted the sleep architecture, leading to 7. A five-component intervention used by Calhoun and Ford may
decreased total sleep time and REM sleep. be useful [79]:
I. Schedule a consistent bedtime that allows 8 hours in bed.
Management of headaches and sleep
II. Avoid watching TV, reading, and listening to music in bed.
Primary headache syndromes such as migraine and cluster headaches
occurring during the night must be differentiated from acute severe III.
Use visualization techniques to shorten the time to
secondary headache seen in patient with brain tumors, intracranial sleep onset.

IV. Supper should be at least 4 hours before bedtime and only the preventive treatment of migraine. There are several classes of
limited amounts of fluids should be taken within 2 hours of medications used in preventive therapy, including antiepileptics
bedtime. (eg, topiramate and divalproex soldium), antidepressants (eg, ami-
V. Discontinue daytime naps. triptyline), beta-blockers (eg, propranolol), calcium channel block-
ers (eg, verapamil), and botulinum toxin. A detailed discussion
8. Psychiatric comorbidities should be identified and treated of these agents is beyond the scope of this chapter. Patients with
as well. three or more episodes per month may be candidates for preven-
tive treatment. Generally, these medications should be started at
Pharmacological treatment a small dose and slowly titrated to the maximum recommended
Acute treatment is needed to abort a single severe attack of migraine and tolerated dose. An adequate trial of 2–3 months is reasonable.
headache. The appropriate medications can be used at home, in the Comorbid conditions, insurance coverage, drug interactions, and
emergency room or urgent care center, or in an inpatient setting. side effects should be considered when making a choice.
They consist of analgesics and migraine-specific therapies (triptans
and ergotamines). Migraine in women
Triptans and nonsteroidal anti-inflammatory drugs (NSAIDs) are Women present with unique issues in the management of migraine
considered the first-line treatment for an acute attack of migraine headaches. There are several unique features that may impact head-
headache. Antiemetics (including ondansetron and promethazine), aches and their treatment. Menarche, pregnancy, pre-menopause,
neuroleptics (including chlorpromazine and prochlorperazine), menopause, and late-life migraine are different phases in women’s
ketorolac, magnesium, divalproex sodium, and a steroid (methyl- life related to changes in hormones.
prednisolone oral or IV) have been used to abort a short or pro- Menstrual migraine and menstrual-related migraine are unique
tracted course of headache in office, home and inpatient settings. conditions related to fluctuations in estrogen level [88]. Standard
abortive and preventative treatment can be applied, with a special
Triptans precaution of contraception failure and teratogenic effects. Folic
Triptans are selective serotonin 5-HT1B and 5-HT1D receptor acid 0.4–0.8 mg is recommended for every woman on migraine-
agonists [80]. Three postulated mechanisms of action of these preventive treatment. Women with a history of migraine and a
medications are the following: intracranial vasoconstriction (1B), history of thrombosis, ischemic heart disease, stroke, or smoking
peripheral neuronal inhibition (1D) and presynaptic dorsal horn should not be offered combined oral contraceptives [88]. Women
stimulation (1D). with migraines should not smoke if using oral contraceptives.
Efficacy has been reported in multiple randomized trials [81]. Triptans are designated category C for use during pregnancy, but
Current evidence suggests nearly equivalent efficacy among oral approved during breastfeeding.
triptans except frovatriptan, which is less efficacious but has a Pregnancy may lead to improvement in more than 55% of
longer half-life [82]. The choice of agent may often be determined patients with migraine, mostly in the second half of pregnancy.
by insurance coverage and patient preference. Improvement in migraine has been noted in one-third of women
Ergots after spontaneous menopause, but worsening is reported in more
Ergots are less specific than triptans in their serotonin receptor ago- than two-thirds after surgical menopause. High-dose hormone
nism, which possibly explains their more robust side effects [83]. replacement treatment has been shown to increase the risk for stroke.
Dihydroergotamine (DHE) is currently the only widely available Finally, a history of physical and sexual abuse in women with
ergot alkaloid. Available preparations include a nasal spray and chronic migraine is common and needs to be addressed at the time
injections. The nasal spray is used as one puff of 0.5 mg in each of treatment.
nostril, repeated after 15 minutes, with 2 mg maximum daily dose.
Injectable DHE is 0.5–1 mg repeated after 1 hour, with a 3 mg
Emerging treatments
maximum daily dose. It is usually administered in the emergency In late 2009, antagonists to calcitonin gene-related peptide (CGRP),
department and inpatient setting, but can be self-administered known as gepants, became a new hope for the treatment of acute
[84]. Repetitive intravenous administration of DHE over several migraine [89]. The absence of vasoconstrictive effects with gepants
days (according to the Raskin and other protocols) is helpful in can be considered an advantage over triptans. Gepants are in differ-
managing chronic migraine and status migrainosus. ent phases of development.
Oral lasmiditan, a 5-HT1F receptor agonist that is centrally acting
Preventive treatment and highly selective, without the vasoconstrictive effects of triptans
There are several medications used as preventive treatment for high- and DHE, has shown to be effective in a small placebo-controlled
frequency migraine, chronic migraine, and medication-overuse trial. [90].
headache. Possible mechanism of action include stabilization of
the reactive nervous system, enhancement of the anti-nociceptive Interventional treatments
pathway, inhibition of central and peripheral sensitization, and There have been several open label non-randomized studies using
inhibition of cortical spreading depression [80,85–87]. Preventive neuromodulation: the ONSTIM (Occipital Nerve Stimulation
treatment is used to reduce the frequency, duration, and intensity for the Treatment of Chronic Migraine Headache) study, the
of headache, along with improved responsiveness to acute therapy. PRISM (Precision Implantable Stimulator for Migraine) study,
It has also been shown that preventive treatment slows progression and a St Jude’s study involving around 1200 patients with chronic
to chronic migraine. migraine. Results have shown some promise, but several questions
Methysergide was the first preventive medication used in the (including that of cost) need to be answered before any further rec-
1960s. Since then, no specific medication has been developed for ommendations can be made [91].

Occipital nerve stimulation (ONS) is a surgical procedure for of risks), lithium, and divalproex sodium can also be used. Some
refractory headache, including chronic migraine. A 60% improve- patients may benefit from topiramate and melatonin [95].
ment was seen in 17 patients with chronic daily headache after
Acute treatment
ONS, including two patients with chronic migraine [92]. Lead
High flow oxygen, 100% at 12–15 L/min for 15–20 minutes has been
migration and infections were common problems after ONS
shown to be very effective [96]. Injectable sumatriptan 6 mg is the
replacement in area studies. Peripheral procedures such as occipital
only US-approved treatment for cluster headache. Nasal sprays of
nerve blocks or trigger point injections are promising rescue treat-
sumatriptan 20 mg and zolmitriptan 5 mg are also effective [97,98].
ments for migraine and may be effective in medication-overuse
The choice of agent may often be determined by insurance cover-
and chronic migraine. Tobin and Flitman reported a 56% improve-
age and patient preference (see Tables 31.1 and 31.2]).
ment in medication-overuse patients [92]. In a single blinded ran-
domized controlled trial with chronic migraine patients, occipital Prophylactic treatment
nerve block with triamcinolone combined with lidocaine was not For the prophylactic treatment of cluster headache, verapamil and
superior to lidocaine alone [93]. lithium remains the mainstay of treatment, bridging with a short
course of steroid (prednisone) [99,100].
Cluster headaches
The medical management of cluster headache includes both acute Nonpharmacological treatment
therapy aimed at aborting individual attacks and prophylactic ther- Diet and lifestyle modification
apy aimed at preventing recurrent attacks and clustering [94]. Agents Cluster headache is a chronobiological disorder, with attacks occur-
used for acute therapy include inhalation of oxygen and sumatriptan. ring during REM sleep. Alcohol is a known trigger and should be
Transitional prophylaxis involves a short course of steroid (pred- avoided during the cluster period. The prevalence of sleep apnea is
nisone). The mainstay of prophylaxis is verapamil, but methysergide very high in patients with cluster headache, and therefore main-
(which entails a risk of retroperitoneal fibrosis but may be used tenance of ideal weight and treatment of sleep apnea are highly
in refractory cases after proper patient education and explanation recommended.
Table 31.1 Summary of practical clinical pharmacology of the medication used in acute headache management
Drug Indications Dose Drug interactions and Typical adverse effects Cost-effectiveness
(maximum dose/ contraindications
day)
Almotriptan: Migraine 6.25–12.5 mg Contain sulfur Dizziness, chest pressure, Expensive
tablets (25 mg) Dose reduction with CYP3A4 nausea, abnormal taste,
inhibitors paresthesias, vasospasm
Eletriptan: Migraine 20-40 mg Dose reduction with CYP3A4 Dizziness, chest pressure, Expensive
tablets (80 mg) inhibitors nausea, abnormal taste,
paresthesias, vasospasm
Rizatriptan: Migraine and cluster 5-10 mg Dose reduction with Dizziness, chest pressure, Expensive
tablets headache (30 mg, 15 mg if propranolol nausea, abnormal taste,
propranolol) Do not use within 2 weeks of paresthesias, vasospasm
monoamine oxidase inhibitor
(MAOI)
Sumatriptan: Migraine and cluster 25–100 mg tablet Do not use within 2 weeks of Dizziness, chest pressure, Moderate
tablets, nasal spray, headache (200 mg) MAOI nausea, abnormal taste,
and injection 5–20 mg spray paresthesias, vasospasm
Combination with (40 mg)
naproxen 4–6 mg injection
(85/500 mg) (12 mg)
Zolmitriptan: Migraine and cluster 2.5–5 mg (10 mg) Do not use within 2 weeks of Expensive
tablets and nasal spray headache MAOI
Frovatriptan: Migraine 2.5 mg (7.5 mg) Expensive
tablets
Naratriptan: Migraine 1–2.5 mg (5 mg) Expensive
tablets
Dihydroergotamine: Migraine and cluster 1–3 mg (3 mg) Do not combine with triptans Dizziness, chest pressure, Inexpensive
tablets, injection, and headache nausea, vomiting,
nasal spray abdominal pain, vasospasm

Table 31.2 Preventive treatment for migraine, cluster headache, and hypnic headache
Drug Indications Usual daily dose Drug interactions and Typical adverse effects Cost-
contraindications effectiveness
Propranolol: Migraine 80–240 mg Contraindicated in asthma Dizziness, bronchospasm, Inexpensive
tablets Major interaction with Bradycardia
thioridazine and calcium
channel blockers
Verapamil: Migraine and cluster 180–480 mg Major interactions with Dizziness, Inexpensive
tablets headache lomitapide and clozapine Bradycardia, constipation
Amitriptyline: Migraine 25–150 mg Major interaction with Dizziness dry mouth and Inexpensive
tablets MAOIs dry, constipation
Topiramate Migraine and cluster 25–150 mg Major interaction with Dizziness weight loss, renal stones, Inexpensive
headache metformin anomia and paresthesias
Divalproex sodium Migraine and cluster 250–1500 mg Do not use in hepatic failure Weight gain, hair loss, tremor Inexpensive
headache
Indomethacin Hypnic headache and 75–150 mg Renal failure Dizziness, abdominal pain Inexpensive
migraine headache
Lithium Cluster headache and 300–600 mg Major interaction with several Tremor, ataxia, dizziness, Inexpensive
hypnic headache medications. multisystem adverse effects
Monitor lithium level
Caffeine Hypnic headache 40–60 mg at None Dizziness, insomnia Inexpensive
bedtime
Botulinum toxin Chronic migraine 155 units IM None Weakness, headache Expensive
every 3 months
Interventional procedures positive airway pressure (CPAP), oral appliances, surgical interven-
Posterior hypothalamic neurostimulation may be considered tion, or conservative treatment [104]. The headache is expected
in medically refractory cases of cluster headache. There is now to improve with treatment of sleep apnea. Avoiding sedation with
enough experience with this approach to suggest that about two- hypnotics or opiates until effective treatment of sleep apnea has
thirds of patients benefit [101]. ONS is an alternative approach been established is very important. Treatment of headache that
[102]. Recently, sphenopalatine ganglion stimulation has been persists despite standard treatment of sleep apnea requires evalua-
proposed tion before a symptomatic treatment can be provided on long-term
basis. A reevaluation is required in 2–3 months to monitor the
Hypnic headache effectiveness of treatment.
Based on case series and uncontrolled studies, improvement in
Treatment of an acute attack of hypnic headache is limited because
headache is expected in one-third to one-half of patients after effec-
of the short duration of headaches. Triptans, oxygen, and NSAIDs
tive treatment of sleep apnea [104].
are ineffective. Because of the rarity of this condition, most rec-
ommendations are based on case reports. A cup of coffee or caf- Tension-type headaches
feine 40–60 mg at bedtime can be used as a prophylactic treatment.
Sustained-release indomethacin 75 mg at bedtime or lithium 300– The diagnostic problem encountered most often is discriminat-
600 mg daily can be used as a second-line treatment [103]. ing between TTH and mild migraines. Significant comorbidities,
There are case reports of successful treatment with topiramate including anxiety, depression, and insomnia, should be identified
25–100 mg at bedtime and oxeterone 60–120 mg at bedtime and treated.
Diet and lifestyle modification are important in the management Triggers frequently reported with TTH include stress, irregular
of hypnic headaches. meals, high intake of coffee and other caffeine-containing drinks,
There is a high association of OSA in patients with hypnic head- dehydration, sleep disorders (including too much or too little
ache, and this should be carefully screened and treated. sleep), reduced or inappropriate physical exercise, psychological
Maintaining sleep hygiene, appropriate weight, and diet and problems, and hormonal swings in females during the menstrual
smoking cessation cannot be overemphasized. cycle [105].
Nonpharmacological management
Sleep apnea-related headaches This should be considered for all patients. Physical therapy is the
Sleep apnea may present as an independent generator of head- most frequently used nonpharmacological treatment of TTH and
ache or associated with cluster or hypnic headaches. OSA requires includes improvement of posture, relaxation, exercise programs,
treatment according to the published guidelines using continuous hot and cold packs, ultrasound, and electrical stimulation [106].

Psychological treatment, including electromyographic (EMG) 10. Levitan H. Dreams which culminate in migraine headaches.
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CHAPTER 32
Sleep after traumatic brain injury

Christian R. Baumann
In the last ten years or so, it has become increasingly obvious that delivered markedly lower frequencies [3,11]. The most likely expla-
sleep–â•‰wake disorders (SWDs) after traumatic brain injury (TBI) nation for this very large range is the heterogeneity of the methods
are frequent and chronic conditions. TBI, which is defined as an used to assess insomnia, the different definitions of insomnia, and
“an alteration in brain function, or other evidence of brain pathol- the heterogeneous intervals between TBI and insomnia assess-
ogy, caused by an external force,” is a frequent condition, with an ments. For instance, an early study showed that insomnia symp-
incidence of up to 600 per 100 000 [1,2]. Given the observation that toms might prevail shortly after TBI, but then fade and unmask
more than half of TBI patients suffer from SWDs, a yearly inci- enhanced sleep pressure [12]. On the other hand, and in contrast
dence of about 300 patients with post-â•‰traumatic SWDs must be to findings regarding sleepiness, there is some evidence that TBI
assumed [3]â•„. might overestimate insomnia symptoms, when comparing objec-
This brief chapter is intended to offer a short clinical introduc- tive with subjective assessments [13].
tion to the variety of SWDs that may emerge after TBI.
Post-â•‰traumatic sleep-â•‰related breathing
Post-â•‰traumatic pleiosomnia disorders
After TBI, patients sleep significantly more than carefully matched
Extensive evaluations of pre-â•‰TBI sleep–â•‰wake behavior, including
controls [4]â•„. To avoid confusion with the term hypersomnia (which
detailed interviews with bed partners, suggest that OSA emerges
is used for both increased sleep need and increased sleepiness), we
in a large proportion of TBI survivors as a de novo post-â•‰traumatic
coined the term pleiosomnia for increased sleep need of 2 hours
feature [14]. The prevalence of OSA after TBI ranges from 11%
or more per 24 hours compared with pre-â•‰TBI conditions [5]. Six
to36% [15]. After all, it is still unclear whether or not the preva-
months after trauma, pleiosomnia is present in about 20–â•‰25% of
lence of OSA is higher in the TBI than in the general population,
TBI patients [3]. Excessive daytime sleepiness (EDS) is not present
and whether de novo sleep-â•‰related breathing disorders persist or
in all pleiosomnia patients, but increased slow-â•‰wave sleep (SWS)
constitute a transient phenomenon.
appears to be common in this condition [5]. The severity of TBI, as
assessed by the presence of intracranial hemorrhage, is a predictor
for the development of post-â•‰traumatic pleiosomnia [4]. Post-â•‰traumatic sleep-â•‰related movement
disorders
Post-â•‰traumatic excessive daytime Evidence on post-â•‰traumatic sleep-â•‰related movement disorders is
sleepiness scarce. In our own controlled prospective study, we did not find
A variety of studies applying questionnaires or sleep laboratory increased periodic limb movement indices after TBI [4]â•„. Some
tests, including the multiple sleep latency test (MSLT), identified of our colleagues identified 6 of 87 TBI patients with PLMS [9].
EDS as a prevalent complication after head trauma, occurring in The entity of post-â•‰traumatic restless legs syndrome probably does
up to 50–â•‰60% of TBI patients [3,4,6–â•‰10]. On comparing subjec- not exist.
tive with objective measures of sleepiness in the same population,
there is growing evidence that TBI patients often underestimate the Post-â•‰traumatic circadian rhythm
presence and severity of EDS [3,4]. In a proportion of TBI patients, sleep–â•‰wake disorders
EDS is linked to underlying sleep–â•‰wake comorbidities such as
obstructive sleep apnea (OSA) syndrome and periodic limb move- Again, there is not much evidence on circadian malfunctioning
ments during sleep (PLMS), but in many patients, no other causes after TBI. Some authors used actigraphy studies, saliva melatonin
of sleepiness than the trauma itself could be identified [3,6,9]. In measurements, and body temperature assessments in 42 TBI sub-
contrast to pleiosomnia, severity of TBI is not associated with the jects with insomnia complaints and found circadian rhythm disor-
development of EDS. ders in 36% [16]. This well-â•‰designed study suggests that circadian
rhythm SWDs may be frequent after TBI, and that they can be eas-
ily misdiagnosed as insomnia. Others confirmed the existence of
Post-â•‰traumatic insomnia post-â•‰traumatic circadian rhythm disorders such as delayed sleep–â•‰
Most studies report a prevalence of insomnia of about 30–â•‰70% wake phase disorder or non-â•‰24-â•‰hour sleep–â•‰wake rhythm disorder
in TBI patients, but some other studies, including our own, have [17,18].

5. Sommerauer M, Valko PO, Werth E, Baumann CR. Excessive sleep

Pathophysiology of post-traumatic need following traumatic brain injury: a case-control study of 36
sleep–wake disorders patients. J Sleep Res 2013;22:634–9.
6. Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime
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9. Castriotta RJ, Wilde MC, Lai JM, et al. Prevalence and consequences
lating neuronal systems, particularly histaminergic neurons in of sleep disorders in traumatic brain injury. J Clin Sleep Med
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died from fatal TBI [19]. Thus, a reduction of wake drive might 10. Castriotta RJ, Murthy JN. Sleep disorders in patients with traumatic
contribute to pleiosomnia and EDS. Furthermore, a case–control brain injury: a review. CNS Drugs 2011;25:175–85.
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Diagnosis of post-traumatic sleep–wake 13. Ouellet MC, Morin CM. Subjective and objective measures of insomnia
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2006;7:486–97.
Sleep–wake questionnaires that have been developed for other pop- 14. Guilleminault C, Yuen KM, Gulevich MG, et al. Hypersomnia
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19. Valko PO, Gavrilov YV, Yamamoto M, et al. Damage to histaminergic
Contributing factors or comorbidities should be identified and
tuberomammillary neurons and other hypothalamic neurons with
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CHAPTER 33
Sleep disorders
in multiple sclerosis
Luigi Ferini-Strambi and Sara Marelli
Introduction It has recently been reported that treatment of the underlying

sleep disorder led to an improvement of MS-â•‰related fatigue [13].
Multiple sclerosis (MS) is an inflammatory condition of the central Thus, an increased clinical awareness of sleep-â•‰related problems is
nervous system (CNS) presumably induced by an environmental warranted in the MS population because they are extremely com-
trigger(s) in a genetically susceptible subject. Sleep disorders are mon and have the potential to negatively impact overall health and
common, although clinically under-â•‰recognized, in MS patients. quality of life.
Approximately half of all patients with MS report sleep-â•‰related
problems [1–â•‰3]. It is clear that some physical and psychological
factors, such as pain, anxiety and mood disorders, sleep disordered Insomnia in multiple sclerosis
breathing, nocturia, and nocturnal spasticity-â•‰related discomfort, Insomnia is a widespread complaint, estimated to affect at least
may all contribute to sleep disturbances. Moreover, it is also well 10% of the adult population, but only 6% fulfill the criteria of the
known that disease-â•‰modifying and symptomatic therapies com- Diagnostic and Statistical Manual, Fourth Edition, Text Revision
monly used in MS can also affect sleep, by causing either insomnia (DSM-â•‰IV-â•‰TR) [14]. Causes of insomnia common in the MS popu-
or hypersomnia [4]â•„. The list of these therapies includes interferon lation include pain associated with muscle spasms, periodic limb
beta, methylprednisolone, baclofen, tizanidine, gabapentin, prega- movements (PLM), RLS, nocturia, medication effect, and psychi-
balin, and oxybutynin. A recent study showed dynamic changes of atric illness such as depression. Chronic insomnia can also predis-
sleep architecture in mice with experimental autoimmune enceph- pose an individual to the development of major depression [15].
alomyelitis (EAE), a model of multiple sclerosis [5]. The changes of In patients with MS, sleep difficulties have been shown to be asso-
sleep patterns were mainly reflected by altered sleep stage distribu- ciated with the yearly exacerbation rate and with disease severity
tion and increased sleep fragmentation; the extent of sleep frag- [16]. Table 33.1 lists studies investigating insomnia in MS.
mentation correlated with the severity of disease. This is the first Only the study of Tachibana et al. [1]â•„reported a prevalence of
study of sleep profile in EAE mice demarcating specific changes insomnia similar to that of the general population. However, none
related to the autoimmune disorder without confounding factors of the studies investigating insomnia in MS have used standardized
such as psychosocial impact and treatment effects. Since several diagnostic criteria, except for a cross-â•‰sectional study by Veauthier
immunological factors in serum (including tumor necrosis factor et al. [17], which reported insomnia in 25% of MS samples using
α and other cytokines) have been implicated in the development of the criteria of the International Classification of Sleep Disorders,
sleep disorders and since MS is shown to have immune abnormali- Second Edition (ICSD-â•‰2) [18]. The multifactorial etiology of
ties, it is reasonable to think that MS and sleep disorders share a insomnia in MS patients must be considered before any decision is
similar background [6]. made on therapeutic strategy.
Common sleep disorders in patients with MS include insomnia,
sleep apnea, restless legs syndrome (RLS), narcolepsy, and rapid Pain
eye movement (REM) sleep behavior disorder (RBD). In a cross-â•‰ Pain is a common finding, but often under-â•‰recognized, in MS
sectional epidemiological survey, Patel and colleagues [7]â•„evalu- patients. It is estimated to affect 29–â•‰86% of MS patients in vari-
ated middle-â•‰aged women (n = 60 028) who reported a habitual ous stages of the disease and severely influences rehabilitation and
sleep duration of 7 hours or more. MS (odds ratio (OR) 3.7, 95% quality of life [22]. The pain experienced by MS patients is gener-
confidence interval (CI) 3.0–â•‰4.5) was the factor most strongly asso- ally caused by nervous system damage during the course of the dis-
ciated with prolonged sleep. It has been reported that sleep distur- ease and can usually be characterized as central neuropathic pain
bance in MS is a predictive factor and contributor to fatigue [8], (less frequently as peripheral or nociceptive pain). In a large study
supporting the hypothesis that recurrent arousals from sleep (sleep that examined 364 MS patients [23], 57.5% reported pain during
fragmentation) lead to excessive CNS activation with subsequent the course of their disease (21% nociceptive, 2% peripheral neuro-
excessive fatigue [8–â•‰10]. More than 80% of MS patients complain pathic, and 1% related to spasticity); 27.5% had central pain. It has
of fatigue and approximately one out of four considers fatigue as been reported that chronic pain in MS is not significantly related
the most burdensome symptom of the illness [11]. On the other to age, disease duration, or disease course, but is correlated with
hand, fatigue is a major reason for early retirement in MS [12]. aspects of health-â•‰related quality of life [24]. Pain has the potential

Table 33.1 Insomnia in MS patients
Authors Study site Number of Mean age (years) Findings

subjects
Tachibana et al., 1994 [1]‌ UK 28 Range 22–67 Three patients had non-organic insomnia
Stanton et al., 2006 [19] UK 60 41 (median) Sleep diaries for 1 week:
42% of patients had an incapability of initiating sleep
(>30 min) at least two nights per week
53% of patients had disrupted sleep at least two nights
per week
Nocturia was the most common cause of disrupted nights
(72.5%)
Bamer et al., 2008 [20] Washington, USA 1063 50.9 Using the Medical Outcomes Study Sleep Scale [21],
moderate or severe sleep problems in 33.1%
Veauthier et al., 2011 [17] Germany 66 43.2 25% of patients had insomnia according to ICSD-2 criteria
Pokryszko-Dragan et al., 2013 [8]‌ Poland 100 42 Sleep complaints in 49% of patients (non-validated sleep
questionnaire)
to disrupt sleep, with consequent daytime somnolence, worsening relative to both healthy individuals and those with other long-term
fatigue, and a lower pain threshold [25]. Indeed, the presence of medical illnesses [35].
chronic pain can be associated with a vicious cycle pattern. A day In particular, patients with MS aged 18–45 years had a one in four
with intense pain can be followed by a night of poor sleep quality, chance of developing depression over the course of 1 year. Further
and a night of poor sleep can increase pain the next day. Treatment epidemiological data from a community sample of 1374 patients
options include medications such as gabapentin and pregaba- with MS revealed a 41.8% prevalence of depression, and the authors
lin, which have been shown to improve nocturnal pain and pro- noted the importance of disease severity as a robust correlate [36].
mote restorative sleep [26,27]. Other medication options include McGuigan and Hutchinson [37] performed a study to assess the
carbamazepine and pharmacotherapy directed at treating muscle point prevalence of previously unrecognized symptoms of depres-
spasticity (baclofen, dantrolene, tizanidine, botulinum toxin, and sion in a community-based population with MS. They found that
diazepam). Cannabis-based medicine may also be effective in one in four patients had unrecognized and therefore untreated
reducing pain and sleep disturbance in MS patients with central symptoms of depression. These data are consistent with the find-
neuropathic pain [28,29]. ings of another study [38] that evaluated 260 MS patients and found
25.8% of patients with major depressive disorder: among these
Nocturia depressed patients, 65.6% received no antidepressant medication
Urinary bladder dysfunction is a common problem for MS patients. and 4.7% received sub-threshold doses. Depression in patients with
The severity of symptoms often correlates with the degree of spinal MS has a complex and multifactorial pathogenesis: adverse psy-
cord involvement and hence the patient’s general level of disability chosocial impact of a chronic, usually progressive, disabling illness,
[30]. Nocturia or urinary incontinence affects 70–80% of patients atrophy of frontal and temporal regions, a lack of family support,
with MS [31]. Spasticity or involuntary contraction of the bladder and possible depressogenic effects of drugs such as corticosteroids
causing nocturia and incontinence can lead to frequent awakenings and interferon [39].
and sleep fragmentation [32]. Depression has the potential to cause insomnia, leading to
Awareness and treatment of this sometimes under-recognized excessive daytime sleepiness (EDS) and worsening fatigue. Early
cause of sleep disruption may lead to significant improvements recognition and treatment can prevent psychiatric sequelae and
in the quality of life in patients with MS. Treatment options for improve sleep and the overall quality of life [40]. Treatment options
nocturnal bladder spasticity include fluid restriction, intermit- for patients with depression and MS include psychotherapy and
tent catheterization, anticholinergic agents such as propantheline medications such as the selective serotonin reuptake inhibitors
or oxybutynin, and the hormone desmopressin [33]. Botulinum (SSRIs), tricyclic antidepressants, and non-tricyclic antidepres-
neurotoxin-A injection represents a significant advance in the sants. However, it should be considered that several studies have
management of voiding dysfunction among MS patients failing found that antidepressant use is associated with increased PLM in
first-line therapy. It significantly improves patients’ urodynamic sleep (PLMS), a possible cause of sleep fragmentation [41,42].
parameters and quality of life, with efficacy sustained by repeated
injections with minimal risk of adverse events [34]. Nocturnal movement disorders
The incidence of RLS and PLMS is higher in patients with MS than
Depression in the general population [43,44]. In the general population, con-
The association between MS and depression has been well estab- servative estimates report RLS affecting between 5% and 15% [45]
lished. A survey of 115 071 adults living in Canada confirmed an and PLMS affecting 5% between the age of 30 and 50 years [46].
elevated 12-month prevalence of depression in patients with MS, A recent meta-analysis that reviewed 24 studies found that the RLS

Chapter 33 sleep disorders in multiple sclerosis 329
prevalence ranged from 12.12% to 57.50% among patients with Medication

MS and from 2.56% to 18.33% among people without MS: pooled
Immunomodulatory therapy for the treatment of MS has been
analysis further indicated that the odds of RLS among patients with
associated with hypersomnolence, increasing fatigue, depression,
MS were fourfold higher compared with people without MS [47].
and insomnia. In patients with relapsing MS, 5% of those treated
A study estimated the prevalence of RLS in 82 MS patients, and
with interferon-β1a three times a week in one series had hypersom-
compared the neurological damage between patients with and
nolence, as compared with 1% of controls [32]. In another study
without RLS using conventional and diffusion tensor (DT) MRI
[60], 3–17% of patients treated with interferon-β1b for 1 month
[48]. Thirty patients were affected by RLS. Patients affected by RLS
had insomnia and described fatigue as a common (33%) side effect.
showed a higher disability according to the Expanded Disability
Corticosteroids are widely believed to disrupt sleep. The most
Status Scale (EDSS) score than patients without RLS. No difference
consistent effect of corticosteroids on polysomnographic (PSG)
between the two groups was found in whole-brain, cerebellar, and
data in normal subjects is a marked decrease in REM sleep [61].
brainstem T2 lesion loads or in T2 lesion loads of the two cerebral
Approximately 50% of patients treated with prednisone for optic
and cerebellar hemispheres when considered separately. Among
neuritis reported sleep disturbance, compared with 20% on placebo
the MRI metrics analyzed, cervical cord fractional anisotropy
[62]. Preliminary data [63] also demonstrated that treatment of MS
was significantly reduced in patients with RLS compared with MS
patients with methylprednisolone causes sleep electroencepha-
patients without RLS, suggesting that cervical cord damage repre-
logram (EEG) changes typically seen in patients with depression
sents a significant risk factor for RLS among MS patients.
(reduced REM sleep latency, decreased REM sleep density, and
Other studies have also reported a relation between cord involve-
decreased slow-wave sleep). Earlier data suggesting that treatment
ment caused by different pathologies (eg, intramedullary lesions,
with interferon-β therapy predisposes patients to depression has
schwannoma, and MS) and RLS and/or PLMS [49–53]. A pos-
been questioned. However, Mohr et al. [38] suggested that, con-
sible explanation is that cord damage may interrupt descending
sidering the uncertainty of a link between interferon and depres-
or ascending pathways, resulting in brain–spinal disconnection,
sion, a well as the complete remission of psychiatric complications
which in turn leads to the appearance of RLS. The hypothesis that
after interferon discontinuation, physicians should closely monitor
impairment of a descending cerebrospinal inhibitory pathway could
the psychiatric status of patients. To date, disrupted sleep, depres-
lead to a higher spinal motor excitability in RLS patients is indeed
sion, and increased fatigue have not been described with the use
supported by several clinical and neurophysiological data [54,55].
of glatiramer acetate [64], mitoxantrone [65], or immunoglobu-
A possible target of the spinal lesion could be represented by the
lins [66]. Insomnia has been reported in MS patients treated with
dopaminergic descending neurons projecting from the A11 hypo-
laquinimod [67], while there are no specific data on natalizumab
thalamic area to D3 receptors located in the dorsal and interme-
and fingolimod.
diolateralis spinal nuclei [56]. Several findings support the notion
that this nervous pathway is central in RLS genesis: the A11 area
receives a diffuse innervation from the suprachiasmatic nucleus, Sleep disordered breathing
which is the main physiological drive for the circadian rhythm; The medullary reticular formation is responsible for controlling
artificial lesions of A11, as well as systemic administration of selec- automatic breathing during sleep. In MS patients, demyelinating
tive D3 antagonists, increase locomotor activity in rats; knockout lesions in this area could affect nocturnal respiratory effort, leading
mice for D3 receptors exhibit hyperactivity; and D3 agonists indeed to sleep disordered breathing and even nocturnal death (Ondine’s
represent the first-choice drugs in RLS [56,57]. Moreover, the curse) [68]. CNS and brainstem-related nocturnal respiratory
hypothesis that the spinal lesion related to RLS is a consequence abnormalities such as paroxysmal hyperventilation, hypoventila-
of ascending pathway damage cannot be excluded. The RLS may tion, respiratory muscle weakness, and respiratory arrest have all
indeed be the result of a central somatosensory processing dysfunc- been described [68,69], and these should be considered in MS
tion due to an abnormal peripheral afferent input [58]. patients in the evaluation of symptoms of daytime somnolence,
Treatment options for RLS and PLMS are similar and include increased fatigue, and nonrestorative sleep.
dopaminergic agents (levodopa/carbidopa, pramipexole, ropin- Concerning the prevalence of obstructive sleep apnea (OSA)
irole, and rotigotine), anticonvulsants (gabapentin, pregabalin, and in MS patients, the estimates based on PSG studies vary widely
clonazepam), and opioids [59]. These compounds should be also (0–58%, Table 33.2). Differences in PSG acquisition and scoring
considered for the treatment of RLS and PLMS in MS patients. methods may in part explain variability in study results. Of note,
Table 33.2 OSA in MS patients
Authors Study site Number of subjects Mean age (years) Prevalence of OSA (%)
Ferini-Strambi et al., 1994 [73] Italy 25 39.9 12
Kaynak et al., 2006 [74] Turkey 37 37 0
Veauthier et al., 2011 [75] Germany 66 43.2 9.1
Neau et al., 2012 [76] France 205 40 (for 25 subjects 0 (from 205 patients selected
selected for PSG) to undergo PSG)
Kaminska et al., 2012 [71] Canada 62 47.3 58

a recent cross-sectional study suggests that progressive MS sub- Modafinil is a CNS activating and wake-promoting agent,
types and increased level of disability are risk factors for OSA in and is pharmacologically distinct from other CNS stimulants.
MS [70]. Preclinical studies [87] have demonstrated that modafinil can
Kaminska et al. [71] found that OSA (apnea–hypopnea index selectively activate lateral hypothalamic neurons that produce
≥ 15) was frequent in MS (36 of 62 patients) and was associated wake-promoting hypocretin-1. It is well known that modafinil
with fatigue but not sleepiness, independent of MS-related disabil- significantly improves EDS associated with narcolepsy [88], and a
ity. A recent study showed that CPAP therapy in some MS patients preliminary study [89] showed that it effectively manages fatigue
with OSA was associated with a significant reduction in Fatigue associated with MS. However, a recent meta-analysis [90] showed
Severity Scale scores [72]. Future work on large samples of MS that existing trials of modafinil for fatigue and EDS associated
patients is needed to understand the real impact of CPAP therapy with MS provided inconsistent results. Thus, modafinil is not yet
on quality of life in this patient group. sufficient to be recommended for EDS and fatigue in MS until
solid data are available.
Narcolepsy
Narcoleptic symptoms have long been recognized in patients with REM sleep behavior disorder
MS. Studies published in the first half of the twentieth century RBD is a parasomnia characterized by complex motor behaviors,
report cases of MS associated with sleep attacks termed “narco- such as kicking, punching, and dream enactment, which occur dur-
lepsy” [77,78]. Symptoms of narcolepsy may appear before or after ing REM sleep. RBD may be idiopathic or associated with various
other symptoms of MS [79,80]. neurological conditions such as brainstem neoplasm, MS affecting
There is a coincidence of genetic susceptibility between nar- the brainstem, olivopontocerebellar atrophy, diffuse Lewy body
colepsy and MS [81]. Studies involving Caucasian Americans, disease, Parkinson disease, Alzheimer dementia, progressive supra-
Japanese, Afro-Brazilians, and African Americans show a strong nuclear palsy, or Shy–Drager syndrome and pure autonomic failure
association (>90%) between narcolepsy with cataplexy and certain [91,92]. RBD has been described as an initial presenting symptom
human leukocyte antigens: HLA-DR2, -DQB1*0602, -DQA1*0102, in a 25-year-old woman with MS, and subsequently resolved after
and -DQw1 [82]. treatment with adrenocorticotropic hormone [93]. However, in
The susceptibility to MS is coded by genes within or close to that study, no MRI images documenting the described pontine
the HLA-DR–D Q subregion. Indeed, in the MS population, an and bilateral periventricular cerebral lesions were presented. More
increased prevalence (50-70%) of HLA-DR2, -DQB1, -DQA1, -A3, recently, another RBD case in a 51-year-old woman with MS has
-DQw1, and -B7 has also been found [83]. The finding that both been reported [94], and the RBD onset was attributed to the large
narcolepsy and MS are strongly linked to similar HLA expression, MS plaque in the dorsal brainstem: MRI showed a large confluent
a hallmark of most autoimmune diseases, suggests that similar area of increased T2 signal in the dorsal pons lesion similar to that
autoimmune factors may play a role in the development of both provoked in animal models (eg, cats, with bilateral peri-locus coer-
diseases and may be partially responsible for similar symptoms of uleus lesions inducing REM sleep without atonia accompanied by
fatigue and somnolence. Hypocretin-1 and -2 (orexin-A and -B) motor behaviors). A study showed that the estimated prevalence of
are neuropeptides released by lateral hypothalamic neurons that RBD in MS was 1.4% [95].
are involved in wake promotion and sleep regulation [82]. These Clonazepam is first-line therapy for RBD. However, if RBD
neurons are reduced in patients with idiopathic narcolepsy. Most occurs in association with an acute brainstem inflammatory lesion,
sporadic, HLA-D QB1*0602-positive, narcoleptic patients with high doses of methylprednisolone should be tried first [4]‌.
cataplexy have undetectable levels of hypocretin-1 in the cerebro- In relation to the reported association between MS and depres-
spinal fluid (CSF). This evidence, taken in the context of a strong sion, the literature over the last three decades has provided evi-
narcolepsy HLA association, suggests the possibility of an auto- dence for tricyclic antidepressants causing REM sleep without
immune disorder directed against hypocretin-containing cells muscle atonia and inducing RBD in healthy subjects as well as in
in the lateral hypothalamus, although no direct cause-and-effect patients with neuropsychiatric disorders [96,97]. There are similar
relationship has been established. Hypothalamic MS plaques have reports of RBD symptoms being triggered by SSRIs, and a system-
been shown to cause hypersomnia and narcoleptic symptoms in atic PSG study of patients taking serotonergic antidepressants, such
the context of low CSF hypocretin-1 levels [84]. Additionally, as fluoxetine, paroxetine, citalopram, sertraline, and venlafaxine,
abnormally low levels of hypocretin-1 in MS patients with hypo- found an increase in REM sleep electromyographic (EMG) tonic
thalamic plaques have been found. Therefore, it is possible for activity compared with control subjects [97,98]. MS patients taking
CNS inflammation and demyelination, in this area, to cause such medications may be at an increased risk for developing RBD,
somnolence by altering CSF hypocretin-1 levels [85]. One study particularly with increasing age.
evaluated lesions on magnetic resonance imaging (MRI), CSF In conclusion, the association between MS and sleep disorders
hypocretin-1 levels, and serum anti-aquaporin 4 (AQP4) anti- is common. Though often unrecognized, sleep disorders in MS are
body titer in seven MS patients with narcolepsy [86]. Bilateral seen at higher frequency than in the general population, and they
and symmetrical hypothalamic lesions associated with marked may contribute to pain, fatigue, and depression—symptoms com-
or moderate hypocretin deficiency were found in all seven cases. monly observed in MS patients. An increased clinical awareness
Four of these patients met the ICSD-2 narcolepsy criteria. Three and appropriate treatment of sleep disorders in MS population may
patients, including two with narcolepsy, were seropositive for significantly improve the overall quality of life in these patients.
anti-AQP4 antibody and diagnosed to have neuromyelitis optica- As has recently been suggested [13], it would be desirable to cre-
related disorder. ate more sensitive and specific questionnaires for sleep disorders

Chapter 33 sleep disorders in multiple sclerosis 331
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CHAPTER 34
Sleep and dreams
A clinical neurological perspective
Mark Solms
Background fundamentally to this emerging picture. The bewildering array of

clinical phenomena may perhaps best be grouped under two head-
Historically, there has been little systematic investigation of changes ings: (1) deficits of dreaming and (2) excesses of dreaming.
in dreaming due to neurological disease, despite numerous clinical
reports of marked abnormalities in some patient groups. Accordingly,
the topic remains poorly understood. This reflects a lack of develop- Deficits of dreaming
ment in the field of dream research itself: an understanding of the The earliest clinical observations of changes in dreaming with
brain mechanisms of dreaming lagged behind that of other cogni- neurological disease concerned cessation of dreaming (or ces-
tive functions. There are two main reasons for this. First, unlike most sation of aspects of dreaming). The terms “Charcot–â•‰Wilbrand
cognitive functions that were the focus of nineteenth-â•‰and twentieth-â•‰ syndrome” and “anoneira” have been used to describe this abnor-
century behavioral neuroscience, dreaming is almost entirely subjec- mality, which is typically seen in the acute phase of posterior cor-
tive. The observable data are retrospective, single-â•‰witness qualitative tical pathology.
descriptions, only indirectly related to the phenomenon of dreaming
itself. This poses special methodological problems. Charcot–â•‰Wilbrand syndrome
The second reason for the undeveloped state of this field is closely The concept of this syndrome, based on two single-â•‰case reports by
related to the first. Researchers seeking an objective approach to Charcot [15,16] and Wilbrand [17,18], was first articulated by Pötzl,
dreaming eagerly alighted on a physiological state that correlates who defined the syndrome as “mind-â•‰blindness with disturbance of
closely with it—â•‰namely rapid eye movement (REM) sleep [1–â•‰4]. This optic imagination” ([19], p. 306). Nielsen defined it as “visual agno-
physiological state was then conflated with dreaming itself, result- sia plus loss of the ability to revisualize” ([20], p. 74). Critchley’s
ing in the development of neuropsychological models of dreaming widely cited definition was:
that were in fact models of REM sleep [5]â•„. This conflation was com-
a patient loses the power to conjure up visual images or memories, and
pounded by the fact that the models were empirically grounded in
furthermore, ceases to dream during his sleeping hours. ([21], p. 311)
animal studies (where dream reports are of course precluded) rather
than human lesion studies of the kind that classically informed Reproduced from Critchley, M, The parietal lobes,
Copyright (1953), Macmillan.
models of other cognitive functions. When the conventional human
lesion studies were belatedly performed, it became apparent that Critchley described prosopagnosia and topographical agnosia or
dreaming and REM sleep are in fact doubly dissociable states [6]. topographical amnesia as associated features. The localization of
A traditional neuropsychology or behavioral neurology grounded the lesion producing this syndrome was never precisely defined,
in the clinico-â•‰anatomical method—â•‰which was widely applied to but the occipital cortex (especially area 19) was implicated by most
other cognitive functions from the mid-â•‰nineteenth century—â•‰is early authors—â•‰usually bilaterally. The Charcot–â•‰Wilbrand syndrome
less than 30 years old in the case of dreaming. Incidental reports remained in late twentieth century nosographical usage, although
of changes in dream phenomenology associated with focal cer- the condition was (until recently) considered rare. A modern defi-
ebral lesions did nevertheless accumulate in the literature over a nition of the syndrome, by Murri et al., reads:
long period, albeit without any attempt to synthesize the scattered the association of loss of the ability to conjure up visual images or
observations into a coherent picture. Systematic clinico-â•‰anatomical memories and the loss of dreaming … [indicates] a lesion in an acute
studies were first published in the 1980s [7–â•‰9], and the available phase affecting the posterior regions. ([8]â•„, p. 185)
evidence was not comprehensively reviewed before the 1990s [10–â•‰ Reproduced from Arch Neurol, 41(2), Murri, L., Arena, R.,
12]. The conventional clinico-â•‰anatomical studies have since been Siciliano, G., Mazzotta, R., & Murarorio, A, Dream recall in
complemented by a slew of functional brain imaging studies, with patients with focal cerebral lesions, pp. 183–185,
Copyright (1984), American Medical Association.
strongly convergent findings [13]. Rigorous probes of the neuro-
chemistry of dreaming (as opposed to REM sleep) have surpris- Deficient revisualization (called “irreminiscence” in the nomen-
ingly not yet been conducted [14]. clature of Nielsen [20]) was the fundamental deficit in almost all
An understanding of the brain mechanisms of dreaming is nev- definitions of the syndrome. Cessation of dreaming (“or at least,
ertheless beginning to emerge. Systematic observation of abnor- an alteration in the vivid visual component of the dreaming state”;
malities of dreaming in neurological disease has contributed Critchley [21], p. 311) was seen as a secondary consequence of the

visual imagery deficit. The associated visual agnosias, too, were strongly suggests a common underlying image-generation deficit
originally attributed to the defective revisualization, since visual causing the same disorder in both waking and dream cognition.
agnosia was classically understood as a loss of “visual memory Various forms of visual agnosia are commonly associated features,
images” [21–23]. but agnosia is definitely absent in some cases and therefore cannot
Subsequent advances in the agnosia concept, and a misreading of be considered integral to the syndrome [12].
the original French and German case reports, have resulted in con- Most published reports of deficits in visual dream imagery
siderable nosographic confusion regarding this syndrome [12,24]. derive from retrospective accounts in a clinical setting. However
It is widely assumed that Wilbrand’s case—an elderly female patient such reports have been confirmed by REM awakenings in a sleep-
with bilateral posterior cerebral artery thrombosis—could not vis- laboratory setting in at least three cases [32–34].
ualize familiar places [20,21,25,26]. However, the original report
stated only that she was unable to recognize familiar places. This Negative findings
symptom (which we would today call topographical agnosia) was Interestingly, unimodal deficits of dream imagery outside the higher
conceptualized, in accordance with classical theory, as a disorder of visual sphere have never been demonstrated, nor have unimodal
“topographical memory” (Wilbrand [17], p. 52, emphasis added). deficits been observed in any modality other than vision. Thus
This conceptualization was then misconstrued by secondary although achromatopsic, akinetopsic, prosopagnosic, and hemine-
authors as a disorder of topographical revisualization. The original glect disorders are duplicated in dreams, patients with lower visual
report reveals that Wilbrand’s case actually lacked the cardinal fea- disorders such as cortical blindness and hemianopia invariably
ture of the so-called Charcot–Wilbrand syndrome. As the patient report normal vision (full fields) in their dreams. This, incidentally,
herself clearly stated: “With my eyes shut I see my old Hamburg has important implications for theories of visual consciousness.
in front of me again” [15,16] (Wilbrand [17], p. 56). Charcot’s case Moreover, hemiplegic patients experience normal somatomotor and
[15,16]—an elderly male patient also with a probable posterior cer- somatosensory functions in their dream imagery (as do acute-phase
ebral artery thrombosis (autopsy findings were lacking)—was quite paraplegic and quadriplegic patients) [12,42].The same applies to
different. He described a striking absence of visual mental imagery. the extrapyramidal movement disorders. Similarly, nonfluent apha-
The Charcot–Wilbrand syndrome is therefore misconceived. sics claim to speak normally in their dreams [12].
It is also misnamed. Charcot’s [15,16] patient ceased to dream Of related interest, perhaps, is the fact that the dreams of patients
in visual images, but he continued to dream in words. Wilbrand’s with substantial impairments of executive function due to mas-
[17,18] patient, on the other hand, dreamed “almost not at all any- sive dorsolateral prefrontal lesions are indistinguishable from the
more” ([17], p. 54). The original report is ambiguous as to whether dreams of controls [43]. This suggests that dreams (apart from their
Wilbrand’s patient merely dreamed infrequently or actually lost the higher visual aspects) do not involve simple activations of the entire
capacity to dream completely (and then gradually recovered it); but cortex, as Hobson and McCarley’s [5]‌activation-synthesis model
either way, there is no question of an isolated loss of visual dream originally proposed. The clinico-anatomical findings point to a
imagery, which is what Charcot’s patient unequivocally described. differentiated network of forebrain structures involved in dream
The “Charcot–Wilbrand syndrome” therefore appears to be two dif- cognition, a conclusion that is strongly confirmed by neuroimaging
ferent (but related) syndromes, Charcot’s variant is characterized findings (see the discussion later in this chapter).
by unimodal loss of visual dream imagery and Wilbrand’s variant
by global (heteromodal) cessation or suppression of dreaming. This Wilbrand’s variant: global (heteromodal)
distinction is supported by my review of the world literature [12]. loss or suppression of dreaming
However, the further conclusion drawn from that review, namely, At least 108 cases of global loss of dreaming have been reported,
that Charcot’s variant occurs with occipital lesions and Wilbrand’s excluding leucotomy cases, which will be discussed separately
variant with parietal lesions, is probably incorrect (see the discus- (see [12] for a nearly complete tabulation of these cases). A larger
sion later in the chapter). number of cases in group studies, where individual case data were
lacking and where “loss of dreaming” was defined in variable ways
Charcot’s variant: unimodal loss of visual [7–9], have also been reported.
dream imagery As with Charcot’s variant, global loss of dreaming (which I called
At least 10 case reports of unimodal loss of visual dream imagery “anoneira” [12]) is typically—but not invariably—associated with
have been published, together with five further reports of patients acute-onset, focal cerebral lesions. Thrombosis, hemorrhage, and
who experienced deficits of specific aspects of visual dream imagery trauma are the most commonly reported pathologies. The first
(eg, color, movement, and faces). Cessation of visual imagery or systematic attempt to identify the lesion site responsible for global
aspects thereof results from various pathologies, usually of acute cessation of dreaming pointed to the inferior parietal lobule [12].
onset (thrombosis, hemorrhage, trauma, or CO poisoning), but it Unilateral lesions of either hemisphere were shown to be common-
has also been described in cases of neoplasm, probable Alzheimer place, with no lateralizing bias. However, at least two cases have
disease, callosal dysgenesis, and Turner syndrome). The lesion is since been reported in which the parietal lobe was apparently spared
typically localized to the mesial occipitotemporal or lateral occip- [44,45], as indeed it appears to have been in Wilbrand’s original
itoparietal regions, and is usually bilateral, but precise localizing case [18]. Members of my group will shortly be reporting five fur-
information is lacking in many of the published cases [12,15,26–41]. ther cases of this type [46]. However, it is difficult to imagine how a
Defective revisualization (irreminiscence) is a constant feature lesion in unimodal cortex can produce a heteromodal disorder. It is
in these cases, although it is typically restricted to the disordered therefore worth noting that in Bischof and Bassetti’s case [44], as in
aspect of vision (eg, color, movement, and faces) in cases where ours [46], lacunar infarction of the posterolateral thalamus (which
the loss of visual dream imagery is partial (i.e, submodal). This modulates parietal functions) was present. Similarly, Poza & Marti’s

Chapter 34 sleep and dreams: a clinical neurological perspective 335
case [45] (ruptured arteriovenous malformation) was not suitable cases was forthcoming from many other authors [26,62–65] (see
for localizing purposes; there may very well have been a parietal also Slater, cited by Humphreys and Zangwill [66]). Moreover, Jus
aspect to his extensive lesion. Moreover, a re-analysis of my data et al. [62] confirmed the absence of morning dream reports follow-
by Yu [47] revealed that the lesions in my “parietal” cases almost ing prefrontal leucotomy by the REM awakening method.
always extended into adjacent occipitotemporal tissues (especially In apparent contradiction to these reports, however, Humphrey
Brodmann areas 22, 19, and 37). The parietal lobe therefore may or and Zangwill [66], Cathala et al. [7]‌, Murri et al. [8,9], and Doricchi
may not have been the constant feature in my clinical series. It is and Violani [10] all observed a relatively low incidence of cessation
therefore, sadly, still not possible to make a more precise localizing of dreaming with frontal versus posterior cerebral lesions. The same
statement than the one offered by Murri et al.: “a lesion in an acute applies to the observation reported earlier in this chapter to the
phase affecting the posterior regions” ([8]‌, p. 185). Hopefully future effect that the dreams of frontal patients are indistinguishable from
studies will refine this statement. those of controls [43]. This apparent contradiction was resolved
The reference to an acute phase is not superfluous. I observed that when I reviewed the lesions in the previously reported cases and
almost all cases of global anoneira recover the capacity to dream described nine new cases with cessation of dreaming following
within 12 months [12]. This fact, which suggests diaschitic effects, naturally occurring bifrontal lesions [12]. My conclusion was that
may further help explain the imprecise localization of the causal dreaming was entirely spared with dorsolateral prefrontal cortical
lesion. lesions but lost with deep white matter lesions in the ventromesial
Of particular clinical interest is the observation [12] that hydro- quadrant of the frontal lobes (see Figs. 34.1 and 34.2). The lesion
cephalus is associated with cessation of dreaming, and that dream- site in these nine cases coincided exactly with the area that was tar-
ing recovers after successful ventriculoperitoneal shunting (or geted by prefrontal leucotomy: “a circumscribed lesion just anterior
shunt revision) in these cases. Cessation of dreaming might there- to the frontal horns of the ventricle, in the lower medial quadrant
fore be used as a clinical warning of shunt malfunction. of the frontal lobes” ([67], p. 177). A reanalysis of the original data
Defective revisualization (irreminiscence) is a relatively common in 35 cases from my series [12] with global cessation of dreaming
but by no means invariable feature of the global cases. It was over- associated with subcortical lesions revealed that the lesion was
represented in the earlier case reports for the probable reason that located in either the deep frontal white matter (areas F09 and F14
patients were only asked about their dreams once irreminiscence in the classification of Damasio and Damasio [68]; see Fig. 34.3), or
had been established. The more recent cases that I reported in [12] the head of the caudate nucleus, or both [69]. The lesion is typically
were part of an unselected series and are therefore more likely to but not exclusively bilateral. Of theoretical importance is the fact
be representative of the clinical population as a whole. Global ano- that the region defined as the “head of the caudate nucleus” in the
neira (unlike unimodal visual dream deficits) therefore cannot be latter study [69] included the nucleus accumbens, which is situated
reduced to irreminiscence. immediately beneath it.
Not surprisingly, considering the lesion site, global anoneira is It is noteworthy that the psychotropic medications that replaced
frequently associated with disorders of spatial cognition, including prefrontal leucotomy as the treatment of choice for psychotic dis-
visuospatial short-term memory deficits [12]. The lack of association orders block dopamine (DA) transmission at D2-type receptors in
between cessation of dreaming and long-term memory disorder of a mesial forebrain pathway that projects primarily to the nucleus
any kind excludes the possibility that cessation of dreaming is really accumbens. Probably related to this is the observation that both
a memory disorder—i.e., failure to remember dreams as opposed to prefrontal leucotomy in general and cessation of dreaming in
cessation of dreaming per se [48–50]. This applies also to the vari- particular, due to lesions in this general area, are associated with
ous language disorders that were previously thought to explain loss reduced motivational incentive [12], as indeed are most antip-
of dreaming [10,51–54]. In my systematic survey of the literature sychotic medications [70]. Leu-Semenescu et al. [71] recently
and my own cases [12], I found no relationship between cessation of described strikingly reduced dream frequency and intensity in
dreaming and any form of language disorder or amnesia. neurological patients with auto-activation deficits (i.e, adynamia/
The veracity of retrospective reports of absence of dreaming on abulia). Also of interest in this connection are the observations by
morning awakening has also been repeatedly confirmed by the Piehler [64] and Schindler [65] to the effect that early recovery of
REM awakening method [44,45,55,56]. This further supports the dreaming after prefrontal leucotomy typically predicted psychiat-
assumption that anoneira concerns cessation of dreaming per se, as ric relapse, suggesting that absence of dreaming could serve as an
opposed to loss of memory for dreams. Even severe amnesiacs with index of the clinical success of the operation. Dreaming is, after all,
bilateral hippocampal lesions report dreams on awakening from a psychotic state.
REM sleep and at sleep onset (Ramachandran, 2004 personal com-
munication). This is consistent with the reports of Stickgold et al Effects of pontine brainstem lesions
[57] and Torda [58] and also with Corkin’s [59] observations upon Cessation of dreaming following circumscribed pontine lesions—
the celebrated case of “HM.” with or without cessation of REM sleep—has never been dem-
onstrated (for reviews, see [6,12]), despite the longstanding
Cessation or suppression of dreaming following assumption that dreaming is caused by—if not identical with—the
prefrontal leucotomy cyclical, spontaneous activation of cholinergic (ACh) cell groups in
In a survey of 200 cases of prefrontal leucotomy, Frank observed the mesopontine tegmentum during the REM state, together with
that a common result of the procedure was “a poverty or entire lack reciprocal inhibition of serotonergic (5-HT) and noradrenergic
of dreams” ([60], p. 508). In a later report on the same series of (NA) cell groups in the dorsal raphe and locus coeruleus complex
cases, then comprising more than 300 patients, he confirmed this [72,73]. Consciousness in general is of course frequently compro-
finding [61]. Replication of Frank’s findings in prefrontal leucotomy mised by pontine lesions, but at least eight cases with cessation

Fig. 34.1 Combined facsimile of scans in nine cases with global cessation of

dreaming caused by deep frontal lesions, illustrating the strong involvement of the
white matter surrounding the frontal horns of the lateral ventricles.
Reproduced from Solms, M, The Neuropsychology of Dreams: A clinico-anatomical study,
Fig. 34.2 Combined facsimile of scans in 14 cases with preserved dreaming
Copyright (1997), Taylor & Francis.
with bifrontal lesions, illustrating the relative preponderance of cortical convexity
involvement.
Reproduced from Solms, M, The Neuropsychology of Dreams: A clinico-anatomical study,
Copyright (1997), Taylor & Francis.
or near-cessation of REM sleep have been reported in which the
patients were capable of communicating meaningfully about their
dreams [74–77]. Indeed, one such patient did actually report loss of linked with dreaming in the clinical lesions studies reviewed above.
dreaming [74], but the pathology—ruptured traumatic aneurysm Significant increases in regional brain activity have been observed
of the basilar artery—almost certainly extended beyond the pon- in the basal forebrain and other limbic and paralimbic structures,
tine brainstem and included the visual–spatial cortical areas dis- including the hippocampal complex, the anterior cingulate cortex,
cussed earlier in this chapter. Even this isolated case therefore does and the pontine tegmentum, during REM sleep. Also consistent
not support the old equation of pontine brainstem mechanisms with the lesion studies [43] is the fact that the dorsolateral convex-
with dream generation [72,73]. This conclusion is buttressed by the ity is strikingly deactivated during REM sleep [87–89].
fact that drugs that suppress REM sleep do not suppress dreaming Braun et al. [90] reported a dissociated pattern of activity
[78]; in fact, the opposite is the case [79–85]. There is further dis- between visual association areas (extrastriate cortices—fusiform,
cussion of the relationship between dreaming and REM sleep later inferotemporal, and ventral lateral occipital) and primary visual
in this chapter. areas (striate cortices) during REM sleep compared with slow-
wave sleep (SWS). Activation within the visual association cortices
Neuroimaging and transcranial magnetic was also shown to correlate positively with activity within para-
hippocampal gyri and contiguous portions of the hippocampus,
stimulation studies and with deactivation of dorsolateral and orbital prefrontal asso-
Neuroimaging studies have determined patterns of regional brain ciation areas. Based on these findings, the authors concluded that
activation and deactivation during REM sleep, the stage of sleep “during REM sleep, the extrastriate cortices and paralimbic areas
during which dream reports are most frequently obtained [86]. to which they project may be operating as a closed system, func-
These patterns of activity are highly consistent with the brain areas tionally disconnected from frontal regions in which the highest

Fig. 34.3 Global cessation of dreaming is associated with subcortical lesions located in the deep frontal white matter.
Reproduced from Damasio, H., & Damasio, A, Lesion analysis in neuropsychology, Copyright (1989), with permission from Oxford University Press.
order integration of visual information takes place. Such a disso- as during wakefulness, when compared with low dream recallers
ciation could explain many of the experiential features of dreams” [93]. Using a novelty oddball paradigm, high dream recallers were
([90], p. 94). This notion of a closed loop between certain medial shown to have enhanced P3a and late latency event-related poten-
forebrain and limbic regions and higher order visual association tials (ERPs) to novel and unexpected auditory stimuli. As the P3a
areas is consistent with my suggestion [6,12] that dreaming is a and late latency potentials are associated with complex cognitive
product of deep ventromesial frontal (mesocortical–mesolimbic) processes such as familiarity, episodic memory, and emotional pro-
structures activating higher visual association areas during sleep, cessing [94–96], Eichenlaub et al. [93] have argued that the robust
instead of the dorsolateral frontal (executive and motor) areas they differences in brain responsivity show that the cerebral organiza-
activate during waking, thereby generating imaginary versus real tion of high recallers is intrinsically different to that of low recallers,
action. and that this difference may potentially facilitate either production
A recent study, using [15O]H2O positron emission tomography or encoding of the dream.
(PET) in healthy subjects with habitually high and low dream recall The propensity to be more reactive to the external environment
frequencies, also showed that high dream recallers—compared with is consistent with enhanced activation of the posterior attentional
low dream recallers—had greater regional cerebral blood flow in networks in high dream recallers. Whether increased dream recall
the temporoparietal junction during SWS, REM sleep, and waking, in high dream recallers is due to more efficient encoding of the
as well as greater regional cerebral blood flow in the medial prefron- memory trace of the dream into long-term memory, or whether
tal cortex during REM sleep and waking [91]. These brain regions activity within these regions indicates a genuine increase in dream
are highly consistent with those identified by the lesion studies as activity, remains inconclusive. However, the latter possibility is sup-
being critically related to the dream process. As the temporopari- ported by a recent set of transcranial magnetic stimulation (TMS)
etal junction may facilitate the orientation of attention during sleep studies, which found that visual dream imagery could be enhanced
to external stimuli, it has been argued that the increase in activa- by inhibiting certain frontal regions while stimulating the right
tion of this region may be responsible for the observed increase posterior parietal cortex during stage 2 sleep but not during SWS
in intra-sleep wakefulness in high dream recallers. According to [97,98]. This finding must be understood in relation to the fact that
the arousal–retrieval model of dreaming [92], intra-sleep wakeful- TMS is unable to propagate through connected networks during
ness may facilitate the encoding of dream content into long-term SWS as efficiently as during lighter NREM sleep [99]. It neverthe-
memory, consequently facilitating dream recall upon awakening in less corroborates the notion that activity in the posterior association
high dream recallers. cortex is responsible for the perceptual construction of dreams, and
Consistent with this model, high dream recallers are more reac- moreover that activity in these regions during sleep represents an
tive to their external environments during all stages of sleep, as well increase in dream activity.

Despite all the strong evidence that higher visual association Hallucinations and dream/reality confusion are also common
cortices are responsible for the perceptual construction of dreams, in narcolepsy [106]. In these cases, hallucinations may accompany
it has recently been shown that primary visual areas may also be or follow attacks of cataplexy and sleep paralysis. Hallucinations of
somehow involved. In an innovative combined electroencepha- the presence of someone nearby (“sensed presence”) or a pressure
lographic/functional magnetic resonance imaging (EEG/fMRI) on the chest with breathing difficulties (“incubus/succubus”), and
study, participants’ dream imagery (as verbally reported) was floating/flying and “out-of-body” experiences, are typical in these
decoded from neural activity measured during sleep onset, by soft- cases. Dreams can occur at sleep onset (at night or during daytime
ware trained to correlate discrete visual stimuli (i.e, pictures) with naps), as well as on awakening (Rosenthal syndrome). The retention
brain activity during waking [100]. Horikawa et al. concluded that of elements of normal waking mentation, such as volitional control
the “principle of perceptual equivalence, which postulates a com- or environmental awareness, is characteristic of narcoleptic dreams.
mon neural substrate for perception and imagery, generalizes to Various other rare disorders are associated with dream/reality
spontaneously generated visual experience during sleep” ([100], confusion. Idiopathic hypersomnia manifests in excessive daytime
p. 642). As lesions to primary visual regions do not result in dream sleepiness, prolonged unrefreshing sleep and “sleep drunkenness”
loss, or any visual disturbances in dreams [12], the exact contri- on attempting to wake up. Habitual dreaming, hypnagogic hal-
bution of the primary visual regions to conscious dream imagery lucinations, and sleep paralysis are common in these cases [106].
remains unclear. Kleine–Levin syndrome (KLS) is a rare disorder characterized by
recurrent episodes of hypersomnia, compulsive eating behavior,
Excesses of dreaming and various psychopathological changes like hypersexuality, irri-
tability, and apathy. Hallucinations, delusions, and “dreamy states”
Dream/reality confusion are reported in 14–24% of patients with KLS [107]. In fatal familial
In [12], I loosely grouped together 12 case reports in the litera- insomnia, a variant of Creutzfeldt–Jakob disease (CJD), progres-
ture and 10 of my own cases under the heading of dream/reality sive insomnia is coupled with an oneiric stuporous state in which
confusion (or “anoneirognosis”). These patients reported excesses patients perform complex, jerky movements that correspond to
of dreaming, ranging from increased frequency and/or vivacity of reported dream content [108]. Dream/reality confusion with hal-
dreams to intrusions of dreaming and dream-like thinking into lucinations also occurs in sporadic CJD [109].
waking cognition. The principal justification for collecting these In populations without neurological disorders, excessive dream-
cases under a unitary nosological heading was the fact that the ing has been reported as a primary complaint in certain sleep clin-
focal lesions (representing a wide variety of pathologies) that ics [110]. A study comparing these patients with controls revealed
cause “anoneirognosis” are typically located in the transitional that complaints of excessive dreaming were related to significant
zone between the anterior diencephalon and basal forebrain. microstructural changes, including increased arousals, intra-sleep
Kindred phenomena are, however, also observed with visual de- awakenings, periodic leg movements, alpha–delta sleep, and REM
afferentation, peduncular hallucinosis, delirium, parkinsonian density; however, no macrostructural changes were noted, and no
syndromes or medications (see below), Guillain–Barré syndrome, differences in REM sleep and sleep onset latencies were observed.
and a variety of toxic and metabolic conditions, as well as by many Excessive dreamers were also found to be significantly more
psychoactive drugs. The common denominator in these cases may stressed, fatigued, and anxious than controls, and to have more
therefore simply be degradation of constraints on consciousness. headaches.
Certainly, any suggestion on the basis of the currently available
evidence that dream/reality confusion may be considered a focal Nightmares
symptom is unjustified. Nocturnal seizures (and temporal lobe seizures in particular)
Dream/reality confusion in parkinsonian syndromes is difficult sometimes present as recurring nightmares [111,112]. In [12], I
to interpret. Increased dreaming and hallucinations are frequently identified 24 cases of this type in the literature and 9 in my own
seen with Parkinson disease (PD), but this may be iatrogenic. It is clinical series. Of theoretical interest is the fact that such night-
well-established that hallucinations and excessive dreaming can be mares typically occur during NREM sleep. The content of the
provoked by the administration of L-DOPA, both in PD [101] and nightmares frequently coincides with that of the patient’s typical
in normal subjects, independently of any concomitant changes in aura or ‘dreamy state’ seizures [12,113]. Penfield was able to artifi-
REM sleep [102]. Accordingly, it has been shown that both reduc- cially generate a waking aura resembling the recurring nightmare
tion of dopamine agonists and administration of dopamine block- reported in one case by stimulating exposed cortex in the region
ers reduce hallucinations and excessive dreaming in PD [103]. of the epileptogenic focus [114–116]. Successful pharmacological
However visual hallucinations in PD may also be an indication of or surgical treatment of the seizure disorder invariably results in
the presence of Lewy body pathology, with involvement of parieto- disappearance of the recurring nightmares. These facts further sup-
occipital and limbic regions [104,105]. Apart from the iatrogenic port the interpretation of the nightmares in these cases as seizure
explanation, excessive dreaming in parkinsonian syndromes may equivalents (and indeed as NREM phenomena).
also have a different mechanism in cases with and without cortical As with dream/reality confusion (which frequently co-occurs
Lewy bodies. In PD, hallucinations occur late in the course of the with nightmares), increased frequency of nightmares is associ-
disorder, whereas they are an early feature of dementia with Lewy ated with a wide range of toxic and withdrawal states and meta-
bodies (DLB). All of these phenomena must of course be differenti- bolic abnormalities. The grounds for detaching these two “excesses
ated from REM behavior disorder (RBD), which may occur early in of dreaming” from each other are not entirely clear. The common
a variety of parkinsonian diseases (see the subsection later in this denominator here may therefore, once again, simply be general
chapter). degradation of constraints on consciousness.

It is important to note that nocturnal panic attacks and sleep ter- The REM state is also characterized by minimal prefrontal gluta-
rors are not instances of nightmares. Detailed dream recall is often mate release [140], which presumably coincides with the observa-
lacking in such attacks [117,118], although in certain studies dream tion reported above to the effect that dorsolateral prefrontal lesions
content has been reported [119]. have no obvious effect on dream content (and with the observa-
tion that this region is strongly deactivated in PET imaging studies
REM behavior disorder of REM sleep [87]). The chemical signature of the REM state, as
In this disorder, dreamed behaviors are physically acted out. This is regards the neurotransmitter interactions underlying the observed
due to disruption of the pontomedullary mechanisms that induce regional patterns of forebrain activation and deactivation, is there-
REM atonia [120]. The enacted behaviors may be dramatic or even fore certainly more complex than was previously assumed [141].
violent, and usually relate to vivid, frightening dreams. A fair pro- This complexity is underscored by the impenetrable thicket of
portion of cases injure their bed partners [121]. The disorder is psychopharmacological evidence. Of particular value is any evi-
most common in males, with onset often in the sixth or seventh dence that could clarify the pathophysiology of dream cessation
decade. RBD manifests mainly in the second half of the sleep cycle following deep ventromesial frontal lesions. Since the sleep cycle
(where REM is predominant). Increased SWS and periodic limb is unaffected by such lesions [62], it is reasonable to assume that
movements across all sleep stages are also seen [122–125]. they impair a mechanism that is specific to dream generation (as
Of special interest is the association of RBD with parkinsonian syn- opposed to REM generation). Two competing hypotheses have
dromes. The presence of RBD in PD patients is associated with cog- been advanced to account for dream cessation following deep
nitive deficits and appears to predict dementia [126,127]. Disorders ventromesial frontal white matter lesions (and the commensurate
with Lewy body pathology often involve RBD. The incidence of hyperactivation of this region in fMRI and PET imaging of dream-
RBD in PD is 25–50%, and more than 50% in DLB and multisystem ing sleep and schizophrenic hallucinations [87,142]). The first
atrophy (MSA). In contrast, disorders without Lewy bodies rarely hypothesis is that it reflects activation of ACh cells in the basal fore-
involve RBD. Notably, idiopathic RBD may present many years brain; the second is that it reflects activation of DA cells in the VTA.
prior to the other symptoms of an incipient Parkinsonian process Against the former hypothesis is the observation that ACh antag-
[121,128–133]. The prognostic significance of RBD as a precursor onists (like scopolamine), rather than suppressing dreaming and
to PD, DLB, and MSA is now well established, resulting in the sug- dream-like thinking, have the opposite effect: they produce dream/
gestion that the term “cryptogenic” RBD should replace “idiopathic” reality confusion [143]. In fact, in this respect, anticholinergic
RBD [124,134]. The propensity to instinctual behaviors in RBD, and drugs mirror the effects of lesions in cholinergic basal forebrain
in animal models of the disorder, is of distinct theoretical interest, as nuclei [144]. These and other considerations led Braun [145] to
it suggests that dreams are instinctually motivated mental states (see observe that activation of these nuclei during REM sleep may actu-
the section later in the chapter), as Freud [135] classically proposed ally reflect inhibition of forebrain ACh in dreaming sleep.
on the basis of purely psychological investigations. In favor of the latter hypothesis is the observation that DA ago-
nists increase dream bizarreness, vivacity, complexity, and emo-
tionality without having any commensurate effects on REM sleep
Pharmacological findings [102]. DA agonists, of course, also provoke other psychotic symp-
The neurochemical and pharmacological evidence is extremely dif- toms. Systematic studies of the effects on dreaming of DA antago-
ficult to interpret. This is due partly to the dynamic interactions nists have not yet been performed. However a preliminary study by
that characterize neurotransmitter systems and to the paucity of Yu (unpublished observation) concerning the effects on dreaming
rigorous pharmacological studies [14]. Mention will only be made of antipsychotic medications found significant dream-suppressing
here of recent findings that seem particularly relevant to under- effects.
standing dream generation and the distinction between dreaming Also incompatible with the view that dreaming and REM sleep
and REM sleep. are generated by the same pontine mechanisms is the accumulat-
The neurochemical signature of the REM state is well established, ing evidence to the effect that 5-HT agonists (selective serotonin
namely, autochthonous activation of ascending pontine ACh cell reuptake inhibitors, SSRIs), like anticholinergics, have the opposite
groups—which is thought to produce characteristic pontine– effect to what the REM-dreaming hypothesis would have predicted.
geniculate–occipital (PGO) waves—and reciprocal inhibition of As already noted, SSRIs suppress REM sleep but produce excesses
pontine aminergic (5-HT and NA) cell groups—which is thought of dreaming, of both types described above [79–85].
to demodulate the dreaming forebrain [136]. Equally well estab- The available pharmacological evidence therefore supports the
lished is the fact that NREM sleep has the opposite pattern. Less view that dreaming—like other forms of psychosis—is primar-
widely known is the fact that, unlike other aminergic brainstem ily generated by (demodulated) DA mechanisms rather than ACh
cells, the source cells in the ventral tegmental area (VTA) of the ones [146]. The role of reward processing in the “drug dreams” of
mesocortical–mesolimbic DA pathway described earlier in this addicts in withdrawal and remission, as it relates to mesocortical–
chapter in connection with prefrontal leucotomy continue to fire at mesolimbic DA activation, has recently been used to further eluci-
similar rates during sleeping and waking [137,138]. These cells also date the dream process [147]. It is likely that interactions between
fire with far greater interspike variability during REM than NREM DA and other neurotransmitter systems also affect dreaming, since
sleep [137]. This has recently been shown to indicate prominent enhanced dreaming has been shown in populations receiving
burst activity in the REM state [139], resulting in greater terminal noradrenergic beta-blockers [148]. However the neurochemical
DA release in the nucleus accumbens. DA delivery to the nucleus basis of dreaming is likely to be far more complex than demodu-
accumbens is in fact maximal during REM sleep when compared lated DA activation, the partial conclusion that the limited current
with NREM sleep and waking [140]. evidence reasonably allows.

Reward and motivational processes having prognostic and management implications. Dreams can also
be a major source of distress to patients. There is every reason to
during sleep and dreaming expect that systematic studies of clinical dream phenomena will
DA circuitry is central to reward processing. The mesocortical– continue to provide valuable new insights into the functions and
mesolimbic DA system is defined as the “system [that] is formed by malfunctions of the human brain and mind. The extension of our
dopamine neurons located in the ventral tegmental area … which understanding of dreams to healthy populations by means of con-
project to the nucleus accumbens, prefrontal cortex, septum, amyg- temporary neuroscientific research methods has been extremely
dala, and hippocampus” [139]. This system, termed the SEEKING valuable in furthering our knowledge of the dream process.
system by Panksepp, is thought to “drive and energize many mental Consistencies in certain neurophysiological models of dreaming in
complexities that humans experience as persistent feelings of inter- these two populations are providing the field with sound theoretical
est, curiosity, sensation seeking” ([149], p. 145). It is also involved departures from which the dream process can be better understood.
in reward processing, which refers to “an instinctual affective and
exploratory drive to seek biologically-important stimuli in the
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CHAPTER 35
Neurological diseases and their

effects on the sleep–â•‰wake cycle
Paul J. Reading
Introduction Typically, these involve nocturnal hypoventilation related to res-

piratory muscle weakness or apnea from upper airway obstruc-
Although the precise reasons why every organism with a brain tion secondary to palatal or bulbar involvement. This potentially
has an absolute need for sleep are hotly debated, there remains no extremely important but indirect consequence of neuromuscular
doubt about the importance of sustained good-â•‰quality sleep for disease on the sleep–â•‰wake cycle will not be addressed in detail here.
optimal cerebral function and mental health. Similarly, it is recog-
nized that virtually every pathological process involving the brain
has the potential to adversely affect the sleep–â•‰wake cycle, with A brief neuroanatomy of sleep
increasingly defined cognitive and neuropsychiatric consequences. It is increasingly clear that normal overnight sleep architecture is
Of note, accumulating evidence from a variety of sources also sug- highly orchestrated. Moreover, the state of sleep should be consid-
gests that a prolonged abnormal sleep–â•‰wake cycle may actually fuel ered an active process, contingent on neural activity in several key
irreversible cerebral pathology, particularly in an aging brain that areas, rather than resulting simply from cortical inactivity or the
is already at risk of neurodegenerative disease [1,2]. It is therefore absence of wakefulness [3]â•„. Traditionally, the wakeful or conscious
imperative that neurologists managing both common and rare state is considered to be mediated by an ascending arousal system
brain diseases should have a working knowledge of sleep neuro- comprising several pathways that course through the brainstem
biology and the main manifestations of identifiable sleep disorders and innervate the cortex in a widespread and relatively nonspe-
that associate with neurological disease. Although evidence-â•‰based cific distribution. There appears to be significant redundancy in
treatment pathways for sleep-â•‰related symptoms remain relatively the “wake system” such that specific lesions to one area or a sin-
poorly defined, improvement of the sleep–â•‰wake cycle in affected gle neurochemical system have little observable effects. The key
neurological subjects is likely to have immediate as well as potential neurochemical components of the ascending reticular system are
long-â•‰term benefits. noradrenergic and serotonergic, comprising a ventral branch, with
If the neurological importance of an abnormal sleep–â•‰wake cycle an additional important dorsal branch that is cholinergic [4]. This
is accepted, it is disappointing that exposure to the principles of latter pathway comprises thalamic projections from predominantly
sleep medicine remains limited in many neurology training pro- cholinergic areas in the dorsal pons such as the pedunculopontine
grams. This chapter attempts to address the definition of abnormal nucleus, thereby providing an indirect thalamocortical activating
sleep patterns in neurological disease given our current knowledge input to the cortical mantle. Other important cortical wake “sig-
of the underlying neurobiological processes. Although clinico-â•‰ nals” arise from the cholinergic nuclei in the basal forebrain and
pathological correlations are often speculative, particularly in mul- also from the histaminergic tuberomammillary nucleus (TMN) in
tisystem neurodegenerative diseases, it will be emphasized that the posterior hypothalamus. The precise role of dopamine in gen-
recognizing an abnormal sleep–â•‰wake cycle may have important erating conscious awareness remains obscure, especially as it has
implications for treatment strategies and even provide important been difficult to demonstrate clear diurnal variation in dopaminer-
diagnostic clues. Furthermore, any improvement in sleep-â•‰related gic neuronal activity across the sleep–â•‰wake cycle [5]. Furthermore,
symptoms may well have a positive impact on the underlying neu- cortical dopaminergic projections are limited to prefrontal areas
rological disorder itself, particularly in progressive disease. and have been presumed to play little overall role in generating
If studied systematically, the effects of normal aging on the sleep–â•‰ alertness. However, the observation that most stimulant drugs are
wake cycle are profound, although the underlying neuroanatomical highly dependent on a dopaminergic mechanism of action suggests
basis for the changes remains largely undefined. These age-â•‰related that dopamine does play a key role, perhaps via a thalamic pathway
effects will be covered before exploring how the main sleep-â•‰related as with the dorsal cholinergic arousal system [6].
symptoms of insomnia, hypersomnia, and the consequences of The assumption that a wakeful or conscious brain will always
abnormal clock mechanisms potentially relate to defined neurolog- show observable signs of reaction to external stimuli has been chal-
ical disease. A summary of the main sleep-â•‰related symptoms and lenged by recent functional imaging studies [7]â•„. In a proportion of
their relation to neurological disorders is given in Table 35.1. unfortunate patients exhibiting a persistent vegetative state, often
A variety of neuromuscular diseases have the potential to cause for many years, specific cerebral responses to verbal commands
significant adverse effects on breathing, specifically during sleep. and imagined scenarios have provided convincing evidence of

Table 35.1 Table listing the main sleep-related symptoms and their possible association with defined neurological conditions
Predominant sleep complaint Associated neurological condition Proposed pathological correlate or mechanism
Sleep-onset insomnia Subcortical cerebrovascular disease Anterior thalamic ischemic change
Prion disorders, particularly fatal familial insomnia Thalamic prion pathology at early stage of disease
Autoimmune or paraneoplastic encephalitides Autoantibodies (eg, against voltage-gated potassium channels)
disrupt thalamocortical generation of EEG sleep oscillations
Restless legs syndrome and neuropathic pain Peripheral neuropathies and central inflammatory disease
(eg, multiple sclerosis) increase chances of developing symptoms
Sleep-maintenance insomnia Most neurodegenerative conditions, particularly Increased cortical thinning, particularly medial prefrontal cortex;
Alzheimer disease hypothalamic pathology (particularly SCN)
Restless legs syndrome and neuropathic pain Peripheral neuropathies and central inflammatory disease
(eg, multiple sclerosis) increase chances of developing symptoms
Excessive daytime sleepiness Most neurodegenerative conditions, particularly Damage to ascending reticular activating systems; hypothalamic
parkinsonian syndromes pathology
Lesions in or around hypothalamus Tumors or cysts in third ventricle may damage posterior
hypothalamus; inflammatory lesions, particularly in
neuromyelitis optica
Traumatic brain injury Transient reduced activity in hypocretin system may contribute
Myotonic dystrophy Often a central nervous system component after breathing-
related problems have been excluded
Circadian dysrhythmia Most neurodegenerative conditions, particularly Blunted circadian rhythms due to direct damage to the SCN or
Huntington disease and Alzheimer disease its efferent pathways
Non-24-hour sleep phase syndrome (usually in blind) Retinohypothalamic tract absent or dysfunctional
comprehension and presumed conscious awareness. It is a worry- and how it can be influenced by internal or external factors. The
ing thought that there may be subjects who appear entirely “locked suprachiasmatic nucleus (SCN) within the hypothalamus has long
in” to outside observers but who retain some degree of cognitive been considered the “master clock” and is capable of controlling
awareness of their surroundings with the potential to respond or entraining the vast majority of processes within the body that
appropriately to verbal stimuli or questions. have a circadian rhythm [15]. Although there are hundreds of out-
The discovery in 1999 that full-blown narcolepsy with cataplexy put pathways from the SCN, one of the most important for regula-
is due to a specific deficiency of the neuropeptide hypocretin (also tion of the sleep–wake cycle is to the neighboring paraventricular
known as orexin) in the posterolateral hypothalamus has greatly fur- nucleus, which ultimately relays to the pineal gland to cause mel-
thered our knowledge of how the brain maintains the wakeful state atonin release via the intermediolateral cell column in the spinal
[8–10]. Activity in this small area of the brain numbering around cord [16]. This pathway involves the sympathetic autonomic nerv-
40 000 neurons is capable of stimulating all the major “alerting” ous system and may be blunted by beta-blockade, for example.
nuclei via its widespread efferent connectivity. Hypocretin appears Melatonin release normally occurs between 1 and 2 hours before
to stabilize or consolidate wakefulness, potentially inhibiting the sleep and is thought to facilitate the process of sleep onset. This and
natural homeostatic sleep drive that builds exponentially with the other important “rhythms” are potentially controlled by external
passing of time. The neural origin of sleepiness or the drive to sleep factors or “zeitgebers,” the most important of which is light expo-
remains largely speculative, although a key component is likely to sure, although daytime physical activity and food availability are
reflect extracellular levels of adenosine in certain important areas also increasingly recognized [17]. The retinohypothalamic tract
such as the basal forebrain [11]. As a breakdown product of general is a key input to the SCN, and melanopsin-containing photocells
neuronal activity during wakefulness, extracellular adenosine levels within the retina are key to the process of collecting information on
rise with time and potentially may trigger sleep onset. levels of daylight, ultimately helping to coordinate circadian timing
The perception of sleepiness increases exponentially after sig- with the day–night cycle [18].
nificant periods of wakefulness and is mostly contingent on the Defining sleep onset with precision is difficult, although increased
homeostatic sleep drive, termed “process S,” although circadian or activity of neurons containing gamma-aminobutyric acid (GABA)
“clock” factors, process C, have an important interactive influence and the neuropeptide galanin in the anterior hypothalamus plays a
[12,13]. The field of chronobiology has made enormous advances key role. The ventrolateral preoptic area (VLPO) can be considered
over the last two decades, particularly at a subcellular level, where a true “sleep center.” It interacts with the arousal system by a process
the mechanisms of the clock have been thoroughly dissected at of mutual inhibition, allowing sleep to become initially established
a molecular level [14]. It is clear there is very little fundamental and then stabilized [19]. The subsequent generation and particu-
difference between fruit flies and primates at the level of protein larly the so-called “ultradian” regulation of light and deep sleep,
expression and genetic control. Significant challenges remain in characterized primarily by EEG markers of sleep spindles and slow
defining how the clock effectively communicates with the organism waves in the delta frequency, are only partly understood. Parts of

Chapter 35 neurological diseases and their effects on the sleep–wake cycle 347
the thalamus, particular the surrounding reticular nuclei, play a key very well with parameters of reduced SWS quality [28]. Of further
role in the generation of thalamocortical oscillations that ultimately note, these changes also predicted mnemonic performance and
define the stages of non-rapid eye movement (NREM) sleep as provided some evidence that minimal cognitive changes in normal
defined neurophysiologically [3]‌. The tendency to enter the deep- aging might result from impaired ability to obtain deep SWS.
est stages of NREM (slow-wave) sleep dissipates through the night, The strength of circadian influences on sleep almost certainly also
although the neurobiological basis of the homeostatic mechanism diminish with age and the diurnal variation of melatonin levels, for
to regulate and monitor this sleep drive remains obscure [20]. example, are less robust. The neuroanatomical basis of this is not
Rapid eye movement (REM) sleep can be considered an enigmatic well established in normal aged subjects, but age-related atrophy
state of brain arousal that occurs in discrete phases that increase in of the hypothalamus, including the SCN, has been proposed [29].
length through the night, in the absence of conscious awareness.
Largely from animal studies, the concept of “REM-on” centers has Insomnia in neurological conditions
evolved that negatively interact with “REM-off ” centers in a similar
fashion to the sleep–wake switch described by Saper and colleagues Sleep onset insomnia
[21]. Although some form of “sleep mentation” can occur from any The inability to fall asleep when it is both appropriate and desired is
stage of sleep, arousals from REM sleep suggest that this state is clearly an extremely common complaint and most commonly asso-
most often associated with true dreams or nightmares that contain ciated with psychological states of increased, presumed cortical,
typically bizarre narrative themes, often involving previous frag- arousal. Rarely, however, discrete neurological pathology, particu-
ments of memory [22]. From a neurochemical perspective, REM larly in the anterior thalamus, may directly result in an inability to
sleep is associated with activity in the ascending cholinergic system achieve sleep and might be regarded as a cause of “organic insom-
from dorsal pons to thalamus in the complete absence of equivalent nia” [30]. This is not surprising, given the key role of the thalamus
activity in the brainstem noradrenergic and serotonergic systems in the generation of both sleep spindles and slow oscillations of
that are normally associated with wakefulness [3]‌. The neurobiol- deeper sleep. The condition most strongly associated with intrac-
ogy of REM sleep homeostasis or regulation is largely unknown. table sleep onset insomnia, however, is the extremely rare prion
However, suppression of REM sleep pharmacologically by tricyclic disorder, fatal familial insomnia (FFI), in which thalamic pathol-
agents or alcohol, for example, produces a rebound response of ear- ogy is an early and prominent feature [31]. The term “agrypnia” has
lier and more intense REM sleep on discontinuation [23]. been used to describe the persistent state of stuporose wakefulness
seen in this disorder [32]. It is likely that other more familiar prion
The effects of normal aging on disorders such as sporadic Creutzfeldt–Jacob disease (CJD) are also
associated with significant insomnia and sleep–wake disruption as
the sleep–wake cycle initial or even prodromal features [33].
Through the lifespan of a normal individual, there are profound and Thalamic infarction can certainly cause sleep–wake disturbance
measurable changes in the nature and quality of sleep, particularly as a prominent clinical feature, although pure insomnia is rare.
the deep NREM phase [24]. Indeed, a diminution of the amplitude Acute onset of severe insomnia with mania and unilateral dyski-
of slow (delta) waves in the early part of the night when sleep is at nesia has been reported following unilateral thalamic strokes [34].
its deepest can be observed even in young men, potentially reflect- Generalized encephalopathy in the context of significant head
ing one of the earliest biomarkers of aging. It is clear that the depth injury or certain inflammatory autoimmune disorders may also
of slow-wave sleep (SWS) continues to diminish with age as meas- produce sleep onset insomnia. Regarding the former, it is dif-
ured by the parameter of slow-wave activity (SWA). Normal aging ficult to be certain whether associated psychological factors are
is also associated with poorer sleep consolidation and an increasing more important than any specific neural damage. In a prospec-
number of spontaneous arousals through the night, not all of which tive study, only 5% of brain trauma subjects developed insomnia
are necessarily registered consciously. Typically, a 70-year-old will on objective testing [35]. It is possible that head-injured patients
sleep for only 85% of the nocturnal sleep period, whereas a younger may have a tendency to overestimate their sleep-related difficul-
subject would expect to achieve a figure of well over 90% [25]. ties. Autoimmunity, however, particularly when directed against
As a subject ages, there is also a tendency to awake earlier in the voltage-gated potassium channels, can cause severe insomnia as
morning in association with an earlier sleep onset time, reflecting a part of an encephalitic picture [36]. Agitation, hallucinations, sei-
shift of around 30 minutes for every decade of aging. Cultural fac- zures, as well as enhanced peripheral neuromuscular excitability
tors may well play a role but are not considered the key mechanism. (neuromyotonia) may accompany the lack of ability to sleep. The
It is not clear whether there are true changes in the circadian tim- term Morvan’s syndrome is often used, and it is tempting to specu-
ing of sleep with age or whether reduced homeostatic regulation is late that potassium channels in the thalamus are sensitive to the
largely responsible for this observation [26]. presence of antibody as a potential pathogenetic mechanism [37].
The neuroanatomical correlates of the observed age-related More rarely, encephalitis due to antibodies against the N-methyl-D-
changes in sleep patterns remain largely speculative. An obvious aspartate (NMDA) receptor may cause a very similar picture with
candidate is the normal and nonspecific process of cortical neu- profound insomnia [38].
ronal pruning that occurs with age, potentially interfering with It might be expected that anterior hypothalamic lesions would
the generation of thalamocortical oscillations that define SWS. cause severe insomnia if the VLPO is damaged. Indeed, it is inter-
Of interest, this has been proposed to occur even through cortical esting that von Economo in his original neuropathological obser-
maturation in adolescence [27]. A recent study provided interest- vations of encephalitis lethargica noted that a small proportion
ing evidence that the medial prefrontal cortex, an area particularly of patients exhibited severe insomnia if anterior hypothalamic
prone to age-related atrophy, exhibits neuronal loss that correlates changes predominated [39]. However, it is extremely rare for

modern imaging techniques to demonstrate specific hypothalamic progressive lack of SWS [28]. Similar profiles of profoundly altered
pathology in cases of suspected “organic” insomnia. sleep continuity and timing can also be seen in Huntington disease
Restless legs syndrome (RLS) is a relatively common treatable [HD], whereas the evidence for altered circadian control of sleep is
cause of significant sleep onset insomnia and has a variety of poten- even stronger [49].
tial treatment options [40]. RLS is considerably more prevalent in
a number of disorders such as peripheral neuropathy and central
inflammatory conditions, notably multiple sclerosis [41]. Unless Hypersomnia in neurological conditions
specifically questioned, this potentially treatable or secondary The term “hypersomnia” is often used loosely and simply inter-
cause of sleep onset insomnia may be missed or interpreted simply preted as a synonym for excessive daytime sleepiness (EDS). Strictly,
as a (neuropathic) pain symptom. it refers to the situation where the total sleep time over a 24-hour
period is at least 2 hours more than might normally be expected.
Sleep maintenance insomnia As such, some subjects with a longer sleep need than average who
Numerous factors associated with neurological disease may inter- are effectively sleep-restricted by a conventional sleep–wake sched-
fere with sleep continuity either directly or indirectly, producing ule might be considered to have hypersomnia. In this situation,
poor-quality or unrefreshing sleep with negative consequences on the diagnosis of idiopathic hypersomnia (IH) can be difficult to
daily functioning. In neurological patients, other than sleep disor- determine, although there is increasing evidence that there may be
dered breathing, typical “sleep toxins” include neuropathic pain, a neurochemical correlate in a proportion of IH subjects, and this
nocturia, and either excessive or reduced movements at night, usu- finding will improve diagnostic precision and allow more focused
ally in the context of an extrapyramidal movement disorder. Even treatments [50]. In most neurological conditions, troublesome
if full arousals from sleep are not observed, pain, such as that seen daytime sleepiness stems from impaired or insufficient nocturnal
in diabetic neuropathy or post-herpetic neuralgia, may alter sleep sleep rather than reflecting a primary increased sleep drive per se,
architecture by increasing the proportion of light NREM sleep although making this distinction can be very difficult and, clini-
compared with deep SWS [42]. Reduction of the latter almost cer- cally, be only of academic interest.
tainly produces sleep that is less restorative. Planned daytime napping is usually perceived as an accepted
Many neurodegenerative conditions appear to have direct and and common feature of normal aging. However, in the absence of
adverse effects on the sleep–wake cycle, often producing poor- a sleep disorder or a “siesta culture,” napping probably relates more
quality sleep that, at face value, may appear to mimic those of to general physical inactivity or even boredom, given the increasing
an accelerated aging process [43]. Parkinsonian syndromes, par- evidence that objective or measurable daytime sleepiness actually
ticularly when advanced, are associated with sleep that is gener- declines with normal aging [51]. However, excessive or unplanned
ally “destructured,” with poor sleep maintenance and an abnormal napping should not be regarded as normal at any age, particularly
sleep architecture across the night [44]. These changes are seen in the context of neurodegenerative disease. The causes of EDS in
early, potentially predating clinical motor disease and can be very significant dementia, typically AD, are nearly always multifacto-
significant in advanced cases, almost certainly fuelling daytime rial, reflecting sleep–wake dysregulation akin to accelerated aging
somnolence and fluctuating cognitive performance. Although with behavioral and pharmacological factors playing a significant
there are well-characterized changes in REM sleep associated with role. Impaired “clock mechanisms” with respect to both timing and
Parkinson disease (PD) and other synucleinopathies such as multi- amplitude of the circadian rhythm are almost certainly contribu-
ple system atrophy, particularly the lack of REM sleep atonia, these tory, partly explaining the reversed sleep–wake cycle and poten-
do not necessarily impair subjective sleep quality. Correlating any tially the phenomenon of “sundowning” present in many advanced
sleep disturbance in PD with pathology in specific brain regions subjects [52]. Pathological changes in the SCN are well documented
remains speculative, although REM sleep behavior disorder (RBD) in AD, although correlating this with the clinical picture of a dis-
is most likely due to Lewy bodies in key brainstem nuclei involved turbed sleep–wake cycle is difficult given the widespread nature of
in producing muscle atonia during REM sleep [45]. These include any cerebral pathology.
areas caudal to the locus coeruleus (equivalent to the sublaterodor- The sleep–wake disturbance in Lewy body disease, whether
sal nucleus in the rat) and the pedunculopontine nucleus, brain- Lewy body dementia or advanced PD, is particularly compli-
stem locations known to be vulnerable to Lewy body pathology. cated. Pathology in the hypothalamus and brainstem nuclei key to
From primate PD models, it is likely that dopaminergic depletion sleep regulation such as the pedunculopontine nucleus and sub-
also directly impairs the sleep–wake cycle, although dissecting the coerulean area almost certainly contribute to symptoms of EDS
secondary motor consequences on sleep maintenance from any directly and indirectly [53]. Despite the absence of cataplexy, the
primary effects on sleep regulation remains difficult. Particularly resemblance to classical narcolepsy can be striking given the nature
in advanced cases, it also seems likely that hypothalamic pathology and degree of EDS together with specific disruption of processes
plays an increasing role such that the clinical picture from a sleep underlying REM sleep regulation [54]. In accordance with this,
perspective may mimic narcolepsy in the degree of sleep–wake dis- there is some evidence that partial hypocretin deficiency may be an
ruption and poor control of state switching [46]. important factor in generating EDS [55].
Given the widespread nature of pathology in advanced cases The concept of “secondary narcolepsy” is increasingly invoked,
of dementia such as Alzheimer disease (AD), it is very difficult to particularly when structural or inflammatory pathology involving
determine specific neural substrates to account for the virtually the (posterior) hypothalamus is proposed to produce significant
universal sleep–wake disruption. However, hypothalamic pathol- EDS [56]. A variety of pathologies have been reported, including
ogy is likely to explain some of the major problems with sleep cysts or tumors in the region of the floor of the third ventricle adja-
timing [47,48], whereas general cortical pruning may explain the cent to the hypothalamus (Fig. 35.1). The clinical similarity of such

(a) response exclusively in the hypothalamus with destruction of hypo-

cretin neurons [58].
True hypersomnia without specific narcoleptic features such as
abnormal REM sleep is a recognized consequence of subcortical
cerebrovascular disease, particularly in the context of bilateral para-
median thalamic strokes [59]. This may occur with occlusion of the
artery of Percheron, an anatomical variant whereby a single trunk
from the posterior cerebral artery supplies the mesial aspect of both
thalami and the rostral midbrain. The most striking clinical mani-
festation is profound hypersomnolence and reduced alertness, often
with vertical gaze palsy and variable cognitive deficit. Sleep record-
ings usually demonstrate an abnormal excess of stage 1 sleep with
reduced spindle density [60]. Hypersomnia usually improves after
a few months despite persistent abnormalities of sleep spindle gen-
eration. Recovery is presumed to reflect the integrity and possible
adaptation of underlying reticular ascending arousal systems [61].
The effects of traumatic brain injury (TBI) on the sleep–wake
(b)
cycle have been difficult to elucidate, given the heterogeneous
nature of any pathology and the lack of prospective studies address-
ing sleep in detail. However, the most common significant sleep-
related sequela appears to be hypersomnia with increased sleep
need over 24 hours seen in over 20% of a nonselected group stud-
ied prospectively [62]. Correlations with trauma severity or site of
pathological damage have not been established, although transient
reduction in CSF hypocretin levels and reduced melatonin rhythms
have been proposed as relevant observations in some subjects.
A variety of neuromuscular diseases have the potential to cause
significant EDS, which may masquerade clinically as fatigue or
lethargy. Most commonly, respiratory or palatal muscle weakness
in the context of a progressive myopathic or neuromuscular dis-
order may fuel sleep disordered breathing as the primary cause
of EDS [63]. Indeed, nocturnal hypoventilation with or without
obstructive apnea is almost certainly under-diagnosed in progres-
sive conditions such as motor neuron disease. However, other fac-
tors, including presumed central nervous system pathology, almost
certainly contribute to pathological EDS in certain neuromuscular
disorders, notably myotonic dystrophy (MD, types 1 and 2) [64].
MD1, in particular, is associated with increased fatigue and som-
Fig. 35.1 Magnetic resonance imaging brain scans, sagittal (a) and axial (b) views, nolence beyond the potential effects of sleep disordered breathing,
of a 20-year-old man who developed severe sleepiness resembling a form of
including central sleep apnea. In a proportion of subjects, hypo-
narcolepsy after removal of a low-grade tumor (glioma) in the region of the third
ventricle. The arrows show abnormal signal indicating postoperative scar tissue
cretin deficiency has been documented as a possible underlying
(gliosis) predominantly in the posterior hypothalamus. mechanism, although this does not appear to be a consistent find-
ing [65]. In MD2, levels of EDS are generally less striking, but a
number of sleep-related phenomena such as significant RLS have
been identified [66].
cases to idiopathic narcolepsy is variable, although some have all
the hallmarks of narcolepsy including cataplexy and other REM Abnormal circadian rhythms
sleep-related phenomena. For example, inflammatory plaques as a
consequence of multiple sclerosis or, more commonly, neuromyeli- in neurological disease
tis optica (NMO), in which there is a predilection for involvement Despite increasing knowledge of the underlying neuroanatomy of
of the hypothalamus, may produce narcoleptic symptomology, central clock mechanisms, identifying or attributing problems of
occasionally with cataplexy and objective hypocretin deficiency circadian timing to a specific neurological disease or process is dif-
in the cerebrospinal fluid (CSF) [55,56]. Other rarer presumed ficult. Indeed, with very few exceptions, the underlying pathological
autoimmune or paraneoplastic conditions with specific antibody processes that might alter a subject’s clock to cause a so-called “circa-
markers may also produce recognizable symptom complexes with dian dysrhythmia” remain obscure. At the subcellular level, genetic
striking levels of EDS as a main feature. The presence of anti-MA2 factors, including point mutations and polymorphisms of key clock-
antibodies most commonly associated with testicular carcinoma is related genes, are increasingly implicated in abnormal sleep timing
a well characterized example [57]. Recent post-mortem evidence in defined sleep disorders, notably, delayed sleep phase syndrome
suggests that this antibody may induce a cytotoxic lymphocytic and the far less common condition, advanced sleep phase syndrome

[67]. In neurological disease, however, problems of circadian timing It is not clear whether other causes of autonomic dysfunction,
usually stem from a blunted or absent daily rhythm (irregular sleep either in the context of primary disorders such as multiple system
phase syndrome) or a clock that is not entrained to a 24-hour cycle atrophy or peripheral neuropathies caused by diabetes, for exam-
(non-24-hour sleep phase syndrome) [68,69]. The latter occurs with ple, also have blunted melatonin cycles. The few studies that have
subjects blind from an early age, typically causing a “free-running” assessed dysautonomia have focused primarily on the potential
rhythm usually of around 24.4 hours such that the propensity to adverse effects on nocturnal breathing, including significant central
sleep rarely coincides with a conventional sleep–wake cycle. This sleep apnea [82,83]. However, it is likely that subjects with primary
lack of light entrainment reflects disruption of the retinohypotha- autonomic failure also have poor sleep efficiency in general and
lamic tract and may also contribute to sleep-related problems in a also blunted cardiac responses to any arousals from sleep [84]. The
variety of conditions associated with acquired severe visual impair- underlying mechanisms causing sleep disruption in such patients
ment [70]. A totally irregular or chaotic sleep–wake cycle with no remain largely speculative.
discernible rhythm is most often encountered in severe dementia
syndromes. Hypothalamic pathology specifically in the region of the Abnormal sleep in epilepsy
SCN is presumed to be the main underlying pathophysiological pro-
A disturbed sleep–wake cycle has particular clinical relevance for
cess [71]. Some patients with frontotemporal dementia (FTD) also
epileptic patients, given the widely accepted adverse effects of inade-
exhibit striking abnormalities of the sleep–wake cycle early in the
quate sleep in promoting seizure activity in predisposed individuals,
disease course characterized by sleep fragmentation and possible
particularly in generalized epileptic syndromes [85]. It is well estab-
advanced sleep phase syndrome despite normal core body tempera-
lished that certain seizure types are prone to occur at certain times
ture rhythms [72]. This contrasts to the pattern in many subjects
of the day or night. For example, temporal lobe seizures peak in the
with AD, who, if anything, show phase delay [72].
mid-afternoon both in humans and in rat models [86]. This prob-
Less striking disruption of circadian rhythms may play an
ably reflects a true circadian effect, given the opposite rest–activity
important role in the sleep–wake problems associated with sev-
cycles in rodents compared with humans. Frontal lobe seizures are
eral other neurodegenerative conditions. For example, parkinso-
commoner from a state of sleep, particularly the light NREM stage,
nian subjects appear to have blunted melatonin rhythms compared
and myoclonic epilepsies are most noticeable at the sleep–wake
with controls, with particularly severe changes in those patients
transition. Some evidence also suggests that focal epilepsies such as
reporting significant EDS [73,74]. Furthermore, even in newly
temporal lobe epilepsy may blunt endogenous circadian rhythms,
diagnosed PD patients, reduced circulating melatonin levels and
causing reduced melatonin peaks [87] as well as affecting the pulsa-
altered clock gene expression have been documented [75]. Given
tile secretion of sex hormones under circadian control [88].
the widespread pathology from retina to cortex in PD, the neu-
Active epilepsy clearly has the potential for disturbing sleep–
roanatomical basis of any circadian abnormalities remains specu-
wake patterns in a nonspecific manner. Indeed, several studies have
lative. In HD and associated animal models, abnormal circadian
commented on the increased incidence of sleep-related symptoms,
rhythms may also contribute significantly to sleep-related prob-
particularly daytime somnolence, in epileptic populations, with up
lems and potentially the cognitive aspects of the disease [76].
to twice the level of symptoms [89]. Often, it is assumed that antie-
As with other neurodegenerative conditions, there is no clear or
pileptic medication is the main culprit, although some evidence
specific “signature” associated with the sleep disorder in HD, and
suggests that epilepsy itself may disturb sleep quality even during
any problems are typically not readily recognized by the subjects
nights that appear seizure-free [90]. Certainly, when nocturnal
themselves. However, the rest–activity cycles are disrupted in
seizures are recorded early in the night, the subsequent adverse
early disease, and biomarkers of clock function are reliably dis-
effects on sleep quality through the night are profound, particu-
rupted in mouse animal models [77]. Of interest, in the mouse
larly regarding REM sleep [91]. Aside from daytime sleepiness, it is
HD model, pharmacological treatment of the abnormal sleep–
likely that resistant epilepsy might also worsen cognitive functions
wake cycle appeared both to improve performance in cognitive
sensitive to chronic sleep disruption, particularly memory.
testing and to reverse dysregulation of circadian gene expression
Coexisting sleep disorders such as sleep apnea may often be over-
[78]. The anatomical basis of clock dysfunction in the HD model
looked in sleepy epileptic subjects, and a low threshold for screening
is suggested to arise from a dysfunctional output from the central
is appropriate. The associated weight gain with many antiepileptic
clock, potentially within local circuits, since the subcellular circa-
agents might well increase the likelihood of sleep-related breathing
dian oscillator appears intact [79]. This dysfunctional output from
disorders.
the central clock has interesting peripheral effects, particularly on
liver metabolism even though self-sustaining oscillators in liver
cells remain intact [80]. Conclusions
Spinal injuries may not be readily associated with altered cir- Evidence is emerging from a variety of sources that a disturbed
cadian rhythms, but tetraplegic patients have been shown to have sleep–wake cycle is not only extremely prevalent but also a sig-
absent melatonin cycles [81]. This reflects disrupted output from nificant cause of reduced life quality in a significant proportion of
the intermediolateral cell column in the upper spinal cord to those suffering from neurological disease. Furthermore, epidemio-
the superior cervical ganglion, which provides the sympathetic logical studies, data from animal models of dementia, and analysis
postganglionic output to the pineal gland. This, together with of subcellular mechanisms for handling stress such as the unfolded
reduced levels of daily physical activity that would be expected in protein response all indicate that chronically impaired sleep may
such subjects, potentially contributes significantly to a disturbed actively contribute or fuel any underlying disease process, particu-
sleep–wake cycle. larly in neurodegenerative conditions.

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Neurology. 2000;55(11):1746–8.

CHAPTER 36
Clinical and neurophysiological

aspects of fatigue
Sushanth Bhat and Sudhansu Chokroverty
Introduction cognitive components. However, from a practical point of view,

a patient complaining of fatigue may be experiencing a variety
It has long been appreciated that fatigue is a common occurrence in of other symptoms, such as muscle weakness, inability to sustain
patients with various medical, neurological and primary sleep dis- voluntary activity (muscle fatigability), exercise intolerance, EDS,
orders. The French physician Duchesne [1]â•„first described fatigue inability to concentrate and perceived cognitive deficits, apathy,
in medical disorders in 1857, and Klenner [2] gave an account of and a loss of motivation. These other symptoms may coexist with
fatigue in multiple sclerosis (MS) and myasthenia gravis in 1949. the overwhelming lack of energy, making a precise description of
Patients with a variety of medical and neurological disorders also the situation difficult for the patient. Nevertheless, each of these
have secondary disturbances of sleep, resulting in both fatigue and symptoms has different clinical implications, and a careful his-
excessive daytime sleepiness (EDS). In many cases, fatigue may tory and physical examination are therefore paramount. In many
be attributed to EDS, but it is important for the practitioner to be cases, fatigue is attributable to a previously diagnosed neurologi-
aware of fatigue and EDS as distinct and independent symptoms, cal, medical or sleep disorder. In a significant number of cases,
with different etiologies and treatment approaches. however, no apparent cause of the patient’s fatigue can be found,
The Multiple Sclerosis Council in 1998 established clinical guide- and the complaints may be labeled psychosomatic, at great dis-
lines and defined fatigue as a “subjective lack of physical and/â•‰or service to the patient. Fatigue management is not made easier by
mental energy that is perceived by the individual or the caregiver to the fact that the underlying pathophysiology remains conjectural,
interfere with usual and desired activities” [3]â•„. Fatigue is often per- and optimal treatment protocols have hardly been optimized.
ceived as a pervasive sense of tiredness impacting quality of life. EDS, Chronic fatigue is an extremely common and undertreated prob-
on the other hand, refers to an inability to stay awake, with the patient lem. Published data suggest that it is present in 21–â•‰38% of primary
often involuntarily closing their eyes, lapsing into episodes of micros- care patients, with up to 18% complaining of fatigue lasting greater
leep with inattention, yawning, and succumbing to irresistible attacks than 6 months [8,9]. Despite the significant impact of chronic
of sleepiness. This “pressure to sleep” is not a feature of pure fatigue fatigue on quality of life, studies have shown that more than half of
[4], but the distinction is often fine and patients may not be able to patients often do not report it to their physicians, and only a small
distinguish between them unless very pointed questions are asked
and a thorough history elicited. Useful tools in this regard include
questionnaires that assess daytime sleepiness, notably the Epworth
Sleepiness Scale, where high scores are seen in patients with EDS Box 36.1â•‡ Fatigue severity scale
but not in those with pure fatigue. A number of self-â•‰reported fatigue
scales with proven validity and reliability are used in clinical prac- Patients choose a number from 1 to 7 that shows their degree
tice, including the Fatigue Severity Scale (Box 36.1) [5], the Checklist of agreement with every statement, where 1 indicates strongly
Individual Strength, and the Abbreviated Fatigue Questionnaire disagree and 7 indicates strongly agree.
(AFQ) [6,7]. However, they are heavily weighted toward measur- ◆ My motivation is lower when I am fatigued
ing cognitive fatigue, which, as discussed below, may not be the only
◆ Exercise brings on my fatigue
source of disability in these patients. Nevertheless, these self-â•‰reported
patient tools may help distinguish fatigue from EDS. ◆ I am easily fatigued
This chapter focuses on the neurophysiological basis of fatigue, ◆ Fatigue interferes with my physical functioning
and the causes and management of fatigue in a variety of neuro-
◆ Fatigue causes frequent problems for me
logical conditions, primary sleep disorders and general medical
disorders. ◆ My fatigue prevents sustained physical functioning
◆ Fatigue interferes with carrying out certain duties and
Defining fatigue responsibilities
The classic meaning of fatigue is, as described above, a feeling of ◆ Fatigue is among my three most disabling symptoms
generalized tiredness and trouble initiating and sustaining motor ◆ Fatigue interferes with my work, family, or social life
tasks despite intact motor strength, and has both physical and

minority receive specific treatment for this disabling symptom [10]. stimulation (TMS) studies of the motor cortex support the concept
These figures emphasize the need for a high level of vigilance for of central fatigue; patients with CNS lesions have been shown to
fatigue-related issues in the clinical setting. have prolonged recovery of TMS-induced motor evoked potential
amplitudes, which reflect conduction in the CNS, whereas meas-
Pathophysiological mechanisms for fatigue urements of conduction in the peripheral nervous system (PNS)
were no different from controls [14]. Other reports have suggested
Attempts have been made to develop neurophysiological models
that central fatigue might be related at least in part to a reduced
for fatigue. In this context, it is useful to classify fatigue as being of
safety factor of cortical synaptic transmission in the CNS [15].
either a central or peripheral etiology [11]. Peripheral fatigue is due
Recent magnetoencephalographic data suggest that prolonged
to a failure of the motor unit (the anterior horn cell, the motor axon,
mental fatigue-inducing tasks cause overactivation of the visual
the neuromuscular junction, or the muscle fiber itself). A common
cortex, manifest as decreased alpha power in this brain region
model for measuring peripheral fatigue involves recording and
[16]. However, in most CNS disorders, both central and peripheral
comparing the force generated by electrical stimulation of muscle
fatigue play a role in the patient’s symptomatology; these patients
before and after exercise. Typically, after a pre-exercise electrical
may therefore experience physical fatigue that may not be explain-
stimulation, the subject performs a maximum voluntary contrac-
able by clinically demonstrable neurological deficits. Thus, fatigue
tion (MVC) for a pre-determined period of time, generally 30 or 60
as a symptom appears to defy localization to a particular site or
s, which is measured with a force transducer. A subsequent post-
structure; it involves diffuse as well as multifocal dysfunction across
exercise electrical stimulation is then performed and the force gen-
large neuroanatomical pathways and endocrinological feedback
erated is compared with the pre-exercise tracing. Lower amplitudes
systems, with immunological abnormalities playing a role in cer-
of the waveform and slow relaxation phases are characteristic of
tain disease processes [17].
peripheral fatigue (Fig. 36.1) [12,13].
Certain sites of dysfunction at the central level have been impli-
On the other hand, central fatigue is generated in the cen-
cated in fatigue [18]. While voluntary physical activity originates
tral nervous system (CNS), namely, the brain, spinal cord, and
in the motor cortex, feedback control from a number of areas
descending central motor pathways. This is assessed by measuring
(including cognitive input) must be present to convert intention
central activation failure (CAF), which suggests suboptimal CNS
into action. Such input may be pathologically altered in psychiatric
output to the motor unit. CAF can be measured by analyzing the
disorders or with certain centrally active medications, contribut-
force generated during MVC and providing superimposed electri-
ing to the overall perception of fatigue. The prefrontal cortex, as
cal stimulation. The resulting twitch interpolation is then analyzed;
well as multiple subcortical areas, including the hypothalamus, the
the absence of a significant twitch amplitude suggests full voluntary
brainstem, and the cerebellum, all influence motor output; unsur-
contraction and no central fatigue, whereas a large superimposed
prisingly, diseases affecting them may result in fatigue in addition
twitch suggests significant CAF (Fig. 36.1). Transcranial magnetic
to obvious neurological deficits on clinical examination. Neuronal
systems subserving arousal and attention (i.e, the ascending reticu-
lar activating system and the limbic system) are particular areas of
Force Maximum voluntary contraction (MVC) focus inasmuch as their dysfunction would naturally be expected to
limit motivation and cognitive drive to work.
Neuroimaging studies in central fatigue, while still largely
research tools, have produced interesting results. No single ana-
A
tomical substrate has been identified, but cortical atrophy of the
parietal lobe on magnetic resonance imaging (MRI) in patients
B
C D with MS was found to have the strongest correlation with fatigue
[19]. Another study found that complaints in the physical and
cognitive domains of fatigue in patients with MS correlated with
MRI findings in different parts of the brain [20], suggesting that
lesions in different parts of the brain may be responsible for physi-
cal and cognitive central fatigue, even in the same disease. White
Time matter lesion burden and atrophy of the corpus callosum on MRI
have been correlated with cognitive impairment and fatigue in MS
Fig. 36.1 Peripheral fatigue can be studied by measuring the maximum voluntary [21,22]. Functional MRI studies in MS patients with fatigue have
contraction (MVC) of muscle as recorded by a force transducer. Note the normal
shown greater activation of the motor–attentional network when
linear decrease in force generated attributable to peripheral fatigue. Superimposed
tetanic stimulation (denoted by the arrows) is used to detect the presence of performing a simple motor task [23], as well as greater activation
central fatigue. Absence of significant twitch amplitude (A) suggests the absence of the contralateral cingulate motor area [24], and more diffuse
of central activation failure (CAF), whereas a large twitch amplitude (B) suggests cervical cord recruitment [25] compared with controls or with
the presence of CAF. A pre-MVC tetanic contraction (C) and post-MVC tetanic MS patients without fatigue. Positron emission tomography (PET)
contraction (D) are compared. The lower amplitude and slower relaxation phase scans, which measure cerebral perfusion, have shown widespread
of the post-MVC contraction is suggestive of the development of peripheral cerebral hypometabolism [26], as well as selective hypometabolism
fatigue.
in the bifrontal and basal gangliar regions [27] in fatigued patients
Reproduced from Sleep Med Clin., 8(2), Bhat and Chokroverty, Fatigue in neurological
disorders, pp. 191–212, Copyright (2013), with permission from Elsevier; Adapted from Clinical
with MS. A recent study found no brain atrophy on MRI in patients
neurophysiology, 119(1), Zwarts et al., Clinical neurophysiology of fatigue, pp. 2–10, Copyright with post-polio syndrome (PPS) and fatigue, whereas atrophy was
(2008), with permission from Elsevier. present in MS patients [28].

Chapter 36 clinical and neurophysiological aspects of fatigue 357
Cognition and fatigue are distinct symptoms [34]. Rather, fatigue in OSA appears to be
closely related to co-occurrence of depressive symptoms [35].
While physical fatigue is at least partly explainable by the con- Nevertheless, treatment of OSA with continuous positive airway
cepts of central and peripheral fatigue as discussed above, less well pressure (CPAP) improves both fatigue and EDS [36].
understood is cognitive fatigue, defined as a failure to endure sus- Fatigue is also commonly seen in narcolepsy, a sleep disorder
tained mental tasks in patients with fatigue. There is also a deficit of characterized by EDS, fragmented nocturnal sleep, and intrusion
self-motivation, and overall debilitation not attributable to motor of rapid eye movement (REM) sleep phenomena (such as cataplexy,
weakness, dyscoordination, or sensory loss. In addition, patients hypnagogic and hypnopompic hallucinations, and sleep paraly-
with central fatigue perceive greater expenditure of effort in com- sis) into non-REM (NREM) and waking states. The prevalence of
pleting a task, even in the absence of deficits that would limit them fatigue may be as high as 63% in patients with narcolepsy, although
from performing the task, and even if the task is completed success- the degree of EDS does not correlate with the degree of fatigue,
fully. This cognitive component of central fatigue can be assessed again suggesting that these are two independent symptoms [37].
by cognitive and motor-task processing parameters [29]. The fac- Modafinil has been shown to improve both symptoms [38].
tors leading to the development of cognitive fatigue remain poorly Restless legs syndrome (RLS, recently renamed Willis–Ekbom
elucidated. Recent data suggest that in patients with depression disease, WED) is characterized by uncomfortable sensations in
and insomnia, unhelpful beliefs about sleep and symptom-focused the legs accompanied by an urge to move them, usually occurring
rumination were predictive of both physical and mental fatigue around bedtime and often hampering sleep onset, but improving
[30], suggesting that at least part of the cognitive aspects of fatigue with movement. It is associated with depression, sleep disruption,
may be a manifestation of the patient’s responses and attitudes and insomnia, and, unsurprisingly, frequently results in fatigue.
toward their underlying illnesses. A recent study suggested that this is particularly true in patients
with comorbid diabetes mellitus [39]. Similarly, periodic limb
Fatigue as a comorbid symptom movements of sleep (PLMS), present in over 80% of RLS patients,
Chronic fatigue occurs in a wide variety of medical conditions. have been found to correlate with sleep disruption and fatigue [40].
These include anemia, autoimmune disorders such as systemic Circadian rhythm disorders are a common cause of sleep disrup-
lupus erythematosus (SLE) and sarcoidosis, chronic infectious tion and fatigue. In particular, many shift workers (patients who
diseases such as HIV and Lyme disease, cardiopulmonary disor- work nontraditional hours such as late evening, early morning, or
ders such as chronic obstructive pulmonary disease (COPD) and full nights) complain of EDS and fatigue, independent of mood dis-
congestive heart failure (CHF), rheumatological disorders such orders [41]. Frequency of night shifts correlates positively with the
as fibromyalgia, and cancers. In addition, it may be a side effect degree of fatigue. The underlying pathophysiology remains specu-
of a wide variety of medications, most commonly beta-blockers, lative, but may be related to lower morning serum cortisol levels in
anxiolytics (eg, benzodiazepines and barbiturates), antiepileptics shift workers [42].
(valproic acid, carbamazepine, and levetiracetam), antipsychotics, Insomnia, either as a primary disorder or as a symptom of
dopaminergics, proton pump inhibitors, chemotherapeutic agents, another sleep disorder or medical condition, is commonly associ-
and beta-interferons, to name the most commonly prescribed ated with fatigue. PET scans have demonstrated that, compared
classes [17]. Fatigue is also a frequent complaint in psychiatric with controls, patients with insomnia have increased global cer-
disorders such as major depression, and there is a high correlation ebral metabolism during sleep and wakefulness, a smaller decline
between complaints of fatigue and psychological morbidity, sug- in relative metabolism from waking to sleep states in wake-
gesting a large overlap [31]. Fatigue occurs in a multitude of neu- promoting regions, and reduced relative metabolism in the pre-
rological disorders, both central (eg, MS, Parkinson disease (PD), frontal cortex while awake [43]. In addition, studies of spectral
and post stroke) and peripheral (neuromuscular junction diseases, electroencephalogram (EEG) patterns in patients with primary
Guillain–Barré syndrome (GBS), PPS, and myopathies). As a symp- insomnia suggest that stress patterns impact neurophysiologi-
tom, it occurs with virtually all known primary sleep disorders and cal systems [44]. The role of mood and anxiety on insomnia and
is a major source of disability, impacting the ability of the patient to therefore fatigue in these patients is quite convincing. Cognitive–
lead a productive life. behavioral therapy (CBT) appears to not only improve sleep but
also reduce comorbid psychological and fatigue-related symp-
Fatigue in primary sleep disorders toms [45]. In any patient with insomnia, of course, a careful eval-
uation for an underlying comorbid sleep disorder such as OSA or
Most patients with sleep disorders complain of fatigue. It is impor- PLMS is warranted.
tant to differentiate this from EDS. Among patients with sleep
disorders, younger age, female sex, and a high number of awak-
enings and arousals have been shown to be predictive of fatigue Fatigue in neurological disorders
[32]. Obstructive sleep apnea (OSA), a disorder in which there
is sleep fragmentation due to recurrent episodes of upper airway Fatigue in CNS disorders
narrowing and collapse, results in EDS. In addition, fatigue occurs Fatigue in multiple sclerosis
in up to 42% of patients with OSA [33]. However, no correlation Over 80% of patients with MS complain of fatigue, including cog-
between the degrees of reported fatigue and the severity of OSA, nitive fatigue, as one of their most disabling symptoms [4]‌. The
or even between fatigue severity scores and objective measures seminal work on fatigue in MS was published by Krupp et al. [46].
of EDS (such as multiple sleep latency testing, MSLT) have been However, the etiology of fatigue in MS remains unclear and is
established, suggesting that in these patients, sleepiness and fatigue likely multifactorial, with no single area of the brain identifiable

as a source of the problem. Hypothalmopituitary axis hyperactiv- salient feature during the recovery period [73]. Risk factors for the
ity, elevated adrenocorticotropic hormone levels, and higher levels development of post-stroke fatigue appear to be younger age, post-
of circulating proinflammatory cytokines have been implicated stroke depressive symptoms, and infratentorial infarctions [74]. No
[47,48]. Neurophysiologically, fatigue in MS has been associated neuroimaging findings predict post-stroke fatigue [75], and it does
with more anteriorly widespread event-related desynchronization not appear to correlate with degree of neurological deficit, although
during a movement (indicating hyperactivity during movement there appears to be a relationship between fatigue and pain [76].
execution), and lower post-movement contralateral event-related Unfortunately, at this time, there are no clear guidelines or rec-
synchronization (indicating failure of the inhibitory mechanisms ommendations for treating post-stroke fatigue. Antidepressants,
intervening after movement termination) compared with normal though commonly prescribed to post-stroke patients, have not
subjects and MS patients without fatigue. This is consistent with been conclusively proven to be helpful [77], and the role of CBT
a central origin of fatigue in MS [49]. While MS is a major cause and medications like modafinil or amantadine remain uncertain in
of chronic fatigue, paradoxically, its treatment may be responsible this setting.
for fatigue as well. Interferon therapy is generally acknowledged
as a major contributor to MS-related fatigue [50]. Glatiramer Fatigue in traumatic brain injury
acetate is effective in treating MS-related fatigue [51]. In addition, Patients with traumatic brain injury (TBI) often suffer from a vari-
sleep dysfunction is a major predictor of fatigue in MS patients ety of long-term consequences, including sleep complaints such
[52]. Insomnia is a common complaint, and is strongly associated as insomnia and daytime sleepiness, cognitive impairment, mood
with fatigue in MS [53]. MS patients with severe fatigue are more disorders, and fatigue [78]. Notably, the degree of initial injury
likely than controls or those with mild fatigue to have a circadian does not seem to predict the severity of post-TBI impairment [79].
rhythm disorder [54]. OSA is frequent in MS, seen in up to 40% Fatigue, in particular, is present in nearly half of all patients post
of patients [55,56], and is associated with fatigue but not EDS, TBI, and does not appear to significantly improve with time [80].
independent of MS-related disability and other covariates [57]. It seems to be independent of depression or EDS [81]. The natural
Several studies have consistently shown that moderate to severe history of fatigue in TBI remains unclear, but CBT, lifestyle modifi-
RLS is more frequent in MS than in the general population, and cation, pharmacological treatments with modafinil and melatonin,
this has a significant impact on sleep quality [4]. Another factor and light therapy have been suggested as possible interventional
that may contribute to daytime fatigue is the carryover effect of the strategies [82].
hypnotic agents, particularly over-the-counter diphenhydramine-
containing products, that are frequently used by MS patients [58]. Fatigue in PNS disorders
Treating comorbid sleep disorders in MS patients has been shown Fatigue in post-polio syndrome
to improve fatigue [59]. Management of fatigue in MS has proven The prevalence of significant fatigue has been reported to be as
to be quite challenging. Modafinil [60] and amantadine [61], are high as 77% among patients with PPS, while polio survivors with-
most commonly prescribed, but have performed unevenly in out PPS have fatigue rates comparable to those of healthy controls
large trials. On the other hand, nonpharmacological measures [83]. A recent study showed that younger PPS patients who had
for managing fatigue are more consistently beneficial in patients shorter polio duration, more pain, and higher body mass index
with MS-related fatigue, with exercise programs and CBT showing were more fatigued and had a lower quality of life [84]. Fatigue
heartening results and compliance rates, as well as improvement of seems to worsen as the day progresses in PPS [85]. Both central
quality of life [62,63]. and peripheral causes seem to be at play; while neurophysiologi-
Fatigue in Parkinson disease cal studies have shown that fatigue in these patients originates at
the neuromuscular junction [86], neuropsychological evaluation
In patients with PD, sleep disturbances and fatigue have been
of patients with PPS has shown defects of attention and informa-
shown to be the most disabling non-motor symptoms, affecting
tion processing, while cognitive abilities and verbal memory were
up to two-thirds of PD patients [64,65]. Functional neuroimaging
unaffected [87]. White matter hyperintensities in the reticular for-
has suggested that reduced serotonergic function in the basal gan-
mation, putamen, medial lemniscus, and white matter tracts were
glia and limbic structures, insular dopaminergic dysfunction [66],
found in more than half of PPS patients with high levels of fatigue
and frontal lobe dysfunction may be responsible for fatigue [67].
and correlated with fatigue severity and subjective problems in
Although sleep disorders are common in PD (including insomnia,
attention, concentration, and recent memory [88]. Sleep is com-
circadian rhythm abnormalities, RLS/PLMS, nocturnal bradykine-
monly adversely affected, and sleep fragmentation due to PLMS
sia and discomfort, complicated sleep apnea, and REM sleep behav-
is frequent [89]. Hypersomnolence due to sleep-related breath-
ior disorder) and worsen with disease progression [68], fatigue in
ing dysfunction is frequently seen, and these patients may have
PD seems to be independent of excessive daytime sleepiness [69].
OSA, hypoventilation, or a combination of both [90]. Medically
The fatigue may respond to levodopa therapy [70], but the roles of
supervised and graded exercise seems to be beneficial in strength
CBT or exercise programs remain to be elucidated.
preservation in PPS, although the improvement in fatigue scores,
Post-stroke fatigue if any, remains to be clarified [91]. From a pharmacological per-
Fatigue plagues nearly half the patients who suffer strokes, and is spective, amantadine, modafinil, and intravenous immunoglobu-
consistently associated with a poor outcome. Indeed, it was recently lin (IVIg) have all been studied, but no consistent benefit has
shown that fatigue in the acute phase is an independent predic- been found [17]; a very small trial suggested that bromocriptine,
tor of poor physical health 18 months after stroke [71] Functional another dopamine agonist used in the treatment of PD, might be
recovery seems to be worsened by concomitant depression [72]. efficacious in alleviating all aspects of PPS fatigue, including cog-
Fatigue impacts post-stroke patients in several dimensions and is a nitive fatigue [92].

Fatigue in neuromuscular junction disorders (DM-1), a multisystem disorder characterized by muscle weak-
Neuromuscular junction disorders are characterized by failure ness and myotonia, cataracts, cardiac conduction defects, frontal
of transmission across the neuromuscular junction and may be balding, and endocrine abnormalities, and caused by an autosomal
presynaptic (eg, Lambert–Eaton myasthenic syndrome) or post- dominantly inherited triple nucleotide expansion mutation of the
synaptic (eg, myasthenia gravis). Models of peripheral fatigue in CTG sequence of the DMPK gene on the long arm of chromosome
these disorders have been well studied and well understood, and 19, deserves special mention because of the frequency of sleep dys-
are easily demonstrated in the electrophysiology laboratory using function in these patients; sleep disordered breathing, numerous
repetitive nerve stimulation studies. More difficult to explain are microarousals, and periodic limb movements are all very common,
the reports of patients with myasthenia gravis experiencing signifi- as are both fatigue and EDS (76% and 52% respectively in one study)
cantly more cognitive fatigue in addition to physical fatigue than [105]. DM1 patients have short sleep latencies on MSLT as well as
control subjects, and their perceptions of this fatigue increasing sleep onset REM periods (SOREMPs), suggesting a narcoleptic
significantly following completion of demanding cognitive work phenotype. Periodic paralyses (hypokalemic and hyperkalemic
[93]. It has been suggested that fatigue in neuromuscular junction periodic paralysis, myotonia congenita, paramyotonia congenita
disorders may be related to autonomic dysfunction [94]. As in most and Andersen–Tawil syndrome are examples of periodic paraly-
other neurological conditions, there appear to be poorly under- ses) are channelopathies that present with paroxysmal attacks of
stood central fatigue mechanisms at play. An interesting recent periodic generalized weakness as well as muscle fatigability brought
study suggests that in patients with myasthenia gravis and fatigue, on by exposure to cold, carbohydrate-rich meals, exercise, or rest,
supplementation of low vitamin D levels may be of benefit [95]. depending on the exact disorder. Except for the first mentioned,
these patients also have myotonia on electromyography (EMG) and
Fatigue in amyotrophic lateral sclerosis can be diagnosed by genetic testing. Muscle weakness in these dis-
The prevalence of fatigue in amyotrophic lateral sclerosis (ALS) has orders may last from a few minutes to a few hours per attack, with
been reported to be as high as 83% in some studies, more frequent a normal neurological exam, including normal strength testing, in
in younger patients, and tending to worsen as the disease progresses between the attacks. The symptoms are often treated with aceta-
[96]. Again, both central and peripheral fatigue seem to contribute zolamide, although the exact mechanism of action of this agent in
to the overall decreased quality of life. Patients with ALS show evi- these conditions is unknown [17].
dence of CAF on MVC studies, as well as less intramuscular phos-
phocreatine depletion and less fatigue of stimulated tetanic force Fatigue in general medical conditions
during exercise compared with controls, suggesting that central
fatigue plays a major role in this condition [97]. Maladaptation of Fatigue in major cardiopulmonary diseases
cortical processes related to degeneration of inhibitory GABAergic Fatigue is a common complaint in patients with a wide variety of
intracortical circuits is a feature of ALS that significantly corre- chronic cardiopulmonary disorders. Fatigue is highly prevalent in
lates with development of fatigue and weakness [98]. Peripheral sarcoidosis and interstitial lung disease. It also frequently occurs in
fatigue has been demonstrated in muscles that show no evidence patients with COPD, a chronic, inflammatory disorder of the air-
of denervation-related injury, suggesting that motor weakness and ways and lung parenchyma characterized by obstructive pulmonary
fatigue in ALS are distinct entities. As in most other neurological dynamics, hypoxemia, and hypercapnia. The prevalence of daily
conditions causing fatigue, sleep disruption plays a major role [99]. fatigue in COPD has been reported to be as high as 68–80% [106],
and nearly half of COPD patients describe it as their most disabling
Fatigue in other neuromuscular diseases symptom, affecting cognitive, physical, and psychosocial well-being
The vast majority of patients with acquired immune-mediated [107]. High fatigue scores negatively impact quality of life in COPD
neuropathies (history of GBS, stable chronic inflammatory demy- [108]. A recent study demonstrated positive correlation between
elinating polyradiculoneuropathy, or monoclonal gammopathies) fatigue severity and disease severity in COPD; patients with the
complain of persistent, disabling fatigue years after recovery or most intense fatigue had the higher risk of hospitalization [109].
stabilization of their neurological deficits [100]. Central sources of The etiology of fatigue in COPD is incompletely understood, but
fatigue seem to be responsible, as neurophysiological studies show is most likely multifactorial. Exercise intolerance is a hallmark fea-
no evidence of residual peripheral nerve dysfunction; similarly, the ture of COPD that contributes to the pervasive feeling of fatigue
severity of fatigue does not depend on time between evaluation and has been shown to be related to pulmonary function and lung
and recovery from GBS [101]. Medically supervised home exercise hyperinflation [110]. Interesting preliminary data suggest that
programs may be beneficial in these patients [102]. Modafinil has increased dependence on glycolysis for muscle energy production
shown some benefit in alleviating fatigue in patients with heredi- in COPD may be an explanation for the exercise intolerance [111].
tary motor and sensory neuropathy type 1 (HMSN-1, also known Patients with COPD often have comorbid sleep disorders that are
as Charcot–Marie–Tooth disease 1, CMT-1), the most common major overall contributors to fatigue. Although OSA has not been
inherited neuropathy [103]. “Fatigue” in metabolic myopathies is demonstrated to occur with greater prevalence in COPD patients,
characterized by cramping, painful contractions, and myalgias after the combination of COPD and OSA, known as the “overlap syn-
exercise, while being asymptomatic at rest. This “exercise intoler- drome,” is a common cause of severe nocturnal hypoxemia, sleep
ance” may occur in the absence of motor weakness or clinical disruption, and subsequent EDS and fatigue [112] More severe
exam abnormalities. Genetic testing is often required for diagno- COPD is also associated with complaints of insomnia and non-
sis. Fatigue has also been described in a large number of patients restorative sleep [113]. In a small study, Cavalcante et al. recently
with a variety of inherited myopathies like facioscapulohumeral found that RLS was present in almost 31% of patients with COPD,
dystrophy and myotonic dystrophy [104]. Myotonic dystrophy type 1 and these patients complained of sleep fragmentation and high

levels of fatigue [114]. Concurrent mood disorders were also pre- Cancer-related fatigue
dictive of fatigue in COPD [115].
Treatment of fatigue in COPD is challenging and is closely linked Fatigue is near universal in patients with cancer, and markedly more
to improvement of pulmonary status and comorbid sleep dysfunc- severe than in controls. It occurs in patients undergoing chemo-
tion. Multidimensional programs that include pharmacotherapy to therapy, radiation therapy, bone marrow transplantation, and treat-
improve lung function and pulmonary rehabilitation have shown ment with biological response modifiers. There is some evidence
promising results [116]. Patients with COPD and insomnia may that it worsens with age, possibly owing to lower hemoglobin levels
benefit from CBT [117]. [132]. Many factors contribute to cancer-related fatigue. Nutritional
In addition to orthopnea, peripheral edema, nocturnal cough status and comorbid mood disorders play a major role. It is often
and exertional dyspnea, fatigue is a significantly distressing symp- difficult to determine how much of this fatigue is due to the under-
tom in patients with CHF. Prevalence rates are quite high, approxi- lying cancer itself and how much to chemotherapy; early data sug-
mating 70–90% in various studies [118]. A recent small study gest this may depend on the location of the underlying malignancy,
suggested that fatigue was indicative of a poorer prognosis in CHF but both factors are likely contributory in most patients [133]. In
[119]. Although there is some evidence that the severity of fatigue patients with cancer, poor sleep quality correlated positively with
may correlate with pulmonary arterial pressures [120], a consist- fatigue and depression and negatively with quality-of-life indica-
ent relationship between fatigue and degree of cardiac dysfunction tors [134]; it has been postulated that altered cytokine profiles and
has not been demonstrated [121]. Nevertheless, there are multiple circadian rhythm abnormalities may play a role [135]. Treatment of
proposed causes of fatigue in CHF, including impaired peripheral cancer-related fatigue is best individualized, with proper treatment
perfusion during exercise, reduced oxidative capacity of skeletal of any comorbid medical or sleep-related conditions forming the
muscle, impaired muscle strength, and possibly reflex mechanisms cornerstone. Anemia is a major underlying cause of fatigue in can-
associated with alterations in the metabolism of skeletal muscle. cer patients, and several studies have shown that fatigue responds
However, researchers have failed to demonstrate consistent reduc- to improvements in hemoglobin levels in anemic patients with a
tion in fatigue even with optimization of cardiac output, oxygen variety of malignancies, both on and off chemotherapy [136].
delivery, and blood flow, leading to the hypothesis that a structural Several studies have shown that erythropoietin-stimulating agents
abnormality of muscle itself may be the ultimate culprit [122]. improve subjective fatigue, although the exact magnitude of benefit
As with COPD, comorbid sleep complaints contribute to fatigue is unclear and needs to be weighed against the risks of thrombosis
in CHF, with sleep disordered breathing, nocturia, and insomnia [137]. Daily exercise appears to have a significant effect on cancer-
being the most common [123]. Fatigue and depression appear to related fatigue [138]. Early trials of pharmacotherapy with antide-
occur independently in CHF [124]. In addition, pharmacotherapy pressants, wakefulness-promoting agents, and psychostimulants in
of CHF, especially with beta-blockers, has been linked to fatigue cancer-related fatigue have shown encouraging results, but their
and has often necessitated its discontinuation [125]. Unfortunately, routine use has yet to be elucidated [139]. Recent data also suggest
optimal management of fatigue in CHF is unclear, and much a role for CBT in cancer patients in improving both sleep quality
research obviously needs to be done in this regard. Individualized and perception of fatigue [140].
exercise training programs for all patients with stable CHF have
been advocated by some groups [126] Fatigue and psychiatric disorders
Fatigue is a prominent symptom in many primary psychiatric dis-
Fatigue in other medical conditions
orders, and fatigue or fatigue-like symptoms are described as part
Patients with chronic renal failure often experience debilitating of a large number of diagnoses in the Diagnostic and Statistical
fatigue. This is likely multifactorial, due to anemia, cachexia, and Manual of Mental Disorders, Fourth Edition (DSM-IV) including
abnormal calcium and phosphate metabolism. Fatigue is particu- attention deficit hyperactivity disorder, major depressive disorder,
larly debilitating in patients on dialysis; almost half of patients bipolar disorder, generalized anxiety disorder, substance intoxica-
with end-stage renal disease (ESRD) on hemodialysis complain of tion and withdrawal, and post-traumatic stress disorder [31]. In
major fatigue, which appears to affect both physical and cognitive addition, the frequent co-occurrence of psychiatric disorders and
function and is often associated with depression [127]. In addition, sleep dysfunction, both of which can cause insomnia, daytime
patients on dialysis often have poor sleep quality [128], and fre- somnolence, and fatigue, makes the exact prevalence of fatigue
quently have OSA and RLS/PLMS that fragment their sleep, leading in psychiatric disorders difficult to estimate. Many patients with
to both insomnia and EDS. Optimal treatment of fatigue in ESRD chronic fatigue syndrome (CFS) meet the criteria for a mood disor-
patients on hemodialysis is unclear, but may include strengthening der [141], and even in patients with chronic fatigue not diagnosed
of social support structures [129], exercise programs, erythropoi- with CFS, there is a high likelihood of a concurrent psychiatric dis-
etin supplementation, and L-carnitine supplementation [130]. order [142]. However, fatigue can exist without a comorbid psy-
Fatigue is also very commonly seen in chronic anemia, and often chiatric disorder [143]. The treatment of fatigue as an individual
responds to judicious use of erythropoietin-stimulating agents symptom in patients with depression and other psychiatric dis-
and blood transfusions as necessary. In several autoimmune con- orders has been poorly studied; it is often resistant to treatment
ditions such as SLE and Sjögren syndrome, fatigue is a promi- with antidepressants. Graded exercise therapy, CBT, dopaminer-
nent syndrome that is resistant to treatment and may be caused gic therapy, psychostimulants, and wakefulness-promoting agents
by underlying inflammatory states and coexistent fibromyalgia such as modafinil have all been advocated in the literature, but data
[131]. Endocrinological disorders such as hypothyroidism and are sparse and their routine use remains to be validated with large
hypothalamopituitary axis dysfunction are other causes of chronic trials [144].
fatigue [10].

Chronic fatigue syndrome were concurrently studied showed a severe hypometabolism of the
medial and upper frontal regions bilaterally, whereas the metabo-
CFS is a complex and still somewhat poorly defined entity, with lism of the brainstem was normal [149]. Nevertheless, the signifi-
estimates of prevalence varying greatly, from 0.002% to 11.3% in cance of these findings, and their clinical relevance, is unclear at
primary care practices [145]. It appears to occur more often in this time.
women, minority groups, and lower socioeconomic and educa- CFS is comorbid with a variety of other conditions that can also
tional classes, with a significant comorbidity with psychiatric dis- cause fatigue. In a recent study, nearly half of patients with CFS
orders [17]. Attempts to develop standard diagnostic criteria for had a coexistent primary sleep disorder (mainly OSA, as well as
CFS have proven challenging; the US Centers for Disease Control psychophysiologic insomnia and PLMS), and 45% had a psychiat-
(CDC) diagnostic criteria (Box 36.2) are among the most widely ric disorder (mostly mood and anxiety disorder) [150]. Sleep com-
accepted, but are highly dependent upon patient self-reporting of plaints, in particular, are extremely common in patients with CFS,
symptoms. most of whom complain of poor-quality, unrefreshing sleep, EDS,
Its alternate nomenclature, “myalgic encephalitis” may mistak- and insomnia. Polysomnography studies have not shown consist-
enly imply that its pathophysiology is clearly defined, but in truth ent sleep-architectural abnormalities in CFS [151], but a number of
the etiology of CFS remains elusive. The concept of a post-viral small studies have described a variety of nonspecific changes, sug-
cause remains popular, although no particular organism has been gesting that much more work needs to be done in this area. Notably,
consistently identified. Many patients complain of relatively acute it has been demonstrated that treatment of any comorbid primary
onset of fatiguing symptomatology after a flu-like illness, but nei- sleep disorder in patients with CFS does not improve fatigue. Thus,
ther antibody nor immune dysfunction studies have been conclu- the symptoms of CFS do not seem to be due purely to underlying
sive [146]. Numerous neurophysiological studies have failed to sleep disorders in these patients; the diagnosis of a primary sleep dis-
establish a peripheral cause of fatigue in CFS [147]. While studies order should therefore not be an exclusion criterion for CFS [152].
have shown that there is a delay in information processing speed EDS and fatigue exist as distinct symptoms in this disorder as well.
in patients with CFS [148], levels of cognitive fatigue are com- The optimal treatment of CFS is unclear. High-dose glucocorti-
parable to those in patients with major depression, and twice as coids [153] and IVIg therapy have not been found to be beneficial
many patients with CFS as those with neuromuscular diseases meet [154]. More recently, valganciclovir showed promising results in
criteria for a psychiatric illness [141]. Similarly, MRI and single- a subset of CFS patients with elevated IgG antibody titers against
photon emission computerized tomography (SPECT) studies human herpesvirus-6 (HHV-6) and Epstein–Barr virus [155].
have not identified structural or functional markers for CFS [17]. Another study suggested that hyperbaric oxygen may have a role to
However, in one study of PET scans in patients with CFS, there was play [156]. Intriguing as these results are, they await validation with
significant hypometabolism in the right mediofrontal cortex and larger studies. However, several studies have consistently shown
brainstem compared with controls; patients with depression who the superiority of nonpharmacological interventions in CFS. While
CBT is clearly beneficial, patient outcome seems to be dependent
on the degree of patients’ attribution of symptoms to exclusively
Box 36.2 Centers for Disease Control (CDC) criteria for the physical causes [157]. Low-impact, graded aerobic exercise therapy
diagnosis of chronic fatigue syndrome (CFS) was also found to be a beneficial strategy [158].
In order to be diagnosed with chronic fatigue syndrome, a patient
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CHAPTER 37
Role of positive pressure therapy

on sleep disordered breathing
and cognition in the elderly
Molly E. Zimmerman and Mark S. Aloia
Sleep disordered breathing in older adults using the apnea–â•‰hypopnea index (AHI: the number of apneas and
hypopneas per hour of sleep) and the respiratory disturbance index
Prevalence rates of sleep disordered breathing (SDB) in the elderly (RDI: the number of apneas and hypopneas associated with arous-
have been reported to reach as high as 62%, considerably greater als from sleep). An effective treatment for OSA is nightly use of a
than those of middle-â•‰and younger-â•‰aged adults [1,2]. Several positive airway pressure (PAP) device, such as a continuous posi-
theories have been proposed for these staggering rates, including tive airway pressure (CPAP) machine. PAP functions as a pneu-
age-â•‰related changes in the upper airway musculature and age-â•‰ matic splint for the upper airway through use of an external air
related changes in sleep architecture [3]â•„. SDB is a general term pump and a nasal mask. Although studies have shown that proper
that describes the presence of abnormal respiratory events in sleep. use of PAP significantly reduces behavioral and biological sequelae
Sleep apnea syndrome is diagnosed when apneas (complete breath- associated with OSA (eg, excessive daytime sleepiness, impaired
ing pauses) and hypopneas (partial breathing pauses) are present driving performance, depressed mood, and hypertension), long-â•‰
during sleep in conjunction with other symptoms (eg, excessive term adherence is often poor owing to mask discomfort, claustro-
daytime sleepiness). Breathing events must last at least 10 s to be phobia, and general aversions to nightly use of the machine in bed
characterized as a breathing abnormality. These breathing events [14–â•‰17]. Several studies have shown dose–â•‰response relationships
may occur up to several hundred times per night and frequently between exposure to PAP and various behavioral outcomes, with
result in variable arterial oxygen desaturations (hypoxemia) and “optimal” levels of adherence varying as a function of outcome
involuntary arousals that lead to sleep fragmentation. SDB is [17,18]. Efforts to improve PAP adherence include device design
related to cognitive dysfunction as well as changes in brain struc- enhancements (eg, heated humidification of the mask and pres-
ture and function [4–â•‰6]. SDB is also associated with a wide range sure ramp settings) and behavioral interventions (eg, motivational
of cardiovascular and cerebrovascular conditions (eg, hypertension interviewing and cognitive–â•‰behavioral therapy) [19–â•‰22].
and stroke), depression, anxiety, obesity, metabolic syndrome, and
motor vehicle accidents [7–â•‰10]. There are three primary types of
sleep apnea events: obstructive sleep apnea (OSA), central sleep SDB and cognition in older adults
apnea, and mixed sleep apnea. OSA is typically diagnosed when The identification of both age and SDB as risk factors for cognitive
breathing events number at least 5 (apneas or hypopneas) per hour decline in the elderly has led researchers to focus on relationships
of sleep. If the patient has fewer than 15 events per hour of sleep, between SDB and cognition among older adults (for a review, see
then associated daytime symptoms or cardiovascular comorbidities [23]). Table 37.1 summarizes characteristics of these studies and
are required to make the diagnosis. The International Classification their major findings. Study samples are largely drawn from three
of Sleep Disorders (ICSD) diagnostic criteria currently do not populations: community-â•‰dwellers, sleep or general medical clinics,
have age-â•‰specific definitions for OSA, although different age-â•‰ and memory disorders clinics or nursing homes. Herein, we sum-
based thresholds have been proposed, given the prominent preva- marize extant findings and highlight key studies.
lence differences between younger and older adults [11,12]. CSA
is characterized by the presence of apneas and hypopneas associ- Community-â•‰based studies
ated with a patent upper airway and reduced respiratory muscle Community-â•‰based studies of SDB provide observations that are
effort. Individuals sleeping at high altitudes, with stroke, or with applicable to the general population, particularly older adults
Cheyne–â•‰Stokes respiration commonly experience central sleep who may experience abnormal respiratory events during sleep
apnea events [13]. Mixed sleep apnea refers to a combination of but have never been formally diagnosed with a clinical sleep dis-
obstructive and central features, such as the presence of upper air- order. Some community-â•‰based studies have been largely negative,
way collapse at the end of a central apnea event. Obstructive, cen- reporting no significant relationships between SDB and cognition
tral, and mixed respiratory events cause both sleep fragmentation [24–â•‰27]. Others have reported relationships between abnormal
and intermittent drops in arterial oxygenation that are quantified nocturnal respiratory events and poorer performance on tests of

Table 37.1 Sleep disordered breathing and cognition in elderly adults
Authors, year Sample setting, Subjects Major findings

reference design
N Age Gender SDB severity
Yamout et al., Memory clinic, 108 (65 MCI, 74 (9) 49 M DI = 7 (11) ◆ ↑DI associated with attention and
2012 [43] cross-sectional 43 dementia) 59 W executive function
◆ Strength of association influenced by
cardiovascular disease
Yaffe et al., Community, 105 SDB 83 (3) SDB Women AHI N = 298: ◆ SDB: ↑hypoxemia had ↑risk of
2011 [35] longitudinal 193 NC 82 (3) NC median=10; developing MCI or dementia over
interquartile range = 5 years of follow-up
5–20 ◆ Sleep fragmentation and duration not
associated with cognition
Kim et al., Clinic, cross- 30 MCI 68 (4) MCI 42 M AHI: 13 (12) MCI; ◆ ↑AHI associated with ↓language in MCI
2011 [39] sectional 30 NC 67 (4) NC 18 W 15 (14) NC
Blackwell et al., Community, 2909 76 (6) Men 43% had AHI ≥ 15 ◆ ↑hypoxemia associated with ↓vigilance
2011 [28] cross-sectional
Sforza et al., Community, 827 68 (2) 343 M AHI: 20 (15); 53% had ◆ No relationships
2010 [27] cross-sectional 484 W AHI ≥ 15
Cooke et al., Clinical trial 10 (5 CPAP+, 76 (6) 7 M N/A ◆ CPAP+ showed less cognitive decline
2009 [59] follow-up 5 CPAP−) with 3M with sustained use (mean 13.3 months)
dementia following completion of previous clinical
trial [60]
Ancoli-Israel Clinical trial 52 (27 CPAP, 79 (7) CPAP; 39 M Baseline AHI: 30 (16) ◆ 3 weeks of therapeutic CPAP in both
et al., 2008 [60] 25 placebo) 78 (8) placebo 13 W CPAP; 27 (16) placebo groups associated with ↑ executive
with dementia function and memory
Spira et al., Community, 448 83 (3) Women AHI: 16 (15); 13% had ◆ ↑AHI and ↑hypoxemia& ↑ central apnea
2008 [32] cross-sectional AHI ≥ 30 associated with ↓global cognition
◆ APOE4+ associated with 5× risk of
cognitive impairment
Alchanatis et al., Sleep clinic, 58 OSAS Range = 32–65 N/A AHI: range 31–137 ◆ OSAS patients ≥ 50 years had ↓reaction
2008 [36] cross-sectional 41 NC OSAS; Range = OSAS; range 1–7 NC time compared with age-matched
33–63 NC controls and younger OSAS and
controls
Mathieu et al., Sleep clinic, 28 OSAS 38 (2) OSAS 26 M AHI: 51 (4) OSAS ◆ No group-by-age interaction for
2008 [40] cross-sectional 30 NC younger; 62 2W younger; 43 (4) OSAS cognitive performance
(2) OSAS older older ◆ Main effects for both group and age
O’Hara et al., Community, 36 70(6) APOE4+ 12 M AHI: 9 (8) APOE4+; ◆ ↑AHI associated with ↓verbal delayed
2005 [33] cross-sectional 72 (10) APOE4− 24 W 6 (7) APOE4− recall memory in APOE4+ only
◆ Hypoxemia not associated with
cognition
Kim et al., Community, 611 Range = 35–74 346 M AHI: median = 2.8; ◆ SDB associated with ↓vigilance in older
2007 [31] cross-sectional 265 W range = 0–121 adults
Aloia et al., Clinic, cross- 12 65 (6) OSAS N/A RDI: 51 (20) OSAS ◆ ↑RDI associated with verbal delayed
2003 [37] sectional compliant; 65 (3) compliant; 46 (22) recall memory
noncompliant OSAS noncompliant ◆ ↑hypoxemia associated with verbal
delayed recall memory and construction
Foley et al., Community, 718 Range = 79–97 Men 71% had AHI ≥ 5; ◆ No relationships
2003 [25] cross-sectional 19% had AHI ≥ 30
Boland et al., Community, 1700 62; range = 837 M RDI median ◆ No relationships
2002 [24] cross-sectional 52–75 923 W range: 0.4–23
Cohen-Zion Community, 46 80 (3) 7 M RDI: 10 (9) ◆ ↑ EDS associated with ↓ global cognitive
et al., 2001 [34] longitudinal 39 W decline over 3 years of follow-up
◆ Hypoxemia and RDI not associated with
cognition
(continued)

Chapter 37 role of positive pressure therapy on sleep disordered breathing and cognition 369
Table 37.1 Continued
Authors, year Sample setting, Subjects Major findings

reference design
N Age Gender SDB severity
Dealberto et al., Community, 1389 65 (3) 574 M Questionnaire: ◆ Breathing stoppage and snoring
1996 [29] cross-sectional 815 W breathing stoppage associated with ↓ attention
and snoring
Hayward et al., Community, 96 78 (4) 21 M RDI: 6 (6) ◆ RDI associated with “cerebral efficiency”
1992 [30] cross-sectional 75 W factor (attention and executive function
measures) at baseline assessment
Phillips et al., Community, 92 64 (9) 44 M AHI:3 (4) ◆ No relationships
1992 [26] cross-sectional 48 W
Ancoli-Israel Nursing home, 235 Median age 83 M 70% had RDI ≥ 5 ◆ Severe SDB associated with ↓ attention,
et al., 1991 [42] cross-sectional 80 M, 84 W 152 W executive function, and memory
Berry et al., Sleep clinic, 8 OSAS 67 (5) OSAS Men AHI: 28 (12) OSAS; 3 ◆ OSAS: ↓ nonverbal IQ and nonverbal
1990 [38] cross-sectional 12 HC 68 (2) HC (3) NC memory delayed recall
Yesavage et al., Sleep clinic, 41 70 (6) Men RDI: 26 (30); 73% had ◆ RDI associated with ↓ attention and
1985 [41] cross-sectional RDI > 5 executive function
Age and symptom severity presented as mean (standard deviation) unless otherwise specified; M: men; W: women; DI: desaturation index (number of drops of oxygen saturation ≥4% per
hour recording; AHI: apnea–hypopnea index; RDI: respiratory disturbance index; EDS: excessive daytime sleepiness; MCI : mild cognitive impairment; NC: normal control; OSAS: obstructive
sleep apnea syndrome; CPAP: continuous positive airway pressure; APOE4: apolipoprotein E ε4 allele; IQ: intelligence quotient.
vigilance, attention, and executive function [28–31]. The possi- on tests of attention and executive function. In the first study to
ble contributing role of the apolipoprotein E ε4 (APOE4) allele, include a healthy control comparison group, Berry and colleagues
a genetic risk factor for late-onset Alzheimer disease, was high- [38] reported that SDB was associated with overall cognitive abili-
lighted in two studies that found associations between SDB and ties and memory in eight older men with OSA compared with 12
general cognitive impairment [32] or impaired memory [33] that healthy controls. Finally, the first study to examine cognition as a
were unique to older adults who were APOE4+. Two notable lon- function of PAP adherence in older adults [37] found that RDI was
gitudinal community-based studies distinguished between the associated with memory performance, while hypoxemia measures
negative impacts of excessive daytime sleepiness (EDS), sleep frag- were associated with memory and construction abilities. Other
mentation, and/or hypoxemia on cognitive function in the elderly. clinic-based studies have conducted direct comparisons between
Cohen-Zion and colleagues [34] found that EDS, but not hypox- older and younger adults with OSA in order to specifically address
emia or RDI, was associated with decline on a global cognition the possible compounding effect of age on cognition and SDB rela-
measure over a 3-year period. However, Yaffe and colleagues [35] tionships. While one study [40] reported that younger adults with
found that it was hypoxemia associated with SDB, and not sleep OSA may be more vulnerable to the effects of hypoxemia on cogni-
fragmentation, that was the strongest contributor to the devel- tion because they are unable to adapt to the intermittent oxygen
opment of dementia or cognitive impairment in older women. desaturations, another study [36] reported an opposing finding that
In addition to providing some etiological specificity, these stud- it is actually older adults with OSA who are more vulnerable to the
ies are noteworthy because they provide valuable information on effects of hypoxemia on cognition owing to the availability of fewer
the directionality of the relationship between SDB and cognitive neural resources to support compensatory efforts.
function, suggesting that SDB may lead to cognitive decline in
community-dwelling older adults. Memory disorders clinic or nursing home studies
Studies of SDB that draw their samples from memory disorders
Sleep or general medical clinic studies clinics or nursing homes are important because they are able to
Sleep clinic-based studies have the advantage of being able to exam- focus on individuals whose primary presentation is clinically sig-
ine detailed measures of SDB using overnight polysomnography nificant cognitive impairment. This provides a comparison for
(PSG) in study participants with the most severe respiratory events. samples drawn from sleep clinics and indirect cross-sectional
Many of these studies show significant relationships between SDB evidence for possible bidirectionality of the relationship between
and cognitive performance, with the most consistent findings being SDB and cognition in older adults. That is, while it is commonly
in the memory domain, although reaction time, attention, executive proposed that SDB may cause brain dysfunction that may be clini-
function, visuospatial construction, and language have also been cally expressed as cognitive impairment, it is also possible that
reported [36–41]. Three notable studies will be highlighted here. brain dysfunction associated with dementia may lead to the devel-
In 1985, Yesavage and colleagues [41] conducted the first clinic- opment of abnormal breathing events. Such causal attributions,
based study of SDB and cognition in 41 older men. They found however, can only be determined through longitudinal study
that more severe SDB was associated with poorer performance designs. A seminal investigation by Ancoli-Israel and colleagues

[42] conducted cognitive assessment and portable sleep studies in APPLES study demonstrated intact cognitive performance on spe-
235 nursing home patients. They found that 70% demonstrated an cific cognitive tests and overall high general intellectual function-
RDI ≥ 5 and 96% displayed cognitive impairments consistent with ing at baseline (for example, the average IQ score was nearly one
a diagnosis of dementia. Older adults with more severe SDB had standard deviation above the standard population mean); there-
poorer scores on subscales measuring attention, executive func- fore it is inherently clinically and statistically unlikely that such
tion, and memory. These findings support the notion that SDB individuals would demonstrate a cognitive gain in response to any
and dementia are strongly associated, but do not provide evidence type of intervention. It may also be that these high-functioning
of directionality or outcomes associated with treatment. A more individuals have some genetic protective factor against apnea. This
recent study by Yamout and colleagues [43] used ambulatory noc- is an important but subtle issue that should be a critical consid-
turnal pulse oximetry screening to report that more severe levels eration for any future investigation that seeks to study cognitive
of hypoxemia were associated with poorer performance on tests performance.
of attention and executive function among 108 older adults with
dementia and mild cognitive impairment (MCI: a term used to
describe individuals at high risk for developing dementia). These
Role of PAP with regard to cognitive
findings persisted after accounting for age, sex, education, and function in older adults with SDB
depressive symptoms. In addition, they were most prominent Randomized clinical trials focused on older adults are necessary
among individuals with a history of cardiovascular disease, con- to fully explicate the complex relationship among aging, SDB, and
sistent with other literature that suggests that vascular disease has cognitive function. An important series of randomized, double-
a critical moderating or mediating effect on these relationships in blind, placebo-controlled clinical trials from Ancoli-Israel and
the elderly. colleagues examined the effect of PAP on a range of neurobehav-
ioral outcomes in older adults with SDB and dementia. Although
Role of PAP with regard to cognitive the generally small sample size varied slightly across studies (i.e,
39–52), the overall design included community-dwelling older
function in middle-aged adults with SDB adults with mild–moderate Alzheimer disease and SDB who were
PAP is the treatment of choice for OSA because it effectively randomly assigned to either (1) 6 weeks of therapeutic PAP or (2) 3
reduces the sleep fragmentation and hypoxemia that define the weeks of sham PAP followed by 3 weeks of therapeutic PAP. Initial
disorder. Given that longitudinal community-based studies [34,35] studies demonstrated that dementia patients were able to toler-
have shown that subclinical SDB is a strong predictor of the devel- ate PAP treatment [57], reported a reduction in excessive daytime
opment of cognitive impairment and dementia, much research has sleepiness in response to PAP treatment [58], and demonstrated
focused on PAP with the hope that it may mitigate or even reverse improvements in sleep architecture associated with PAP use [59].
the deleterious effects of SDB on cognition. Findings from many When cognitive function was examined as an outcome [60], the
of these studies, largely carried out in middle-aged adults, have results indicated that cognitive performance improved after 3 weeks
been positive. Reviewed in detail most recently by Ferini-Strambi of therapeutic PAP, particularly in the domains of memory and
and colleagues [44], studies vary by design (eg, case–control or executive function. This finding was particularly exciting, as it sug-
within-subjects), inclusion/exclusion criteria, adherence to PAP, gested that cognitive dysfunction could be reversed in those older
and length of PAP treatment. Nonetheless, reports provide sup- adults who stand to benefit the most from interventions, namely,
port for improvements in vigilance, attention, psychomotor speed, those with dementia. Finally, a preliminary study from the same
executive function, and memory following PAP treatment [18,45– research group [59] examined sustained PAP use among a subset
51]. However, it is important to note that some studies found of study participants from the parent randomized clinical trial who
only modest cognitive gains of uncertain clinical significance in continued to use PAP by their own choice following the comple-
a small number of cognitive domains relative to the total number tion of the study. Although the sample sizes were small (five who
surveyed (eg, [46,51]). The Apnea Positive Pressure Long-Term continued PAP versus five who discontinued PAP), after an average
Efficacy Study (APPLES) [52–54] was the first large-scale rand- 13-month follow-up period, those dementia patients who contin-
omized, double-blind, sham-controlled, multicenter trial to exam- ued to use PAP demonstrated less cognitive decline, an improve-
ine whether PAP improved cognitive function in middle-aged ment in sleep quality, and stabilization of depressive symptoms and
adults within a 6-month follow-up period. Baseline data [54] were daytime sleepiness compared with dementia patients who discon-
essentially negative and did not survive adjustment for demo- tinued PAP. This was an important contribution to the literature, as
graphic confounders. Follow-up data [53] were also negative for it provided additional evidence supporting the role of PAP in the
cognitive improvement, revealing a small improvement in execu- alleviation of cognitive decline in a highly prevalent and clinically
tive function at 2 months that did not persist at a 6-month follow- devastating neurodegenerative disease.
up visit. The authors concluded that “CPAP use resulted in mild,
transient improvement in the most sensitive measures of execu-
tive and frontal-lobe function for those with severe disease, which Conclusions and future directions
suggests the existence of a complex OSA-neurocognitive rela- Epidemiological and community-based studies have convincingly
tionship.” Bliwise [55,56] commented in detail on several aspects shown that SDB is common among the elderly and is associated
of the APPLES study design that may have influenced findings, with a wide range of neurobehavioral and psychosocial outcomes
including the primary emphasis on cardiovascular outcomes and that include cognitive dysfunction. Although PAP is an effective
the exclusion of individuals with mild cognitive impairment and treatment for SDB, its impact on SDB-associated cognitive seque-
dementia. In addition, as Bliwise has argued, the individuals in the lae in the elderly requires further systematic examination. Guided

Chapter 37 role of positive pressure therapy on sleep disordered breathing and cognition 371
by the previously reviewed studies, the following considerations for 5. Bucks RS, Olaithe M, Eastwood P. Neurocognitive function in
future work are provided: obstructive sleep apnoea: a meta-review. Respirology 2013;18(1):61–70.
6. Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive
1. Additional randomized clinical trials of PAP use in older adults sleep apnea. J Clin Sleep Med 2006;2(4):461–71.
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2011;34(1):111–19.

SECTION 8
Parasomnias

CHAPTER 38

Ronald B. Postuma
Introduction synucleinopathies are more common in men, selection bias is also

possible. Men may be more likely to present to medical attention
Rapid eye movement (REM) sleep behavior disorder (RBD) is with dream enactment behavior, owing to potential differences in
caused by loss of the normal atonia of REM sleep, allowing patients aggressivity of dream content and consequent need for medical
to “act out their dreams.” Manifestations range from mild occa- attention, different levels of awareness or concern of bed partners,
sional sleep-â•‰talking and transient movements to severe yelling, and a lower likelihood of being widowed, owing to sex-â•‰specific
kicking, and thrashing. The primary differential diagnoses are mortality rates. A second demographic cluster occurs among psy-
non-â•‰REM (NREM) parasomnia and pseudo-â•‰RBD due to obstruc- chiatric patients, mainly because of antidepressant-â•‰induced RBD
tive sleep apnea (OSA). Usually a careful history can accurately dis- (perhaps better termed antidepressant-â•‰triggered RBD, since many
tinguish the two, but only a polysomnogram (PSG) to document patients show signs of prodromal neurodegeneration [4]â•„). Among
loss of REM atonia and rule out mimics can confirm the diagnosis. medication-â•‰associated RBD, demographics are skewed younger
The goal of treatment is mainly to reduce injury. In addition to bed and there is no longer a clear male predominance [5].
safety measures, melatonin and clonazepam are generally effective, Risk factors for idiopathic RBD are somewhat similar to those
although surveillance for side effects of somnolence, falls and cog- of PD and DLB. Patients with RBD are more likely to have had
nitive impairment is required. In its idiopathic form, RBD occurs occupational pesticide exposure and to have experienced head
in just over 1% of the population over 60. RBD also can be trig- trauma [6]â•„. They may be more likely to report a family history of
gered by medications, particularly antidepressants. However, RBD dream enactment; this may either reflect differential recognition of
is most commonly associated with neurological disease, in particu- dream enactment (patients with RBD are more likely to ask family
lar neurodegenerative synucleinopathy: Parkinson disease (PD), members about similar symptoms) or could point to a true genetic
dementia with Lewy bodies (DLB), and multiple system atrophy component to RBD [7]. Family history of dementia also increased
(MSA). In this case, it is related to neurodegeneration of pontine risk of conversion to defined neurodegenerative disease [8]. Like
(subcoeruleus) and/â•‰or medullary (ventromedial medulla) struc- dementia, patients with idiopathic RBD also have lower levels of
tures that regulate REM atonia. Most cases of “idiopathic” RBD are education than controls. Strikingly unlike PD, patients with RBD
in fact in early prodromal stages of neurodegeneration, and are at are more likely to smoke, and do not have lower exposure to caf-
over 70% risk of eventually developing parkinsonism or dementia. feine (and neither caffeine nor smoking affected risk of conversion
This has profound implications for patient counseling and manage- to neurodegenerative disease [8]). RBD patients are also more likely
ment, as well as for the understanding and eventual treatment of than controls to report a history of ischemic heart disease, as well as
neurodegenerative disease. a history of depression (the latter association is probably consistent
with antidepressant-â•‰triggered RBD) [9].
Epidemiology of RBD
Few comprehensive studies of idiopathic RBD prevalence have Clinical diagnosis of RBD
been performed, mainly because proper study requires conduct- Rigorous and careful history taking is key in making a diagnosis.
ing PSG in the general population. The only true population-â•‰based The majority of RBD patients in sleep clinics present with a com-
PSG study was recently performed in Korean men and women plaint of dream enactment behavior. Typically, the bed partner first
aged 60 and over [1]â•„. PSGs were evaluated for abnormal REM becomes aware of the problem, and bed partners remain the key
tone, and all those with increased tone were assessed for dream to obtaining accurate history. Patients without bed partners may
enactment behavior. This produced a prevalence estimate of 1.2%. present with injuries from falls out of bed or from striking objects,
Asymptomatic loss of REM atonia was diagnosed in an additional or may have noticed items from the bed table knocked over. Often,
5%. This estimate is consistent with population-â•‰based estimates of especially among patients with neurodegenerative synucleinopathy,
0.4% and 0.5% for severe RBD (i.e, only assessing cases that have the history is subtler, and must be actively elicited. For example, any
resulted in injury) [2,3]. The great majority of patients never pre- PD patient who falls from bed while asleep probably has RBD. They
sent to sleep clinics, so RBD is vastly underdiagnosed. may also present with isolated sleep-â•‰talking/â•‰laughing, or minor
In sleep clinics, the majority of patients are male, and most are movements that have not concerned the bed partner.
over 50. The age distribution likely reflects the demographics of The range of manifestations of dream enactment in RBD is very
neurodegenerative synucleinopathy in the population. The reason broad, and reflects the diversity of dream content. Generally, most
for the sex difference is less clear. Although neurodegenerative bed partners will be able to identify the movement as “acting out

376 Section 8 parasomnias
of their dreams,” particularly if patients waken soon after an epi- example, they may talk back when addressed, use objects appro-
sode. Although many patients will mumble, sleep-talking can also priately, open doors, etc. RBD patients will not generally respond
be clearly articulated, often sounding like “one half of a conversa- to the environment in a meaningful way, unless woken.
tion.” Movements in the limbs can be minor, sometimes confined 4. Unlike NREM parasomnia, if woken during an episode, RBD
to myoclonic twitches (note that occasional myoclonic twitches can patients often become rapidly alert and appropriate. They may
be a normal phenomenon of REM sleep). When of larger ampli- be able to provide an explanation for the movements, related
tude, there is often a subtle limb ataxia [10]. Hands are often limp, to their recent dream content. In contrast, NREM parasomnia
and held in a wrist-flexion posture. Movements related to aggres- patients usually have a gradual emergence from episodes, or will
sive dream content are notably common in idiopathic RBD; this quickly return to sleep.
may reflect a true change in dream content, or may be an artifact
of selection bias (those with disturbing dream enactment are more 5. The nature of sleep-talking differs. Although both groups may
likely to seek out medical attention). Of note, movements can be mumble or yell out, the characteristic sustained “one half of a
quite brisk in parkinsonian patients who are unable to perform conversation” (like being in a room with a person speaking on
these rapid movements during wakefulness [11]. the telephone) does not occur in NREM parasomnia.
Dating the onset of RBD can be particularly problematic. Most 6. Demographics differ— NREM parasomnia patients have a
patients without a medication trigger will have noticed a gradual younger onset and often have a family history. Idiopathic
onset of symptoms. In many cases, bed partners can recall a very RBD patients are usually older and male, or, in the case of
long history of milder symptoms, dating from the beginning of the medication-induced RBD, have a history of psychiatric disease
relationship. It is unclear whether these symptoms were a true pro- and antidepressant use.
drome of RBD, a general susceptibility to sleep movements unre-
7. The time of behavior differs. NREM parasomnia episodes emerge
lated to degeneration of REM atonia nuclei, or variations of normal
from slow-wave sleep, which predominates early in the night.
behavior. Mild symptoms of dream enactment can occur in up to
RBD episodes predominate later, in the early morning hours.
15% of normal controls [12]; in most of these cases, there is no loss
of REM atonia, and, given a 3–5% lifetime prevalence of synucle- It should be noted that patients can have both RBD and NREM
inopathies, most presumably do not have an underlying neurode- parasomnia, the “parasomnia overlap” syndrome [14]. These
generative cause. patients are generally younger, and the NREM parasomnia com-
In evaluating a complaint of dream enactment behavior, there ponent is most prominent in the clinical presentation. Psychiatric
are two critical differential diagnoses; NREM parasomnia and OSA disease and antidepressant exposure occur in some, but associated
(a.k.a. pseudo-RBD [13]). A third alternate diagnosis is of frontal neurodegenerative disease is uncommon.
lobe seizures, which can also occasionally appear like dream enact-
ment with bizarre behavior, yelling, and posturing; for this reason,
epileptic abnormalities on the sleep electroencephalogram (EEG)
PSG diagnosis of RBD
should be ruled out. Other, very different sleep movements (peri- In cases of idiopathic RBD, PSG is essential for making the diag-
odic limb movements of sleep, hypnic myoclonus, etc.) can usually nosis. Diagnostic criteria for RBD (according to the International
be readily distinguished on history. OSA is often more prominent Classification of Sleep Disorders, Second Edition, ICSD-2 as well as
during REM sleep, because the normal REM atonia exacerbates ICSD-3 [15]) primarily center on two features:
apnea. Episodes probably reflect arousals from REM sleep rather 1. Loss of the normal atonia associated with REM sleep;
than true dream enactment. In many cases, patients will be hypoxic
or will waken incompletely, resulting in prolonged episodes of con- 2. Dream enactment behavior—this can be diagnosed either on
fused or bizarre behavior. It should be recognized that OSA is com- history or on direct observation during the PSG.
mon, and so many patients with true RBD may have OSA that is By definition, patients presenting to sleep clinics with complaints of
unrelated to their RBD. If REM atonia is clearly abnormal on PSG, dream enactment behavior have already met criterion 2. So, obser-
and if manifestations continue despite successful treatment with vation of dream enactment behavior during PSG is not required for
continuous positive airway pressure (CPAP), then idiopathic RBD diagnosis. The main purpose of PSG in this setting is to document
can still be diagnosed. loss of REM atonia.
Usually, the most difficult differential diagnosis is between RBD The gold standard method for tone evaluation is manual scor-
and NREM parasomnia. The following clues can help distinguish ing during REM sleep (see Figs. 38.1 and 38.2 for examples of PSG
these conditions: findings in RBD). There is no universally agreed upon standard for
1. Unlike NREM parasomnia, RBD patients cannot walk during an what constitutes abnormal REM atonia. The Montplaisir method
episode; if they leave the bed, they might take one or two steps, quantifies both phasic and tonic REM in the chin (mentalis) [16].
but will soon fall. If tonic REM (defined as amplitude 2 times baseline) exceeds 30%
of REM epochs, or phasic activity (defined as amplitude 4 times
2. During RBD episodes, eyes are closed. This limits contact with baseline) exceeds 15%, then tone is defined as abnormal. Using
the environment; for example, they cannot deliberately reach this method, sensitivity was 89% and specificity 83% (compared
for an object that is not in their immediate vicinity. They may with the gold standard of final clinical impression). The SINNBAR
grab objects that happen to touch their hands or may hit partners method combines phasic and tonic REM in a combined “any” tone
because of random thrashing, but will not deliberately reach. measure, and a cut-off of 18% in the mentalis is defined as abnor-
3. Since patients with NREM parasomnia are “half awake,” they mal [17] (with >90% sensitivity and 100% specificity in the origi-
may interact with their environment during an episode. For nal publication). Addition of limb muscles (particularly the flexor

Chapter 38 rem sleep behavior disorder 377
Tonic Tonic Phasic, then tonic
Phasic
Fig. 38.1 Illustration of abnormal tonic and phasic REM in a patient with RBD. Measurements are taken from the mentalis muscle.
1) E1 - A1
2) E2 - A1
3) C3 - A2
4) C4 - A1 Dream Enactment
5) O1 - A2
6) Chin EMG
7) L. Arm EMG
8) R. Arm EMG 150 µV
9) L. Ant. Tib. EMG 2 sec
10) R. Ant. Tib. EMG

11) EKG
12) F7 - T3
13) T3 - T5
14) T5 - O1
15) F8 - T4
16) T4 - T6
17) T6 - O2
Fig. 38.2 Illustration of a severe RBD episode on PSG. Electromyography (EMG) leads show severe loss of REM atonia, followed by an episode of dream enactment
(arrow) with generalized EMG activity related to vigorous movements.
digitorum superficialis) can further increase sensitivity without transitory myoclonic movements can be observed during normal
sacrificing specificity. For this, the combined cut-off is 32%. Neither REM sleep. In addition, care must be taken to distinguish dream
of the methods has perfect sensitivity, so it is possible that some enactment from movements during arousals. Moreover, it has been
true cases of RBD are missed with current quantification methods. suggested that occasional apparent dream enactment movements
For practical reasons, most centers use a single-night recording, as (termed “REM behavioral events”) may occur normally (among
night-to-night variability is relatively modest. However, a second 15% of controls in one single-night study [12]). Therefore, caution
night can be useful in the case of equivocal results on the first night. must be used in diagnosing RBD in patients with no dream enact-
Manual scoring is time-consuming and requires specialized ment history. In fact, the ICSD-3 draft criteria require repeated
training, limiting real-world applicability. Recently, automated episodes of sleep-talking or movements; this prevents RBD from
scoring techniques to quantitate REM atonia have been developed being diagnosed in asymptomatic patients based only upon a
[18,19]. These techniques still require manual correction to elimi- single-night PSG.
nate artifacts and arousals. Although currently confined to research
contexts, these may eventually be used as an alternative to manual
scoring in non-specialized centers.
Screening for RBD
In the absence of a history of dream enactment, criterion 2 can PSG is time-consuming and expensive, and especially given the
also be met by direct observation of dream enactment movements importance of RBD as a prodromal marker of neurodegeneration,
during REM sleep on overnight video. There are no clear criteria for it is important to develop methods to screen for RBD. To this end,
what constitutes dream enactment. Clinicians must be aware that several screening questionnaires have been developed. The simplest

are single-question screens; the Mayo Sleep Questionnaire (which bisoprolol have also been reported to trigger RBD, although only in
queries bed partners), and the RBD1Q (which queries patients). small series or case reports.
Both are very similar questions (although independently designed), If pharmacological treatment is required, there are two primary
and are simple to administer. Sensitivity and specificity are good, options: melatonin and clonazepam. Clonazepam (0.5–2 mg at
and the Mayo Sleep Questionnaire has the advantage of being the bedtime) was the first medication used for RBD, and can help up
only RBD questionnaire tested in the general population (with sen- to 90% of patients. Clonazepam does not appear to directly influ-
sitivity 98% and specificity 74%) [20]. The Mayo sleep question is ence tonic REM, but may reduce phasic REM and alter dream con-
as follows: tent. Melatonin (3–12 mg at bedtime) also helps to reduce RBD,
Have you ever seen the patient appear to ‘act out his or her dreams’ although perhaps less effectively. Observational studies have sug-
(punched or flailed arms in the air, shouted, or screamed) while sleeping? gested that melatonin directly increases REM tone. Melatonin also
has a small randomized trial supporting its utility [26].
Follow-up questions are provided in the case of a positive response.
The choice of first-line agent is not straightforward. There have
The RBD1Q has been tested in sleep center patients, with 94% sen-
been suggestions that clonazepam is more effective—in a recent
sitivity and 87% specificity (sensitivity assessments must be taken
observational study, clonazepam resulted in at least moderate
with caution, as sleep center patients are already aware of having
improvement in 78% of users, compared with 48% of melatonin
RBD) [21]. It is free for use, and has been translated into eight lan-
users [27]. On the other hand, melatonin is generally better toler-
guages. It is as follows:
ated: 33% of patients on melatonin reported side effects, compared
Have you ever been told, or suspected yourself, that you seem to ‘act out with 61% of clonazepam users. Of concern, the primary side effects
your dreams’ while asleep (for example, punching, flailing your arms in of clonazepam (falls, somnolence, and impaired cognition) are also
the air, making running movements, etc.)?
common symptoms of neurodegenerative synucleinopathy; there-
Other screening alternatives include the 14-item RBDSQ (96% fore, patients with idiopathic RBD may be at especially high risk. We
sensitivity but only 56% specificity) [22], the 13-item RBDQ-HK have recently observed that idiopathic RBD patients taking clon-
(82% sensitivity and 87% specificity) [23], and the simpler 5-item azepam at baseline were more likely to develop a “dementia-first”
Innsbruck Questionnaire (91% sensitivity and 86% specificity) [24]. neurodegenerative synucleinopathy than patients with melatonin.
The RBDQ-HK queries the frequencies of mild to severe manifesta- Although alternate explanations are possible (eg, confounding by
tions of dream enactment; therefore, with minimal modification, it indication), it may also suggest that clonazepam is causing substan-
can be used as a severity scale. tial cognitive impairment. Given these considerations, melatonin
It is essential to realize that idiopathic RBD is uncommon, so the may be a safer first-line option.
positive predictive value of even an excellent-specificity tool is low. If monotherapy with clonazepam or melatonin is ineffective,
Assuming 1% prevalence, with a 90% specificity screen, only 9% then the next step is probably combined therapy with both agents.
of screen positives will actually have the condition. Therefore, PSG If this fails, options may be limited. There have been reports that
remains essential for diagnosis in the general population. Within dopamine agonists may reduce RBD symptoms—this is not con-
neurodegenerative synucleinopathy, the prevalence of RBD can sistently observed, but remains a reasonable third-line option. As
exceed 50%, so the positive predictive value approximates the spec- mentioned above, antidepressants can reduce RBD episode fre-
ificity, and PSG may be less essential in making at least an empirical quency. Other possible options, which have been supported only
diagnosis. with case report evidence, include levodopa, cholinesterase inhibi-
tors (also reported by others to trigger RBD), sodium oxybate, and
Treatment of RBD zopiclone [28].
The goal of treatment is primarily to reduce the risk of injury to
bed partners and patients. There is no clear evidence that dream Pathophysiology and disease associations
enactment itself causes substantial impairment of sleep in most During normal REM sleep, skeletal muscles (except for the eyes
cases; therefore, specific pharmacological RBD treatment to and diaphragm) are essentially paralyzed, via hyperpolarization
improve sleep quality or reduce somnolence is probably not war- of spinal neurons. The control of REM atonia relies upon several
ranted. Nonpharmacological bed safety measures must always be brain regions and several neurotransmitters. The most critical
considered; simple measures like placing a soft mattress beside the of these are located in the tegmental pons and medial medulla.
bed, having a pillow barrier between bed partners, and clearing In 1965 (before the description of RBD as a clinical syndrome),
the night table of glass or sharp objects can help improve safety. Jouvet produced RBD-like symptoms in cats by lesioning the pons,
Spouses often elect to sleep apart to prevent bed partner injury. in areas corresponding to the subcoeruleus area in humans [29].
The next step in treatment is to look for reversible triggers. Selective loss of REM atonia has also been produced by lesioning
Primary among these are antidepressant medications. If no longer rodents in the analogous sublaterodorsal tegmental nucleus, where
clearly necessary, they can be stopped. If medications are needed, the existence of a REM atonia flip-flop switch has been proposed
bupropion may be an option, as there have been suggestions that it [3]‌0. The subcoeruleus area projects both to spinal cord motor
causes less REM atonia loss [25]. Paradoxically, in severe treatment- neurons and/or spinal interneurons via a direct pathway, and to
resistant cases of idiopathic RBD, antidepressants can be used to the ventromedial medulla via an indirect pathway [31]. The direct
reduce REM sleep, and thereby reduce episode frequency (in this and indirect pathways both inhibit muscle tone via glycinergic and
case, caution must be used when withdrawing the antidepressant— GABAergic innervation of spinal motor neurons and interneu-
the only known fatality due to RBD occurred in the context of anti- rons. The different pathways may differentially regulate phasic ver-
depressant withdrawal). Selegiline, cholinesterase inhibitors and sus tonic REM.

In humans, there are several case reports documenting that neurology; for example, documentation of RBD in any patient with
lesions of the pons and medulla can induce RBD, consistent with amnestic dementia implies that the patient almost certainly has a
predictions from animal models. There are reported cases of RBD neurodegenerative synucleinopathy (i.e, DLB/PD dementia), and
secondary to pontine/medullary strokes, hemorrhages, brain not Alzheimer disease.
tumors, and demyelinating lesions. Autoimmune causes, includ- Within established neurodegenerative synucleinopathies, RBD
ing voltage-gated potassium channel encephalitis, other limbic is common. Approximately 75% of DLB patients, 70–90% of MSA
encephalitides, and a newly described parasomnia overlap syn- patients, and 35–50% of PD patients have RBD. Within PD, the
drome with antibodies against the neural cell adhesion molecule presence of RBD is associated with features of cognitive and auto-
IgLON5, have been clearly documented [32]. There are also reports nomic dysfunction (i.e, the primary features of DLB and MSA)
of RBD occurring in progressive supranuclear palsy, spinocerebel- [38], and, similarly, DLB patients with PD are more likely to present
lar ataxias (especially type III), and the Guam PD–dementia–ALS with early parkinsonism [39]. This highlights the interconnected
complex [33]. Many of these syndromes are associated with brain- nature of the synucleinopathies (of note, a recent task force of the
stem pathology. Apparent dream enactment behavior has also been Movement Disorders Society concluded that DLB and PD should
frequently described in Huntington disease, although a recent no longer be considered mutually exclusive diagnostic conditions
detailed PSG analysis has suggested that this is not true RBD. [40]). RBD also has prognostic implications: PD patients with asso-
However, RBD may also occur without apparent pontine/medul- ciated RBD are at much higher risk of dementia [41] and have a
lary lesions. An animal model with generalized motor activation worse overall prognosis [42], and DLB patients with RBD have
during sleep, including RBD, has been created by selective reduc- higher mortality [39].
tion of GABA and glycine transmission [34]. There are also exam- Of profound interest to the neurological community is the time
ples of human RBD not associated with focal neurological damage. course of the RBD/synucleinopathy connection. In 1996, Schenck
Antidepressants commonly trigger RBD, possibly by increasing the et al. described the follow-up of their initial cohort of idiopathic
direct serotoninergic activation of lower motor and cranial nerves RBD; over a 5-year period, 38% of their patients had developed
(an activation that normally turns off during REM sleep) [10]. RBD PD or dementia [43]. Over the subsequent 10 years, 81% of these
is also commonly seen with narcolepsy, suggesting a role of the patients had developed neurodegenerative disease [44]. In the
hypocretin system in REM atonia; RBD in narcolepsy is part of a Barcelona cohort of idiopathic RBD patients, 82% had devel-
general dysregulation of sleep state and sleep stage instability, sug- oped either defined neurodegenerative disease or mild cognitive
gesting potential for a different mechanism. Increased tone (and impairment [45] (see Fig. 38.3). An autopsy study of one of these
potentially dream enactment) in narcoleptic RBD may be related “still-idiopathic” patients documented moderately advanced synu-
to frequent and often partial intrusions of wakefulness during REM cleinopathy [46], and a recent study in this cohort has documented
sleep. Reported cases of RBD in Guillain–Barré syndrome [35] and synuclein deposition in submandibular gland needle biopsies in the
in limbic encephalitis without evident brainstem involvement have majority (suggesting the exciting possibility of in vivo pathological
not been completely explained. Finally, post-traumatic stress has diagnosis) [47]. In our cohort, we have seen over 70% of our idi-
commonly been associated with dream enactment behavior [36]; opathic RBD patients develop neurodegeneration [8,48]. Moreover,
this might suggest that severe nightmares in the context of general in all these cohorts, disease conversion rates will continue to climb
stress can “override” otherwise functioning REM atonia systems. over time. This has profound implications for our understanding
This mechanism may also underlie the occasional dream enact- of RBD and of synucleinopathy in general; the large majority of
ment behavior that can occur in otherwise normal young persons. patients with a diagnosis of “idiopathic” RBD are in fact in prodro-
Although many conditions are associated with RBD, the large mal stages of a neurodegenerative disease.
majority of patients have a specific underlying neurodegenerative The ability of RBD to anticipate PD, DLB, and MSA has a patho-
etiology. This is arguably the most critical feature of RBD, and is logical correlate. This has been best encapsulated in the six-stage
discussed in detail in the next section. PD staging system of Braak [49]. Based upon a large series of autop-
sies stained for synuclein deposition, Braak hypothesized that PD
first starts in the dorsal motor nucleus of the vagus, peripheral
RBD and neurological disease autonomic nerves, and olfactory structures. At stage II, pontine and
By far, the most common association with RBD is neurodegenera- medullary structures are affected, including the structures associ-
tive synucleinopathies. Synucleinopathies refer to diseases asso- ated with RBD in humans and animal models. This implies that
ciated with deposition of alpha-synuclein in the form of Lewy idiopathic RBD probably corresponds to stage II PD. Only at stage
bodies, Lewy neurites, or glial cytoplasmic inclusions. The three III does the dopaminergic substantia nigra become involved (and
principal synucleinopathies are PD, DLB, and MSA. Combined, because of redundancy of the dopaminergic system, patients may
they occur in 3–5% of persons over 70. All three conditions have not present until stages IV or V). The last three stages are character-
extensive degeneration in pontine structures, consistent with the ized by spread of synuclein to the cortex, resulting in PD dementia.
patho-anatomy of RBD. This synucleinopathy association dwarfs Although the model remains incomplete (eg, DLB is incompletely
all other associations with neurological disease; in a recent neuro- explained), and with numerous exceptions to this pattern (i.e, many
pathological study, 94% of patients with probable RBD and neuro- PD patients present with relatively “pure” motor PD), it nonetheless
degenerative disease (mostly dementia) had synuclein deposition at illustrates why RBD is a prodromal feature of PD.
autopsy [37]. Restricting analysis to those with PSG confirmation Recognizing that most idiopathic RBD patients are in prodro-
(i.e, excluding possible false positives) increased this proportion to mal stages of neurodegenerative synucleinopathy has immediate
98%. If 94–98% of neurological patients with RBD have underly- clinical relevance. First, a duty of disclosure by the sleep clinician
ing synucleinopathy, this is of clinical diagnostic importance in exists. This can range in detail according to the patient’s values and

100
90
Neurological disease-free survival (%)

80
70
60
50
40
30
20
10
0
0 5 10 15
Years from RBD diagnosis
Number of
patients at risk 174 65 10 0
Fig. 38.3 Kaplan–Meier analysis of risk of neurodegenerative disease in a cohort of 174 patients followed in Barcelona. It can be seen that less than 25% of patients
remain free of neurodegenerative synucleinopathy at 10 years.
Reproduced from PLoS One, 9, Iranzo A, Fernandez-Arcos A, Tolosa E, et al., Neurodegenerative disorder risk in idiopathic REM sleep behavior disorder: study in 174 patients, pp. e89741, Copyright
(2014), PLOS ONE, reproduced under the Creative Commons Attribution License 4.0.
preferences; although patients have the absolute right to know all MDS criteria, in any male over 70, RBD alone can suffice to make a
the details of their condition, they also have the right “not to know.” diagnosis of prodromal PD; something that no other marker can do
Deciphering the degree of information that is desired requires a [52]. Studying patients with idiopathic RBD can provide a “test-lab”
great deal of judgment and subtlety. At a minimum, patients need to assess whether other prodromal markers of neurodegeneration
to be aware that their disorder may be an early sign of other neu- can predict disease. Using RBD, the predictive values of abnormal
rological problems and so ongoing follow-up is important. Second, olfaction [53], color vision, quantitative motor testing [54], auto-
there may be treatment opportunities. Currently, there are no nomic function [55], dopaminergic functional neuroimaging [56],
clear neuroprotective (or disease-modifying) therapies available substantia nigra ultrasound [56], PD-related network patterns of
for synucleinopathy. So, idiopathic RBD does not imply automatic glucose utilization on PET scanning [57], hippocampal perfusion
treatment implications. However, there are numerous excellent [58], and electroencephalographic slowing [59] have been directly
symptomatic treatments for DLB, MSA, and especially PD, even in confirmed. Moreover, following patients with idiopathic RBD
their prodromal stages. These can range from dopamine replace- allows one to directly witness the evolution of neurodegenerative
ment therapy for motor problems to cholinesterase inhibitors for disease from its prodromal stages; this has led to studies directly
cognitive impairment and hallucinations (from personal experi- observing the pace of evolution of quantitative motor slowing, car-
ence particularly effective in this population), as well as effective dinal parkinsonian signs, dopaminergic denervation [60], olfac-
medications for orthostatic hypotension, constipation, urinary tory loss, color vision loss, and autonomic dysfunction before fully
dysfunction, psychiatric symptoms, etc. Therefore, all patients defined neurodegenerative disease. Finally, and most critically,
with idiopathic RBD should be offered regular follow-up with neu- RBD patients offer the ideal group in which to test future neuropro-
rologists equipped to diagnose and treat these conditions as they tective therapies against neurodegenerative disease. In idiopathic
emerge. This regular follow-up also provides the opportunity to RBD, one can intervene early in the disease course (when disease-
provide neuroprotective therapy when it becomes available (given modifying agents are most likely to be effective), and before symp-
the profoundly high risk and early stage of neurodegeneration in tomatic therapies for parkinsonism and dementia make the reliable
idiopathic RBD, these patients may be the ideal candidates for neu- assessment of outcome impossible. Stratification of patients by
roprotective therapy to prevent parkinsonism and dementia) [50]. documenting other prodromal features can identify patients with
The ability of RBD to anticipate neurodegenerative synucleinop- conversion rates exceeding 90% over 5 years, and 60% over 3 years,
athy has attracted considerable interest from the PD and DLB com- well within the required parameters for neuroprotective trials [61].
munity. There is no other marker of prodromal synucleinopathy
with anywhere close to the predictive value of RBD. For example,
olfactory loss, another well-established prodromal marker, is asso- Conclusions
ciated with a two-to fourfold increased risk of PD compared, with a RBD is an intriguing parasomnia, with symptoms that are read-
more than 100-fold increase with RBD [51]. In the new prodromal ily treatable. However, its underlying pathology is not treatable. In

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CHAPTER 39
NREM and other parasomnias

Caterina Ferri, Maria Turchese Caletti,
and Federica Provini
Introduction The pathophysiology of ADs is unknown. It has been proposed

that a dysfunctional and independent action of the system involved
Parasomnias are undesirable, but not always pathological, events. in NREM sleep and wakefulness is at the basis of these disorders
They consist of abnormal behaviors during sleep due to an inap- [6,7]. It has been suggested that the occurrence of ADs is due to the
propriate activation of cognitive processes or physiological sys- association between an abnormal deep sleep and a high SWS frag-
tems such as the motor and/â•‰or autonomic nervous systems. mentation [8]â•„. Patients with ADs show a normal sleep macrostruc-
Parasomnias may occur during sleep or during the transition ture, even though they may present a high arousal index and an
from wake to sleep and vice versa. According to the International increased number of awakenings during sleep, with reduced sleep
Classification of Sleep Disorders, parasomnias are distinguished efficiency [8–â•‰10]. An intracerebral EEG study has reported the per-
on the basis of the stage of sleep in which they appear: (1) para- sistence of delta activity in the hippocampal and frontal associative
somnias arising from non-â•‰rapid eye movement (NREM) sleep, cortices, accompanied by a local activation of the motor, cingulate,
which comprise arousal disorders and sleep-â•‰related eating disor- insular and temporopolar cortices, and amygdala during episodes
ders; (2) parasomnias associated with rapid eye movement (REM) of confusional arousals in a young boy [11].
sleep; (3) “other parasomnias” occurring in any sleep stage [1]â•„. Loss of the inhibitory function of the frontoparietal cortices,
Most parasomnias constitute unusual but physiological manifes- together with activation of the motor and cingulate cortices, could
tations, occurring especially during childhood; they can become explain the appearance of innate, complex motor patterns [12,13].
pathological if they appear or continue at an inappropriate age or Many other factors have been involved in determining ADs,
when they are very frequent, associated with a significant impair- such as developmental, genetic, psychological, and organic ones.
ment of nocturnal sleep or daytime alertness. Nevertheless, paras- In most cases, as the child grows up, ADs become less frequent and
omnias may also manifest themselves in a violent way with tragic intense until they disappear altogether. Genetic influence has been
consequences; this is especially true for REM behavior disorder seen in many studies: the concordance between twins is high and
(RBD), which is an REM sleep parasomnia (see Chapter 38 of this the prevalence in first-â•‰degree relatives of individuals with ADs is
volume). In this chapter, we will describe the NREM parasomnias higher than in the general population [14]; however, the transmis-
and the “other parasomnias.” sion mode is still unknown. Psychological factors are sometimes
involved, since an association has been found between ADs (espe-
NREM parasomnias: arousal disorders cially sleep terrors and sleepwalking) and anxiety level [15–â•‰17]. It
Arousal disorders (ArDs) are motor behaviors arising from deep seems that vulnerability to stress and inadequate coping strategies
sleep, usually only once per night and in the first part of the night are common factors predisposing to parasomnias. Stress is related
when deep sleep is prominent. They are most common in children—â•‰ to AD frequency, and experiences like hospitalization, parental
probably because of the abundance of slow-â•‰wave sleep (SWS). ADs divorce, and traumatic events may aggravate the disorder. In sus-
include a spectrum of manifestations with overlapping features and ceptible individuals, some stimuli such as deepening sleep factors
increasing complexity, from confusional arousal to sleep terror to can precipitate or influence the frequency of ADs: fever, sleep dep-
sleepwalking [2,3]. They are dissociated states in which awakening rivation, intense physical activity, hyperthyroidism, alcohol, and
and sleeping features coexist [4]â•„. During the episode, the patient use of central nervous system (CNS) depressant drugs. Also, forced
seems to be alert, but is sleeping, appearing confused, disoriented, arousals during SWS, such as those induced by auditory stimula-
and unresponsive to environmental stimuli. The patient should not tion and by intrinsic sleep disorders like obstructive sleep apnea
be awakened, because this would be counterproductive, prolonging (OSA), periodic limb movements in sleep (PLMS), and restless legs
the episode and resulting in resistant or even violent behavior [5]. syndrome (RLS), may trigger ADs, inducing repeated arousals [18–â•‰
Usually, there is no recollection of the event the following morning. 20]. Children with neurodevelopmental disorders, like cerebral
During ADs, a wide range of behaviors can be seen: inconsolable palsy or Down syndrome, are more likely to have upper airway
crying, moaning, screaming, stereotyped and complex actions such obstruction, and therefore their prevalence of ADs is higher than
as dressing, playing an instrument, or driving a car, or aggressive that in healthy children.
and injurious behavior, which may have forensic implications. An It is important to differentiate ADs from other parasomnias
autonomic activation can also be present. and from nocturnal frontal lobe epilepsy (NFLE) because of their

specific and different management [21]. A detailed description of Table 39.1 Behavioral advice and management for arousal disorders
AD episodes (better if accompanied by home videos) generally
facilitates the diagnosis [4]‌. Attention should be paid to the time Confusional Sleep Sleepwalking
of occurrence during the night, the duration of the episodes, and arousals terrors
the condition of the patient immediately after the episode [22].
Reassure parents + + +
Features supporting the diagnosis of NFLE are the presence of
stereotyped and bizarre motor behavior or sustained dystonic– Avoid precipitating factors + + +
dyskinetic postures, several attacks per night, brief duration of the Avoid waking the patient up + + +
attacks, onset or persistence into adulthood, and response to antie- Remove obstructions in the − − +
pileptic medication [21,23–25]. A physical and neurological exami- bedroom
nation should be done to identify any signs of possible associated
sleep disorders [4]. Nocturnal video-polysomnography (VPSG) is Cover windows with heavy − − +
curtains
useful in the case of frequent attacks or atypical manifestations or
when other sleep disorders are associated. If nocturnal seizures are Secure windows − − +
suspected, multiple EEG channels should be included in the VPSG Install locks or alarms on − − +
recording montage, even though the EEG presentation of NFLE is outside doors
often without abnormalities. Rarely, seizures emerge from REM
Use a nightlight − − +
sleep; most such seizures appear during stage 2 NREM. Seizures
may occur throughout the night, whereas ADs usually occur dur- Place barriers in stairways − − +
ing the first hours of sleep. A simple and validated clinical scale Sleep on the ground floor − − +
called the Frontal Lobe Epilepsy and Parasomnia (FLEP) scale or Scheduled awakenings − ± ±
a structured interview (SINFLE) may be useful for the differential
diagnosis [24–26]. Pharmacological treatment ± ± ±
Pharmacological treatment is not usually necessary in ADs: the Psychotherapy ± ± ±
child’s parents must be reassured about the benignity of the disor- Hypnosis − ± ±
der, which is in most cases self-limiting [3]‌. Some behavioral advice
should be followed, particularly in case of complex motor attacks,
to ensure the child’s safety. Medications like benzodiazepines and
tricyclic drugs should be reserved for children with severe and fre- fact has not received sufficient emphasis in the research literature
quent episodes, when other measures have failed. Adults more often or in textbooks. The EEG during a CA shows a mixture of brief epi-
than children require pharmacological treatment—also because of sodes of delta activity with theta rhythms and poorly reactive alpha
the frequent association of ADs with other disorders. This is shown waves intermixed with muscle and movement artifacts [22]. The
in Table 39.1. diagnosis is primarily based on clinical features: a detailed descrip-
tion is sufficient in most cases to identify a CA. Generally, additional
Confusional arousals information can be obtained by a homemade video recording of the
Confusional arousals (CAs) are a less severe form of AD and are episodes [4], but if the diagnosis remains unclear or if other sleep
defined as “mental confusion or confusional behavior during or fol- disorders are suspected, nocturnal VPSG is mandatory. CAs do not
lowing arousals from sleep” [1]‌. They are generally characterized require medical treatment, since in most cases the disorder is self-
by incomplete and confused awakenings from deep sleep. This is limiting, remitting spontaneously [5].
shown in Fig. 39.1. CAs in adulthood are clinically more heterogeneous than those of
Isolated CAs are a common experience also in normal subjects and childhood, they are more often associated with other sleep or psy-
may affect both children and adults, but in a different way [5]‌. CAs in chiatric disorders and with violent behaviors, and they may conse-
childhood are almost ubiquitous, rare, or confined to a period of life, quently lead to legal complications.
and they are not always considered pathological. CAs affect primar- The prevalence of CAs in the adult population is about 3–4%
ily infants and toddlers, arising in almost all cases before the age of [15], with no gender influence. CAs in adulthood may present as
5 years [22]. Their exact prevalence is unknown: detailed epidemio- typical CAs similar to those of childhood or as sleep drunken-
logical studies are lacking and the information is largely anecdotal ness, sleep inertia, or “automatic episodes.” Sleep drunkenness, also
[5,17]. Clinically, during the episode, the child may open his or her known as Elpenor syndrome (from Homer’s Odyssey), was for-
eyes, seeming to be alert but appearing confused and unresponsive merly considered a synonym of CA. Actually, sleep drunkenness is
to environmental stimuli. Movements, moaning, vocalization, and not strictly a CA: it is defined as a prolonged transition from sleep
autonomic activation may be present during the episodes, but the to waking, with partial alertness, disorientation, poor coordina-
attacks are usually quite mild. The episodes can have different duration, instability, and sometimes excited or violent behavior; exces-
tions, from seconds to 15 minutes, subsequently resolving in rest- sive daytime sleepiness is usually present [5]‌. Some authors also
ful sleep [4]. Usually, on awakening in the morning, the child does consider sleep inertia as a CA, even though it is a state of impaired
not remember the episode, even though the recall ability depends vigilance with confusion and disorientation occurring immedi-
on child’s age. Usually, only one episode occurs during the night, ately after awakening in the morning or after a prolonged daytime
within the first 2 hours after going to sleep [5]. Multiple episodes nap and not during the night [22]. Sleep inertia has a variable and
of confusional arousal, however, are not uncommon, although this sometimes long duration. The only common feature between sleep

Chapter 39 nrem and other parasomnias 385
(a)
1 2 3 4 5 6
(b) 1 2 3 4 5 6
Fp2 - F4
F4 - C4
C4 - P4
P4 - O2
Fp2 - F8
F8 - T4
Fz - Cz
Cz - Pz
Fp1 - F3
F3 - C3
C3 - P3
P3 - O1
Fp1 - F7
F7 - T3
R. EOG
L. EOG
Mylo.
EKG
R. Tib. ant.
L. Tib. ant.
h 04:38:37 h 04:38:58
Fig. 39.1 Confusional arousals (CAs). (a) Photo-sequence of a CA episode: (1) the patient is sleeping; (2) he opens his eyes and raises his head and his right arm;
(3) he then sits up in bed looking to his left; (4) he scratches his head; appearing confused; (5) he utters some nonsense words while staring into space; (6) he then falls
asleep again.
(b) PSG excerpt of the episode. There is an abrupt and brief arousal from deep sleep (note the movement artifacts on the EEG tracing), which is associated with a slight
increase in heart rate. EOG: electro-oculogram; Mylo.: mylohyoideus; EKG: electrocardiogram; Tib. Ant.: tibialis anterior muscle; R.: right; L.: left.
inertia and CAs is the presence of mental confusion. In adulthood, psychiatric problem is suspected, an appropriate psychiatric evalu-
motor behavior during a CA can be more vigorous, and violent acts ation could be useful.
or sleep-related sexual behavior have been reported, with possible
legal consequences [27–30]. As in children, CAs may be triggered Sleep terrors
by sleep deprivation (due both to recreational activities and to shift Sleep terrors, also called “pavor nocturnus,” are the most dramatic
or night work), but they are more often associated with other sleep form of AD [1,31]. For a long time, sleep terrors and nightmares
disorders like OSA, sleep bruxism, and CNS hypersomnias [15]. were considered synonymous; however, in 1949, Jones was the first
It should be emphasized that in adulthood, CAs can be related to to differentiate these two disorders. Later, some studies demon-
the presence of psychological disorders such as adjustment disor- strated that sleep terrors occurred during SWS and were quite dif-
der, depression, and bipolar and anxiety disorders. Other medical ferent from nightmares, a typical REM sleep parasomnia [32,33].
conditions predisposing to CAs are endocrine disorders, heavy Broughton first suggested the hypothesis that sleep terrors were
sedation, alcoholism or substance abuse, viral infection, and CNS disorders of arousal [34].
lesions. More often than children, adults require VPSG in order to Sleep terror emerges in a sudden and unexpected way: the
clarify the clinical features of the episodes and the possibly associ- child wakes up, sometimes also opening his or her eyes, cries and
ated sleep disorders. screams exaggeratedly and inconsolably, and does not respond
The medical treatment depends on the etiology and the relation- to external stimuli like parents’ voices. This state of intense agita-
ship with other sleep disorders: pharmacological therapy with clon- tion and fear is reflected in the patient’s facial expression, which
azepam or with antidepressants such as imipramine, paroxetine, appears terrified. Sleep terrors are also accompanied by a “fight or
and trazodone may be useful, while if OSA is present, continuous flight response,” which implies a considerable autonomic activation
positive airway pressure (CPAP) is needed [5]‌. If an underlying characterized by tachycardia, tachypnea, and increased respiratory

tidal volume, flushing of the skin, diaphoresis, and mydriasis [4,35]. intense autonomic arousal and ambulation. RBD is characterized
Patients usually tend to stay in bed during sleep terrors; neverthe- by loss of REM sleep atonia, resulting in dream enacting behavior
less, they sometimes get out of bed and walk or run around the (DEB). This may be associated with violent behavior, vocalization,
house, with the risk of injuring themselves or other people [29]. The and walking during sleep, but the autonomic response is usually
episode ends in a few minutes, most often from 1 to 5, but it can absent or mild; nevertheless, some patients have elements of both
last up to 20 minutes. As the attack stops, the patient simply con- sleep terrors and RBD with an overlap syndrome. Patients with
tinues to sleep and generally the next morning does not remember nocturnal panic attacks frequently show associated psychopathol-
the episode although sometimes remembers feeling completely iso- ogy and present similar episodes during daytime. Psychogenic dis-
lated and frightened [19]. These attacks occur often only once per sociative episodes can be distinguished by the presence of a waking
night. Patients suffering from sleep terrors are usually prepuber- EEG pattern during the attack.
tal children: the peak prevalence is between 5 and 7 years, but the Management of sleep terrors includes adoption of safety meas-
disorder may appear as early as 2–3 years and may continue up to ures to protect patient during the attack, although pharmacological
adolescence [31]. Usually, the child outgrows sleep terrors sponta- treatment is not usually necessary. The patient should be counse-
neously before adolescence [4,15]. The prevalence is not influenced led to prevent sleep deprivation and avoid other triggering factors
by sex, race, or cultural background, but heredity may play a role [3,4]. When the episodes are frequent and occur at a particular
since more than one family member may be affected [15,16]. When time, scheduled awakenings, 15–30 minutes before the attack,
sleep terrors arise during adulthood, it may be symptomatic of a may curtail the episode [3,5]. Drug therapy is rarely indicated,
neurological disease, like a brainstem lesion or a thalamic tumor. and is used only when sleep terrors are very frequent or when the
During the episode, the EEG records a diffuse and hypersyn- patient’s violent behavior puts themself or other family members in
chronous delta rhythm with intermixed faster frequencies (alpha danger. Benzodiazepines (eg, clonazepam or diazepam), tricyclic
or theta) or prominent alpha and beta activity; there are also associ- antidepressants (imipramine), and paroxetine or trazodone have
ated increases in muscle tone, respiratory and heart rate. been used successfully [5]‌. Attention must be paid to the appear-
The diagnosis of sleep terrors may be suspected on the basis of ance of daytime sedation when using benzodiazepines, especially
a clinical evaluation which must include a detailed description of those with long half-life (diazepam): the dose must be increased
the nocturnal episodes from a witness and also a physical, neu- slowly. In children, satisfactory results have been reported also with
rological, and developmental examination [3]‌. If doubt remains, L-5-hydroxytryptophan and melatonin [36]. Specific treatment is
it is necessary to perform a nocturnal VPSG. The VPSG is useful required when sleep disordered breathing or other neurological
especially for the differential diagnosis between sleep terrors and diseases are associated. Hypnosis has been found to be effective in
other disorders like sleep-related epilepsy (Table 39.2), nightmares, both children and adults [37]. The coexistence of psychopathol-
confusional arousal, RBD, nocturnal delirium, and nocturnal panic ogy, in adults, may be treated with psychotherapy and progressive
attacks. VPSG also allows determination of the presence of comor- relaxation.
bid sleep disorders such as OSA [4].
Differential diagnosis between sleep terrors and nightmares is Sleepwalking
based mainly on clinical features. Nightmares are not usually asso- Sleepwalking (SW) is a series of complex behaviors, initiated dur-
ciated with vocalization, major motor activity, or autonomic symp- ing an arousal from SWS, such as changes in body position, turning
toms, and patients are more easily aroused, do not appear confused and resting on one’s hand, staring with open “glassy” eyes, play-
after being awakened, and can describe their dream. CAs overlap ing with the sheets, sitting up in bed, and resting on the knees [1]‌,
with less severe sleep terror episodes, but they do not present terror, which may culminate in walking behavior [20,35]. Both in a scien-
tific and a literary context, different descriptions have been given
of a typical sleepwalker; perhaps the best one was given by Roger
Table 39.2 Several differentiating features to establish the correct in 1932: “The sleeper performs various acts with a certain degree
diagnosis of arousal disorders (ArDs) or nocturnal frontal lobe of dexterity and can avoid obstacles. But his behavior is character-
epilepsy (NFLE) ized by a rigidity, which gives him the appearance of an automation.
He can answer questions correctly and is quite receptive to sug-
ADs NFLE gestions. At the end of 15–30 minutes of activity, he goes back to
Age/gender Childhood Any age bed, sometimes fully clothed, and wakes up the next morning quite
Any gender Male predominance surprised to find himself dressed” [38]. Episodes occur rarely, on a
weekly or even monthly frequency, usually in the first third of the
Episodes’ time of One per night Several per night night [39]. Somnambulistic episodes can last from a few seconds to
occurrence and First third of the night Any time more than 30 minutes [20,35], and subjects are typically completely
frequency
or partially amnestic of the event, with little or no recall [40].
Clinical course Sporadic episodes Many episodes every night Because SW is coupled with an altered state of consciousness
throughout life Tendency to disappear Increasing frequency and impaired judgment [1]‌, during the episode, sleepwalkers are
Triggering factors Usually present (fever, Absent difficult to awaken and generally confused upon forced awak-
sleep deprivation) ening. Agitation and aggressive behavior occur rarely, usually
when prompted by people attempting to restrain the subject [39].
Motor pattern Heterogeneous Stereotyped
Nevertheless, there have been isolated reports of sleep-related vio-
Absence of abnormal Dystonic–dyskinetic
lence, homicide, and suspected suicide [41], raising fundamental
movements postures
questions about the medico-forensic implications of these acts

and the neurophysiological and cognitive states that characterize sexual arousal, however, has also been reported: sexual behavior in
patients during such episodes [20,35]. Although only few studies sleep may arise from either a dreamlike experience, arising from
have investigated the mental content of sleepwalkers during epi- NREM sleep, or from dreams with sexual content (a feature of
sodes, some thought-like mentation or fragmentary images have REM sleep). Complete amnesia on waking occurs in all reported
been described [42]. The prevalence of SW in the general popu- cases of sexsomnia [28]. The exact cause of sexsomnia has not yet
lation is 1–11% [43] and, more specifically, it has a prevalence of been identified, although several precipitating factors have been
around 3% in toddlers [17], increasing to about 13.5% at 10 years reported, including stress, sleep deprivation, alcohol use, and drug
[24], before falling significantly after age 25 [15]. Adults who sleep- abuse [28,50,51]. Sexsomnia has been described in association with
walk almost invariably report a history of childhood somnambu- REM parasomnias, RLS, and narcolepsy [28]. A particular psycho-
lism or other ADs previously in life [3]. SW can also arise de novo logical history of major trauma during childhood, namely, sexual
in adults [24], posing some problems of differential diagnosis with abuse, and rape of the mother, as well as particular psychiatric con-
organic, neurological, or psychiatric disorders. Even if there is no ditions, such as depressive disorder, obsessive personality trait, and
evidence suggesting that SW during adulthood is associated with generalized anxiety, have also been reported [51,52].
the subsequent development of neuropathological disorders [24], In order to differentiate voluntary violence from sexual behavior
there is a high prevalence of AD in some neurological disorders provoked by an automatism during sleep, the history must include
[39]. Antiarrhythmic medications, cocaine and alcohol abuse, ben- a detailed description of the event and the degree of amnesia of
zodiazepines, and tricyclic agents have been reported as possible the patient, as well as his or her attitude when fully awake after the
triggering factors for SW. Recently, zolpidem has been specifically event [49]. A collateral history from the bed partner or a family
implicated as a possible inducer of SW episodes in people with member is also helpful. Diagnosis of sexsomnia usually relies on
sleep-related eating disorder (SRED) [44]. neurological and psychiatric evaluation in order to detect particu-
A detailed history of the episode is necessary for the diagnosis; lar personality traits, anxiety, or depressive disorders, early demen-
homemade video-recordings can be useful to capture events clos- tia, or Kleine–Levin syndrome, all of which can be responsible for
est to real-life episodes. If events are stereotypic or repetitive and abnormal behavior during sleep. This clinical examination must be
occur frequently, the patient should be considered for video-EEG completed by EEG and VPSG recordings, to rule out the presence
monitoring in a sleep laboratory [45]. VPSG is also required in the of other sleep-related disorders [52]. According to PSG findings,
presence of simultaneous sleep pathologies to establish the precise sleep structure is usually normal, but sudden arousals from SWS
relationship with these events, and to differentiate SW from NFLE, are frequently observed.
especially in adults [21,23,46]. Usually, medications are not neces- As with other parasomnias, sleep hygiene measures reduce the
sary to treat SW [3]‌and the “first aid” treatment involves provid- negative effect of the precipitating factors. Psychotherapy may be
ing a safe sleep environment [39] (Table 39.1). Precipitating factors, helpful, especially in the case of associated anxiety or depression.
such as sleep deprivation or bladder fullness, should be avoided, In patients with other sleep disorders, treatment should be aimed
as should certain medications known to exacerbate SW, including at the main disorder [50]. Positive therapeutic responses to ben-
thioridazine, fluphenazine, perphenazine, desipramine, chloral zodiazepines, especially clonazepam from 0.5 to 2 mg at bedtime,
hydrate, and lithium. If SW episodes are very frequent, or when antidepressant medications such as SSRIs, valproic acid, and lamo-
a child or others are in danger because of the related behaviors, trigine have been observed [50,51].
imipramine 25–150 mg, diazepam 2–5 mg, or clonazepam 0.5 mg
at bedtime can be used [47]. Alternatively, trazodone and selec- Sleep-related eating disorder
tive serotonin reuptake inhibitors (SSRIs) have been successfully SRED, first described by Schenck and colleagues in 1991 [53], is
employed [48]. Treatment of all related sleep disorders seen as pos- a parasomnia characterized by recurrent episodes of involuntary
sible precipitating factors should also be addressed [39]. In par- compulsive eating during sleep, with morning anorexia and fre-
ticular, children with respiratory sleep disorders should be referred quent comorbid sleep disorders [1]‌. Episodes typically arise from
for specialist treatment, such as adenotonsillectomy for OSA [19]. NREM sleep, mostly stage N3, but there are cases of episodes
Alternative therapies such as hypnosis have proven helpful and safe occurring during REM sleep [1,53].
in several cases [37]. During an SRED episode, patients usually get out of bed to eat
and drink after having fallen asleep normally. Eating is compulsive,
Sexsomnia unassociated with any feeling of hunger, and chewing starts right
Sexsomnia, also called somnambulistic sexual behavior, or sleepsex, after awakening (eating latency is less than 30 s in about half of
is a particular form of parasomnia, usually occurring in NREM the episodes) [54]. Once food is ingested, the feeling abates and
sleep, characterized by atypical sexual behavior during sleep [49]. the patient is able to resume sleep [1,55]. The spectrum of the sub-
Although not classified as a unique parasomnia, sexsomnia is men- stances ingested is wide, varying from ordinary to unusual sub-
tioned in the ICSD-3 as a variant of confusional arousal [1]‌. stances, generally with high-caloric nutrients [1,53]. More than
The frequency of sexsomnia is underestimated, since most 65% of SRED patients ingest unpalatable substances, such as frozen
afflicted individuals do not seek therapeutic intervention [50], food or buttered cigarettes [56]. Alcohol consumption during noc-
because of ignorance of the condition [51]. The majority of reports turnal episodes is rare. Eating may occur up to eight times nightly,
in the literature concern male patients. Common features of sex- although one or two episodes nightly are more common, lasting an
somnia include sexual arousal with autonomic activation (eg, average of 3–5 minutes [54]. Episodes are associated with variable
nocturnal erection, vaginal lubrication, ejaculation, sweating, and degrees of awareness, ranging from dense unawareness, typical of
cardiorespiratory response), explicit sexual vocalizations, mas- parasomnias like somnambulism, to partial awareness [57]. Ninety
turbation, and complex sexual activities [52]. Sexsomnia without percent of patients report being half or fully asleep [58], although

impaired consciousness is not a universal finding [54,59,60]. RLS, clonazepam, codeine, and carbidopa/levodopa or bromocrip-
Morning amnesia for the event may be present [61]. tine are often effective [63]. Dopaminergic agonists, such as low
The onset of SRED can be sudden, associated with precipitating doses of pramipexole, are also effective (0.18–0.36 mg at bedtime),
factors, such as major life stresses, medical, neurological, sleep, or especially in patients with RLS [63,67]. Success with combinations
psychiatric disorders, administration of medications [62], includ- of dopaminergic and opioid drugs, with the occasional addition
ing triazolam, amitriptyline, olanzapine, risperidone, and zolpi- of sedatives, has also been described in a small series of patients
dem [44,62–64] or cessation of cigarette smoking, alcohol abuse, without associated sleep disorders [60]. In those for whom opioids
or marijuana use. SRED can also develop gradually, without any and sedatives are relatively contraindicated (eg, those with a
identified precipitant. history of substance abuse), a combination of bupropion, levodopa,
Obesity and daytime sleepiness are the most important conse- and trazodone has been suggested [68]. Fluoxetine may also help,
quences of SRED; weight gain may precipitate or aggravate pre- either alone or in combination with dopaminergic agonists, espe-
existing diabetes mellitus, hyperlipidemia, hypercholesterolemia, cially in patients with depression and a history of substance abuse
hypertension, and OSA. Furthermore, injuries from careless food [63]. SSRIs, especially sertraline, have been shown effective in the
preparation, such as burns and lacerations, seem to occur in almost treatment of both SRED and NES [69]. Topiramate, given at a dose
one-third of patients [63]. As initially described by Schenck and range of 100–400 mg at night, can reduce night eating, improv-
colleagues, SRED is often associated with other sleep-related motor ing nocturnal sleep and producing weight loss in patients with
disorders, such PLMS, RLS, SW, and, to a lesser extent, OSA, brux- SRED [60].
ism, and circadian rhythm disorders [54,58,63,65,66]. SRED is not
associated with daytime eating disturbances, and behaviors such as
self-induced vomiting or excessive exercise, typical of bulimic/ano-
Other parasomnias
rexic disorders, are absent [61]. This section describes parasomnias that are independent of sleep
There are no current prevalence data on SRED in the general stage, appearing during both REM and NREM sleep [1]‌. These con-
population, and the reported prevalence results are inconsistent sist of the following:
(0.5–4.7%) [53]. Although SRED can affect both sexes and all ages, 1. Sleep enuresis.
it is more common in young adult women [55]; the average age
2. Exploding head syndrome (EHS).
of onset of SRED is approximately 22–27 years [55,57]. A familial
relationship has been described, suggesting a role of genetic fac- 3. Sleep-related hallucinations, hallucinatory experiences, princi-
tors. The pathophysiology of SRED remains largely unknown. In pally visual, that occur at sleep onset (hypnagogic hallucinations)
patients with concomitant sleep disorders, it has been suggested or on awakening from sleep (hypnopompic hallucinations).
that arousals may provoke varying levels of consciousness, prompt- 4. Parasomnias due to drug or substance or medical condi-
ing SW and sleep-related eating in predisposed individuals [58]. tion, behaviors emerging with a close temporal relationship
The association of SRED with dopaminergic responsive disorders between exposure to a drug medication or biological substance
such as PLMS and RLS [53,55], its clinical response to dopaminer- or as a manifestation of an underlying neurological or medical
gic drugs [55], and the major role of dopamine as a mediator of the condition.
mesolimbic reward mechanism support a link between SRED and
dopaminergic dysfunction.
A thorough sleep history is essential for the recognition and Sleep enuresis
diagnosis of SRED. The timing, frequency, and description of food Sleep enuresis is one of the most common and distressing paras-
ingested during eating episodes should be elicited. A complete omnias of childhood, consisting of involuntary micturition during
medication history, including when medications were started, is sleep in children after the age of 5 years [70]. Sleep enuresis includes
required [56]. If drugs have been implicated in the initiation of primary enuresis, meaning that the child has never achieved uri-
SRED, their cessation will stop eating episodes. If other sleep dis- nary control, which represents most cases in early childhood (75–
orders are suspected, or if the episodes are stereotypical or have 80%), and secondary enuresis, which implies that the child has had
resulted in injury, VPSG should be performed, ideally with food at least 6 months of dryness before bedwetting. The prevalence of
placed at the bedside [54–56,58]. The most frequent PSG findings sleep enuresis in 5-year-old children is between 15% and 25%, with
are an increased number of arousals, most of which occur during a decrease with age of 15% per year and with a prevalence of up to
NREM sleep or exclusively during SWS [59], together with chewing 1% in 15-year-old patients. The prevalence is influenced by many
and swallowing movements during stage 2 (Fig. 39.2). factors, such as male gender, low socioeconomic status, institution-
SRED shares some clinical features with night eating syndrome alization, and black race. Even if it is no longer believed that enure-
(NES), such as a chronic course, familial association, comorbid sis is mainly a psychiatric disorder, psychosocial factors may have
neuropsychiatric diseases, and a frequent association with weight a role: children with post-traumatic stress or bullied children are
gain and obesity [56,60,67]. There is a debate as to whether SRED more likely to have sleep enuresis [70]. Enuresis can also have psy-
and NES should be classified as independent entities or whether chological consequences such as low self-esteem, which disappears
they should be considered as a continuum of a single condition with dryness. Several studies have shown the important role of
involving eating urges and sleep disorders. In fact, NES is best char- genetic and familial factors in determining sleep enuresis; children
acterized as a circadian delay in meal timing [60], associated with whose parents have a history of sleep enuresis are more frequently
insomnia, rather than as a parasomnia [56]. affected, and in some patients, it has been seen to have an autosomal
Treatment of SRED usually involves the management of concom- dominant inheritance with high penetrance [70]. Finally, a more
itant sleep disorders if present. For patients with SW, PLMS, and important factor involved in the pathogenesis of sleep enuresis is

F3 - A1
Cz - A1
C3 - A2
O1 - A2
R. EOG
L. EOG
Mylo.
R. Orb. Oculi.
R. Orb. Oris.
R. Mass.
R. SCM
R. Bic. Brac.
L. Bic. Brac.
R. Tib. ant.
L. Tib. ant.
EKG
Microph.
Chest
3 sec.
Fig. 39.2 Sleep-related eating disorder (SRED). The PSG excerpt shows an eating episode occurring some seconds after a complete awakening from stage 3 NREM sleep.
During the episode, the 45-year-old woman consumes some crackers. The episode is characterized by rhythmic masticatory-muscle activity, chewing and swallowing
movements on EEG, and masseter muscle traces. EOG: electro-oculogram; Mylo.: mylohyoideus; Orb.: orbicularis; Mass.: masseter; SCM: sternocleidomastoideus; Bic.Brac:
biceps brachii; Tib. ant.: tibialis anterior; EKG: electrocardiogram; Microph.: microphone; Chest: chest respirogram; R.: right; L.: left.
the developmental delay in the brain areas involved in micturition present signs of both forms of enuresis and consequently require
control network [71,72]. combined therapy with antidiuretic and detrusor-relaxant drugs.
Enuretic episodes can occur from once a week to every night, Secondary enuresis may be caused by a variety of disorders, such as
usually in the first half of the night. The sleep pattern of enuretic diabetes mellitus, diabetes insipidus, epilepsy, neurogenic bladder,
children is not significantly different from that of non-enuretic urinary tract infection, and ureteral malformations. Other diseases
children; it can be characterized by an increased number of sleep may facilitate sleep enuresis, including, for example, attention-defi-
cycles and by a longer time spent in bed. Enuretic children are con- cit hyperactivity disorder, sickle cell anemia, and other sleep disor-
sidered “deep sleepers,” showing decreased arousability, and, dur- ders such as OSA [70,75]. From 8% to 47% of children with OSA
ing the night, they present more parasympathetic activity and less have nocturnal enuresis, which improves with adenotonsillectomy.
sympathetic activity than controls [70]. If sleep enuresis is monosymptomatic, then only urinalysis and
Primary enuresis can be monosymptomatic (without other clini- urine cultures are needed [76]. When other symptoms coexist, fur-
cal manifestations referable to the urogenital or gastrointestinal ther investigations should be performed: ultrasonography, vesical
tracts) or polysymptomatic (associated with daytime symptoms like sphincter electromyography, cystometry, cystoscopy, and MRI of
urgency, chronic constipation, or encopresis). Polysymptomatic the spine to exclude spinal malformations.
enuresis has been associated with a polymorphism in the gene Sleep enuresis usually resolves spontaneously; treatment options
encoding 5-hydroxytriptamine receptor 2A [73]; the etiopathogen- include lifestyle modification, medications, and alternative therapies.
esis of monosymptomatic enuresis is uncertain. Behavioral techniques are nowadays preferred to medications and
Basing on clinical and pathogenetic features, two different forms consist of behavior modifications such as evening fluid limitation and
of sleep enuresis can be distinguished: diuresis-dependent and caffeine avoidance, wetness alarms, and retention control exercises.
detrusor-dependent enuresis [70]. Diuresis-dependent enuresis The bell-and-pad method is based on the use of a urine detector, with
is characterized by nocturnal polyuria that may be due to poly- an alarm sounding and waking the child as voiding starts; its success
dipsia or to a reduced ability to concentrate urine. In these cases, rate is 65–80%, with relapses occurring in 10–15% of cases. Drug
enuretic children show a decreased vasopressin peak during sleep, therapy includes desmopressin for patients with vasopressin defi-
with a high overnight urine production exceeding the functional ciency with a diuresis-dependent enuresis, coupled with anticholiner-
bladder capacity. It has been proposed that a defect at the central gic drugs if needed, such as oxybutynin and the newer tolterodine, in
arginine vasopressin receptor level or in the signal transduction therapy-resistant patients [70,76–79]. Desmopressin side effects like
pathway causes deficiency in arginine vasopressin in these patients. hyponatremia and water intoxication are possible but rare. Tricyclic
Detrusor-dependent enuresis is associated with detrusor overac- antidepressants, especially imipramine, may also be used; however,
tivity. In these cases, enuretic children, usually non-responders to because of their high relapse rate and risk of fatal overdose, they are
antidiuretic therapy, show frequently uninhibited detrusor contrac- not considered as a primary treatment. Reboxetine may be used as an
tions during sleep that fail to awake the child and result in bedwet- alternative to imipramine. Medications usually provide a decrease in
ting [74]. These children may also have daytime symptoms such the frequency of episodes, but only a few patients reach complete dry-
as urgency and incontinence or may be constipated. Children may ness and the treatment effect is not sustained once the medication is

stopped. Psychotherapy, hypnotherapy, and electro-acupuncture are To date, the nature and mechanisms of many parasomnias, as well
alternative therapies, but their effectiveness is not so clear. as their effective and specific treatment, remain largely unknown.
In recent years, many significant advances have been made in
Exploding head syndrome understanding the clinical features of parasomnias and elucidating
EHS is a rare parasomnia characterized by a violent sense of explo- their pathophysiology. A full comprehension of these mechanisms
sion in the head [80], which arises abruptly and awakes the patient will also constitute an invaluable tool for the comprehension of the
from sleep. The syndrome is confined to sleep and occurs predomi- mechanisms that regulate sleep.
nantly when the patient is falling asleep, as well as during daytime
naps [80]. Patients experience a tremendously loud imagined noise References
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SECTION 9
Sleep and medical

disorders

CHAPTER 40
Sleep and the heart

Winfried J. Randerath and Shahrokh Javaheri
Introduction OSA remains greatly underdiagnosed [4,5]. A telephone survey

in Great Britain showed that 31% of 5000 participants had con-
There is a bidirectional relationship between sleep and the heart. tacted a physician more than 6 times within the preceding year
Normal non-â•‰rapid eye movement (NREM) sleep is peaceful for the because of symptoms of SRBD during sleep. Surveys in practices
cardiovascular system, since favorable autonomic changes occur of general practitioners revealed that 32% of the patients with high
that result in a decrease in heart rate and blood pressure. Therefore, probability for OSA were not diagnosed [4,5]. Undiagnosed OSA
cardiac workload and oxygen consumption decrease. On the other may result in a variety of cardiocerebrovascular disorders such as
hand, sleep pathology such as sleep apnea or periodic limb move- hypertension, coronary artery disease, neurocognitive dysfunction,
ments can adversely affect cardiac function and structure, while transient ischemic attack, and stroke.
cardiac pathology such as heart failure disrupts sleep architecture, OSA syndrome (OSAS)—â•‰that is, an AHI ≥ 5/â•‰h plus exces-
which in turn adversely affects the heart. In this chapter, we review sive daytime sleepiness (EDS)—â•‰remains among the most preva-
some of these disorders in detail. lent sleep disorders. Patients present with diurnal and nocturnal
symptoms such as EDS (hence the syndrome), fatigue, loud and
Sleep-â•‰related breathing disorders irregular snoring, nocturia, waking up not refreshed, and morning
The main two phenotypes of sleep-â•‰related breathing disorders headache. Partners often report breathing cessations during sleep
(SRBDs) that are the focus of this review are obstructive and central [6]â•„. EDS may result in crashes, lack of attention, and poor perfor-
sleep apnea [1]â•„. While there is some overlap between the mecha- mance. The current estimates of the syndrome in US adults are 14%
nisms underlying these two sleep breathing disorders, the sine in males and 5% in females aged 30–â•‰70 years [3].
qua non of obstructive sleep apnea (OSA) (Fig. 40.1) is occlusion Obstructive breathing disturbances are associated with repeti-
of the upper airway, while central sleep apnea (CSA) (Fig. 40.2) is tive oxygen desaturations, increases in PaCO2 (the arterial partial
of diverse etiology, with varying underlying mechanisms. Among pressure of carbon dioxide, PCO2), and arousals. Futile ventilatory
these are increased loop gain, explaining periodic breathing in efforts of the diaphragm and the thoracic muscles against a closed
heart failure, and failure of the breathing rhythm generator, the pre-â•‰ upper airway may result in a paradoxical breathing pattern of tho-
Bötzinger complex, in opioid-â•‰induced CSA. rax and abdomen (Fig. 40.1). Obstructive disturbances terminate
Also, since this review is focused mostly on sleep apnea and the abruptly, often in association with arousals, which are themselves
heart, we emphasize the bidirectional relationship of sleep apnea associated both with increased sympathetic activity resulting in high
and heart disease such that, when comorbid, a vicious circle ensues. arterial blood pressure and with decreased parasympathetic activ-
ity causing tachycardia. The level of pleural pressure generated by
Obstructive sleep apnea respiratory effort, seems to be one potential trigger of arousals from
OSA is characterized by increased collapsibility and obstruction NREM sleep [7]â•„. Nevertheless, any causal relationship between
of the upper airways leading to complete cessation (apnea) or par- these phenomena is ambiguous. One important question that has
tial reduction of airflow (hypopnea). Predispositions include male therapeutic implication is the role of the arousals in perpetuating
gender, obesity, old age, family history, and altered upper airway obstructive breathing disorders. Younes et al. found that inspira-
anatomy (eg, macroglossia, retrognathia, large tonsils, or adenoids) tory flow increased in 22% of events before arousal and was restored
resulting in a narrow airway. The last of these, along with increas- in 70% without an arousal [8]. In these situations, combinations of
ing prevalence of obesity, accounts for the increased prevalence of stimuli, such as elevated levels of carbon dioxide and negative pres-
childhood OSA. sure reflexes, can activate upper airway dilator muscles, and delay-
The Wisconsin cohort longitudinal studies [2,3] are the most ing the arousal may be beneficial to restore pharyngeal patency. The
systematic epidemiological data on the prevalence of OSA in the limited flow through the narrowed airways during hypopneas and
general population, and the most recent updated data indicate the abrupt reopening at the end of an apnea represents the correlate
increasing prevalence of OSA in the USA [3]â•„. Using a definition for of the typical loud and irregular snoring sound [9–â•‰11].
OSA of an apnea–â•‰hypopnea index (AHI) ≥ 5 per hour of sleep, the
current estimates are 34% in adult males and 17% in adult females Central sleep apnea
aged 30–â•‰70 years. The prevalence of moderate to severe OSA, CSA is characterized by recurrent cessations (central apnea) (Fig.
defined as an AHI ≥ 15/â•‰h is 13% in men and 6% in women aged 40.2), or reduction of airflow with a simultaneous proportional
30 –â•‰70 years [3]. reduction of the breathing effort (central hypopnea). Ventilatory

EOG
EOG
CHIN EMG
EEG C A
EEG O A
EKG
50 mV
THERMOCOUPLE
CO
Paradoxical thoraco-
abdominal excursions
RC + ABD
RC
ABD
5.0 sec
20 P (cmH O)
10
0
–10
–20
Fig. 40.1 A 30-second epoch of obstructive sleep apnea.

Reproduced from Javaheri S, Heart Failure. In: Kryger M, Roth T, Dement W, [eds], Principles and Practices of Sleep Medicine, pp. 1400–15, Copyright (2011), with permission from Elsevier.
EOG
EOG
CHIN EMG
EEG C A
EEG O A
EKG
50 mV
CO
RC + ABD
RC
ABD
5.0 sec
P (cmH O)
20
10
0
–10
–20
95
% SaO 85
75
65
Fig. 40.2 A 30-second epoch showing central sleep apnea [13].

Reproduced from Am Rev Respir Dis., 141(4 Pt 1), Dowdell WT, Javaheri S, McGinnis W, Cheyne-Stokes respiration presenting as sleep apnea syndrome. Clinical and polysomnographic features,
pp. 871–9, Copyright (1990), with permission from American Thoracic Society.

Chapter 40 sleep and the heart 397
impulses generated by the brainstem respiratory centers are limited at times sustained oxygen desaturations, due to hypoventilation.
or lacking. In contrast to OSA, the upper airways are not necessar- These SRBD occur in the background of Biot and cluster breath-
ily narrowed, although passive closure of the pharyngeal airways ing [17,18,25]. This pattern of breathing characterized by irregular
may occur [12]. This was shown in patients with heart failure in respiratory pauses and gasping without periodicity (Fig. 40.3) is
whom an esophageal balloon was in place, who exhibited frequent the most typical PSG finding in opioid-induced sleep apnea and is
upper airway occlusions at the end of central apneas [13]. These distinguished from periodic breathing (HCSB) in heart failure (Fig.
events were considered mixed apneas. 40.2). The mechanism of opioid-associated sleep apnea is beyond the
CSA as a polysomnographic (PSG) finding is associated with a large scope of this chapter, and is reviewed here only briefly (for reviews,
number of clinical conditions, including Cheyne–Stokes breathing see [17,18,25]). Opioid receptors are prevalent in carotid bodies,
(hereinafter referred to as Hunter–Cheyne–Stokes breathing, HCSB, brainstem, and respiratory-related neurons. The pre-Bötzinger
as John Hunter, a Scottish surgeon, described this unique pattern of complex, the site of breathing rhythm generation, is inhibited by
breathing almost four decades before John Cheyne; see [14]), expo- opioids and underlies the mechanism of central apneas. In addition,
sure to high altitude, brainstem lesions, stroke, endocrine disorders, opioids inhibit hypoglossal neuronal pool, diminishing genioglossal
and opioids [14–19]. Similar to OSA, CSA can—but does not neces- muscle activity and promoting upper airway occlusion.
sarily has to—be associated with daytime sleepiness, frequent noctur- In recent years, additional phenotypes have been described, such
nal awakenings, and decreased sleep insufficiency and insomnia [18]. as central disturbances emerging under therapy with continuous
HCSB is characterized by recurrent central apneas and hypo- positive airway pressure (CPAP). Moreover, several patients suffer
pneas and a crescendo–decrescendo pattern of flow and effort not only from one type, but from coexisting obstructive and central
(Fig. 40.2) [13]. Although these events are characterized by central disturbances [14,15,25–27]. This hybrid breathing pattern was first
apneas, upper airway obstruction has been documented at the end recognized in early studies of patients with heart failure [14,15,25]
of the events before resumption of breathing, as noted above [13]. and is also well recognized in patients taking opioids [16–18].
Cardiocerebrovascular disorders, especially atrial fibrillation, A clear separation of the different entities is not feasible, owing
heart failure, and stroke, predispose to the development of CSA to limitations of standard PSG on the one hand and overlap of the
[14,15,20–24]. HCSB describes a pattern of periodic breathing in pathophysiologies on the other [28].
patients with heart failure [23]. The mechanisms underlying HCSB
will be discussed in detail later. Pathophysiology of OSA
Opioid-induced sleep apnea presents with mixed SRBD consist- The pharyngeal region, which is not stiffened by bony or carti-
ing of both obstructive and central apneas and hypopneas, and laginous structures, represents an unstable, collapsible part of the
CSA CSA CSA Hypopnea CSA CSA CSA CSA
Fig. 40.3 A 5-minute epoch of opioids and sleep apnea.

Reproduced from Compr Physiol., 3(1), Javaheri S, Dempsey JA, Central sleep apnea, pp. 141–63, Copyright (2013), American Physiological Society.

398 Section 9 sleep and medical disorders
airways. Its width depends, among other things, on morphologi- mortality are associated with greater respiratory disturbance dur-
cal factors, namely, the volume of the surrounding soft tissue and ing sleep [53–58].
the structure and position of the tongue and mandible into which The association of SRBD and cerebrovascular events has been
it inserts. The degree of upper airway collapse varies continuously studied intensively. A cross-sectional analysis showed a fourfold
according to sleep stage or body position. It can be quantified by the increased risk of stroke in patients with an AHI ≥ 20/h. Moreover,
critical closing pressure, which represents the pressure of the sur- an AHI ≥ 20/h also increased the risk of developing stroke in
rounding collapsible segment when it collapses [29,30]. the next 4 years which failed to reach statistical significance after
Obesity, via multiple mechanisms, is the major risk factor for adjustment of confounders [49]. A meta-analysis of studies on
OSA [31]. One such mechanism is narrowing of the upper airway sleep apnea and stroke showed a strong correlation with OSA [51].
by excess fatty tissue. There is growing evidence that, in the supine The relative risk of stroke in sleep apnea may differ between the
position, fluid shifts from the lower to the upper body compart- genders. While there is a continuous increase of the risk by 6% per
ments and accumulates in the soft tissue of the upper airways, pro- AHI unit in men, the risk increases in women with an AHI ≥ 25/h
moting upper airway closure during sleep. The extent of this fluid [50]. These data need to be reconfirmed.
shift correlates with the number of respiratory disturbances [32]. OSA also adversely affects the prognosis of patients, mainly owing
Under normal circumstances and in most individuals, the activity to cardiovascular consequences [56–58]. Survival is reduced in
of dilating upper airway muscles counterbalances these unfavora- OSA patients in a dose-dependent manner, with AHI as the metric;
ble predispositions. Several muscles show phasic activity depend- however, mortality becomes significant in those with an AHI ≥ 30/h
ing on inspiration, although tonic activity of some decreases during [56–58]. Observational studies show that survival improves with
sleep. Local reflex mechanisms additionally contribute to the mus- CPAP therapy [56], even in the those with less severe OSA [59].
cle tone [33]. The tonic muscular activity is increased in sleep apnea The latter observation is consistent with dose-dependent associa-
patients during wakefulness as a compensation for the mechani- tion of OSA with mortality. If this observation is further confirmed,
cal load—a mechanism that fails during sleep [34–36]. It has been it has major implications, since most patients with sleep apnea fall
hypothesized that the continuous stress on the muscles or the long- in the category of mild to moderate disorder. OSA-related mortality
term vibrational trauma of snoring might change the ultrastructure is primarily due to cardiovascular disease [58].
and integrity of the muscle bundles [6,37]. Moreover, impairment
of the sensory characteristics of the upper airway mucosa [38] Pathophysiology of CSA
might interrupt the reflex mechanisms that counterbalance nega- The pathophysiology of CSA is complex, as it is associated with many
tive intraluminal pressure (negative pressure reflex). conditions, as noted earlier [14,15]. Below, we discuss the mechanisms
underlying development of CSA in heart failure, the most common
Cardiovascular consequences of OSA cause of CSA in the general population. We discuss the loop gain,
The complete (apnea) or partial (hypopnea) obstruction of the which is the ratio of the ventilatory response to internal or external
upper airways leads to oxygen desaturation, arousals, and neuro- stimuli, the proximity of the prevailing PaCO2 to the apnea threshold
hormonal activation and excretion of catecholamines during sleep PCO2 during sleep, referred to as PCO2 reserve, and the instability of
[39–47]. The frequent changes between hypoxia and reoxygenation the respiratory control system during transition to sleep, shift in sleep
seem to be the most relevant factor contributing to the develop- stages and arousals. All of these collectively increase the likelihood of
ment of cardiovascular consequences via reactive oxygen species developing periodic breathing and central apneas during sleep.
[41]. Altered blood gas chemistry increases muscle sympathetic We also briefly discuss the mechanism of CSA associated with
nerve activity, blood pressure, and vascular resistance. The oxi- opioids, since this category of drugs is among the most commonly
dative stress leads to endothelial dysfunction and atherosclerosis used, and central apneas are prevalent in chronic opioid users.
[39,48]. Several studies have shown that OSA is an independent During wakefulness, ventilation is mainly regulated by behavio-
risk factor for the development of arterial hypertension, heart fail- ral, non-chemical factors. As these factors become irrelevant dur-
ure, and stroke [45,46,49–51]. ing NREM sleep, owing to withdrawal of the wakefulness drive to
Most studies on the prevalence of SRBD in heart failure focus breathe, ventilation is influenced mainly by PaCO2 level. For the
on patients with systolic dysfunction, which is characterized by a same reason, small changes in PaCO2 level have profound influ-
reduction of the left ventricular ejection fraction. In contrast, iso- ence on ventilation [15,60]. Furthermore, the apnea threshold,
lated diastolic heart failure is pathophysiologically due to a non- which defines the PaCO2 level below which breathing ceases, is
compliant, stiff left ventricle. The left-ventricular end-diastolic unmasked during NREM sleep. Third, if the difference between the
pressure increases and leads to pulmonary congestion and edema. actual prevailing PaCO2 and the apnea threshold is narrowed, as
However, the left-ventricular ejection fraction is commonly pre- is in some patients with heart failure, the likelihood of developing
served [44,52]. Both OSA and diastolic dysfunction are common CSA is increased [61]. With these powerful mechanisms exposed
disorders of the elderly population. The pathophysiological effects in NREM sleep, small variations in ventilation may either lower
of OSA, including sympathetic activity, arterial hypertension, and the PaCO2 below or elevate it above the apnea threshold, a self-
intermittent hypoxia, may contribute to the development of dias- sustaining mechanism for recurring central apneas.
tolic heart failure [40,45,46]. Although the body of evidence is still Central apneas are prevalent during NREM sleep, but are rare
limited, the coherence between OSA and diastolic dysfunction is during REM sleep, as the difference between the prevailing PaCO2
supported by the finding that PAP therapy may reverse the remod- and the apnea threshold is wide (for reviews, see [15,60]).
eling of the myocardial structure [44–46]. Loop gain is an engineering term and when applied to the nega-
In addition, coronary artery disease is also adversely influenced tive feedback system controlling breathing, it defines the ratio of
by OSA. Major cardiac events, restenosis of coronary vessels, and ventilatory response to a disturbance in ventilation, for example an

(a) 8 is accompanied by a low PCO2 reserve (see [15,60]). In the absence
Ventilation (L/min)
Low loop gain of a low PCO2 reserve, a low PaCO2 is protective against developing
b
central apnea as dictated by the alveolar ventilation equation [65].
6
As noted earlier, heart failure patients with CSA/HCSB exhibit an
c augmented hypercapnic ventilatory response while awake [66,67].
a
4 This results in an overshoot in ventilation even in the face of a small
0 30 60 90 120 150
rise in PCO2 that may occur after a short pause in breathing, or
(b) 8 High loop gain promotes as PCO2 rises in the course of an apnea or hypopnea. This over-
Ventilation (L/min)
breathing instability
shoot in ventilation transiently lowers the prevailing PCO2 toward
or below apneic threshold, causing another hypopnea or apnea. The
6
cycle is maintained, as central apnea begets central apnea.
The reactivity of cerebral blood flow response to hyper-and
4 hypocapnia differs between healthy persons and heart failure
0 30 60 90 120 150
Time (sec)
patients with CSA. Normally, the homeostatic response of the cer-
ebral vascular bed to changes in PaCO2 is an important protector
Fig. 40.4 The ventilatory response (at B) to a reduction in ventilation (at A), of brain extracellular fluid PCO2/[H+]. Specifically, when PaCO2
for example a hypopnea. In (a), the magnitude of the compensatory ventilator increases, cerebral vessels dilate, and if the mean arterial blood
response, i.e, the amount of hyperventilation, is less than the disturbance. In this pressure remains unchanged, then cerebral blood flow increases,
case, the loop gain is less than 1 and shortly the ventilation returns to normal level
washing out CO2 from the brain, maintaining brain PCO2 as close
(at C). In (b), the loop gain is more than 1. Consequently, the disturbance elicits
periodic breathing [85].
to normal as possible. The reverse occurs when PaCO2 decreases.
Adapted from Comprehensive Physiology, 3(1), Javaheri S, Dempsey JA, Central sleep apnea, Therefore, this homeostatic regulation of cerebral blood flow in
pp. 141–163, Copyright (2013), with permission from John Wiley and Sons. response to changes in PaCO2 (either increases or decreases)
reduces the impact of arterial hypercapnia and hypocapnia on
brain and central chemoreceptor PCO2/[H+]. It has been shown
apnea or hypopnea [15, 62]. The higher the loop gain, the greater that in heart failure patients with CSA, the physiological increase in
the tendency toward breathing instability (Fig. 40.4). When the cerebral blood flow following elevation of PaCO2 is diminished (for
magnitude of the increase in ventilation is greater than or equal details, see [15]). As an example, therefore, with a central apnea, for
to the magnitude of the preceding apnea or hypopnea (i.e, loop a given rise in PaCO2, the brain and central chemoreceptor PCO2/
gain ≥ 1), the respiratory system is unstable and periodic breathing [H+] will be higher, resulting in overshoot and breathing instability.
occurs in NREM sleep. The three major components of the loop The instability of ventilation becomes aggravated by arousals
gain are increased in some patients with heart failure, and these are from sleep. Arousals stimulate ventilatory drive and reduce the
the patients who suffer from periodic breathing. These three com- CO2 level, as the sleeping PCO2 is excessive when the brain arouses
ponents (gains) are increased chemosensitivity (increased control- from sleep. Furthermore, the CO2 hypersensitivity of the chemore-
ler gain), decreased functional residual capacity (increased plant ceptors in some heart failure patients, discussed earlier, augments
gain: a large change in PCO2 for a given change in ventilation), and hyperventilation during transient arousals, resulting in PCO2 fall-
increased circulation time (mixing gain). The longer the circula- ing below the apneic threshold, with consequent central apnea.
tion time, the time it takes for the changes in pulmonary capillary
blood PCO2 and partial pressure of oxygen (PO2) to reach the sites CSA in cardiac diseases
of chemoreceptors, the longer the cycle of periodic breathing. This CSA is quite rare in the general population, but occurs frequently in
increased circulation time converts a negative feedback system to a number of cardiovascular disorders, including heart failure with
a positive one. It follows that the greater the magnitude of chemo- either reduced or preserved ejection fraction, atrial fibrillation, and
sensitivity to PCO2 and PO2, and the lower the functional residual pulmonary hypertension [14,15]. In this section, we concentrate on
capacity, the higher the loop gain. The three gains discussed above heart failure with reduced ejection fraction, which has been most
describe the characteristics of the loop gain under steady -state systematically investigated.
conditions, whereas the loop gain is dynamic and more complex Several studies have consistently shown high prevalence of CSA
during sleep, while periodic breathing is occurring [62]. in patients with reduced left-ventricular ejection fraction (LVEF)
PaCO2 is chronically reduced in some patients with heart failure (for reviews, see [23,66], even in the absence of symptoms of
and pulmonary congestion [20,62–64]. In these patients, increased heart failure [21]. Central apneas and hypopneas are interspersed
pulmonary capillary pressure stimulates juxtacapillary receptors, between long cycles of waxing and waning of ventilation, a unique
causing hyperventilation. Pulmonary capillary wedge pressure pattern of breathing that, as already mentioned, is referred to as
(PCWP), normally measured by insertion of a Swan–Ganz catheter HCSB [66,68]. It is of crucial clinical relevance that many of these
through the jugular vein into the pulmonary artery, is a measure patients do not present with the classical symptoms of habitual snor-
of mean left-atrial pressure and left-ventricular end-diastolic pres- ing or with subjective daytime sleepiness [14,15,18]. Furthermore,
sure (in the absence of mitral valve disease), and it correlates sig- heart failure patients with CSA are normally not obese [14,18]. The
nificantly with PaCO2 [20]. Medical therapy of heart failure reduces absence of these risk factors for sleep apnea was recognized in early
the PCWP, PaCO2, and respiratory disturbances during sleep [20]. studies of heart failure [14,15,18], and therefore we have referred
At this point, however, we need to emphasize that although an to sleep apnea as an occult sleep disorder [15]. These findings have
awake low steady-state PaCO2 is highly predictive of CSA [63], a low subsequently been confirmed by others [69]. This lack of subjective
steady-state PaCO2 by itself is protective against CSA [65], unless it daytime sleepiness may contribute to under-diagnosis of CSA in

heart failure, particularly since these patents are generally not obese as hypertension, coronary artery disease, atrial fibrillation, and
or hypertensive and do not snore much [24]. heart failure, the best treatment option for OSA is CPAP therapy.
Heart failure patients with CSA have higher levels of brain Treatment of CSA is more difficult than that of OSA, and multiple
natriuretic peptide as compared with those without breathing dis- options are available as discussed below.
turbances [70]. Moreover, the urinary norepinephrine (noradrena-
Treatment of OSA
line) concentration—a measure of integrated overnight sympathetic
activity—is increased in heart failure with CSA as compared with The pathophysiology of OSA is characterized by an imbalance
heart failure without breathing disturbances [71]. Moreover, CSA between dilating and obstructing factors in the upper airways.
significantly increases malignant cardiac arrhythmias [72,73] and Mechanical properties and neuromuscular control of the upper air-
cardioverter–defibrillator therapies [72] as compared with heart way muscles are the key factors contributing to upper airway occlu-
failure patients without breathing disturbances. Importantly, effec- sion. In some patients, a high loop gain also plays a role.
tive treatment of CSA decreases the number of nocturnal ven- Intensive education and advice of patients and relatives, coupled
tricular arrhythmias [74] and the associated mortality [75] when with reduction of body weight in obese patients, is generally rec-
effectively treated [76]. ommended [81,82]. However, weight loss as a single procedure is
The mechanism underlying arrhythmias is in part due to the insufficient in most cases. Therefore, frequently, additional therapy
increased sympathetic activity already discussed. It is therefore not is offered, particularly in patients with preexisting cardiovascular
surprising that heart failure patients who smoke have an excess disease. In these patients, we invariably recommend treatment
probability of nocturnal ventricular arrhythmias [73] and perhaps with positive airway pressure devices, for which there are multiple
sudden cardiac death. Nicotine, the active chemical in tobacco, options available [83–86].
increases efferent sympathetic activity through stimulating the nic- CPAP for treatment of OSA
otinic receptors in peripheral arterial chemoreceptors in the carotid Since its first description in the early 1980s, CPAP treatment has
bodies. Active discussion regarding cessation of smoking needs to become the therapy of choice for OSA [87]. The positive airway
be part of any physician visit, and is critical in patients with cardio- pressure is provided by a flow generator device and applied to the
vascular disease and heart failure. patient via a tube and a mask, usually placed on the nose. Thus, the
So far, we have concentrated on heart failure with reduced intraluminal pressure of the upper airways is increased enough to
LVEF, but in passing we also note a high prevalence of CSA and counterbalance the obstructive tissue pressure. The device also pro-
OSA in isolated diastolic heart failure and in heart failure with pre- vides humidity to prevent nasobuccal dryness [88].
served ejection fraction (HFpEF). Isolated diastolic heart failure The optimal treatment pressure is individually adjusted by man-
is pathophysiologically due to a noncompliant, stiff left ventricle. ual or automatic titration, aiming at complete resolution of apneas,
This altered remodeling of the left ventricle causes increased left- hypopneas, snoring, and flow limitations. CPAP stabilizes the upper
ventricular end-diastolic pressure and consequent pulmonary con- airways independent of the localization of the obstruction, which
gestion and edema. makes it the most effective treatment option. It normalizes respira-
In spite of the large number of studies in heart failure with tory disturbances and sleep quality, daytime performance, neuro-
reduced ejection fraction, there has been only one large, though cognitive deficits, and the ability to drive cars and operate machines
excellent, study in HFpEF [52]. In a prospective study, Bitter et al. safely. In addition, CPAP has been shown to reduce the risk of car-
evaluated 244 consecutive patients with HFpEF who were on opti- diovascular comorbidities. Kohler et al. found significant reductions
mal therapy and were well characterized, including by right-heart in the augmentation index and the mean arterial blood pressure in
catheterization. Similar to the prevalence in patients with reduced effectively treated patients [89]. There are contradictory findings in
ejection fraction, using an AHI ≥ 15 per hour of sleep, the prev- terms of arterial hypertension, and this is mostly due to inclusion
alence of moderate to severe sleep apnea was close to 50%, with of patients with “hypertension” whose blood pressure (BP) was not
almost half of these patients suffering from OSA and half from that elevated (they were on antihypertensive medications) at the
CSA. Randomized controlled therapeutic trials are needed to delin- time of CPAP therapy; another issue has been lack of efficacy in
eate the causation and whether treatment of either OSA or CSA CPAP non-adherent patients. We should, however, expect improve-
influences outcomes of HFpEF. ment in hypertension in OSA patients who are truly hypertensive as
In conclusion, SRBDs, both OSA and CSA, are prevalent in defined by blood pressure measurement (not simply being on med-
patients with cardiovascular disorders, including asymptomatic ication with normal or near normal blood pressure) and in those
left-ventricular dysfunction, atrial fibrillation, coronary artery dis- with uncontrolled hypertension. Those with severe OSA are most
ease, and heart failure, both with normal and with reduced ejec- likely to gain the greatest hemodynamic benefit from CPAP treat-
tion fraction. Biomarkers of poor heart function and mortality or ment. Campos-Rodriguez et al. found a significant improvement
severe cardiac events are increased in patients with cardiovascular after 24 months of CPAP in patients with insufficiently controlled
disease comorbid with sleep apnea. These patients may not present hypertension and in those who used their devices for more than 3.5
with daytime sleepiness, but suffer from reduced quality of life and hours a day [90]. However, in the subgroup analysis of 35 patients
excess mortality. Taking these aspects together, we recommend with incompletely controlled hypertension at entry, a significant
routine screening for SRBDs in patients with cardiovascular dis- decrease in the 24-hour mean systolic and diastolic BP ranging
eases and appropriate treatment in order to improve outcome. from 4.2 to 5.1 mmHg was noted. Similarly, in the subgroup analy-
sis of 27 patients who used CPAP for more than 5.3 hours a day,
Treatment options for sleep apnea the range in BP drop varied from 4.3 to 6.7 mmHg. Linear regres-
Treatment options of sleep apnea, both OSA and CSA, in heart sion analysis showed that baseline systolic BP and hours of CPAP
disease have been reviewed elsewhere [23,26–28,44,66,68,77–80]. were independent predictors of reductions in BP with CPAP. In a
In general, in the presence of cardiovascular comorbidities such randomized controlled trial, use of CPAP significantly decreased the

BP of patients with moderate to severe hypertension by about 10 improvements in inflammation, hypertension, LVEF, and mortal-
mmHg within a few weeks [91]. There is also evidence showing a ity. The minimum acceptable adherence criterion for Medicare and
reduction of coronary artery disease in patients treated optimally other insurance companies to pay for the device is an average daily
by CPAP [90]. In addition, CPAP improves the prognosis of OSA use of 4 or more hours, at least 70% of nights. Positive airway pres-
patients. Marin et al. showed significantly more fatal and nonfatal sure compliance depends on several factors, including the patient’s
cardiovascular events in untreated patients with severe OSAS (AHI awareness of symptoms and their improvement, and optimal educa-
≥ 30/h) as compared with untreated patients with lesser degrees tion and support in the first days of the adaptation, but also the social
of the disease, simple snorers, healthy controls, and also patients and economic situation of the patient [100]. In patients with cardio-
effectively treated with CPAP [56]. Büchner et al. followed 449 OSA vascular disease, the better the adherence, the greater is the improve-
patients for 72 months, including 364 effectively treated and adher- ment in outcome, as already eluded to.
ent patients and 85 patients who refused treatment. While both Mandibular advancement devices for treatment of OSA
groups presented with similar cardiovascular comorbidities and risk
Mandibular advancement devices (MADs) widen the diameter of
factors, OSA was more severe in the adherent group [59]. In spite
the upper airways and counterbalance their collapse during sleep
of this, effective therapy with CPAP was associated with a substan-
by protruding the mandible and the tongue [101]. Unfortunately,
tial reduction in fatal and nonfatal cardiovascular events. Although
the efficacy of treatment cannot be predicted in individual patients.
limited by low treatment adherence, a most recently published RCT
Data from prospective and controlled studies show a reduction of
did not show a significant difference between CPAP and usual care
respiratory disturbances in about half of patients by 50–60% of the
on cardiovascular endpoints but found improvements of daytime
baseline AHI [102]. Current guidelines recommend adjustable, two-
symptoms. However, the number of cerebrovascular events was sig-
piece devices custom-made by a specialized dental specialist. Itzhaki
nificantly improved in those patients with good adherence [92].
et al. demonstrated in a case–control study a reduction of respiratory
There are limited studies of patients with heart failure and OSA
disturbances by 40–50% after 1 year of treatment as compared with
treated with CPAP. Overnight application of nasal CPAP has
untreated patients. Notably, this limited effect was associated with an
been shown to eliminate obstructive disordered breathing events,
improvement in parameters of endothelial function and oxidative
desaturation and the large negative swings in juxtacardiac pressure
stress [103]. In addition, Phillips et al. [104] compared CPAP with
that occur during upper airway occlusion [74]. As a result of these
MAD in a prospective, randomized cross-over trial over 1 month
favorable physiological changes, treatment of OSA with CPAP may
each. Although CPAP was more effective in terms of respiratory
increase LVEF, as reported in three [93,94] of the four randomized
disturbances, the authors did not find a difference in arterial hyper-
controlled trials. In one trial, which was the only one with a placebo
tension or symptoms of sleep apnea. However, during the short treat-
arm (i.e, a CPAP device with minimal pressure) [95], there was no
ment period, neither method improved arterial hypertension.
change in BP, but adherence to the device was less than the other
There has been only one observational study of an MAD in
studies [93,94] in which adherence was reported.
patients with heart failure. Eskafi [105,107] studied 11 patients with
Javaheri et al. [96] analyzed more than 30 000 files of a cohort
heart failure with reduced ejection fraction (mean LVEF = 34%)
of Medicare beneficiaries with newly diagnosed heart failure.
and moderate sleep apnea, presumably a combination of both OSA
Normally, such patients are 65 years or older with a high prevalence
and CSA. Mandibular advancement was found to result in a signifi-
of heart failure. Based on the data in the literature and reviewed
cant reduction in AHI from 25 to 15 per hour. After 6 months of
above, all such patients should have been referred for sleep study
therapy, brain natriuretic peptide also decreased significantly; there
as 15 000 of them are likely to suffer from moderate to severe sleep
was, however, no significant change in ejection fraction. This is an
apnea. However, only 4% were suspected of suffering from SRBDs,
area that needs further research.
most probably OSA, which is easier to suspect clinically based
on obesity, hypertension, and snoring. However, only 2% under- Alternatives
went diagnosis and treatment. In multiple regression analysis, There is limited evidence for the use of alternative treatment options
after accounting for a number of covariates, there was a significant [106]. Tonsillectomy can be recommended in children and adults
improvement in survival of those patients diagnosed and treated in the case of tonsillar hypertrophy [107,108]. Maxillomandibular
for sleep apnea, compared with the rest of the patients. osteotomy has proven to be as effective as CPAP and may be suit-
A small observational study from Japan [97] showed significantly able in individual patients who cannot accept the latter [109].
improved survival in heart failure patients with OSA who were Distraction osteogenesis may be useful in patients with congenital
adherent to CPAP compared with those who were not. micrognathia and midface hypoplasia [110].
The principle of positive airway pressure treatment has not been Most recently, hypoglossal nerve stimulation by an implanted
changed since its first description. However, several modifications, device has been tried in a prospective observational (nonrand-
such as automatic expiratory positive airway pressure (EPAP) and omized) trial [111] in which 126 individuals who had difficulty
bilevel and expiratory pressure relief, have been introduced. These in either accepting or tolerating CPAP were implanted. The mean
algorithms may be preferred in individual cases and therefore extend BMI was 28.4 kg/m2 and patients with AHI ≥ 50/h were excluded.
the therapeutic portfolio available to the patients and sleep physician. The mean AHI was 32/h and decreased to 15.2/h at 12 months.
CPAP therapy is not associated with severe adverse effects, but Two secondary outcomes also improved significantly. The Epworth
may be limited by local side effects and inconvenience. The long- Sleepiness Scale score decreased from 11.6 to 7. Disease-specific
term efficacy of CPAP depends primarily on adherence by the quality of life was assessed by the Functional Outcomes of Sleep
patient [98–100].The main symptom of OSA, namely, EDS, normally Questionnaire (FOSQ) score, which increased by 2.9 points—typi-
improves with CPAP use; however, the amount of improvement is cally, a 2-point increase is clinically significant. Stimulation resulted
dose-dependent with average nightly use [100]. This correlation in tongue soreness and abrasions in 40% and 21%, respectively. In
with dose dependence of CPAP use has also been demonstrated with the latter group, the device had to be reprogrammed, and some

required a mouthpiece. About 18% of the participants complained With regard to potential adverse effects of supplemental oxygen,
of tongue weakness, which resolved within a month. Two par- it has been reported that in patients with congestive heart failure,
ticipants required reoperation to reposition the stimulator. This hyperoxia may be associated with adverse hemodynamic effects
was considered a serious device-related adverse complication. No [121]. However, this has been shown primarily with a high frac-
favorable cardiometabolic changes were reported. tional concentration of oxygen, at doses that are beyond what is
necessary to treat desaturation due to CSA [117,120]. Furthermore,
Treatment options for CSA
the results of these studies are not applicable to patients with heart
The treatment options for CSA are evolving (for reviews, see failure and CSA, since supplemental oxygen is used to prevent
[23,62,68]). In general, CSA is more difficult to treat than OSA. desaturation, not to increase it above normal, the way this study
Both positive airway pressure devices and multiple medications [121] was designed.
have been tried. With virtually all of these therapeutic options, sig-
nificant residual events remain, as discussed below. Other medications
The respiratory stimulant theophylline has been shown to reduce
Optimization of cardiopulmonary function
CSA in heart failure [3,122,123]. Javaheri et al. studied oral theo-
Aggressive treatment of heart failure may improve or even eliminate phylline in 15 stable patients with systolic heart failure in a ran-
periodic breathing. Several mechanisms may be invoked, includ- domized double-blind placebo-controlled design. They showed a
ing decreasing wedge pressure, increasing stroke volume, decreas- reduction of the AHI by 50% associated with an improvement of
ing arterial circulation time, and normalizing functional residual oxygen saturation [123]. However, long-term data on the use of the-
capacity [23,62,68], all of which should stabilize periodic breath- ophylline are lacking. Due to potential pro-arrythmogenic potency
ing. Both pharmacological (eg, angiotensin-converting enzyme of theophylline and the limited evidence in CSA/HCSB, theophyl-
(ACE) inhibitors and beta-blockers) [112,113] and nonpharmaco- line should be only used in selected cases under close supervision.
logical device [114,115] therapy of heart failure have been shown Acetazolamide is a mild diuretic and respiratory stimulant,
to improve CSA. In spite of these findings, the prevalence of sleep which has been used to prevent and treat periodic breathing at
apnea has not changed with the introduction of beta-blockers into high altitude, as well as idiopathic CSA [124,125]. A randomized
the armamentarium of therapy for heart failure [23,68], as heart double blind placebo-controlled crossover study in 12 heart failure
failure is a progressive disease and with progression sleep apnea patients showed a significant reduction of CSA under acetazola-
either develops or worsens. mide. Although patients reported improvements in parameters of
A study of 45 patients showed that CSA is virtually eliminated sleep quality and quality of life, respiratory disturbances were only
after cardiac transplantation [116]. The results of this study there- reduced by about 40% [126]. More data are needed to allow general
fore indicate that heart failure is a cause of CSA. Many cardiac recommendations to be made.
transplant recipients develop OSA owing to weight gain, and those
who gain the most are most prone to develop OSA. Cardiac trans- CPAP in the treatment of CSA/HCSB
plant patients with OSA also developed hypertension and had poor Application of positive airway pressure in patients with impaired
quality of life compared with those without OSA [116]. For reasons cardiac function seems to be reasonable, as it might improve oxygen
that are not well known, restless legs syndrome (RLS) and periodic supply, reduce oxygen requirement, and unload the heart mechani-
limb movements in sleep (PLMS) are also prevalent after cardiac cally. CPAP reduces ventilation–perfusion mismatch by recruit-
transplantation [116]. Approximately 31% of patients had PLMS ing poorly/non-ventilated portions of the lungs. Consecutively,
with an index of 55 per hour of sleep, and 45% of these patents suf- oxygen levels in the blood and oxygen delivery to the organs
fered from RLS. increase. Positive airway pressure decreases venous return to the
right heart, which may then decrease right-ventricular stroke vol-
Nocturnal supplemental nasal oxygen
ume and consequently pulmonary capillary volume and pressure.
Systematic studies (reviewed in [23]) of patients with systolic heart Pulmonary capillary pressure may also decrease with reduction in
failure have shown that nocturnal administration of supplemental left-ventricular end-diastolic pressure, as CPAP unloads the left
nasal oxygen improves CSA and desaturation. In the largest study ventricle. Decreased pulmonary capillary pressure is critical in
[117] of 36 subjects with systolic heart failure (mean LVEF about improving periodic breathing and CSA.
22%), it was observed that the central apnea index decreased sig- These pathophysiological considerations are in accordance with
nificantly from 28/h to10/h. the findings of clinical trials. A post-hoc analysis of CanPAP data
Supplemental nasal oxygen improves CSA by multiple mecha- showed that CPAP improved the prognosis of those patients with
nisms [118] (reviewed in [23]), such as decreasing hypoxic and a substantial reduction of SRBDs [76]. No benefit was observed in
hypercapnic ventilatory drives and decreasing sympathetic activ- those whose CSA was not suppressed by CPAP. In fact, CPAP might
ity. In addition, oxygen administration may also widen the PCO2 be harmful in this group [127]. Therefore, we begin our therapeu-
reserve, i.e, the difference between the prevailing PCO2 and the tic approach with a one-night CPAP trial, and if AHI decreases
apneic threshold PCO2 [119]. below 15/h, the patient is considered CPAP-responsive. Otherwise,
The long-term effects of administration of nocturnal oxygen on we proceed with the adaptive servoventilation (ASV) therapy
the mortality of patients with heart failure need to be studied. In a described below.
randomized parallel-design open trial of 56 patients with systolic
heart failure, Sasayama et al. [120] reported that the use of noctur- Adaptive servoventilation devices
nal supplemental nasal oxygen resulted in significant improvements These are the most advanced of positive airway pressure devices
in LVEF and New York Heart Association (NYHA) functional class. [83,84,128]. They interfere most precisely with the pathophysiol-
Such changes were not observed in the control group. ogy of HCSB. The algorithms apply variable inspiratory pressure

support (defined as the pressure difference between inspiratory and (2) provided an aggressive inspiratory pressure support that rose
expiratory pressures) according to the actual requirements of the rapidly and declined slowly. As a result, some patients were under-
patient on a breath-by-breath base (Fig. 40.5). The pressure support pressurized and some over-pressurized by the device. In either
is increased during periods of hypoventilation and reduced during case, the consequences could have been fatal. These deficien-
hyperventilation. Additionally, mandatory breaths are applied to cies were modified significantly in a new-generation device [85].
avoid central apneas. The most advanced algorithms also apply var- Unfortunately, the results are also affected by a low adherence rate
iable expiratory pressure to adapt to changing levels of upper air- (40% of patients with daily use for less than 3 hours), a high cross-
way obstruction. This automatic variable pressure is in contrast to over between the treatment arms (23%), and differences in the
CPAP devices, and should provide the greatest comfort for patients. baseline therapies (higher use of anti-arrhythmic drugs in the ASV
ASV has been proven to effectively suppress CSA/HCSB [129], group). Subgroup analysis suggests that patients with a very low
and observational studies show improved survival of heart failure ejection fraction < 30% and patients using anti-arrhythmic drugs
patients who used the device compared with those who refused represent the groups at risk for cardiac death. More detailed data
or were intolerant [130–133]. These devices are also effective in from per-protocol analyses and subgroup studies of the SERVE-
coexisting obstructive and central disturbances in cardiac patients HF trial are required. In addition, results from another multicenter
[27] and in patients with opioid-induced sleep apnea [25,134]. study (ADVENT-HF) are expected. At present, ASV should not be
However, the recently published SERVE-HF study [135] investi- prescribed to patients with systolic, symptomatic heart failure with
gated the effects of ASV in addition to optimal cardiac treatment LVEF ≤ 45% and predominant CSA/HCSB.
as compared with optimal cardiac treatment alone in patients with
symptomatic systolic heart failure (NYHA II with previous hospi- Phrenic nerve stimulation
talization, NYHA III, and NYHA IV), LVEF ≤ 45%, and predomi- A new device has been introduced into the therapeutic armamen-
nant CSA. While the study failed to show a significant difference in tarium for CSA. This phrenic nerve pacemaker is placed intrave-
the primary outcome parameter of the composite of cardiac events, nously into a thoracic vein where the phrenic nerve overlaps the
secondary analyses showed an increased rate of cardiac death vein. The unilateral phrenic nerve can be stimulated during sleep
and death from any cause in the ASV group. We have discussed at a set frequency to prevent the development of central apnea. In
some potential reasons for the failure of this trial [136]. One of an early study, overnight stimulation resulted in virtual elimination
these, among multiple issues, is the use of an old-generation ASV of central apneas, with consequent improvements in desaturation
device with outdated algorithms that (1) were unable to adjust the and arousals [137]. A multicenter randomized clinical trial with a
expiratory pressure to the changing dynamic of upper airway and control arm has begun.
IPS
IPS
Fig. 40.5 A 5-minute epoch showing the operation of an ASV device with anticyclic changes in inspiratory pressure support (IPS).
Reproduced from Chest, 146(2), Javaheri S, Brown LK, Randerath WJ, Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms, pp. 514–23, Copyright (2014),
with permission from Elsevier.

Periodic limb movements significant independent risk factor for mortality. The hazard ratio
was 2.42, with a 95% confidence interval of 1.16–5.02, p = 0.018.
Since the introduction of PSG to study SRBDs in heart failure, few The third study [144] was a retrospective chart review suggest-
studies [24,129,138,139] have reported on the prevalence of PLMS ing an association between PLMS and left-ventricular hypertrophy.
in heart failure patients. Hanly and Zuberi-Khokhar [139] are cred- These associations [142–144] do not prove causality, and, as
ited with the first report. In their study of 23 patients with severe already noted, the difficulty of recognizing PLMS accurately
heart failure and reduced ejection fraction, the prevalence of PLMS remains a concern.
was 53%, with an average PLMS index of 73 per hour of sleep. In In contrast to CSA, which is eliminated after cardiac transplanta-
a later study of 14 patients with left-heart failure, Teschler group tion, PLMS is not. As noted earlier, in a study of 45 cardiac trans-
[129] reported an index of 12/h. It is not clear how to reconcile such plant patients, about 30% suffered from severe PLMS, and almost
huge differences between the two studies, although the number of half of them had RLS [116].
patients was small in both. In the largest study of 55 patients [24],
also in patients with systolic heart failure, 20% had PLMS (index ≥ Insomnia, poor sleep efficiency,
5/h), with an average index of 35/h. In another study from Brazil
[138], a prevalence of 20% was confirmed. and the heart
It is critical to emphasize a potential misclassification of PLMS, In this section, we briefly review the effects of sleep on the car-
where a leg movement is not part of PLMS, but rather a conse- diovascular system and the effects of cardiac pathology on sleep.
quence of sleep apneas and hypopneas. If arousals occur as a result A more detailed review of these interactions can be found in [145].
of an SRBD, then, if the leg movement occurs after the arousals, it As NREM sleep deepens from stage N1 to stage N3, there is a
should not cause misclassification. However, frequently, there may progressive diminution in sympathetic activity and an increase in
be no arousals in association with an SRBD, but there is leg move- parasympathetic activity. Consequently, arterial blood pressure and
ment. Under such circumstances, misclassification may occur, heart rate decrease by approximately 10–20% relative to the mean
inflating the PLMS index. daytime values. Therefore, NREM sleep, which occupies about 80%
The mechanisms of PLMS in heart failure are not known. One of total sleep time, is associated with cardiovascular quiescence as
risk factor could be iron-deficiency anemia, which is more common the cardiac workload decreases. In contrast, during REM sleep, in
in severe chronic heart failure and could be due to several mecha- association with pontogeniculo-occipital (PGO) waves, sympa-
nisms, including reduced intestinal iron absorption. Another pos- thetic activity increases, with concomitant increases in heart rate,
sibility is increased sympathetic activity, which has been suggested blood pressure, and myocardial oxygen demand. In this period of
to play a primary role in the generation of idiopathic PLMS [140]. sleep, the heart is vulnerable to ischemia, arrhythmias, and poten-
Since increased sympathetic activity is the hallmark of heart failure tially sudden death.
with reduced ejection fraction, it could be the link with PLM. Also, the normal dipping and decrease in heart rate may not
We must emphasize here that there has been no study on RLS occur in the presence of sleep disorders such as sleep apnea or
in heart failure. However, in spite of this, in the setting of conges- PLMS, potentially resulting in deleterious long-term consequences.
tive heart failure, PLMS may have adverse hemodynamic conse- Sleep in patients with heart failure is quite disturbed. In the study
quences, and the question arises whether PLMS should be treated. of patients with systolic heart failure who underwent habituation
Hemodynamic consequences of PLMS, particularly with arous- in the sleep laboratory and had full-night PSG on the second night,
als, are increased heart rate and blood pressure. Pennestri and sleep efficiency was decreased and architecture was disrupted. Stage
colleagues [141] studied patients with RLS without known cardio- N1 occupied 34% of total sleep time, stage N3 was not achieved,
vascular disease, who underwent PSG simultaneously with nonin- and arousals were excessive [17,24]. There was objective evidence
vasive, beat-to-beat blood pressure monitoring. The systolic blood of insomnia, with a sleep efficiency of about 72%, though sleep
pressure increased by an average of 22 mmHg and the diastolic onset was not increased. As noted, patients had been habituated
blood pressure by 11 mmHg with PLMS and arousals. The incre- to the environment of the laboratory, and in the morning they
ments were less in the absence of arousals. Although the long-term invariably felt that they had slept as usual. Historically, this kind of
effects of these alterations due to PLMS remain to be established in insomnia has been referred to as secondary (i.e, secondary to heart
a randomized controlled trial, the rises in blood pressure and heart failure). In these patients, awakenings and insomnia are multifacto-
rate could have deleterious effects on cardiovascular functions, rial. Some of the symptoms of heart failure, such as nocturia, par-
particularly in patients with established cardiovascular disease. oxysmal nocturnal dyspnea, orthopnea, and cough, are disruptive.
Meanwhile three studies [142–144] have investigated the long-term In addition, melatonin synthesis and secretion may be impaired
association of PLMS and cardiovascular disease. In the first obser- owing to administration of certain beta-blockers, as the synthesis
vational study in a large cohort of men older than 65 years, Koo and secretion of melatonin are regulated through the β-adrenergic
and colleagues [143] followed 2911 men for 4 years. Participants signal transduction system [145,146].
had PSG at home. The authors reported a significant association Finally, we should note that insomnia may be due to depres-
between PLMS and incident all-cause cardiocerebrovascular dis- sion, which is frequently comorbid with heart failure. The impact
ease plus peripheral arterial disease, but not coronary heart disease of insomnia comorbid with heart failure and its consequences for
or cerebrovascular disease in isolation. In another observational the morbidity and mortality of the latter are not clear. Being insom-
study, Yumino and colleagues [142] followed 218 consecutive niac and/or awake, in contrast to being asleep, can be associated
patients with heart failure and reduced ejection fraction from 1997 with increased sympathetic and decreased parasympathetic activ-
to 2004. The mean follow-up was about 40 months. After adjust- ity. Not surprisingly, a number of studies have shown that patients
ing for a number of covariates, PLMS index ≥ 5/h remained a with insomnia have elevated heart rate, blood pressure, whole-body

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CHAPTER 41
Pulmonary disorders and sleep

Sandrine H. Launois and Patrick Lévy
Sleep is commonly disrupted in pulmonary disorders, either by may disappear after lung transplant, leading to sleep improvement,
symptoms of the lung disease or by an associated sleep disor- but insomnia may persist after the transplant (Fig. 41.1).
der. This situation is, however, under-â•‰recognized and therefore While the most commonly acknowledged sleep disorder in
untreated. Our goal in this chapter is to broadly underline the patients with chest wall and respiratory muscle diseases is sleep-â•‰
close association between pulmonary disorders and sleep distur- related hypoventilation (see below), sleep studies in these patients
bances, rather than provide an exhaustive compilation of studies demonstrate poor sleep efficiency, fragmented sleep, and decreased
on sleep and pulmonary disorders. In some cases, this association slow-â•‰wave and REM sleep [15,16] (Fig. 41.2). These findings are
is fortuitous and simply reflects the impact of a chronic, serious likely to be multifactorial and, at least in part, caused by SDB, as
medical condition on sleep quality, with patients complaining of sleep is improved by nocturnal noninvasive ventilation [15].
nonrestorative sleep, daytime fatigue, and sleepiness. However, in Adverse consequences of chronic insomnia have been studied
other instances, specific sleep-â•‰related phenomena may adversely only in COPD patients, but are likely to also occur in other lung
affect the pulmonary disorder (eg, restrictive lung diseases and diseases. Not surprisingly, poor sleep strongly affects quality of life
REM-â•‰related hypoventilation). A sleep disorder can coexist with a [8,10,12,17] and cognitive function [12], but excessive daytime
pulmonary disorder and worsen pulmonary outcome or quality of sleepiness (EDS) is uncommon [10,11]. In a recent longitudinal
life—â•‰for example, chronic obstructive pulmonary disease (COPD) study, poor sleep quality was associated with an increased exacer-
and restless legs syndrome (RLS). Lastly, a sleep disorder, namely bation and emergency hospitalization rate and with a trend toward
obstructive sleep apnea (OSA), has been implicated as a risk factor increased mortality in the more severe patients [12]. However,
for pulmonary hypertension and pulmonary embolism. Overall, increased morbidity/â•‰mortality may result from adverse conse-
discounting the possibility of a chance occurrence, the following quences of SDB and sleep hypoxemia, which are likely to play a role
ICSD-â•‰3 disorders are found in association with various pulmonary in more severe COPD patients, rather than insomnia alone [9,11].
diseases [1]â•„: chronic insomnia disorder, sleep-â•‰related breathing
disorders, and restless leg syndrome (RLS) (Table 41.1). Sleep-â•‰related breathing disorders
Obstructive sleep apnea
Chronic insomnia disorder OSA is a highly prevalent disorder in the general population and
In pulmonary disorder patients, insomnia is common [2–â•‰7], often can therefore coexist with any chronic pulmonary disorder. OSA
multifactorial, with anxiety, depression, nocturnal respiratory further deteriorates sleep quality in patients whose sleep may
symptoms and hypoxemia, treatment, and associated sleep dis- already be disrupted (see above). In some diseases such as asthma
orders all potentially contributing to poor sleep. Although preva- [18–â•‰20] and interstitial lung disease (ILD) [21], the prevalence of
lence varies from one study to the other, one-â•‰third to two-â•‰thirds of OSA is even higher than in the general population. The underlying
COPD patients suffer from insomnia or nonrestorative sleep [8,9], pathophysiological mechanism for this relationship, however, is not
a fact that is underestimated by physicians [10]. The prevalence of clear. Patients with end-â•‰stage lung disease waiting for a lung trans-
sleep disturbances does not appear to be closely correlated with plant also have an increased prevalence of OSA, often associated
objective severity of airway obstruction, but rather with the sever- with mixed and/â•‰or central apneas [22-â•‰23]. Resolution of SDB is
ity of symptoms, the exacerbation rate, and the presence of sleep not constant following the transplant, and some patients may even
disordered breathing (SDB) [2,8,10–â•‰12]. develop sleep apneas after the procedure [23,24].
Nocturnal wheezing, nasal congestion due to allergies, esopha- In asthma patients, poor disease control, as evidenced by emer-
geal reflux, and some asthma medications (see Table 41.2) induce gency admission rate or steroid treatment, is a risk factor for OSA
sleep disruption. Indeed, patients suffering from asthma, particu- [19,20]. Consequently, screening for sleep apnea is recommended
larly from nocturnal or allergic asthma, often complain about sleep in patients with uncontrolled asthma or in those who are over-
quality, insomnia, and nonrestorative sleep [13]. weight or obese [25]. Indeed, continuous positive airway pressure
While life-â•‰saving for end-â•‰stage pulmonary disease patients, lung (CPAP) treatment has a beneficial impact not only on sleep quality
transplantation is a long and stressful process, while the patient is on [26] but also on bronchial reactivity [27]. In addition, treating OSA
a waiting list as well as while recovering from the procedure. Sleep with CPAP is likely to improve esophageal reflux [28], which may
may therefore be disrupted by anxiety and depression, in addition contribute to poor sleep and arousals in asthma [20] and ILD [21].
to respiratory symptoms due to the underlying disease, medication, SDB may have a direct deleterious impact on the associated
or associated SDB and RLS (see below) [14]. Some disturbances lung disease outcomes. The most illustrative example is that of the

Table 41.1 Occurrence of sleep disorders in patients with pulmonary diseases
Chronic insomnia disorders Sleep-related breathing disorders Restless

leg
syndrome
Insomnia due to Insomnia due to anxiety Insomnia due Sleep-related Sleep apnea
nocturnal symptoms and/or depression to medication hypoventilation
and hypoxemia
Asthma x x x x
Chronic obstructive pulmonary x x x x x x
disease
Cystic fibrosis x x x x
Lung transplant x x x x x
Pulmonary embolism x
Pulmonary hypertension x
Interstitial lung diseases x x x
Chest wall and neuromuscular x x
disorders
Chronic respiratory failure x x x x
Table 41.2 Role of medication in sleep disorders associated Global Initiative for Chronic Obstructive Lung Disease guidelines
with pulmonary diseases updated in January 2015 do not suggest any recommendation for
performing sleep studies in COPD patients. Yet sleep clinical evalu-
Sleep disorder Medications commonly used in ation of COPD patients is crucial, and if it leads to a suspicion of
pulmonary disorder patients OSA, a full polysomnography (PSG) should be performed, rather
than a portable monitoring study [33].
Restless leg syndrome Antidepressants
OSA is an independent risk factor for deep venous thrombosis
Beta-blockers and pulmonary embolism (PE) [34]. This is not surprising, as plate-
Insomnia Corticosteroids let activation and increases in procoagulant factors, resulting in
Antibiotics: quinolones, isoniazid hypercoagulability, have been demonstrated in apneic patients [35].
Salbutamol, terbutaline These abnormalities are correlated with the severity of nocturnal
Theophylline hypoxemia [36] and are reversible following CPAP treatment [34].
While intermittent hypoxia and the consequent oxidative stress and
PDE4 inhibitors
inflammation are likely to be the main contributors to hypercoagu-
Sleep-related hypoventilation Opiates lability [35,37], the role of comorbid systemic hypertension has also
and hypoxemia Benzodiazepines been suggested [38]. Although there are no guidelines to systemati-
Buspirone cally assess patients with acute PE for sleep apnea [39], one could
Myorelaxants argue that patients with recurrent PE and no obvious risk factors
should undergo a sleep evaluation.
OSA patients are subjected to chronic intermittent hypoxia,
“overlap syndrome” (OS), the fortuitous association of OSA and and severe patients are therefore at risk for developing pulmonary
COPD [11,29]. Compared with patients with COPD alone, patients hypertension (PH) [40,41]. Although the prevalence of PH in OSA
with OS have more frequent exacerbations requiring hospitaliza- is not clearly established, a systematic assessment of sleep apnea
tion and a higher mortality rate [30]. Several potential interactions is recommended in PH patients [41,42]. Treatment of OSA with
have been proposed to account for this finding, such as more severe CPAP significantly reduces elevated pulmonary pressures [40].
OSA-induced intermittent hypoxia [11] and greater systemic
inflammation and oxidative stress in patients with OS compared
Sleep-related hypoventilation
with COPD patients [31]. In OS patients who accept CPAP treat- due to a medical disorder
ment, mortality is reduced compared with patients who decline During sleep, patients with diseases that affect the chest wall or
treatment and is comparable to mortality in COPD alone [30,32], the respiratory muscles may develop alveolar hypoventilation
with CPAP compliance being an independent factor for this [16,43]. Several mechanisms account for this common complica-
improvement [32]. CPAP also has a beneficial effect on COPD exac- tion: the physiological decrease in respiratory drive is superim-
erbation rate [30], but does not improve either pulmonary function posed on already-weakened respiratory muscles and decreased
tests or supplemental oxygen requirements [32]. Surprisingly, the lung volumes, as well as impaired respiratory control. Patients are

Chapter 41 pulmonary disorders and sleep 411
23:00 01:00 03:00 05:00
W
Sleep R
N1
stage N2
N3
100
SpO2 90
(%) 80
70
Fig. 41.1 Hypnogram and pulse oximetry (SpO2) extracted from overnight PSG in a 40-year-old woman performed 3.5 years following lung transplantation for end-
stage emphysema. The patient complained of unrefreshing sleep and daytime fatigue. The PSG showed poor sleep efficiency and architecture with repeated arousals,
74 minutes of wake after sleep onset and 16 minutes of slow-wave sleep. There was no respiratory disturbance; the apnea–hypopnea index was 0.7/h. The mean oxygen
saturation during the night was 94%.
particularly vulnerable in REM sleep, as can be seen in Fig. 41.2, Sleep-related hypoxemia disorders
and during the course of the disease, REM sleep-related alveolar
While physiological changes in ventilation during sleep do not
hypoventilation often precedes NREM and daytime hypoventila-
result in significant hypoxemia in individuals with healthy lungs,
tion. Associated obstructive or central sleep apneas worsen sleep
reduction in functional residual capacity, worsening of ventila-
hypoventilation [16,43]. Although the overnight oximetry pattern
tion/perfusion mismatch, and decreased ventilatory responses to
can be evocative of sleep-related alveolar hypoventilation, meas-
chemical and mechanical stimuli may lead to isolated hypoxemia
urement of CO2 level, through noninvasive means during sleep
during sleep in patients with chronic pulmonary lung diseases.
or arterial blood gases measurement upon morning awakening, is
Oxygenation during sleep has been extensively studied in COPD
required to confirm the diagnosis [1]‌. Treatment of the underlying
patients [9,11,45], in whom the severity of sleep-related hypox-
chest wall or neuromuscular disease is often limited, but nocturnal
emia is closely related to the severity of airway obstruction and
noninvasive ventilation is effective in alleviating sleep hypoventila-
the presence of daytime hypoxemia. Sleep hypoxemia is likely to
tion [16,43,44] and sleep difficulties [15]. However, there is still a
contribute to poor sleep, cardiovascular morbidity, and increased
lack of large controlled trials to demonstrate a long-term effect on
mortality [45], but its relationship to pulmonary hypertension and
symptoms, quality of life, and survival [44].
nc
W
Sleep REM
stage N1
N2
N3
MT
SI
100
SpO2
(%)
50
100
tcPCO2
(mmHg)
50
23h 0h 1h 2h 3h 4h 5h
Fig. 41.2 Hypnogram, pulse oximetry (SpO2), and transcutaneous PCO2 (tcPCO2) monitoring extracted from overnight PSG in a 49-year-old man with left-
diaphragmatic paralysis and severe obesity (body mass index 44 kg/m²). Pulmonary function testing showed a restrictive syndrome with mild daytime hypoxemia but no
alveolar hypoventilation. The patient complained of severe insomnia. The PSG showed prolonged awakenings due to breathlessness, fragmented sleep, and central sleep
hypopneas in NREM sleep with an apnea–hypopnea index of 58/h and REM alveolar hypoventilation. Owing to the patient’s agitation throughout the night, the quality
of both oximetry and CO2 monitoring was poor.

polycythemia is less clear [9,45]. Sleep-related hypoxemia may also pharmacokinetics over the 24-hour period into consideration may
present in patients with cystic fibrosis [46], neuromuscular diseases help patients sleep better [52,53]. Following smoking cessation,
[16], or ILD [47].Associated apneas and/or alveolar hypoventila- weight gain is common and should be closely monitored, as it may
tion, particularly during REM sleep, are common in these patients, worsen pre-existing OSA.
and will obviously contribute to and worsen sleep hypoxemia.
Simple overnight pulse oximetry is inadequate to properly assess Pulmonary rehabilitation
the nature of sleep-induced hypoxemia in pulmonary disorders, This plays a central role in the management of patients with COPD,
and a complete evaluation, including CO2 monitoring, should be but may also benefit patients with other pulmonary diseases, such as
performed in these patients. Determining the mechanisms respon- asthma, ILD or cystic fibrosis [54]. Exercise is the key component of
sible for sleep hypoxemia is crucial to select treatment options rehabilitation programs. Sleep quality and duration play an impor-
(supplemental oxygen, noninvasive ventilation, etc.). tant role in motivation, performance, and post-exercise recovery
[55]. Therefore, improving sleep in patients enrolled in a pulmo-
Restless legs syndrome nary rehabilitation program may help them complete the exercise
regimen more easily. In addition, there is a reciprocal effect between
Like OSA, RLS is a common disorder and can be associated by sleep and exercise, as exercise is a well-established nonpharmaco-
chance with any pulmonary disorder. However, the prevalence of logical treatment option for insomnia and poor sleep quality [55].
RLS is increased in some pulmonary diseases. An observational
study in lung transplant recipients showed that the prevalence of
RLS in these patients was more than double that in the general pop- Conclusions
ulation, with a rate of 48% [48]. Although subjective or objective Sleep disorders and pulmonary diseases are closely associated, but
sleep variables were not recorded in the study, 80% of patients had their relationship is underestimated in routine patient care. Yet,
moderate (25%) or severe (55%) RLS and were likely to suffer from the occurrence of sleep disorders in pulmonary disorder patients
sleep difficulties. One recent study suggests that the prevalence of results in poor quality of life and may worsen morbidity and mor-
RLS is increased in COPD patients and contributes to difficulty tality. This relationship has implications for both pulmonary and
initiating and/or maintaining sleep and to daytime fatigue [49]. sleep specialists. Pulmonary physicians should systematically
Although RLS prevalence has not been studied in other pulmonary assess sleep complaints in patients with pulmonary disorders, par-
disorders, patients should be questioned on possible RLS symp- ticularly COPD and restrictive lung diseases, and, if warranted,
toms. Low blood iron level is a known causal factor for RLS, and order further investigations (Box 41.1), with the goal of improving
ferritin level should be tested and corrected by iron supplementa- quality of life and, in some cases, the outcome of the pulmonary
tion if necessary. Some drugs used for the treatment of pulmonary disease itself. Sleep physicians should be aware that while general
diseases can worsen or cause RLS (Table 41.2), but may not always guidelines for sleep disorder management apply to patients with
be discontinued. When considering drug treatment for severe RLS, pulmonary disorders, there are specific diagnostic and therapeutic
the adverse effects of opiates should be kept in mind, as they can features to take into consideration. We have stressed, for instance,
cause sleep-related hypoventilation and hypoxemia. the importance of documenting sleep alveolar hypoventilation in
these patients, and noninvasive CO2 monitoring is essential in pul-
Miscellaneous situations and considerations monary disorder patients. Because of their potential respiratory-
depressant effect, sedative medications and muscle relaxants should
Acute pulmonary disorders be avoided, and insomnia in patients with compromised respiratory
So far, we have only considered chronic pulmonary disorders. Sleep function should be managed through nonpharmacological options.
is also disrupted in acute pulmonary disorders (eg, bronchitis, In spite of the abundant literature on the topic, many questions
pneumonia, and acute respiratory failure) because of symptoms remain unanswered, such as the long-term negative outcomes of
such as fever, cough, pain, dyspnea, and anxiety. Furthermore, sleep disruption and chronic insomnia in pulmonary disorder
treatment itself may disrupt sleep: medication (Table 41.2), noc- patients, and these need to be addressed by future studies.
turnal noninvasive ventilation, and oxygen therapy may delay sleep
onset and/or cause repeated arousals. Finally, intensive care unit
hospitalization is known to disturb sleep [50]. However, to date, Box 41.1 Evaluation tools in pulmonary disorder patients
with sleep complaints
there have been no studies regarding the potential adverse conse-
quences on acute pulmonary disease outcome. Clinical evaluation
Sleep and tobacco use or withdrawal Pittsburg Sleep Quality Index
Insomnia Severity Scale
Even more than other smokers, patients with lung diseases are Hospital Anxiety and Depression Scale
strongly and repeatedly advised to stop smoking. Nicotine is a Epworth Sleepiness Scale
wakefulness-promoting substance, and may cause difficulties in
initiating sleep and sleep fragmentation [51], therefore contribut- Investigations
ing to chronic insomnia in patients who continue smoking [52]. On
Sleep log/actimetry
the other hand, smoking cessation may also be associated with poor
Overnight oximetry and capnography
sleep, whether because of withdrawal symptoms (craving, insom-
Iron workup
nia, anxiety, and depressive symptoms) or because of use of smok-
Polysomnography with capnography
ing cessation aids [52]. When selecting nicotine substitutes, taking

Chapter 41 pulmonary disorders and sleep 413
25. National Asthma Education and Prevention Program. Expert Panel

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CHAPTER 42
Gastrointestinal functioning
during sleep
William C. Orr
INTRODUCTION Duodenal ulcer and vagotomy

A more complete understanding of how sleep influences gastroin- Prior to the discovery of the important role of Helicobacter pylori
testinal (GI) functioning has only been realized in the past decade in the pathogenesis of DU disease, it was felt to be purely an acid-â•‰
or so. Much of this lack of understanding can be attributed to the related disease, and the healing of DU was felt to be closely related
relative inaccessibility of the GI tract to physiological monitoring to the suppression of gastric acid secretion. The differential diagno-
in the conscious human. Careful monitoring of pH changes and GI sis and treatment of DU disease was detailed by Moynihan, noting
tract motility during the waking state and polysomnographically that many patients had symptoms of nocturnal abdominal pain that
(PSG) determined sleep have revealed significant changes during were alleviated by food [4]â•„. Vagotomy was introduced by Dragstedt
sleep, as well as very different physiological responses to endog- in the late 1940s as an effective strategy for treating chronic DU
enous or exogenous stimuli. For example, responses to esophageal disease theoretically caused by excessive vagal stimulation [5].
acid–â•‰mucosal contact are substantially altered during sleep com- Initially, the procedure was believed to reduce excessive noctur-
pared with the waking state. This chapter provides an overview of nal acid secretion in DU patients [6]. This is most likely due to a
this research as well as a recent proposal that nighttime heartburn larger parietal cell mass producing a larger acid output in response
combined with sleep-â•‰related gastroesophageal reflux (GER) is a to stimuli that provoke gastric secretion. Thus, the greater resting
distinct clinical entity apart from daytime reflux and conventional secretion in patients with DU compared with controls is thought to
heartburn. be caused by a normal basal drive acting upon a larger number of
normally sensitive parietal cells [7,8].
Other investigators were not able to support Dragstedt’s reason-
Acid-â•‰related diseases ing that vagotomy reduces basal secretions; instead, it was revealed
Gastric acid secretion that the procedure reduces histamine-â•‰stimulated secretion [9,10].
The earliest studies of gastric acid and its digestive function were Nevertheless, Dragstedt’s work served to stimulate much fur-
carried out by Dr. William Beaumont around 1830. Beaumont was ther research that lead to a more comprehensive understanding
a US Army surgeon attending Alexis St. Martin, who had sustained of acid secretion during waking and sleep and the relationship of
an accidental shotgun wound to the abdomen. St. Martin devel- acid secretion to the pathogenesis of DU. His hypothesis related to
oped a gastric fistula through which Beaumont could observe the the importance of nocturnal acid secretion in the pathogenesis of
effects of a variety of stimuli on gastric functioning. These observa- DU was particularly significant in bringing sleep into the critical
tions led to the important discovery that stomach acid was essential thinking related to the diagnosis and treatment of a major medical
for digestion. Beaumont also observed the relationship between condition.
gastric function and emotional state, as the gastric mucosa would
become engorged with blood in relation to St. Martin being upset Esophagitis and nighttime heartburn
or stressed [1]â•„. Almost a century later, Johnston and Washeim [2] The regurgitation of “peptic juice and its stagnation” was demon-
studied gastric acid secretion during sleep in normal subjects and strated as the cause for esophagitis in the absence of comorbidities
described a rise in acidity, a decrease in volume, and delayed gas- by Selye in 1938 [11]. Subsequent observations have demonstrated
tric emptying. Later studies described a circadian rhythm of gastric that the condition of esophagitis is much more complex than sim-
acid secretion in healthy subjects characterized by a peak in acid ple occurrence of acid contact with the esophageal mucosa. The
secretion between 10 pm and 2 am, and minimal acid secretion pattern of esophageal acid contact has now been shown to be mark-
during wake [3]. These studies established that gastric acid secre- edly different during the daytime compared with that during sleep,
tion was very labile and altered not only by emotional state, but and the notion that sleep-â•‰related GER played a role in the devel-
also by state of consciousness and time of day. These observations opment of esophagitis and other complications of GER emerged
laid the groundwork for our understanding of the pathogenesis of in the 1970s by the pioneering work of Johnson and DeMeester
gastroesophageal reflux disease (GERD) and duodenal ulcer (DU) [12,13]. Their work, which incorporated the new technology of 24-â•‰
disease. hour esophageal pH monitoring, encouraged further investigation

of the effect of sleep on GER and acid contact time. Indeed, these suppressed during sleep, resulting in prolonged acid–mucosal con-
investigators noted that episodes of reflux occurring in the upright tact [15,20]. The subsequent back-diffusion of hydrogen ions into
position, presumably during the waking state, are rapidly cleared. the esophageal mucosa is related to the duration of acid–mucosal
Episodes of reflux occurring in the recumbent position, presum- contact [21]. Prolonged acid contact with the esophageal mucosa
ably during sleep, are associated with markedly prolonged acid disrupts the normal barrier to the submucosa by increasing inter-
clearance. These studies effectively demonstrated the link between cellular spaces, allowing easier access of hydrogen ions [22]. Thus,
prolongation of acid clearance during the sleeping interval and the the longer reflux episodes noted during sleep carry a greater risk
occurrence of esophagitis. During the same time period, Atkinson of producing mucosal damage compared with the more rapidly
and Van Gelder also showed a relationship between the severity of cleared reflux episodes during the waking state. Thus, clinicians
esophagitis and the duration of nocturnal periods of high esopha- may find it useful to assess symptoms of nighttime heartburn in
geal acidity [14]. Collectively, these studies suggested acid clearance differentiating patients who have a more serious form of GERD and
is prolonged during sleep; however, none monitored sleep via PSG, experience more daytime sleepiness and a decline in work produc-
and thus could not confirm this notion. tivity and quality of life [23]. Much of the literature related to night-
Orr and colleagues [15] conducted the first PSG study on patients time heartburn and sleep-related GER has been reviewed by Orr,
with esophagitis and confirmed that acid clearance from the distal who has postulated that nighttime heartburn constitutes a distinct
esophagus is prolonged during sleep in both healthy participants and clinical entity that merits a more aggressive approach to treatment,
patients with esophagitis, but more so in the esophagitis group. They focusing on the suppression of sleep-related acid reflux [17].
also provided the additional insight that acid clearance is dependent
on a brief awakening from sleep. Thus, patients who reflux during
sleep were at greater risk to develop esophagitis. A later study by
Intestinal motility
Robertson and colleagues [16] in which patients were monitored The small bowel and the colon are difficult to monitor because
with a 24-hour pH probe demonstrated that those with complica- of the invasive techniques that must be employed to obtain
tions of esophagitis have more severe acid reflux than those with direct measurements. This is especially challenging during sleep.
simple uncomplicated disease, and they concluded that this was Characterizing intestinal motility using advanced telemetry or
likely due to prolonged periods of nighttime acid reflux. With this electrodes in conjunction with PSG has yielded a more comprehen-
deeper understanding of the significance of prolonged acid contact sive description of intestinal motor activity in general, and more
time during sleep and its more complicated disease progression, a specifically during sleep. Electromyographic (EMG) recording of
need for clinically differentiating sleep-related reflux and nighttime duodenal muscle activity during the various stages of sleep revealed
heartburn from daytime heartburn has become apparent. an inhibition of duodenal EMG activity associated with rapid eye
Recognizing nighttime heartburn and associated sleep-related movement (REM) sleep and an increase in activity with changes
GER as a distinct clinical entity has been suggested in a review by from one sleep stage to another [24]. Deep sleep is associated with
Orr [17]. Data are reviewed to support the notion that recogniz- decreased motility compared with light sleep, and the motility
ing the presence of nighttime heartburn suggests a more aggres- index for REM sleep is similar to that for light sleep [25], similar
sive treatment approach for GERD patients. Nighttime heartburn to the findings of Tassinari and colleagues [26], who demonstrated
and sleep-related GER are considered a distinct clinical entity due stage 1 sleep to have more duodenal contractions compared with
to several factors, including the following: the association of sleep- stages 2, 3, 4, and REM. An overall greater motility found during
related GER with prolonged acid–mucosal contact, which pro- REM sleep compared with deep sleep is similar to findings that
motes mucosal injury,; the greater risk of developing esophagitis have been reported in the colon [27].
among patients with nighttime heartburn; the higher incidence of Cyclic motor activity, referred to as the migrating motor complex
extra-esophageal symptoms such as chest pain and cough among (MMC), has been observed in the human GI tract in the fasting
patients with nighttime heartburn; and the significantly poorer state with a periodicity of 90 minutes and with significant altera-
quality of life of patients with nighttime heartburn. Two epidemio- tions during sleep compared with wake [28]. The physiological
logical studies have provided similar data suggesting that nighttime significance of the MMC is related to propulsion of intraluminal
heartburn is a common symptom [18,19], and that the majority contents and intestinal absorption of nutrients. Because the human
of patients with nighttime heartburn (approximately 70% in both REM/non-REM (NREM) sleep cycle also has a periodicity of
studies) indicated that this symptom disrupted their sleep. 90 minutes, hypotheses of the MMC and REM/NREM cycles being
Acid reflux is due to the failure of the lower esophageal sphinc- linked initiated several investigations. However, several subsequent
ter (LES) to prevent the retrograde flow of acid from the stomach studies have been unable to document a correlation between sleep
into the esophagus. This may occur as a result of decreased pressure stages and MMC cycling [25,28], thus providing support for the
in the LES or what is called a spontaneous relaxation of the LES, notion that the MMC cycle is separately regulated by the periph-
where the pressure suddenly decreases to the intragastric baseline. eral enteric nervous system, whereas sleep cycling is modulated
Responses to acid–mucosal contact are quite different during sleep within the central nervous system (CNS). These studies confirmed
compared with responses that characterize acid–mucosal contact that sleep does indeed influence GI motility, but further research is
during the waking state. Normal acid–mucosal contact produces needed to confirm the details of exactly how intestinal motility is
the waking sensation of heartburn, enhances salivary flow and modulated by sleep.
bicarbonate concentration, and stimulates a higher frequency of
swallowing. These responses prevent prolonged acid–mucosal con- Irritable bowel syndrome
tact by effectively removing the refluxate from the distal esopha- Irritable bowel syndrome (IBS) is a functional disorder of intes-
gus and neutralizing the mucosa. However, these responses are tinal motility that affects women considerably more frequently

Chapter 42 gastrointestinal functioning during sleep 417
than men [29]. The definition of IBS relates to three distinguish- and its inhibition plays an important role in the pathogenesis of
ing characteristics: intermittent abdominal pain, altered bowel DU and its effective treatment. Sleep-related GER is now accepted
habit (constipation or diarrhea), and no obvious organic cause. In as an important, if not the most important, phenomenon in the
the absence of organic abdominal disease, IBS is characterized by pathophysiology of reflux esophagitis. GI motility differs not only
abdominal distension and pain, relief of pain with a bowel move- between waking and sleeping states, but also between REM and
ment, more frequent and looser stools at the onset of pain, the NREM stages of sleep. Further research is needed to better under-
presence of mucus in the stool, and feelings of incomplete evacu- stand the effects of sleep on GI motility and, in turn, the effects of
ation. Miniature pressure transducers allow long-term manomet- functional disorders of GI motility on sleep. This chapter has pro-
ric recording in ambulatory patients, including during sleep, in vided an overview of evidence-based reasons for the gastroenter-
order to identify abnormal bowel motility. Substantial differences ologists to address sleep symptoms as well as sleep-related changes
in small-bowel motor activity have been observed between wak- in physiological functioning that may have considerable relevance
ing and sleeping in IBS patients [30]. A marked increase in con- to the pathophysiology of GI diseases.
tractility recorded in the daytime is notably absent during sleep.
Comparatively, patients with IBS experience pain accompanied by
propulsive clusters of small-bowel contractions with short MMC References
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CHAPTER 43
Sleep in chronic renal

insufficiency
Giorgos K. Sakkas and Christoforos D. Giannaki
Introduction Restless legs syndrome (Willis–â•‰Ekbom disease)

Chronic kidney disease (CKD) is a significant and growing medi- RLS is very common among the CKD population [14,15]. This type
cal and public health problem, responsible for a substantial bur- of secondary RLS, called uremic RLS, appears to provoke further
den of illness and premature mortality. More than 26 million impairments in the already-â•‰diminished QoL and health status of
American adults have being diagnosed with CKD, while at least uremic patients [16].The prevalence of uremic RLS is significantly
a millions more are at high risk. The Centers for Disease Control higher than that of RLS in the general population, reaching approx-
estimates that over 15% of the US population over 20 years of age imately 30% among the CKD population (range 7–â•‰45%) [14–â•‰17].
may have some form of CKD. Diabetes continue to be the lead- RLS symptoms can also appear during HD therapy. Symptoms can
ing cause of renal failure, accounting for 44% of new cases, while be both sensory [18, 19] and motor [20], significantly disturbing
uncontrolled or poorly controlled hypertension is the second lead- patients’ relaxation and leading to increased anxiety and finally to
ing cause, accounting for 28% of all cases [1]â•„. Sleep disorders are a premature discontinuation of HD therapy [21]. It is known that
remarkably prevalent in end-â•‰stage renal disease (ESRD) patients, RLS symptoms begin or worsen during rest or inactivity, making
affecting 80% of the population, especially in those receiving some HD procedures one of the main triggers of RLS [22].
type of replacement therapy such as hemodialysis (HD). Renal dis-
Periodic limb movements in sleep
ease has a dramatic impact on patients’ quality of life (QoL), while
sleep disorders contribute significantly towards impaired QOL Periodic limb movements in sleep (PLMS) represent another
[2]. Sleep disorders seem to be a major and potentially treatable very common sleep complaint in patients receiving HD therapy,
component of the low QoL and poor health, with implications for affecting almost 80% of patients with uremic RLS [23]. PLMS
mortality [3–â•‰5]. has been recognized as an independent predictor of mortality in
renal patients [24]. It has been recently reported that uremic RLS
patients with severe PLMS experienced further detrimental altera-
Sleep disorders in patients with kidney tions in cardiac structure, including an increased left-â•‰ventricular
diseases internal diameter in diastole (LVIDd), which lead to a significantly
The most common sleep complains in CKD patients are discussed increased left-â•‰ventricular (LV) mass compared with their PLMS-â•‰
in this section. Briefly, up to 80% of HD patients report symptoms free counterparts [5]â•„. Similar results were reported in non-â•‰uremic
of disturbed sleep, including 69% insomnia, 24% sleep apnea, 18–â•‰ patients, where PLMS was independently associated with severe LV
30% restless legs syndrome (RLS), and 12% daytime sleepiness hypertrophy leading to an increased risk for cardiovascular mor-
and fatigue [6,7]. It is notable, however, that a high prevalence of bidity and mortality [25].
renal insufficiency (approximately 30%) was also observed among
patients with sleep apnea, indicating further a relation between Sleep-â•‰related breathing disorders
sleep disorders and renal disease [8]â•„. The prevalence of sleep-â•‰related breathing disorders in HD patients
Patients with ESRD are characterized by low quantity and quality is at least 10 times higher [26] than the values reported in the
of restorative sleep, low score in sleep efficiency, disordered breath- otherwise-â•‰healthy population [27]. Patients with severe apnea
ing during sleep, increased leg activity during sleep, sleep fragmen- during sleep (apnea–â•‰hypopnea index AHI > 30) are characterized
tation, impaired daytime functioning, tiredness, and fatigue. All by insufficient quantity and quality of restorative sleep, impaired
these symptoms will finally cause a significant reduction in QoL daytime functioning, tiredness, and general fatigue, leading to a
and everyday activity [7,9–â•‰11], leading to fatigue and further to significant reduction in QoL [2,9,28]. A strong body of evidence
inactivity, with the result that patients end up in a mode of per- suggests that uremia-â•‰related factors are responsible for the preva-
manent weakness and disability [12]. It is not surprising, therefore, lence of sleep apnea disorders in hemodialysis patients [29–â•‰31],
that sudden cardiac death and heart failure are the two leading since a substantial reduction of symptoms occurs after renal trans-
causes of death in these patients [13]. plantation [32] or nocturnal dialysis [33]. The presence of sleep

apnea is also associated with elevated blood pressure, LV hypertro- Uremic toxicity
phy, and increased mortality [30]. In addition, HD patients with
Uremic toxicity is an “unknown” condition used to describe the
a high AHI were found to have reduced functional capacity and
harmful situation resulting from the accumulation of substances
altered muscle composition favoring fat deposition and increased
that are not efficiently removed from the failing kidney or the
visceral adiposity compared with HD patients with normal AHI
dialysis filter, causing inflammation and oxidative injury to organs
index [2]‌. Body mass index (BMI) and the percentage of total body
or to the whole body. Based on the removal pattern, uremic tox-
fat, however, do not seem to predispose to sleep apnea—it is rather
ins are subdivided into three major classes: (i) small water-soluble
the increased fat deposition in the abdominal area that plays the
compounds, (ii) larger middle molecules, and (iii) protein-bound
pivotal role [34].
molecules. These substances are mostly waste products of protein
catabolism and are collectively called “uremic toxins.”
Daytime sleepiness and fatigue
Uremic toxicity has been involved in sleep disturbances in CKD
More than 50% of CKD patients are subject to daytime sleepiness patients. Patients in the early stages of CKD where their kidneys
[35,36], while the majority of ESRD patients have experienced maintained some function were less prone to sleep disturbances
some symptoms of excessive daytime sleepiness. This daytime compared with HD patients [11]. Serum phosphorus levels above
drowsiness often leads to excessive sleep during the HD session and 7 mg/dL and calcium–phosphorus product above 80 mg2/dL2 were
an increased risk of fall accidents during the day or of car accidents linked to poor sleep quality in DOPPS [10]. Other small protein-
during the journey home after HD therapy [37]. Fragmented sleep bound uremic toxins such as p-cresol sulfate and indoxyl sulfate
due to sleep apnea or nocturnal sleep disruptions due to PLMS has have been linked to cardiovascular disease and oxidative injury that
been implicated in the pathophysiology of daytime sleepiness [36]. could lead to sleep disordered breathing syndromes [43]. However,
HD patients with a high score on the Epworth Sleepiness Scale have the data linking the dialysis efficiency index Kt/V and sleep disor-
been found to suffer from severe sleep apnea syndrome, and these ders in patients on HD are still not clear [2,44]. In kidney transplant
are the patients with the higher reported levels of general fatigue patients, the prevalences of both insomnia and RLS are reduced to
[2,12]. The lack of restorative sleep [3]‌, excess pre-dialysis weight those observed in the general population; however, the prevalence
[38], poor nutritional status [39], RLS [16], and the overall mental of sleep apnea is still very high, reaching almost 30% [45,46]. More
status of the patients [39] are some of the other factors that con- research is required to examine different modalities such as noctur-
tribute to excessive daytime fatigue. Evidently, all these factors can nal HD to fully elucidate the contribution of uremic toxins in the
contribute to a self-exacerbating process, a vicious circle, of fatigue development of sleep problems.
due to inactivity and further inactivity due to fatigue that leads to
a significant reduction of physical activity and functional capacity. Blood pressure
This inactivity in turn contributes to the increased cardiovascular The majority of ESRD patients suffer from renal hypertension.
mortality in ESRD patients [40]. In addition, hypertension has been linked to sleep disturbances
[47], while low blood pressure (hypotension) is one of the main
Insomnia
reason for napping or dozing during the day or after HD sessions,
Daytime dysfunction that accompanies various sleep disorders has disturbing the normal sleep cycle of the patient. The large fluc-
a direct effect on all aspects of QoL, such as fatigue, poor cogni- tuations in patients’ blood pressure during the day, the inability
tive function, mood disturbance, and distress or interference with to maintain adequate control, and the lack of a dipping effect
personality [41]. Insomnia is a common complaint in patients with during the night [5]‌affect physical and mental health as well as
chronic renal disease and is characterized by insufficient quantity disturbing the normal sleep cycle. In addition, antihypertensive
and quality of restorative sleep, low sleep efficiency, sleep fragmen- medication increases the risk for fragmented sleep and daytime
tation, impaired daytime functioning, tiredness, and fatigue. The sleepiness [48].
prevalence in renal patients varies from 25% to 50%, depending on
the patient’s emotional distress related to a different lifestyle dur- Adequacy of hemodialysis
ing the initial years of HD treatment and treatment of their renal
Efficient elimination of uremic toxins has been associated with
disease for many years [42].
a reduction in sleep disturbances [49]. On the other hand, inad-
equate HD may be associated with increased severity of uremic
Factors affecting sleep in CKD patients RLS symptoms [22]. Nocturnal dialysis significantly reduces the
In kidney diseases, various causative factors have been involved in sleep apnea–hypopnea syndrome and the duration of nocturnal
the development of sleep disorders. The most important factors are hypoxemia, possibly as a result of more efficient dialysis, since
presented in this section. this modality has been shown to more effectively control uremia
[50,51]. Another parameter that seems to influence sleep quality is
Cardiovascular diseases the temperature of the dialysate solution during nocturnal HD. The
The Dialysis Outcomes and Practice Patterns Study (DOPPS) reduction of the temperature by 2°C (from 37°C to 35°C) improves
reported that patients with low quality of sleep were those with sleep by decreasing sympathetic activation and sustaining a con-
high comorbidity index, especially patients with diabetes, coronary stant skin temperature [52].
artery disease, congestive heart failure, hypertension, and periph-
Fluid overload
eral arterial disease [10]. It is important to investigate further
whether therapies targeting cardiovascular diseases would improve In patients with ESRD, fluid overload may contribute to their high
sleep quality and quantity. prevalence of obstructive sleep apnea by increasing the amount of

Chapter 43 sleep in chronic renal insufficiency 421
fluid displaced from the legs into the neck overnight, and possibly 10. Elder SJ, Pisoni RL, Akizawa T, et al. Sleep quality predicts quality
compressing the upper airway compartments. It has been shown of life and mortality risk in haemodialysis patients: results from the
that the amount of overnight rostral fluid displacement from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial
Transplant 2008;23(3):998–1004.
legs is related to the frequency of apneas and hypopneas per hour
11. Barmar B, Dang Q, Isquith D, Buysse D, Unruh M. Comparison of
of sleep [53]. sleep/wake behavior in CKD stages 4 to 5 and hemodialysis populations
using wrist actigraphy. Am J Kidney Dis 2009;53(4):665–72.
Conclusions 12. Sakkas GK, Karatzaferi C. Hemodialysis fatigue: just “simple” fatigue or
a syndrome on its own right? Front Physiol 2012;3:306.
Sleep disturbances have emerged as a problem for both CKD and 13. Covic A, Siriopol D, Voroneanu L. Dialysis-induced segmental
ESRD patients, affecting up to 80% of these patients [7,54]. Low wall motion abnormalities, post-dialysis fatigue and cardiovascular
quality of sleep has a remarkable effect on patients’ QoL, jeopard- mortality: the new Bermuda triangle? Nephrol Dial Transplant
izing also the quality of their medical care. Many patients with 2013;28(10):2404–6.
sleep disorders remain underdiagnosed, since many of the signs 14. Murtagh FE, Addington-Hall J, Higginson IJ. The prevalence of
symptoms in end-stage renal disease: a systematic review. Adv Chronic
and symptoms related to poor sleep are thought to be an unavoid- Kidney Dis 2007;14(1):82–99.
able consequence of renal failure or inadequate dialysis. Effective 15. Stefanidis I, Vainas A, Dardiotis E, et al. Restless legs syndrome in
management of sleep disorders could improve patients’ QoL and hemodialysis patients: an epidemiologic survey in Greece. Sleep Med
mortality. A growing body of evidence suggests significant advan- 2013;14(12):1381–6.
tages of nocturnal hemodialysis for control of uremia and therefore 16. Giannaki CD, Sakkas GK, Karatzaferi C, et al. Evidence of increased
for improving sleep quality and daytime sleepiness. Screening for muscle atrophy and impaired quality of life parameters in patients with
sleep disorders should be part of a patient’s routine checkup, espe- uremic restless legs syndrome. PLoS One 2011;6(10):e25180.
17. Schormair B, Plag J, Kaffe M, et al. MEIS1 and BTBD9: genetic
cially when signs and symptoms of sleepiness are overwhelming. It
association with restless leg syndrome in end stage renal disease. J Med
is clear that more research is needed to investigate the mechanism Genet 2011;48(7):462–6.
of sleep disturbance in renal diseases and to explore alternative 18. Merlino G, Lorenzut S, Romano G, et al. Restless legs syndrome in
treatments. dialysis patients: a comparison between hemodialysis and continuous
ambulatory peritoneal dialysis. Neurol Sci 2012;33(6):1311–18.
19. Araujo SM, de Bruin VM, Nepomuceno LA, et al. Restless legs
Acknowledgements syndrome in end-stage renal disease: clinical characteristics and
We would like to thank Dr. C. Karatzaferi (University of Thessaly) associated comorbidities. Sleep Med 2010;11(8):785–90.
for her comments during the preparation of this chapter. 20. Giannaki CD, Sakkas GK, Hadjigeorgiou GM, et al. Non-
pharmacological management of periodic limb movements during
hemodialysis session in patients with uremic restless legs syndrome.
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CHAPTER 44
Sleep in endocrine disorders

Axel Steiger
Introduction male volunteers, pulsatile injections of GHRH near to sleep onset

resulted in increases in SWS and GH and blunted cortisol secretion
During sleep, various endocrine systems are distinctly active. [9], whereas after CRH secretion, SWS and GH are reduced and
A bidirectional interaction exists between the electrophysiological cortisol is elevated [10]. It is thought that in young healthy men
component that corresponds to the rapid eye movement (REM)–â•‰ during the first half of the night, the influence of GHRH prepon-
non-â•‰REM (NREM) cycle and the endocrine component of sleep derates, resulting in the peak activity of GH and SWS. When CRH
corresponding to the nocturnal secretion pattern of various hor- dominates during the second half of the night, the major amounts
mones. Sleep–â•‰endocrine activity in healthy volunteers and patients of ACTH, cortisol, and REM sleep occur. The balance between
with various disorders, including endocrine disorders, is assessed GHRH and CRH is changed in favor of CRH during aging (reduced
by simultaneous polysomnographic (PSG) recordings and collec- GHRH activity) and depression (CRH overactivity) (Fig. 44.2).
tion of blood by long catheters for later analysis of plasma hor-
mone concentrations. Sleep–â•‰endocrine studies in female and male
healthy volunteers from young adulthood to senescence are per- Sleep in disorders of the HPS system
formed under baseline conditions, after manipulation of the sleep–â•‰ All components of the HPS system—â•‰GH, GHRH, ghrelin, soma-
wake pattern (eg, by sleep deprivation), and after administration tostatin, and insulin-â•‰like growth factor 1—â•‰participate in sleep
of synthetic and endogenous compounds influencing the central regulation.
nervous system (CNS), particularly neuropeptides and steroids. In Isolated GH deficiency was initially diagnosed in eight patients
addition, animal models are used, involving administration of hor- by slowing of their growth, an abnormal insulin hypoglycemia test,
mones, sleep deprivation, surgery on endocrine glands, and trans- and retarded bone age. Possibly, the GH deficiency was related to
genic animals. Such studies have shown a specific role of certain reduced GHRH activity. In these patients, SWS was reduced in
hormones in sleep regulation. Changes in the activity of these hor- comparison with healthy volunteers. The total sleep time and the
mones in endocrine disorders result in changes in sleep. time spent in sleep stages 1 and 2 were elevated [11]. Furthermore,
In young healthy male subjects, the major portion of slow-â•‰wave in these patients, a decrease in SWA was found [12]. A small sam-
sleep (SWS) and the major amount of slow-â•‰wave activity (SWA) in ple of children with psychosocial dwarfism was investigated by
quantitative electroencephalogram (EEG) analysis are found dur- Guilhaume et al. [13]. When these previously neglected young
ing the first half of the night. Most of the growth hormone (GH) patients were transferred to a new environment, after several weeks
secretion during 24 hours occurs at this time [1,2], in most male during recovery of growth, their sleep quality improved and SWS
subjects as a single large peak, but in women as a pre-â•‰sleep GH increased. Patients with acquired GH deficiency related to therapy
surge followed by one or more additional GH peaks [3]â•„. During this of pituitary tumors frequently report fatigue during daytime. In
period, the concentration of the hormones of the hypothalamic–â•‰ a sample of these patients, the multiple sleep latency test (MSLT)
pituitary–â•‰adrenocortical (HPA) system—â•‰corticotropin (ACTH) performed to examine daytime sleepiness was in the normal range.
and cortisol—â•‰are low. During the second half of the night, REM Nocturnal sleep did not differ in these patients between baseline
sleep preponderates, and ACTH and cortisol are secreted in several and the end of 1 year with GH replacement [14].
pulses until they reach their acrophase near to awakening in the In patients with acromegaly, GH levels are excessive. Obstructive
morning, whereas the amounts of SWS and GH are low [4]. During sleep apnea (OSA) syndrome (OSAS) develops frequently in these
normal aging and episodes of depression, similar changes in sleep–â•‰ patients owing to hyperplasia of their upper airway soft tissue
endocrine activity are well documented, including increases in SWS [15]. In patients with acromegaly without sleep apnea, an abnor-
and GH (Fig. 44.1). These patterns in young and older healthy sub- mal sleep structure and daytime sleepiness were also observed.
jects and in depressed patients point to the existence of common In a sample of these patients, the time spent in REM sleep and
regulating factors of the electrophysiological sleep pattern and the SWS increased 1 year after therapy by adenomectomy. In this
nocturnal secretion of GH, ACTH, and cortisol. Indeed, there are study, sleep energy was calculated by quantitative EEG analysis.
many hints of a reciprocal interaction of the key hormones of the REM sleep and SWS energy were higher at baseline than after
hypothalamic–â•‰pituitary–â•‰somatotropic (HPS) and HPA systems,—â•‰ adenomectomy [16].
GH-â•‰releasing hormone (GHRH) and corticotropin-â•‰ releasing Besides GHRH, ghrelin stimulates the release of GH.
hormone (CRH)—â•‰at least in men [5]. In short, animal mod- Furthermore, ghrelin is a strong stimulus of appetite [17] and, in
els show that GHRH promotes NREM sleep [6,7], whereas CRH men, of sleep [18]. Nocturnal sleep is disrupted in night-â•‰eating
enhances wakefulness [6] and REM sleep [8]. Similarly, in healthy disorder owing to nocturnal hunger and the resulting food intake.

Controls Patients with depression

25 years 25 years
Wake Wake
REM REM
I I
EEG II EEG II
III III
IV IV
300 300
Cortisol 200 Cortisol 200
ng/mL 100 ng/mL 100
0 0
40 40
GH GH 20
20
ng/mL ng/mL
0
23 1 3 5 7 h 0
23 1 3 5 7 h
65 years
65 years
Wake
REM Wake
I REM
EEG II EEG I
III II
IV III
IV
300 300
Cortisol 200 Cortisol 200
ng/mL 100 ng/mL 100
0 0
40 40
GH GH
20 20
ng/mL ng/mL
0 0
23 1 3 5 7 h 23 1 3 5 7 h
Fig. 44.1 Hypnograms and patterns of secretion of cortisol and GH of four male subjects (young and older patients with depression and healthy volunteers). REM: rapid
eye movement sleep; I–IV: non-REM sleep stages 1–4.
Reproduced from D’haenen H, den Boer JA, Westenberg H, and Willner P, Neuroendocrinology of sleep disorders. In: Steiger A, (ed.), Textbook of Biological Psychiatry, pp. 1229–1246, Copyright
(2002) with permission from John Wiley and Sons.
Distinctly enhanced ghrelin levels were found in a patient with this observed [21,22]. In one study, patients with Addison’s disease were
disorder [19]. compared under two conditions: either continuous hydrocortisone
Reduced nocturnal GH secretion was reported in obese patients replacement or short-term hydrocortisone withdrawal. In com-
by several studies [20]. Nocturnal sleep and GH secretion were parison with withdrawal after hydrocortisone replacement, REM
compared in obese patients without OSA in a longitudinal study latency (the interval between sleep onset and the first REM period)
before and after weight loss due to a hypocaloric diet. As control was shortened and REM time and intermittent wakefulness were
group, lean healthy volunteers were used. Sleep variables did not increased. These data suggest a role for cortisol in the initiation and
differ between groups. A nearly total absence of GH secretion was maintenance of REM sleep [23].
found in the obese patients before weight loss. The mean body mass In Cushing’s disease, excessive cortisol levels occur, of either
index of the patients decreased after weight loss from 37.1 to 31.4 peripheral or central origin. In these patients, SWS is reduced com-
(healthy volunteers 22.3). Whereas sleep architecture remained pared with healthy volunteers [22,24]. In addition, in one study,
unchanged after weight loss, GH levels increased. This finding sug- increases in sleep latency and in intermittent wake time and disin-
gests a partial restoration of GH secretion [20]. hibition of REM sleep (shortened REM latency and elevated REM
density) were found [24]. In particular, the latter study points to
similarities of sleep-EEG changes in Cushing’s disease and depres-
Sleep in disorders of the HPA system sion. Beside similar sleep-EEG changes (for a review, see [25]), HPA
The HPA system is also called the stress axis. It mediates the reac- overactivity [26] and HPS dysfunction [27] are well documented.
tion to acute physical and psychological stress. This is a prerequisite The dysregulation of the HPA system is more subtle in affective dis-
for the individual’s survival. After release of CRH from the parvo- orders than in Cushing’s disease, with elevated cortisol levels being
cellular neurons of the paraventricular nucleus of the hypothala- found throughout the night and elevated ACTH levels throughout
mus, ACTH is secreted from the anterior pituitary. Finally, cortisol 24 hours in comparison with healthy volunteers [27–29]. Nocturnal
is secreted from the adrenal cortex. GH secretion in depressed patients was reduced in most [27,30,31]
The production of corticosteroids by the adrenal glands is dis- but not all [28] reports. A longitudinal study showed persistence of
tinctly reduced in Addison’s disease. There are only a few case reports pathological sleep EEG and low GH levels between acute depression
on sleep EEGs in these patients. No major sleep disturbances were and recovery. In contrast, cortisol decreased after recovery [27].

Chapter 44 sleep in endocrine disorders 425
Young normal control

The persistence of most sleep-EEG changes [32] and blunted GH
secretion [30] after recovery were confirmed over a period of
3 years. Obviously elevated cortisol secretion was eliminated dur-
Galanin ing sleep in remitted patients. It appears likely that elevated HPA
NPY Ghrelin
activity contributes to the sleep-EEG changes in depression and
GHRH CRH + SRIF in Cushing’s disease. As mentioned earlier, depression-like sleep–
endocrine changes occur after CRH administration to healthy con-
Wake
REM
trols [10]. Furthermore, after high-dose glucocorticoid therapy of
I patients with multiple sclerosis for 10 days, sleep-EEG alterations
II
III occurred resembling those in depressed patients [33]. It is thought
IV
that the endocrine changes during acute depression cause a bio-
40 300
GH 200 Cortisol
logical stigma resulting in the persisting changes of sleep EEG and
ng/mL
20
100 ng/mL GH secretion in remitted patients. This view is supported by similar
0 0 findings in male survivors of severe brain injury. Several months
later, the cortisol concentrations of these patients did not differ
from those of healthy volunteers. However, their GH levels and
Patient with depression the amounts of stage 2 sleep were diminished, whereas the cortisol
concentrations were in the normal range at the time of the study.
It appears likely that elevated HPA activity due to stress associated
GHRH CRH + SRIF with brain injury or treatment with glucocorticoids in a subgroup
of patients contributes to changes in sleep and GH secretion [34].
Wake In patients with OSAS, during an episode of apnea, progressive
REM
I hypoxemia due to asphyxia and upper airway constriction, auto-
II
III nomic activation, and sleep-EEG arousal occur. It is thought that
IV OSA results in activation of the HPA system by autonomic hyper-
40 300 activity [35]. This HPA activation may contribute to the develop-
GH 20
200 Cortisol ment of metabolic syndrome in untreated OSA. In addition, it is
ng/mL 100 ng/mL
0 0
suggested [35] that HPA hyperactivity may contribute to the patho-
physiology of hypertension in OSAS.
Sleep fragmentation and reduced SWS are associated with
sleep apnea [36]. Sleep apnea is eliminated by nasal continuous
Aged normal control positive airway pressure (CPAP) therapy [37]. The effect of nasal
CPAP therapy on sleep–endocrine activity was examined in obese
patients with OSAS. At baseline, the amounts of SWS and REM
GHRH CRH + SRIF sleep were low, the number of apneas was enhanced, and the arte-
rial oxygen saturation was diminished. All these variables were
Wake
REM normalized after one night of nasal CPAP therapy. GH secretion,
I
II which was blunted at baseline, increased during the CPAP night,
III
IV whereas cortisol secretion did not differ between baseline and
40 300 the post-CPAP period [38]. Cessation of nasal CPAP therapy in
GH 20
200 Cortisol patients who used this device regularly resulted in an immedi-
ng/mL 100 ng/mL
ate recurrence of sleep apnea. ACTH and cortisol levels remained
0 0
23 24 1 2 3 4 5 6 7 h unchanged, however [39]. Sleep, plasma renin activity, and aldos-
terone levels were compared in patients with OSAS between
Fig. 44.2 (See colour plate section) Model of peptidergic sleep regulation. A baseline and 1 night after CPAP therapy [40]. At baseline, fre-
reciprocal interaction between the neuropeptides growth hormone-releasing
quent awakenings, lack of SWS, and few short REM periods were
hormone (GHRH) and corticotropin-releasing hormone (CRH) appears likely, at
least in male subjects. GHRH is thought to preponderate during the first half of observed. CPAP therapy induced improvements in sleep depth and
the night, whereas CRH (and SRIF, somatostatin) dominate during the second half REM sleep. In some of these patients, regular REM–NREM cycles
of the night. Neuropeptide Y (NPY) influences the time of sleep onset. Ghrelin occurred, whereas in others, the sleep structure remained irregu-
and galanin are cofactors to GHRH. The balance between GHRH and CRH is lar. As is known from healthy volunteers [41], plasma renin activity
changed during aging (reduced GHRH activity) and during depression (CRH profiles reflect the pattern of REM–NREM cycles, with increasing
overactivity). Therefore, similar sleep–endocrine changes are found during aging plasma renin activity during NREM periods and declining activ-
and in patients with depression.
ity during REM sleep. Normalization of the sleep cycles in some
Reproduced from Der Nervenarzt, 66, Steiger A, Schlafendokrinologie, pp. 15–27, Copyright
(1995), with permission from Springer.
of the investigated patients resulted in regular oscillating plasma

renin activity, whereas irregular sleep patterns in other patients led Sleep–endocrine activity was investigated in non-hypoglycemic
to a general non-oscillatory pattern of plasma renin activity. After type 1 diabetic patients and matched healthy controls. The patients
CPAP therapy, the mean concentrations of plasma renin activity spent slightly less time in SWS during the first half of the night.
and aldosterone were enhanced [40]. Stage 2 sleep was increased throughout the night in comparison
with the controls. As expected, plasma glucose and serum insulin
Sleep in hypothyroidism levels were consistently higher in patients throughout the night.
Furthermore, GH and epinephrine (adrenaline) were elevated dur-
and hyperthyroidism ing the night. In the first half of the night, higher levels of ACTH
Changes in sleep–wake behavior are well known in disorders of and cortisol (nonsignificant) occurred in the patients [47], com-
the thyroid gland. It is well established from clinical practice that pared with levels in the second half of the night.
insomnia is a characteristic symptom of hyperthyroidism. On the
other hand, fatigue is frequent in patients with hypothyroidism. Sleep in prolactinoma
Therefore, it is astonishing that there is a paucity of sleep-EEG stud-
ies in these disorders. In one study, reduced SWS was reported in Prolactin is a neuroprotein and a circulating hormone. Exogenous
patients with hypothyroidism when compared with healthy volun- prolactin administration enhances REM sleep in cats, rabbits, and
teers, and after treatment these changes normalized [42]. rats [48]. SWS is increased selectively in patients with hyperpro-
lactinemia (Fig. 44.3) [49]. Compared with other endocrine dis-
orders, the symptoms appear to be unique as they are related to
Insulin, diabetes mellitus, and sleep impaired sleep. Studies on the effect of a moderate exogenous
Insulin is a stimulus for glucose uptake in adipocytes and skeletal enhancement of prolactin levels in humans are lacking. Such inves-
muscles. Circadian rhythmicity and sleep influence the profiles of tigations could clarify whether REM sleep is enhanced in this con-
glucose and insulin secretion rate, resulting in higher mean concen- dition similar to the preclinical studies mentioned before.
trations during nocturnal sleep [43]. After administration of insulin
in rats, either systemic [44] or intracerebroventricular administra- Sleep in disorders related to gonadal
tion for 3 days [45], NREM sleep increased. Reduced amounts of
NREM and REM sleep were observed in rats with experimentally hormones
induced diabetes mellitus, but their sleep normalized after insulin After administration of gonadal hormones to adult animals, only
infusion [46]. minimal effects on sleep or on sex differences in sleep were found
(a)
Wake
REM
II
III
IV
(b)
Wake
REM
II
III
IV
23 24 1 2 3 4 5 6 7
Time
Fig. 44.3 Sleep patterns in a 25-year-old male patient with a prolactinoma (a) and in a matched control (b). REM: rapid eye movement sleep; I–IV, non-REM sleep
stages 1–4.
Reproduced from Journal of Clinical Endocrinology & Metabolism, 83, Frieboes RM, Murck H, Stalla GK, Antonijevic IA, Steiger A, Enhanced slow wave sleep in patients with prolactinoma,
pp. 2706–2710, Copyright (1998), with permission from The Endocrine Society.

Chapter 44 sleep in endocrine disorders 427
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CHAPTER 45
Sleep disturbances
in critically ill patients
Gerald L. Weinhouse
Introduction electrophysiological abnormalities is uncertain, but one interpreta-

tion is that a subset of critically ill patients may be in a dissociative
The intensive care unit (ICU) is an almost uniquely hostile environ- state where the line between sleep and wakefulness is blurred.
ment for sleep. Bright lights throughout the day and night, loud There has been some interest in using additional strategies,
noises, frequent interruptions, numerous medications known to such as spectral analysis and clinical observations of arousal, as an
suppress deep sleep, mechanical support devices, pain, anxiety, adjunct to interpreting the results of polysomnography in the criti-
stress, and severe medical illnesses themselves influence and restrict cally ill [15,16]. However, an improved understanding of (1) the
the amount and quality of sleep attainable by the sickest patients. In significance of these deviations from the R & K criteria, (2) the
fact sleep, as defined by the established criteria of Rechtschaffen & relationship between this altered state of consciousness and nor-
Kales (R & K), may be unrecognizable in some critically ill patients. mal, restorative sleep, and (3) the impact of this altered state of con-
sciousness on patients’ recovery from critical illness may only come
ICU sleep studies from an integrative approach incorporating data from neuroimag-
The challenges of performing systematic sleep studies in the criti- ing and other measures of brain physiology.
cally ill are formidable; however, there have been many studies The abnormal EEG patterns of some ICU patients and their rela-
over the past 40 years using polysomnography, still considered the tionship with critical illness is potentially important. ICU delir-
gold standard, to measure the sleep of critically ill patients. Most ium, for example, is highly prevalent among patients supported
of the studies have included small numbers of patients, but the by mechanical ventilation, and it is an independent risk factor for
results have been consistent across different types of ICU. Critically six-â•‰month mortality, longer length of hospital stay, and higher cost
ill patients, especially those supported on mechanical ventilators, [18,19]. Sleep loss and ICU delirium both share common clinical
often have severely fragmented sleep, deprived of the deep, restora- and neurophysiological features. Both conditions are associated
tive stages of sleep [1–â•‰7]. These patients have a correspondingly with poor thought processing, memory and attention deficits, and
poor perceived sleep quality [3,8]. The total number of hours a crit- fluctuating mental status, and have been found to have altered brain
ically ill patient may sleep in the 24 hours of a day ultimately may activity in the prefrontal and nondominant parietal cortices. In one
be normal, but they are distributed in short periods throughout the small study, critically ill patients with a more severe reduction in
day and night, with no single extended (consolidated) period as is REM sleep were more likely to develop ICU delirium [20]. If the
considered normal. Their circadian rhythm, as measured by core observed deviations from normal sleep patterns experienced by
body temperature and levels of 6-â•‰sulfatoxymelatonin, is abnormal critically ill patients have a relationship with ICU delirium, then it
[9,10]. And survivors of a critical illness often report that they recall may be reasonable to hypothesize that improving the sleep of these
having slept poorly while in the ICU and that it was very stressful patients could also reduce the incidence of delirium and improve
for them [6,11–â•‰14]. the associated outcomes.
Studies of the sleep of mechanically ventilated patients have also
been consistent in demonstrating electrophysiological anomalies. Effect of critical illness on sleep
These studies have found that some critically ill patients have sleep
that cannot be classified with standard scoring criteria [2,6,15–â•‰17]. Sepsis
For example, what has been described in critically ill patients as Between 20% and 40% of admissions to a medical ICU are for sep-
“atypical sleep” is characterized by alpha and/â•‰or theta activity with- sis [21,22]. Sepsis itself has been associated with altered sleep, pos-
out sleep spindles or K-â•‰complexes and may have high-â•‰amplitude sibly by an effect on the neurohormonal environment of the central
continuous, irregular delta activity. “Pathological wakefulness,” nervous system (CNS) or by a more direct effect on the electrical
as described in these patients, is characterized by EEG frequency system of the CNS as manifested by changes in the EEG. These
exclusive of alpha and beta activity in patients with behavioral char- patients have been found to have low-â•‰voltage, mixed-â•‰frequency
acteristics of wakefulness. These anomalies appear to be more prev- waves with variable amounts of theta and delta waves [6,23]. This
alent in patients on sedative medications than those who are not, pattern has been referred to as “septic encephalopathy” and, simi-
but they have been described in both. The clinical relevance of these lar to those patients with “pathological wakefulness” or “atypical

sleep,” the state of consciousness cannot be determined by the EEG more closely mimic natural sleep [33]. Regardless, its theoretical
alone. This pattern has been reported to appear prior to the clinical advantages have not been realized clinically in this regard [34].
manifestations of sepsis [6]‌. Along with this EEG pattern is a reduc- 3. Analgesics. Opioids are a mainstay in the treatment of pain
tion in the percentage of time in REM sleep and loss of normal in critically ill and postoperative patients. These medications
circadian melatonin secretion. potently suppress both slow wave and REM sleep [35–37]. If pain
is the primary cause of sleep disturbance, however, they would
Acute cardiovascular syndromes likely improve sleep efficiency.
Acute cardiovascular events necessitating critical care have been
4. Vasopressors. Adrenergic receptor agonists, such as epineph-
associated with a high incidence of sleep-disordered breathing.
rine and norepinephrine, and dopamine are all associated with
Between 40% and 70% of patients presenting to a coronary care unit
insomnia and the suppression of slow-wave and REM sleep [38].
may have sleep apnea–hypopnea syndrome [24,25]. Obstructive
events predominate, although central respiratory events may be
detected in a minority of patients. A significant number of these Treatment
cases may be transient and improve or resolve with resolution of
There is no protocol that has been demonstrated to improve the
the acute event.
sleep of critically ill patients. One recent protocol, however, was
Respiratory failure designed to improve sleep by controlling noise and light and
increasing daytime activities [39]. An effort was made to engage
Respiratory failure of any cause and its treatments all may be patients in activities during the day and minimize napping in order
associated with a disruption of sleep. Mechanically ventilated to restore circadian rhythms and increase the pressure for night-
patients face a particularly difficult challenge due to the dis- time sleep. Notably, this protocol did lead to a significant reduction
comfort of the endotracheal tube and lack of synchrony with in the incidence of delirium but not to a demonstrable improve-
mechanically supported breaths. Several studies have been done ment in perceived sleep quality.
to investigate the relationship between the ventilator mode and It seems most likely that only through a conscious effort to pro-
the frequent arousals from sleep observed in these patients. In vide a safe, quiet, comfortable, and restful environment for sleep
one such study, patients with congestive heart failure had fewer combined with the judicious use of medications will “natural”
central apneas and associated arousals while supported on assist (non-chemically induced) sleep be preserved.
control ventilation as compared with pressure support ventila-
tion [26]. Other studies have compared proportional assist ven-
tilation with pressure support ventilation and suggested that References
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CHAPTER 46
Sleep and pain
Interactions and syndromes
Gilles J. Lavigne, Samar Khoury, Caroline
Arbour, and Nadia Gosselin
Pain is classically defined as an unpleasant sensory experience that considered a hypervigilance state, may help explain complaints of
may be felt in the presence or absence of injury and can even persist fatigue, anxiety and other associated co-morbidities in chronic pain
after the original injury has healed. Pain is considered chronic when patients. In addition, the influence of mood on sleep quality in pain
persistent or recurrent episodes (eg, interspersed with pain-â•‰free patients seems critical [12–â•‰17]. In fact, in patients with insomnia,
periods) are experienced for more than 3 months. At the physiolog- the endogenous pain inhibitory system that naturally induces anal-
ical level, pain occurs when sensory and emotional brain pathways gesia is dysfunctional. In other words, because of the steady hyper-
are activated, generating an adapted or non-â•‰adapted response. This vigilance state associated with insomnia, the descending inhibitory
pain response is dependent on mood, past exposures, expectations analgesic system is already at its ceiling effect, and consequently
of pain relief, placebo influences, and many other factors [1]â•„. In cannot provide further pain relief when required. The net result is
Europe and North America, about 20% of adults report chronic that more pain is felt in patients with insomnia than those without
pain, and this prevalence increases with age [2–â•‰4]. Pain may be insomnia [18].
associated with unstable sleep, disruption of NREM to REM sleep Other sleep parameters associated with an increased likelihood
cycle continuity, and excessive sleep fragmentation (i.e, interrup- of pain exacerbation or reports are short sleep duration and pres-
tions by overly frequent and powerful arousals, body movements, ence of frequent sleep awakening, periodic limb movements in
or sleep stage shifts), which may in turn increase perceptions of sleep, and breathing disorders [5].
unrefreshing or nonrestorative sleep (NRS) [5].
The pain–â•‰sleep interaction
Sleep characteristics associated with pain The classical notion of an interrelated negative affect between pain
NRS refers to the subjective experience of sleep as insufficiently and sleep cannot be applied to all pain syndromes and conditions. It
refreshing, or the feeling that sleep is restless, light, or of poor qual- is not a case of “one size fits all” [5,15]. Accordingly, the interaction
ity, even though traditional objective sleep parameters (eg, total between pain and sleep has been conceptualized in various models.
sleep duration, sleep stage distribution) may appear normal [6]â•„. In the “linear model,” sleep interacts with acute pain in situations
The prevalence of NRS in the general European population is esti- such as postoperative or post-â•‰traumatic pain. A few days of pain
mated at 10.8%, and more than 40% of individuals with insomnia are accompanied by poor sleep, but everything returns to normal
suffer from at least one chronic painful physical condition [4,7]. when the pain disappears [19]. The “circular model” fits better with
Having either less than 6 hours or more than 9 hours of sleep the pain–sleep interaction idea for most chronic pain conditions,
appears to be critical to predict current day’s pain [8,9]. Reduced but it does not exclusively explain the deleterious effect of pain on
total sleep time is associated with more moderate and severe pain, poor sleep and vice versa [5,20]. Thus, the pain may not necessar-
and more specifically, a reduction in total slow wave is associated ily be more intense on the next day after poor sleep. Instead, after
with more pain only in men. Poor sleep in pain patients may result a poor night’s sleep, a wider range of pain severity is reported [21].
from a common environmental and genetic background; however, While pre-â•‰sleep pain is a weak predictor of sleep quality, level of
data are emerging only slowly, and specific sleep and pain markers arousal before sleep appears to be more critical for predicting poor
are difficult to identify [10]. Diurnal fatigue, mood alteration, and sleep quality (again, the awake time hyperarousal state may be a
work shift schedule have been less often documented as causes of risk factor), which in turn predicts pain for only the first half of the
NRS in chronic pain patients. Fortunately, NRS is reversible, which following day [15]. Again, this model cannot be generalized to all
can potentially benefit most chronic pain patients as the return of patients as the variability could be explained by other predispos-
restorative sleep appears to predict, with an odds ratio (OR) of 2.0, ing risk factors (eg, mood, insomnia, hyperarousal–â•‰hypervigilance,
the resolution of chronic widespread pain (CWP) [11]. and previous pain history) as well as by hyper-â•‰reactivity in the
Insomnia (i.e, difficulty falling asleep or an incapacity to resume hypothalamic–â•‰pituitary–â•‰adrenal stress (HPA) axis, by a protective
sleep after awakening during the sleep period) is a sleep disorder immune or genetic mechanism, the exact nature of which remains
that is frequently reported by chronic pain patients [4,12]. The open to debate [22–â•‰24]. To better understand the strength of the
classical association of pain and insomnia with hyperarousal, both pain–â•‰sleep interaction, it is also worth noting that good sleep

quality is associated with better musculoskeletal health (with an OR such as loud snoring or repeated breathing cessations (OR 1.4–2.7)
of 3.4). In other words, the risk of pain is lower [25]. [34]. We found that CWP patients tend to have three NREM to REM
Several other factors may contribute to a patient’s risk of expe- sleep cycles instead of five, lose about 60 minutes of total sleep time,
riencing an interaction between pain and poor sleep, includ- and experience intermediate numbers of periodic limb movements
ing: (1) the patient’s lifestyle and fitness level; (2) their beliefs and per hour of sleep: more than healthy subjects and less than PLMD
attitudes toward disease and healthcare, including expectations of patients. Furthermore, their EEGs show no alpha–delta sleep, but
relief; and (3) the presence of sleep comorbidities such as insom- instead a loss of slow-wave activity in the first and second NREM
nia, periodic limb movement disorder (PLMD), or sleep disor- cycles (observed in female subjects only) [35,36] Gender predisposi-
dered breathing (apnea/hypopnea or obstructive apnea syndrome, tion to pain and poor sleep is an issue that deserves more attention.
respiratory effort-related arousal (RERA), or upper airway resist- Patients with fibromyalgia have diffuse and widespread muscle
ance syndrome (UARS)). Regarding sleep comorbidities, PLMD pain and tenderness in numerous body sites, along with complaints
and sleep apnea have been reported in patients with fibromyalgia (a of unrefreshing sleep, somatic and cognitive symptoms, mood alter-
musculoskeletal pain subcondition of chronic widespread pain) or ations, and fatigue [37]. Studies have identified a causal sequence
with temporomandibular disorders (TMDs: jaw, muscle, and joint involving sleep problems, pain, poor physical functioning, and
problems)—these can contribute to increasing the likelihood of depression, which strongly suggests that poor sleep in fibromyalgia
sleep fragmentation and influences on perception of sleep quality patients can predict pain over a one-year period [38]. Furthermore,
[26–28]. past history of pain, sleep quality, and delay from onset of fibro-
myalgia symptoms explained 22% of the pain variance in these
Clinical recognition patients at a one-year follow-up. Only a few controlled sleep studies
have compared the strength of this relationship between fibromyal-
When assessing chronic pain, the clinician should consider a his- gia patients and control subjects using quantitative analysis of sleep
tory of fatigue, depression, anxiety, sleep habits, sleepiness, risk variables (polysomnography). From these studies, several distinc-
factors for the sleep disorders mentioned in the previous section, tions between these two populations have been made. Specifically,
and the presence of psychological or physical trauma. Many vali- compared with controls, fibromyalgia patients were shown to have
dated assessment questionnaires are available, but this topic is (1) fewer EEG sleep spindles during light sleep (stage 2 or N2)
beyond the scope of this chapter. Well-known instruments include after controlling for age, depression, and psychiatric conditions in
the Epworth Sleepiness Scale, the Berlin Questionnaire to assess females [39], (2) shorter stage 2 sleep duration (with females having
apnea, the Pittsburgh Sleep Quality Index, and the Beck Anxiety more sleep stage shifts), (3) more cyclic alternating pattern (CAP)
and Depression Inventory. Polysomnographic recordings are per- cycles, scored by measuring the balance between sleep maintenance
formed on pain patients mainly to rule out comorbidities such as and sleep arousal pressure, and (4) clustering and/or phasic alpha
insomnia, sleep movement disorders (PLMD, bruxism, and REM EEG activity in female patients [40,41]. It was also suggested that
behavior disorder), and breathing disorders (see Chapters 7 & 10 the sleep regulatory process differs between chronic fatigue syn-
and Section 8 of this volume) [29,30]. drome and fibromyalgia, although the two conditions may overlap
Among the types of chronic pain reported to interfere with sleep in some individuals [42].
are musculoskeletal pain (eg, arthritis, fibromyalgia/widespread TMDs consist of pain in the jaw joint and muscles; the causes
pain, and temporomandibular pain), neuropathic pain (herpes are unknown and several psychosocial, genetic, inflammatory and
zoster and trigeminal neuralgia), and headaches. In this chapter, hormonal/gender factors are candidates [43,44]. They are reported
we will also introduce a prospective model of minor traumatic by about 7% of the general population [45]. An individual may
brain injury (mTBI), with which we investigate new onset of pain have both chronic orofacial pain and widespread pain/fibromyal-
and sleep problems and consider the sequence and roles of vari- gia, and this comorbidity is often associated with fatigue, mood,
ous risk factors in the transition from acute to chronic pain after and self-regulatory deficits [46,47]. A case–control experimen-
trauma. tal sleep laboratory study revealed that one-third of patients with
myofascial TMD experience insomnia and sleep apnea and that
Chronic widespread musculoskeletal pain, poor sleep quality increases progressively the risk of painful TMD
fibromyalgia, and temporomandibular [26,48]. However, no causal relationship was observed between the
frequency of sleep bruxism motor activity and TMD-related pain
disorders complaints, although a higher frequency of mild sleep disturbances
CWP is characterized by muscle and joint pain in many body sites. causing arousal (RERA) was observed [25,49].
Its prevalence is higher than that of what is referred to as fibromyal-
gia, which is a syndrome that includes, aside from muscle and joint
stiffness, mood, sleep, and gastrointestinal disorders, as described in Sleep and headaches
the next paragraph [31,32]. Adult patients with CWP have a higher The clinical classification of headaches was updated in 2004 by a
risk (OR > 3) of fatigue, headaches, gastrointestinal problems, and consensus statement entitled the International Classification of
sleep disturbances [33]. Patients with CWP who are seen in family Headache Disorders (ICHD; http://www.i-h-s.org). In this clas-
medicine practice report complaints of daytime sleepiness, dozing off sification, primary headaches were grouped into four main cat-
during daily activities, frequent awakenings during the night, and/or egories: (1) migraine (with or without nausea and vomiting);
restless leg syndrome (i.e, uncomfortable sensations associated with (2) tension-type headache; (3) cluster headache; and (4) other
an urge to move and frequent periodic limb movements in sleep). trigeminal autonomic cephalalgia [50]. In this chapter, we will
In addition, they report more signs of sleep-disordered breathing, focus exclusively on sleep-related headaches.

Chapter 46 sleep and pain: interactions and syndromes 435
In the latest ICHD Classification (ICHD-3), primary headaches Recent evidence indicates that MHA can last up to 1–4 hours in
are classified into four main categories: (1) migraine; (2) tension- more than 55–74% of subjects with or without sleep-apnea-related
type headache; (3) trigeminal autonomic cephalalgias; and (4) HA [53,66].
other primary headache disorders [51]. Sleep-related headaches, as The daily functioning of an MHA patient is associated with stress,
defined by the International Classification of Sleep Disorders [52], anxiety, and depressive mood, plus irritability, fatigue, and a feeling
include headaches such as migraine, cluster headaches (related of inefficiency, in addition to oversensitivity to sound, touch, and
to circadian rhythms and REM sleep stage), chronic paroxysmal light [63]. The frequency of sleep complaints in MHA patients is
hemicranias, and hypnic headache, a rare condition occurring upon similar to that for all headaches. Complaints of difficulty initiating
awakening from REM sleep and possibly from deep sleep, stage N3 or maintaining sleep, feeling unrefreshed in the morning, disturbed
[31,50,52–62]. Recent studies on morning headache (MHA) have sleep, and tossing and turning are 2–4 times higher than in controls
focused on the most prevalent types: tension-type and migraine [64]. Risk factors include gender (OR for women is 1.1), age (worse
headaches without aura, nausea, or vomiting. Morning headache is in the 20s and 40s, and lower after age 60), regular alcohol or medi-
empirically defined as a recurrent, bilateral, and pressing pain that cation use, and, in some cases, overuse of medications (also known
is present at awakening three or more times a week [63,64]. MHA is as medication-overuse headache or rebound headache) [63,64].
most frequently a tension-type or migraine headache, with reports
both of pressing (over 60% of cases) and of throbbing (at least 11– Sleep and pain in mild traumatic brain
46%) sensation [53,65–68]. Episodic MHA is a good indicator of
major depressive and insomnia disorders, and has been found to
injury patients
affect 5-8% of the general population [63,64]. Sleep disruptions following mTBI are commonly reported and are
It has now been recognized that tension-type and migraine part of the symptoms that make up chronic traumatic encephalopa-
headaches have different pathophysiologies [69–73]. Tension-type thy. Sleep disruptions can be as high as 44% in the year following an
headache is described by patients as a tight band-like or press- mTBI, making it an interesting model for the study of sleep [87,88].
ing sensation that is bilateral, with no nausea or vomiting. It is a Specifically, several sleep disorders have been reported in mTBI
benign but highly prevalent condition in the general population. In victims, including (1) post-traumatic hypersomnia, (2) insomnia,
the USA, the one-year prevalence of the episodic type of tension- (3) periodic limb movements in sleep, (4) narcolepsy, (5) REM
type headache is 38%. Worldwide, this prevalence varies from 11 to behavior disorder, and (6) obstructive sleep apnea [89–93]. The
60%, depending on the data collection method (interviews, clini- causes of these sleep disturbances are unknown, and quantitative
cal assessments, or lifestyle questionnaires) and country (lower in polysomnographic studies have not provided much helpful evi-
Norway and Switzerland than in the USA) [70,71,74–76]. Women dence. Indeed, findings on sleep stage duration, sleep efficiency,
are slightly more at risk (OR ≥ 1.16), and complaints of tension and REM sleep duration were either inconsistent or showed no
headache frequency peak between ages 30 and 39 years (OR = 1.2) significant differences from healthy controls [94–97]. Still, studies
[76]. MHA is reported by close to 70% of sleep bruxism patients, using EEG spectral power analysis have reported lower delta and
but the tension-type headaches are not strongly associated with higher alpha and beta power during NREM sleep in mTBI patients
sleep bruxism motor activity—a subject of debate [77,78]. compared with controls at one week post-trauma [98]. Similarly, a
Migraine is a common episodic unilateral headache with or with- significant power reduction in low EEG frequency bands (0.5–9.75
out aura, sensitivity to light (photophobia) or sound (phonophobia), Hz) during NREM sleep was found in adolescents post-mTBI [98].
nausea, and vomiting. The population prevalence of migraine with Conversely, no differences in quantitative sleep EEG were reported
aura is about 1%, and in Canada it is 26% for all types of migraine in mTBI patients or in athletes with mTBI compared with healthy
[52,72,74,79,80]. The one-year prevalence of migraine without aura subjects and control athletes [99,100].
is 5–15% in the general population, but is twice as high in females. Pain is a highly prevalent post-concussion symptom in mTBI
[74,75]. Attacks may be triggered by a vast array of conditions, patients, occurring in more than 75% of cases [101]. In fact, patients
including sleep problems (such as sleep apnea), and jaw disorders. with mTBI report more pain compared with patients with severe TBI
Migraine and tension headaches may overlap with TMDs, brux- [101,102]. The presence of pain exacerbates complaints of insomnia
ism, and neck pain [81–84]. Tension-type headache is reported by twofold in mTBI patients [102]. In previous studies, mTBI patients
4.6–32% of diagnosed PLMD patients and by almost 50% of sleep with sleep complaints reported more headaches [103] and about
bruxism patients, again without any relationship to frequency of one-third of mTBI patients progress to chronic pain [104,105].
jaw muscle activity [68,78,85,86]. In a study using high-density spectral analysis, we found that,
Another frequent sleep-related headache is sleep apnea headache. compared with mTBI without pain and healthy controls, mTBI
Based on an etiologic classification, the International Headache patients with pain reported poorer sleep quality on the Pittsburgh
Society (2004) suggests the following diagnostic criteria for sleep Sleep Quality Index (PSQI), which was correlated to higher pre-
apnea headache [50]: dominance of beta and gamma EEG activity during all sleep stages,
A. Recurrent headache with at least one of the following characteris-
including the N3 deep sleep stage [106]. Also, it should be noted
tics and fulfilling criteria C and D: 1. occurs on >15 days per month; that treating one condition may not contribute to reverse the sec-
2. bilateral, pressing quality and not accompanied by nausea, photo- ond, and vice versa.
phobia or phonophobia; 3. each headache resolves within 30 minutes.
B. Sleep apnea (Respiratory Disturbance Index > 5) is demonstrated Management of the pain–sleep interaction
by overnight polysomnography. C. Headache is present upon awaken-
ing; and D. headache ceases within 72 hours, and does not recur after Management is a broad term that covers the management of
effective treatment of sleep apnea. both pain and sleep, with a particular focus on balancing the

predominant factors in the etiology of patient complaints. As a gen- influence of sleep inertia on performance and mood disturbance
eral rule, patients should be advised about lifestyle factors and sleep (grogginess). Reliable studies are lacking on the benefits of this
hygiene, cognitive–behavioral therapies (CBTs), manual therapies simple strategy, for instance, the identification of the best time of
(eg, physical therapy), and medications (see Box 46.1). day to nap or its effectiveness on the pain–sleep interaction [107].
Napping is a strategy used by many chronic pain patients to cope Furthermore, because mTBI patients also tend to nap longer, some
with fatigue and the effects of poor sleep. Naps should not last more sleep behavioral changes would probably be concomitant with
than 20–30 minutes (the exact duration is debated) to avoid the mood alterations, pain, and poor sleep [108]. Exercise, yoga, medi-
tation, and meditative movement are other simple strategies that
could benefit individuals suffering from the pain–sleep interaction.
Box 46.1 Strategies to manage the pain–sleep interaction Solid complementary and alternative study designs are emerging to
corroborate these findings. In addition, the benefits appear to persist
The supporting evidence in the literature for most of the items over time [109–112]. CBTs constitute a well-established approach to
presented below is low to moderate. Some of these medications managing insomnia. However, more recent studies have indicated
are off-label; clinicians should refer to the guidelines provided by that these approaches need to be customized in order to effectively
the appropriate government agencies. manage the pain–sleep interaction and insomnia [113–115].
Among the medications prescribed to manage the pain–sleep
1. Establish a strong differential diagnosis to assess roles or
interaction, the first-line recommendation is a nonsteroidal anal-
exclude comorbidities such as sleep breathing disorders,
gesic alone or in combination with a muscle relaxant. Patients who
periodic limb movement disorder, depression, and anxiety
use aspirin, ibuprofen, or acetaminophen (paracetamol) should be
2. Review lifestyle and sleep behavior patterns and beliefs advised to continue using these medications, but physicians should
3. Assess the patient’s expectations: pain relief or improved be alert for signs of abuse. Nonsteroidal analgesics can actually
sleep or both in relation to his or her definition of quality of induce headache if overused. Stronger medications include low-
life dose anticonvulsants such as clonazepam or pregabalin at bedtime
(daytime use should be avoided if possible to reduce sleepiness),
4. Suggest the use of relaxation therapy, yoga, mild exercise, etc low-dose antidepressive medications such as amitriptyline or tra-
5. Review whether the patient uses complementary alternative zodone, and finally opioids, as long as sleep apnea or addiction risk
medicine (CAM) approaches or other methods to self-man- is not suspected (see Chapter 19 of this volume for insomnia and
age their pain and sleep problems (melatonin, valerian, can- Chapter 20 for a general review) [116–121] Note that some of these
nabis, etc.) medications are off-label, i.e, not authorized as sleep or pain–sleep
6. Guide their choice of over-the-counter (OTC) medications medication.
such as anti-inflammatories (aspirin, ibuprofen) or acetami- In the presence of breathing disorders, it is mandatory to initially
nophen (paracetamol) alone or in combination with a muscle exclude adenoid and large tonsil or nasal obstruction. If the condi-
relaxant or sleep aid (antihistamine) tion is mild, such as RERA or UARS, a mandibular advancement
appliance can be used after performing a polysomnographic sleep
7. Refer the patient to a sleep medicine clinic if sleep disordered test. For more severe cases, a continuous positive airway pressure
breathing or periodic limb movement disorder is suspected system (CPAP) is an alternative that appears to help some patients,
8. Cognitive–behavioral therapy (CBT) is indicated if insomnia although, again, not all patients will benefit from breathing ther-
and/or anxiety mood are concomitant apy (see Chapter 17 for more information on CPAP treatment)
[122–124].
9. Physical therapy or massage may help patients restore
Phenotyping each case for risk factors and possible causative vec-
functionality
tors is a difficult task that requires specialized expertise. The same
10. Prescribe clonazepam (if sleep arousal and anxiety predomi- challenge applies to the selection of the best nonpharmacological
nate), cyclobenzaprine (if muscle pain predominates), or tra- or pharmacological treatment. To date, no simple algorithms have
zodone (if sleep arousal/fragmentation predominates) given been developed, owing to the modest concordance between sleep
PRN and for short periods. Be alert for side effects and risks and pain treatment outcomes [125].
(eg, sleepiness, habituation)
11. Based on pain intensity and impacts on sleep, consider the Conclusions
following medications: antidepressants (eg, duloxetine or
Pain poses a critical obstacle to restful sleep. Although never wel-
amitriptyline), pregabalin (in the evening to reduce day-
come, pain is nevertheless a reminder that something is not normal.
time sleepiness), opioids (earlier during the day if there is a
Patients should be made aware that pain is a signal that their body
risk of sleep breathing disorders; assess risks for misuse and
homeostasis is under threat, and that pain is part of a protective
addiction)
reaction that prevents future action. Therefore, it is not surprising
12. Sleep medications may help, but in the short term only, dur- that acute and chronic pain have been associated with hypervigi-
ing the transition to CBT (see point 8) lance, sleep disruption with excessive sleep fragmentation, and
13. Sleep disordered breathing or periodic limb movement dis- insomnia with hyperarousal. Acute pain may affect sleep for short
orders should be managed according to standard medical periods, after which the pain intensity lessens and sleep resumes
practice (CPAP, oral devices, or dopaminergic medications) as normal. Adequate pain management is critical in this transi-
tional period. The problem arises when pain becomes chronic and

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SECTION 10
Sleep and psychiatric

disorders

CHAPTER 47
Depression and anxiety disorders

Susan Mackie and John W. Winkelman
Depression and anxiety disorders are common conditions, fre- MDD. The most consistent abnormalities are related to REM
quently encountered throughout the practice of clinical medicine. sleep: shortened REM latency (time from sleep onset to the first
The lifetime prevalence in the United States is approximately 17% episode of REM), prolongation of the first REM period, and
and 29%, respectively [1]â•„. These conditions are commonly comor- increased density of eye movements during REM. These observa-
bid with each other. In one recent survey, 75% of those with depres- tions have led to the hypothesis that “disinhibition” of REM sleep
sion met criteria for an anxiety disorder in their lifetime, and 79% may play a role in the pathophysiology of depression. There is also
of those with an anxiety disorder met criteria for lifetime major evidence that REM abnormalities may constitute a biomarker that
depressive disorder [2]. These disorders are also markedly over-â•‰ predicts incident episodes of depression and increased vulnerabil-
represented in a wide array of medical and neurological conditions. ity to relapse in remitted patients. Thus, the abnormalities of sleep
Patients with depression and anxiety disorders frequently dem- observed in depressed patients are closely tied to the precipitation
onstrate disturbances in sleep architecture, sleep quality, and sleep and perpetuation of the mood disorder and may be important as
quantity. There is also a marked over-â•‰representation of many com- novel treatment targets.
mon sleep disorders in these conditions. Although in the past these
abnormalities of sleep were often viewed merely as symptoms of the Insomnia in MDD: epidemiology and clinical features
psychiatric condition, understanding in recent years has shifted. The relationship between insomnia and MDD is perhaps the most
We now recognize that there are frequently complex bidirectional well studied and complex topic in the study of sleep and mood
relationships between sleep disturbances and depression and anxi- disorders.
ety disorders. As already mentioned, insomnia is a common symptom of MDD
This chapter will address several of the most common mood and However, frequently insomnia symptoms are sufficiently severe to
anxiety disorders associated with abnormalities in sleep: major warrant diagnosis as a primary sleep disorder. Such patients may
depressive disorder, post-â•‰traumatic stress disorder, obsessive–â•‰ be most appropriately conceptualized as suffering from comorbid
compulsive disorder, and panic disorder. Changes in objective and depression and insomnia. This approach recognizes that the two
subjective sleep parameters associated with each psychiatric disor- diagnoses, albeit inter-â•‰related, carry distinct symptoms and may
der will be addressed, followed by a discussion of the most com- follow different courses. It should not be assumed that sleep prob-
mon sleep disorders comorbid with these conditions. lems will inevitably resolve with appropriate treatment of the mood
disorder, or vice versa.
Major depressive disorder Estimates of the prevalence of insomnia among depressed
patients vary widely. Most studies agree that sleep problems affect
Major depressive disorder (MDD) is a disorder characterized the majority. In a large epidemiological study including nearly 4000
by discrete episodes (lasting at least 2 weeks) with characteristic unipolar MDD patients in the US (the STAR*D study), 85% of the
changes in mood, cognition, and neurovegetative function [3]â•„. depressed participants met criteria for insomnia, and sleep symp-
Either depressed mood or anhedonia (decreased interest or pleas- toms correlated with more severe depression [4]â•„. Because insomnia
ure) is required for this diagnosis. Other common features include may be either a cause or a consequence of depression, longitudinal
changes in appetite, psychomotor functioning, and energy; feelings studies may provide additional insight beyond that afforded by such
of worthlessness or guilt; decreased concentration; and recurrent cross-â•‰sectional descriptions. One recent meta-â•‰analysis included 21
thoughts of death. The fifth edition of the Diagnostic and Statistical studies examining the incidence of new-â•‰onset depression in insom-
Manual (DSM-â•‰5) includes insomnia or hypersomnia as an addi- niacs without baseline depression. The mean sample size was 3200
tional category of symptoms, though the latter more likely repre- and included a mean follow-â•‰up of 6 years. The meta-â•‰analysis con-
sents increased time in bed (due to decreased energy, interest, etc.) cluded that the overall odds ratio of new onset depression in those
without true excessive need for sleep or inability to maintain wake- with insomnia compared with those without was 2.6 (confidence
fulness. When true hypersomnia is identified, a separate primary interval (CI) = 1.98–â•‰3.42) [5].
sleep disorder should be suspected. One of the most consistently observed and clinically important
features of comorbid insomnia and depression is the association
Abnormalities in sleep characteristic of MDD with increased risk of suicidality. A majority of attempted and com-
Even in the absence of a comorbid sleep disorder, several changes pleted suicides occur in depressed patients [6]â•„. Within this group,
in polysomnographic (PSG) patterns of sleep exist in patents with insomnia is a consistent predictor of suicidal thoughts and actions.

444 Section 10 sleep and psychiatric disorders
This has been demonstrated in cross-sectional as well as longitu- in combination with fluoxetine versus fluoxetine alone [8]. In addi-
dinal population-based studies, and within the context of clinical tion to improvement in sleep, the eszopiclone group showed a faster
trials of MDD. This association persists after adjustment for depres- onset of antidepressant response and a greater magnitude of the
sion severity and other psychiatric comorbidity [7]. In some stud- antidepressant effect. Furthermore, both depression and insomnia
ies, insomnia appears to be a better predictor of suicidality than the remained significantly improved in the combination-therapy group
severity of the depression itself. during the 2-week run-out period after discontinuation of eszo-
piclone [10]. This suggests that patients with MDD can be safely
Special treatment considerations in patients
with comorbid insomnia and depression treated with an adjunctive hypnotic without concern for rebound
or withdrawal and with possible persistent benefits for mood and
Many medications used in the treatment of depression have
sleep even after cessation of the drug.
well-established effects on sleep (Table 47.1). Selective seroto-
Behavioral treatment of insomnia is also appropriate in depressed
nin reuptake inhibitors (SSRIs) and serotonin–norepinephrine
patients.
(noradrenaline) reuptake inhibitors (SNRIs) are frequently first-
Cognitive–behavioral therapy for insomnia (CBT-i) improves
line medications. These agents markedly suppress REM sleep,
sleep acutely with an effect size comparable or superior to pharma-
increase sleep onset latency (SOL: the time from bedtime to first
cological treatment, often with a more sustained benefit [11–13].
onset of sleep), increase arousal index (AI: the number of awaken-
CBT-i is often used adjunctively with medications, and the most
ings per hour of sleep), increase wake after sleep onset (WASO),
effective approach may be a combined treatment. The aspects of
and decrease total sleep time. Despite these PSG observations, the
CBT-i with established efficacy include stimulus control and sleep
experience of patients is often different in that sleep often improves
restriction. Depressed patients may have difficulty implementing
subjectively. Nevertheless, these agents can produce hypersomnia
these techniques owing to amotivation, low energy, and psycho-
in some individuals and insomnia in others.
motor slowing. Despite these theoretical barriers, there is evidence
Treatment of insomnia also has the potential to affect the course
that depressed patients are able to benefit from CBT-i. In a study by
of MDD. Although it is unlikely to be clear whether the sleep dis-
Manber et al., over 300 patients referred for treatment of insomnia
order is a cause or a symptom of depression, it is clear that treat-
underwent seven group CBT-i treatment sessions [12]. The authors
ment of insomnia in this group improves both sleep and quality of
examined differences between depressed and non-depressed indi-
life [8,9]. However, data are mixed regarding the effect of insomnia
viduals in terms of treatment efficacy and adherence. Despite
treatment on the mood disorder itself. The most commonly used
somewhat reduced adherence to CBT-i principles, improvement in
drugs in the treatment of insomnia are the benzodiazepine recep-
insomnia severity, perceived energy, productivity, and self-esteem
tor agonists (BZRAs). Although in the past there was concern that
did not differ based on the presence of depression. Although this
these drugs may adversely affect mood, recent data suggest that
study was not placebo-controlled, another study [14] compared
this is unlikely. In fact, pharmacological treatment of insomnia has
CBT-i with a sham treatment in depressed patients, demonstrating
been studied adjunctively with antidepressants as initial therapy
improvement in both sleep and mood in the CBT-i group. These
for MDD with comorbid insomnia. Fava and colleagues compared
data indicate that CBT-i is effective in depressed insomniacs and
zolpidem extended-release in combination with escitalopram ver-
should be considered an important component of treatment.
sus escitalopram alone [9]‌. Zolpidem extended-release improved
Benzodiazepine receptor agonists have also been studied for
total sleep time, morning energy, concentration, and next-day func-
residual insomnia during otherwise successful treatment of MDD.
tioning. However, zolpidem did not significantly improve mood. In
Asnis and colleagues randomized nearly 200 subjects with persis-
contrast, another similarly designed study compared eszopiclone
tent insomnia despite remitted depression to zolpidem 10 mg or
placebo for 4 weeks [15]. Compared with placebo, zolpidem was
associated with improved subjective sleep quality, fewer awaken-
Table 47.1 Effects of antidepressant medications on sleep ings, less daytime sleepiness, and improved concentration. As with
eszopiclone, there was no evidence of dependence or withdrawal
Drug class Effect on sleep during a wash-out placebo substitution.
Continuity Slow-wave REM % REM
sleep latency MDD and obstructive sleep apnea
Depression is common among patients with obstructive sleep
Tricyclic + 0 − +
apnea (OSA). In the National Health and Nutrition Examination
antidepressants
Survey, snorting/stopping breathing ≥ 5 nights/week compared
SSRIs +/− 0 − + with never was strongly associated with probable major depression
SNRIs − 0 − + in men (OR = 3.1; CI = 1.8–5.2) and women (OR = 3.0; CI = 1.6–
Bupropion 0 0 + −
5.4) [16]. Conversely, in one cross-sectional telephone survey, 18%
of individuals with a diagnosis of MDD also reported symptoms
Mirtazapine + + 0 0 consistent with probable OSA [17]. After controlling for shared risk
Trazodone + + − + factors, the OR of sleep-disordered breathing was 5.26 (CI = 4.29–
6.47) for those with MDD compared with those without MDD.
+ indicates that the drug increases this parameter; − indicates that the drug decreases this
parameter; +/− indicates inter-drug or inter-individual variation; 0 indicates no effect.
Although most of the available data—including those summarized
Adapted from Harv Rev Psychiatry, 8(6), Gursky JT, Krahn LE, The effects of antidepressants
here—are limited by the absence of rigorous identification of either
on sleep: a review, pp. 298–306, Copyright (2000), with permission from Wolters Kluwer OSA or MDD, the consistent over-representation of MDD among
Health, Inc. OSA patients and vice versa is clear.

Chapter 47 depression and anxiety disorders 445
In patients with comorbid depression and OSA, the presence of difficulty falling asleep, waking during the night, or restless sleep.
each disorder affects treatment of the other. Several studies have Predictors of sleep difficulties in this group of patient with anxi-
shown that sleep apnea interferes with the response of MDD to ety disorders were similar to those reported in the general popula-
both CBT [18] and antidepressants [19]. This effect was demon- tion: minority populations; those who were divorced, separated, or
strated in a study of patients with coronary heart disease who were widowed; and older individuals all tended toward higher rates of
being treated with sertraline for MDD [19]. Moderate to severe sleep disturbances [31].
OSA was detected in approximately 30%. This subset had a sig- There are high rates of comorbidity between MDD and anxiety
nificantly poorer response to the antidepressant effect of sertra- disorders. Because of the close relationship between depressive
line compared with those without OSA. This difference remained disorders and sleep, many of the data about anxiety disorders are
significant after controlling for baseline depression, demographic complicated by the presence of comorbid depressive symptoms in
variables, and serum inflammatory markers. It is important to a (frequently unreported) segment of study participants. Despite
emphasize that sleep apnea was untreated in this study. It remains this confound, most clinicians and researchers agree that there is
uncertain whether this effect would persist if OSA were appropri- likely a relationship between anxiety disorders per se and sleep dis-
ately treated. turbances. Mechanisms of this association may vary between anxi-
Continuous positive airway pressure (CPAP) is the mainstay of ety disorders. However, it is clear that sleep deprivation potentiates
treatment for OSA. The effect of CPAP therapy on mood in patients anxiety, and the arousal response due to anxiety impairs sleep. This
with MDD has been the topic of considerable investigation and vicious cycle may provide a common mechanism to explain the
debate. Schwartz et al. examined a group of patients with a pre- strong association between nearly every type of anxiety disorder
treatment respiratory disturbance index (RDI) >15 and confirmed and sleep problems.
a significant response to CPAP (>50% drop in RDI) [20]. In this This review will focus on three anxiety disorders with a clearly
group, nearly all experienced a decrease in depressive symptoms. established relationship to sleep problems: obsessive–compulsive
The mean Beck Depression Inventory fell from 7.2 (moderate disorder (OCD) post-traumatic stress disorder (PTSD), and panic
depression) to 1.8 (normal) after CPAP. An analysis of variance disorder.
showed no effect of gender or baseline RDI, and the improvement
was unaffected by current antidepressant treatment. Despite these Obsessive–compulsive disorder
and other impressive data, [21–23], others have failed to show any OCD is an anxiety disorder characterized by obsessions (distress-
effect of CPAP on mood [24–27]. Inconsistencies may be related ing and recurrent thoughts, impulses, or images) and compulsions
to the variable use of a control group and incomplete (and usually (excessive action taken to relieve the anxiety caused by the obses-
unmeasured) compliance with CPAP treatment. sions, often ritualistic in nature). Although OCD is a chronic ill-
ness, symptoms may wax and wane over time. Similar to MDD,
Effects of antidepressants on motor activity patients with OCD appear to experience increased prevalence of
in sleep (RLS, PLMS, RBD) various sleep abnormalities, some inherent to the anxiety disorder
In addition to the aforementioned effects of antidepressants on and others representing comorbid sleep disorders.
sleep continuity and architecture, these agents also frequently
alter motor activity during sleep. This effect is most pronounced
Abnormalities in sleep characteristic of OCD
in individuals with pre-existing restless legs syndrome (RLS) or Several authors have shown that total sleep time (TST) and sleep
periodic limb movements in sleep (PLMS), but both disorders may efficiency are reduced in patients with OCD compared with healthy
also emerge de novo with antidepressant treatment. Most SSRIs, adults. In one large study using self-reported sleep time, Park et al.
as well as the atypical antidepressant mirtazapine, tend to worsen found that OCD was associated with sleep duration of 5h or less
RLS symptoms [28,29], and the consequent compromise in sleep compared with control subjects [32]. After controlling for socio-
quality may hinder successful treatment of depression. In addition, demographic and other variables, the OR of sleep duration less
SSRIs are associated with abnormal muscle activity during REM than 5 hours was 3.88 (CI = 1.63–9.23) compared with control
sleep and dream enactment behavior, a secondary form of REM subjects. Several PSG studies also found reduced TST [33,34], an
sleep behavior disorder (RBD). Dream enactment may be associ- abnormality that seems to be particularly prominent in women. On
ated with significant injury to the patient or bed partner and should the other hand, a recent study by Marcks et al. found no correla-
prompt consideration of down-titrating or changing antidepres- tion between OCD and sleep duration [31]. Such inconsistencies
sants. In contrast to SSRIs, the norepinephrine–dopamine reuptake may be connected with the complex relationship with OCD and
inhibitor (NDRI) bupropion appears to be free of adverse effects on depression. Bobdey et al. found that OCD patients with depression
motor activity in sleep [29,30] and may be an appropriate alterna- were considerably more likely to have decreased sleep time and
tive for patients who experience problematic nocturnal movements increased sleep latency compared with those in whom depression
due to an SSRI. was rigorously excluded [35].
There are also characteristic changes in sleep architecture in OCD.
Similar to the pattern seen in MDD, REM sleep is often abnormal.
Anxiety disorders Insel et al. compared the polysomnographically recorded sleep
Anxiety disorders are the most frequently occurring type of psychi- of patients with depression, OCD, and normal controls [36]. The
atric disorder, with a lifetime prevalence of 29% in the general pop- most striking difference was a marked reduction in latency to REM
ulation [1]‌. Sleep disturbances are highly prevalent in this group. sleep in OCD patients compared with controls (48.4 minutes, CI =
One survey of primary-care patients with anxiety disorders found 40.4–57.2 in OCD versus 80.5 minutes, CI = 75.3–86.3 in controls).
that 74% reported subjective complaints about sleep, including In this respect, the OCD group was similar to the MDD group

(REM latency 47.3 minutes, CI = 42.2–52.4). A more recent study Post-traumatic stress disorder
has demonstrated an even more striking result. Ten patients with
PTSD is a condition occurring in individuals exposed to actual
OCD without comorbid MDD were compared with controls [37].
or threatened death or serious injury. A subset of such patients
Three of the ten with OCD (compared with zero controls) exhibited
(ranging between 3% and 15%) will go on to develop symptoms
sleep onset REM periods (SOREMPs), defined as REM latency < 10
characteristic of PTSD, including intrusion (recurrent, involuntary
minutes. OCD symptom severity was significantly associated with
memories or traumatic nightmares), avoidance (effortful avoidance
SOREMs.
of distressing trauma-related stimuli), negative alterations in cog-
Delayed sleep phase disorder and OCD nition or mood, and alterations in arousal and reactivity (hyper-
Distinct from other psychiatric disorders, the most consistently vigilance, exaggerated startle response, etc.) [3]‌. Two of these four
over-represented sleep disorder among OCD patients is delayed diagnostic sets of symptoms often include sleep symptoms: night-
sleep phase disorder. Mukhopadhyay et al. conducted a retro- mares as a manifestation of intrusion, and insomnia as a manifes-
spective case review of 187 OCD patients in an inpatient unit. In tation of arousal. These features highlight the centrality of sleep
this sample, 33 of the 187 (17.6%) OCD patients fulfilled criteria disturbance in this disorder (Box 47.1).
for DSPD [38]. This seemed to be linked to OCD as opposed to PSG differences characteristic of PTSD have been a matter of
any comorbid depression, since the presence of DSPD correlated considerable investigation, with conflicting conclusions. Given
with age of onset of OCD (p = 0.005), with a trend to correla- the frequency of nightmares in this disorder, some have hypoth-
tion between OCD severity and DSPD. Consistent with this trend, esized that REM sleep may be abnormal. Indeed, some studies have
another retrospective analysis by Turner et al. found a remark- reported increased REM density and percentage of REM sleep [45].
ably high prevalence of DSPD among patients with severe, treat- However, others have shown contrasting patterns, characterized by
ment-resistant OCD [39]. In a sample of 31 inpatients who had decreased percentage of REM sleep [43]. Still others detected no
failed outpatient psychotherapy and medical management, 13 differences in REM sleep parameters between subjects with PTSD
(42%) met criteria for DPSD (defined as regularly falling asleep compared with control subjects.
after 1 am and awakening after 10 am). Phase-shifted patients Breslau et al. performed PSG of 292 subjects, including 71 with
were significantly younger and had more severe OCD compared lifetime PTSD [46]. On standard measures of sleep disturbance,
with OCD patients without DSPD. Consistent with the aforemen- PTSD subjects did not differ from controls. Those with PTSD
tioned data, levels of depression were not significantly different did, however, have higher rates of brief arousals from REM sleep.
between the groups. The authors proposed that sleep complaints in PTSD may repre-
The cause of increased prevalence of DSPD in OCD is unknown. sent amplified perception of these arousals rather than objectively
One intriguing case report described a 54-year-old woman with
severe OCD who kept sleep and symptom logs as an adjunct to
conventional CBT [40]. Owing to compulsive praying behavior,
Box 47.1 Diagnostic criteria for PTSD
she routinely went to sleep around 5 am, sleeping until 1 pm. Her
therapist worked with her to advance her sleep–wake schedule, and Stressor: exposure to actual or perceived serious injury or death.
this was associated with a decrease in time spent on compulsions At least one symptom in each of four symptom clusters must be
from 8 hours per day to 2 hours. The authors suggest that patients present:
who perform compulsions late at night may inadvertently perpetu- ◆ Intrusion:
ate the OCD as homeostatic and circadian mechanisms interact to
produce fatigue and cognitive deficits that exacerbate OCD symp- – Recurrent and unwanted remembering
toms and perpetuate the sleep disorder. – Nightmares*
The mainstay of pharmacological treatment of OCD is SSRIs.
– Dissociation
Effects of these drugs on sleep have been discussed earlier in
this chapter. When SSRIs and psychotherapy are not adequate, ◆ Avoidance
augmentation therapy generally consists of low-dose atypical – Of external stimuli

antipsychotics. In addition, recent uncontrolled studies have
suggested that agomelatine, a combined melatonin-1 (MT 1), – Of related feelings
MT 2, and serotonin-2 C (5-H T 2C) receptor agonist, may be ◆ Negative alteration of cognition or mood
a promising new approach for pharmacologic augmentation ◆ Increased arousal
in OCD [41–44]. Several mechanisms have been proposed to
explain this benefit. Given the prominence of DSPD among – Irritability
OCD patients, the benefit may be due to the phase-shifting – Increased startle response
effects of melatonin agonism. (All subjects for whom the data
– Hypervigilance
are provided in these reports suffered from comorbid DSPD.)
Another possible mechanism involves serotonin, which may be – Sleep disturbance*
involved in the pathogenesis of OCD. Serotonin transmission * Symptoms overlapping between PTSD and sleep disorders.
exhibits circadian variation [43]. Resynchronization of circadian
Source data from American Psychiatric Association, Diagnostic and
serotonergic patterns and/or the direct effect of agomelatine to
Statistical Manual of Mental Disorders, 5th Edition DSM-5, Copyright
increase serotonergic transmission at the 5-HT2C receptor may (2013), American Psychiatric Association.
explain the benefit of this drug.

decreased total sleep time. Alternatively, as Woodward et al. have poor sleep could contribute to the pathogenesis of PTSD by dis-
suggested, “it is possible that most or all PTSD-related sleep changes rupting the beneficial process of sleep on fear extinction. However,
are substantially ameliorated in the ‘guarded’ context of the labora- because this effect was not observed in those with insomnia, it
tory, and there fall prey, in a statistical sense, to the large underlying seems more likely that pre-exposure nightmares in this group were
normative variation in sleep architecture” [47]. Thus, the lack of a a marker of impaired fear extinction—and therefore increased vul-
detectable difference may be more a consequence of the limitations nerability to PTSD—rather than a mechanism contributing to the
of our tools rather than the true absence of a difference. development of such impairment.
OSA in PTSD Treatment of sleep disturbance in nightmares in PTSD
Sleep disordered breathing (SDB) is common among patients Treatment for nightmares in patients with PTSD may include
with PTSD. It is possible that SDB is responsible for a portion of behavioral and/or pharmacological approaches. Prazosin, an α1-
the disrupted sleep continuity in this group. However, the causal adrenergic antagonist, has been shown in both retrospective [52]
relationship may also be in the other direction: disruption of any and prospective [53] studies to reduce both PTSD symptoms and
cause may destabilize the upper airway and led to SDB events. nightmares. It should be noted that prazosin doses likely to be
Although many PSG studies of PTSD patients have not included beneficial in PTSD may be considerably higher than those com-
respiratory assessment technology designed to rigorously moni- monly used for other indications. Required doses are generally
tor breathing, Krakow and colleagues found that 40 out of 44 significantly higher in men compared with women. One recent
patients presenting for CBT for PTSD met criteria for SDB [48]. study titrated to an average total daily dose of approximately 20 mg
Although many of these cases were considered mild OSA based in men compared with 10 mg in woman, without any increased
on the apnea–hypopnea index (AHI), nearly all were reclassified incidence of adverse events compared with placebo [53]. Prazosin’s
as moderate to severe when flow limitation was measured and benefit may be mediated by suppression of adrenergic mechanisms
respiratory-effort-related arousals were factored in. The authors that lead to excessive CNS hyperarousal. Whether other adrenergic
concluded that the previous lack of recognition of SDB as an antagonists may have similar benefits has not been well established.
important comorbidity of PTSD may be due to the absence of Behavioral treatment of nightmares is also helpful in PTSD
such advanced measurements. patients. The most well-studied behavioral approach is image
Given this close relationship, the treatment of SDB has the poten- rehearsal therapy (IRT). During IRT, the patient is asked to recount
tial to affect PTSD symptoms. Krakow and colleagues retrospec- the nightmare, create a modified, more positive version of the story,
tively examined the effect of CPAP treatment of SDB on sleep and and practice image rehearsal with the new scenario. In one study,
PTSD symptoms in a group of trauma survivors [49]. Whereas a group of 114 patients with moderate to severe PTSD were rand-
all of the untreated patients (n = 9) experienced worsening or no omized to three sessions of IRT or a waitlist control group. The IRT
change in self-reported symptoms, 13 of the 15 CPAP-treated indi- treatment group showed significantly reduced nights per week with
viduals reported improvement in sleep, and 7 of the 9 treated PTSD nightmares, number of nightmares per week, and subjective sleep
patients showed improvement in PTSD-related stress. Regardless of quality, all highly significant changes with medium to large effect
the direction of causality between SDB and PTSD, when approach- sizes. Waitlist control participants showed no significant improve-
ing the patient with PTSD. it is appropriate to test for and treat ment over the same time period [54].
comorbid SDB.
Nightmare disorder in PTSD Panic disorder
Recurrent and troubling nightmares are unusual in adults with- Panic disorder is an anxiety disorder that includes recurrent and
out psychiatric illness. However, this problem is common among unanticipated panic attacks, often characterized by intense fear that
PTSD patients. One recent longitudinal, observational study fol- reaches a peak within minutes. Patients with panic disorder experi-
lowed 80 veterans with recent combat exposure and at least sub- ence frequent somatic symptoms such as palpitations, shortness of
threshold PTSD [50]. Among this group, 61% reported distressing breath, diaphoresis, and nausea. The diagnostic criteria specify that
nightmares, and the presence of nightmares was associated with there must be persistent concern about additional panic attacks
significantly higher PTSD severity at both baseline and 6-month and/or maladaptive behavioral changes related to the attacks [3]‌.
follow-up. Other studies have reported up to 80% prevalence of Nocturnal panic attacks have been reported in 58% of panic dis-
nightmares among PTSD sufferers. Because of this marked increase order patients, with 30–45% experiencing repeated nocturnal panic
in risk for nightmares in PTSD, it is essential that all patients pre- attacks [55]. The majority of those with nocturnal panic also suffer
senting with nightmare complaints be queried regarding trauma from daytime attacks, although a small subset experiences predom-
exposure and PTSD symptoms. inantly nocturnal symptoms.
Although nightmares are frequently considered to be a symp- Patients who frequently experience sleep disturbance due to panic
tom of PTSD, there are also data to suggest that nightmares attacks may be considered to suffer from both a sleep disorder and
prior to trauma exposure predispose exposed individuals to later an anxiety disorder. It has been hypothesized that those with noc-
develop PTSD. Van Liempt and colleagues collected reports about turnal symptoms may have a more severe form of the disease [56]
sleep symptoms in 453 Dutch service members prior to military but this association has been inconsistent [57]. There is evidence
deployment to Afghanistan [51]. PTSD symptoms were assessed that acute sleep deprivation increases anxiety and fear response to a
at 6 months post-deployment. Self-reported pre-deployment CO2 challenge, a common paradigm for modeling the development
nightmares predicted PTSD symptoms at 6 months (OR = 2.992, of panic attacks [58]. Thus, rather than merely a marker of disease
CI =1.096–8.551, p < 0.05). Because unsuccessful fear extinction may severity, it may be that the presence of nocturnal panic attacks has a
play a role in the development of PTSD, the authors suggested that causative effect to exacerbate panic disorder symptoms.

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CHAPTER 48
Sleep in other psychiatric

disorders
Sara Dallaspezia and Francesco Benedetti
Psychiatric patients often complain of their sleep and present sleep change in sleep [7]â•„. Prospective studies have demonstrated that
abnormalities that increase with the severity of the illness. During insomnia is an important predictor of depressive episodes and it
the past few decades, different sleep investigations have been per- is associated with higher chances of recurrences in bipolar depres-
formed in psychiatric patients with the aim of identifying specific sion [8]. Moreover, self-â•‰monitoring of sleep duration has been
sleep patterns associated with psychiatric disorders and, although proven useful to recognize prodromal symptoms early and predict
the majority of these studies have focused on major depression, mood changes [9]. Retrospective studies have consistently showed
sleep abnormalities have also been reported in other psychiatric that insomnia, hypersomnia, and early awakening are frequent
disorders. Moreover, epidemiological studies indicate that about symptoms during depressive episodes, with rates between 77%
half of the patients complaining of chronic insomnia may have and 90% [4].
some psychiatric condition or may develop it within 1 year [1]â•„. Polysomnographic (PSG) studies of sleep in bipolar depression
Indeed, the emerging view is that the relationship between psy- have generally found similar abnormalities in unipolar and bipo-
chiatric and sleep disorders is complex and bidirectional: not only lar depression. For instance, bipolar patients have a tendency for
are sleep abnormalities symptoms of psychiatric disorders, but also more early morning awakenings and more fragmented REM sleep
some sleep disorders increase the risks of developing episodes of periods, but greater total REM sleep density than unipolar patients
psychiatric disorders. Moreover, some disturbances of sleep are [10]. Some clinicians believe that hypersomnia, rather than insom-
generated by drug treatment for psychiatric disorders, and some nia, is more indicative of bipolar than unipolar depression [11], but
drugs used in the treatment of sleep disorders may increase the clinically significant sleepiness has not been found using the multi-
risks for psychiatric diseases [2]. ple sleep latency test (MSLT) [12].
Not only can sleep loss trigger mania, but also the reduction of
Bipolar Disorder sleep duration was found to be a good predictor of hypomania or
mania the next day in rapid-â•‰cycling bipolar patients [13]. There is a
Since the early descriptions of manic depressive insanity by bidirectional causal relationship between sleep loss and mania: the
Kraepelin, sleep disturbances were considered a core characteristic capacity of sleep reduction to cause mania and mania to reduce
of bipolar disorder, being common features of both the manic and sleep is a self-â•‰reinforcing mechanism that could explain the ten-
depressive phases of the disease [3]â•„. Sleep dysfunction is frequently dency of mania to escalate out of control [14]. This relationship
observed in euthymic bipolar patients, who do not currently ful- seems to be important mostly at the beginning of a manic episode
fill the criteria for major mood episodes [4]. Sitaram et al. found [15]. The ability of sleep loss to elevate mood in bipolar disorder
increased REM density and percentage of REM sleep in remitted has been extensively exploited to develop antidepressant treatments
bipolar patients relative to healthy comparison subjects, as well based on a combination of total and partial sleep deprivation and
as an increased sensitivity to the REM-â•‰latency-â•‰reducing effects light therapy [16].
of arecoline (an acetylcholine agonist) [5]. These abnormalities Since PSG examinations are very difficult to carry out in patients
have often been interpreted as the result of a reduced homeostatic affected by mania, only a few studies concerning sleep and mania
process, with abnormally reduced slow-â•‰wave sleep (SWS) in the have been published It is unclear whether the PSG abnormalities
early part of the night. In one more recent study, the majority of seen in mania are caused by the manic state per se or are second-
interviewed euthymic bipolar patients showed poor sleep quality ary to other features of mania. In healthy subjects, sleep architec-
according to the Pittsburgh Sleep Quality Index assessment [6]. ture was found to be influenced by increased daytime activity [17].
Moreover, different actigraphic studies showed that, compared with Thus, in manic patients, PSG measures could be affected by motor
controls, euthymic bipolar patients had longer sleep onset latency, hyperactivity during the day. In unmedicated manic patients,
lower average daily activity, and more fragmentation of the sleep–â•‰ shortened total sleep time and increased time awake in bed were
wake cycle and more night-â•‰to-â•‰night variability [4]. found [18]. REM sleep latency was found to be both normal [19]
Maintaining stable sleep–â•‰wake cycles is of central importance to and shorter than normal, while REM density sleep was found to
the maintenance of stability in bipolar disorder. A clear temporal be higher in unmedicated manic patients compared with healthy
relation between sleep and mood has been described in bipolar subjects [18]. Moreover, Linkowski and colleagues [19] found that
disorder, with mood changes occurring on the day following a although manic patients spent less time asleep during the day and

took longer to fall asleep than healthy subjects, they showed time influence on specific sleep stages is variable. On the other hand,
spent in any stage of sleep similar to that of unaffected people. a deterioration in sleep quality was found with the suspension of
Nevertheless, the clear cut disruption of circadian rhythms in such treatment. As in healthy subjects, second-generation antip-
bipolar disorder allows a correct diagnosis in more than 80% of sychotics seem to influence sleep continuity in schizophrenic
remitted patients based on quantitative and qualitative measures patients, with an increase in either total sleep time or sleep effi-
of sleep [20], with sleep disturbance becoming evident soon after ciency, and a decrease in wakefulness [29]. In contrast, clozap-
the beginning of bipolar disorder and even in high-risk offspring ine was shown to decrease SWS. Moreover, while patients treated
of bipolar patients. with classical neuroleptics were found to have a variety of abnor-
malities in the circadian rest–activity cycle, patients administered
Schizophrenia clozapine were showed to have an highly regular and reproduc-
ible circadian rest–activity cycle, synchronized at the appropriate
Even if it is seldom the predominant complaint, insomnia is a phase to external social zeitgebers, and to have fewer nocturnal
common symptom in schizophrenia, with up to 55% of medicated disturbances [24]. Thus, clozapine increased circadian amplitude
patients reporting sleep alteration [21]. To be considered as a symp- (perhaps through its high affinity to dopamine D4 and serotonin
tom related to the disease, sleep disturbance must last for at least 5-HT7 receptors in the suprachiasmatic nucleus (SCN), thereby
1 month and be associated with impaired daytime functioning or improving entrainment.
daytime fatigue. Patients mainly complain of difficulty in both ini-
tiating and maintaining sleep, and poor subjective sleep quality is
associated with a reduced quality of life [22]. Although alterations Alcohol-related Disorders
in sleep seem to be a characteristic feature of the disorder regardless Several sleep disturbances have been described in alcoholic
of the phase of the clinical course (acute or chronic), severe insom- patients. Although insomnia is the most common complaint, with
nia is often seen during exacerbation of schizophrenia and may an estimated prevalence ranging from 36% to 72%, hypersomnia,
precede the appearance of other symptoms of relapse [23]. On the parasomnia, and circadian disturbances have also been described.
contrary, chronic stable patients may appear as having long peri- The impact of ethanol on human sleep was first studied in the late
ods of uninterrupted sleep. Different PSG studies focused on sleep 1930s by Kleitman and described in his book Sleep and Wakefulness
architecture in patients affected by schizophrenia have found sev- [30]. Since then, a large number of studies have focused on the effect
eral differences from healthy controls. The majority of studies indi- of ethanol on sleep and, in particular, on the sleep of alcoholics.
cate that stage 4 sleep and REM latency are reduced, whereas REM During heavy periods of drinking, alcoholic patients show a rela-
sleep duration tends to remain unchanged. Moreover, increased tively rapid sleep onset, but they have sleep onset difficulties if they
latency to sleep onset, increase wake time during the night, and do not take alcohol before bedtime. Alcohol intake before bedtime
decreased total sleep time were found [2]‌. increases NREM sleep during the first part of the night, while sleep
Some studies have also identified associations between PSG find- during the second part of the night is fragmented, with an increase
ings and specific subsets of symptoms. Both negative and positive of awakenings and reduced amount and disruption of REM sleep
symptoms were found to be associated with reduced REM sleep [31]. Elevated high-frequency activity and reduced SWA (< 4 Hz)
latency, a greater number of positive symptoms were found to be during sleep were found in chronic alcoholic men.
associated with decreased sleep efficacy and higher sleep onset Further support for a potential impact of alcoholism on SWA
latency, and a greater number of negative symptoms were reported comes from a study by Colrain and colleagues of sleep evoked
to be linked to lower non-REM (NREM) sleep EEG slow-wave potentials in alcoholic patients compared with healthy subjects.
activity (SWA). Moreover, REM sleep duration and density were The incidence and amplitude of the evoked δ frequency responses
correlated to a greater likelihood of suicidal ideation. Many of during stage 2 sleep were found to be significantly reduced in the
these sleep disturbances in schizophrenia appear to be caused by alcoholic subjects, with the amplitude reduction being apparent
abnormalities of the circadian system, as indicated by misalign- only over prefrontal and frontal scalp sites [32].
ments of the endogenous circadian cycle and the sleep–wake cycle, During wakefulness, ethanol is a mild respiratory depressant, but
ranging from delayed and advanced sleep phase, to free-running during sleep, it can exacerbate sleep-related breathing disorders.
rest–activity patterns, to irregular sleep–wake patterns [24–26]. Indeed, different studies have indicated that patients affected by
Furthermore, different studies have shown alterations in melatonin alcoholism are more likely than control subjects to develop sleep
profiles, with a change in the circadian phase angle often having apnea, even during abstinence [33].
been found in these patients [27]. Sleep abnormalities are present not only during periods of alco-
In addition, patients affected by schizophrenia are reported to hol abuse but also during withdrawal and abstinence. During acute
have periodic limb movements of sleep (PLMS), sleep-related withdrawal from alcohol, patients take a long time to fall asleep and
breathing disorders, and night-eating syndrome at a higher rate show very small amount of delta (stages 3 and 4) sleep and poor
than the general population [28]. These disorders are considered sleep efficiency [34]. PSG studies performed in patients affected
to be possible adverse effects of antipsychotic drugs [29]. Since by primary alcoholism after 2 weeks of abstinence have found
antipsychotic treatments were found to influence sleep charac- increased sleep latency, decreased total sleep time and delta sleep
teristics in healthy subjects, different studies have focused on the time, and increased REM density [34]. Disturbances in sleep con-
possible influence of treatments on patient sleep characteristics. tinuity (prolonged sleep latency and reduced sleep efficiency) and
The use of typical antipsychotics (haloperidol, thiothixene, and sleep architecture (reduced total sleep time, NREM sleep, and SWS
flupentixol) in patients is consistently associated with an increase or delta sleep) may persist months or even years after abstinence
in total sleep time, sleep efficiency, and REM latency, whereas the and may be associated with the clinical course [35], with different

Chapter 48 sleep in other psychiatric disorders 453
studies finding a relationship between disturbed sleep during absti- healthy subjects [54,55], but some recent studies have not con-
nence and relapse to drinking. In primary alcoholic patients, REM firmed these results [56]. A reduced REM latency, a prolonged first
sleep measures obtained at the time of admission to an inpatient REM period, and increased REM density were found in some stud-
alcohol treatment program have been shown to predict abstinence ies [54,57] but not others [55,58]. These sleep abnormalities similar
or relapse during a period of 3 months after discharge. Significantly to those found in depression were confirmed even when comorbid
shortened REM latency and increased percentage of REM sleep major depression was excluded [59].
were observed in relapsing patients when compared with abstain- Finally, recent findings have confirmed sleep abnormalities in
ers [36]. Other PSG variables that have been found to predict a patients affected by BPD without comorbid major depression or
negative outcome are longer sleep onset latency, decreased sleep post-traumatic stress disorder. Patients exhibited increased sleep
efficiency, and decreased percentage of SWS [2]‌. fragmentation, increased REM sleep density, and reduced REM
sleep latency compared with healthy controls [60].
Drug Abuse
Not only is sleep disturbance often a complaint by drug abusers Eating Disorders
during both their use of substances and their withdrawal from Despite the significant influence of nutrition on sleep regulation,
these, but it is also found to predispose to developing a substance complaints about disturbed nocturnal sleep are rare in patients
use disorder [37]. affected by anorexia nervosa or bulimia nervosa. Indeed, in most
Trouble sleeping is a frequently cited adverse effect of cocaine of the controlled PSG-monitored sleep studies that have been per-
intake. PSG studies have confirmed the stimulant properties of formed, sleep continuity measures were similar in patients with eat-
cocaine, demonstrating longer sleep latency, reduced total sleep ing disorders and age-matched healthy subjects [61]. Conflicting
time, and suppression of REM sleep after acute cocaine adminis- results in REM sleep were found in anorexia nervosa. REM sleep
tration [38]. Both hypersomnia and insomnia have been observed density was shown to be normal [62], increased, or decreased [63],
during cocaine withdrawal [39]. Sleep disorders during abuse of while mean REM latencies were prolonged [64], normal [62], or
amphetamine and methylphenidate are similar to those found shortened [63]. In patients with bulimia nervosa, SWS, REM sleep
in cocaine users [40]. 3,4- Methylenedioxymethamphetamine latency, and density were consistently similar to those in healthy
(MDMA, “ecstasy”) users commonly report restless, disturbed subjects [62,65].
sleep during the 48 hours following MDMA intake [41], and an
increase in wakefulness and an almost complete suppression of Conclusions
REM sleep were found in a PSG study after intake of MDMA [42].
There is some evidence indicating that cannabis reduces stage Alterations in sleep are an important dimension of the clinical pic-
3 but increases stage 4 and total SWS [43,44], but contradic- ture of different psychiatric disorders, although they are not con-
tory effects have also been observed. Moreover, the use of Δ9- sidered diagnostic criteria for these disorders. There is growing
tetrahydrocannabinol (THC) was found to be linked to decreased experimental evidence that the relationship between psychiatric
total REM sleep and REM density [44]. In a few studies with high disorders and sleep is complex and involves bidirectional causa-
THC doses or marijuana-naive subjects, findings were suggestive of tion. The study of this relationship might be useful in the future to
increment in sleep onset latency [45], but the sleep-inducing [46] discover the biological underpinning of psychiatric disorders and
and SWS-enhancing [47] effects showed tolerance during chronic to find effective new treatments.
marijuana administration. The vast majority of studies confirmed
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disorder. Biol Psychiatry 1999;45:1056–8. 64. Katz JL, Kuperberg A, Pollack CP, et al. Is there a relationship between
6 0. Schredl M, Paul F, Reinhard I, et al. Sleep and dreaming in patients eating disorder and affective disorder? New evidence from sleep
with borderline personality disorder: a polysomnographic study. recordings. Am J Psychiatry 1984;141:753–9.
Psychiatry Res 2012;200:430–6. 65. Lauer C, Zulley J, Krieg JC, Riemann D, Berger M. EEG sleep and
61. Lauer CJ, Krieg JC. Sleep in eating disorders. Sleep Med Rev the cholinergic REM induction test in anorexic and bulimic patients.
2004;8:109–18. Psychiatry Res 1988;26:171–81.

SECTION 11
Sleep in children, older

adults, and women

CHAPTER 49
Childhood sleep–â•‰wake disorders

Suresh Kotagal and Julie M. Baughn
Introduction the majority of sleep shifting into the night. Prior to 3 months of age,
the transition from wakefulness tends to be directly into REM sleep,
Sleep disorders found in adults can also be encountered in chil- subsequent to which the mature pattern of wakefulness→NREM
dren; sleep in children differs from that of adults, however, in sleep→ is established. As infants develop, the sleep cycle length-
several important aspects—â•‰there are significant changes in tim- ens and approaches 90 minutes in preschool children. The amount
ing, duration, and architecture that evolve from infancy through of N3 (slow-â•‰wave) sleep declines as adolescence is approached [7]â•„.
adolescence. Disordered sleep can impact the development of the Sleep duration decreases across ages from an average of 14.2 hours
child, and, conversely, developmental stages can influence sleep. in a 24-â•‰hour period at 6 months of age to an average of 8.1 hours
The sleep of parents may also be affected when the child’s sleep is at 16 years of age. Most children give up daytime napping by 4–â•‰5
disrupted. Sleep disorders are fairly common in children—â•‰a sur- years of age [8].
vey of parental reported sleep problems in children from birth to
3 years revealed a 10% prevalence [1]â•„. Other studies have shown
that one-â•‰third of children 6 months to 5 years have difficulty going Sleep-â•‰related history
to sleep or have nighttime awakenings[2]. The prevalence range for The diagnosis of a sleep disorder in children may be challenging
obstructive sleep apnea (OSA) in children is 1.2 to 5.7%[3]. Restless because of their inability to verbalize symptoms. Significant reli-
legs syndrome (RLS) in children has a prevalence of about 2% [4] ance is placed therefore on parental/â•‰caregiver history. In contrast
Developmental changes in childhood sleep, common pediatric to adults, children with sleep disordered breathing (SDB) may not
sleep disorders, and those affecting special populations of children desaturate, owing to their relatively healthy lungs. Snoring may be
will be addressed in this chapter. subtle. Further, the absence of snoring does not exclude the pos-
sibility of obstructive sleep apnea (OSA). Children may present
Sleep through development with hyperactivity, impulsivity, and inattention when they become
sleepy. They may not be able to verbalize their discomfort if suffer-
There are many changes in infant sleep with development. Initially, ing from restless legs syndrome (RLS). Key features of the pediatric
sleep becomes distinguishable from wakefulness by 26–â•‰27 weeks’ sleep history can be found in Table 49.1.
gestation by the appearance of a discontinuous pattern. Minimal
electrical activity may be seen for periods up to several minutes,
with intermittent bursts of rhythmic alpha, theta, and delta activity. Sleep-â•‰related examination
This is called tracé discontinue [5]â•„. By 32 weeks, the bursts of EEG Height, weight, and body mass index are recorded because OSA
activity and the intervals between them have shortened, and this is can be associated with poor weight gain in infants and with obe-
called tracé alternant. This tracé alternant trace is characteristic of sity during adolesence. OSA patients may have a small jaw, dental
“quiet sleep,” which is analogous to NREM sleep of later infancy. malocclusion, large tongue, facial muscle weakness, shallow cheek
A continuous, low-â•‰voltage, irregular pattern termed “active sleep” bones, deviated nasal septum, swollen lining of the nasal passages,
also becomes visible and is the precursor to mature REM sleep. enlarged tonsils or adenoids, and mouth breathing. Consultation
Sleep state may at times be difficult to determine at term; thus, with a pediatric otolaryngologist is required to exclude adenoidal
“indeterminate sleep” may be present in some instances. High-â•‰ hypertrophy. Inattentiveness, irritability, and mood swings can be
amplitude slow waves of 0.5–â•‰2 Hz develop during NREM sleep clues to daytime sleepiness. OSA related to brainstem abnormalities
around 1 month of age. At 32 weeks’ conceptional age, the ratio of like the Chiari type I or II malformations can lead to hoarseness of
active to quiet sleep is 80:20; this drops to 50:50 by full term or 40 voice, decreased gag reflex, and abnormal tendon reflexes. Muscle
weeks’ conceptional age. By the age of 3 years, NREM sleep com- diseases like myotonic dystrophy may be associated with upper
prises 75–â•‰80% of total sleep time, with the remainder being REM airway collapse combined with shallow chest and abdominal wall
sleep. Sleep spindles appear by 2–â•‰3 months of age [6]. K-â•‰complexes movement (obstructive hypoventilation). The parent–â•‰child inter-
appear between 2 and 3 months of age. Mature NREM sleep stages action should be observed for clues toward parental anxiety and
(N1, N2, and N3) are recognizable by 6 months of age. insufficient limit setting of behaviors that can perpetuate insomnia
The newborn shows ultradian sleep–â•‰wake patterns, with 2–â•‰3 in toddlers. Home videos, if available, are invaluable in the assess-
hours of sleep interrupted by brief periods of wakefulness. It is not ment of abnormal movement patterns seen in RLS, parasomnias,
until 3–â•‰6 months of age that a more mature pattern develops, with and nocturnal seizures.

460 Section 11 sleep in children, older adults, and women
Table 49.1 Key features of the pediatric sleep history Table 49.2 Key principles in pediatric sleep hygiene
Chief sleep complaint Bedtime and wake time should be regular and consistent between weekdays
and weekends
Sleep–wake patterns
◆ School
A consistent bedtime routine should be maintained
◆ Weekends Bedtime routines should be relaxing and brief (20–30 minutes)
◆ Vacations/summer break A nighttime bath may be activating for some children
◆ Regular/irregular
Electronics should not be used prior to bedtime or be in the bedroom
Bedtime routine The child should learn to fall asleep on his/her own without parental
◆ Length interference
◆ Use of electronics
A transitional object (blanket, stuffed animal) may be used
◆ Sleep onset association
Bedroom environment should be dark and quiet (night lights may be
Sleep onset time beneficial)
Morning waking time (spontaneous or with alarm) Napping should occur appropriate to developmental age
Night wakings Fluids prior to bedtime can increase arousals due to bladder distension
◆ Length
A small protein-containing snack may be appropriate before bed
◆ Parental involvement
Caffeine-containing beverage intake should be limited
Sleep environment
◆ Bedroom
◆ Own/shared
may be obstructive or mixed respiratory apneas [9]‌. Primary
◆ Electronics central sleep apnea of infancy needs to be differentiated from
◆ Nightlight normal infant breathing, which includes both periodic breathing
◆ Co-sleeping and respiratory pauses. Periodic breathing is a pattern of regu-
Snoring, mouth breathing, breathing pauses, diaphoresis, sleep position lar respiration for 10–18 s cycled with pauses of ≥3 s in length
that occur without clinically significant hypoxemia or heart rate
Restless sleep change [9]. It can occur in up to 94.5% of infants of low birth
Leg complaints or discomfort weight [10] and can persist in normal infants through infancy.
Secondary nocturnal enuresis Infants can have brief (<10 s) respiratory pauses that are self-
limited and, if not associated with significant desaturation or
Daytime sleepiness, hyperactivity, or behavioral problems heart rate change, can be normal [11]. There is a blunted arousal
Age-appropriate napping response to both hypercapnia and hypoxemia in neonates that is
Sleepwalking exaggerated in those with apnea of infancy [12]. Caffeine citrate
is useful as a respiratory stimulant and has been shown to have
Sleep terrors improved neurocognitive outcomes in very low-birth-weight
Medications infants [13].
Caffeine/energy drink use
Brief Resolved Unexplained Events (BRUE)
Family history of obstructive sleep apnea, restless legs syndrome, sleepwalking
Brief resolved unexplained events (BRUE) [14] and sudden infant
death syndrome (SIDS) are two distinct disorders that can be con-
sidered together. While there are risk factors in common between
Sleep hygiene measures the two entities (maternal smoking, male gender, gestational age,
Besides specific therapeutic measures, attention to sleep hygiene is and very low birth weight), other predisposing factors diverge,
extremely important in the management of many sleep disorders in so they should be considered distinct entities [15]. A BRUE is an
children. Key principles in this regard are listed in Table 49.2. event that is frightening to the observer and includes an apnea,
color change, decreased muscle tone, or choking/gagging. A BRUE
should not be considered as a precursor to SIDS. The differential
Specific sleep–wake disorders diagnosis of BRUE is extremely broad; a careful history and exam
Primary central sleep apnea of infancy are needed, with additional focused testing based on the clinical
Primary central sleep apnea of infancy consists of both apnea of picture. The most common etiologies identified in a large review
prematurity (occurring in an infant < 37 weeks’ conceptional age) were gastroesophageal reflux, seizures, and lower respiratory tract
and apnea of infancy (occurring in an infant > 37 weeks’ concep- infections [16]. Polysomnography (PSG) may be useful in the eval-
tional age). It consists of prolonged central respiratory pauses of uation of BRUE when there is a concern for upper airway obstruc-
≥ 20 s or of shorter pauses that are associated with decreased tion or other concerns for SDB. A normal PSG does not rule out
heart rate, hypoxemia, clinical changes such as pallor, cyanosis future BRUE events; many children with BRUE will have a normal
and limpness, or need for intervention. Shorter-duration events sleep study [17].

Chapter 49 childhood sleep–wake disorders 461
SIDS is defined as the sudden unexplained death of an infant of Sleep Disorders, Third Edition (ICSD-3), OSA is prolonged or
that remains unexplained after a thorough investigation [18] that intermittent, partial or complete, upper airway obstruction that
includes evaluation of clinical history, complete autopsy, and impairs ventilation and/or causes sleep disruption [9]‌. The etiology
examination of the death scene. While the cause of SIDS remains includes adenotonsillar hypertrophy, craniofacial anomalies (eg,
unknown, a “triple-risk” model has been suggested that includes micrognathia, macroglossia, maxillary hypoplasia), neuromuscular
the vulnerable infant, a critical developmental period, and exog- disorders (eg, muscular dystrophies), and obesity [25].
enous stressors [19]. Infant sleep position is an important con- The parent may report snoring, labored breathing, and/or
sideration in SIDS. When infants sleep in the prone position, obstructed breathing. Additional observations may include the
the auto-resuscitation reflex to hypoxemia and hypercarbia may following: paradoxical respiratory effort; restless sleep with fre-
not get activated; startle and arousal followed by gasping may be quent movement, diaphoresis, and airway-protective maneuvers
absent, leading to asphyxiation [20]. Prone sleep position is asso- such as neck extension; poor weight gain; early morning headache;
ciated with a decreased arousal response [21]. In addition, a criti- and secondary enuresis. Symptoms of daytime sleepiness may
cal developmental period occurs between 2 and 5 months of age be present, but hyperactivity or behavior changes can be also be
when the infant transitions from subcortical to cortical arousal. seen. Children are more likely to have partial airway obstruction,
Consequent disorganization of arousal development during this in contrast to adults, who are more likely to have complete airway
critical period increase the risk of SIDS [22]. The prevalence of obstruction [9]‌.
SIDS has significantly decreased following the “Back to Sleep” On PSG, there are one or more scorable respiratory events
campaign that was introduced in the United States in the 1990s. per hour [9]‌. A scorable respiratory event, according to the 2012
This recommends supine sleep until 12 months of age. The decline American Academy of Sleep Medicine (AASM) Manual for the
in SIDS incidence has now leveled off, underscoring the persis- Scoring of Sleep and Associated Events, includes obstructive
tence of other risk factors such as bed sharing, maternal smoking, apneas or hypopneas. An obstructive apnea is defined by a decrease
and upper respiratory tract infections [23]. In 2011 the American in amplitude of the oronasal thermal sensor recording by ≥ 90% of
Academy of Pediatrics (AAP) expanded its recommendations baseline for at least two breaths with continued respiratory effort
to promote safe sleep in infants and target other preventable throughout the event. A hypopnea is scored if there is a decrease in
causes of sleep-related deaths in addition to SIDS. A summary of nasal pressure signal by ≥ 30% for at least two breaths and there is
these recommendations for safe sleep in infants can be found in either an associated oxygen desaturation of ≥ 3% or an associated
Table 49.3 [24]. arousal [26].
First-line treatment for most children with OSA is adenoton-
Sleep disordered breathing sillectomy. The gold standard for diagnosis of OSA in children
Obstructive sleep apnea is attended PSG in the sleep laboratory. Recent guidelines from
the AAP and the AASM recommend PSG for diagnosing OSA
OSA is the most common form of sleep disordered breathing
prior to adenotonsillectomy in children when there is a clinical
(SDB) in children. As defined by the International Classification
suspicion of sleep disordered breathing [3,27]. The American
Academy of Otolaryngology–Head and Neck Surgery Foundation
Table 49.3 Summary of recommendations for infant safe sleep recommends a sleep study in patients with complex medical con-
ditions or in the uncomplicated patient in whom the diagnosis
Infant should be placed supine for every sleep of SDB is not clear [28]. Children at high risk for complications
from adenotonsillectomy should be monitored postoperatively in
A firm sleep surface is recommended the hospital setting. They include those with age < 3 years, severe
Loose bedding and soft objects should not be used in the crib OSA (apnea–hypopnea index (AHI) ≥ 10 or oxygen desatura-
Sleep positioners, wedges, and special mattresses are not recommended tion < 80%), cardiac complications from OSA, failure to thrive or
obesity, craniofacial anomalies or genetic disorder, neuromuscu-
Room-sharing is recommended lar disorder, or current respiratory infection [28, 29]. Overnight
Bed-sharing is not recommended oximetry as a screening test is less useful in children than it is in
Breastfeeding is recommended the adult population. An abnormal oximetry in an uncomplicated
child with enlarged tonsils is highly suggestive of OSA (with a
The offering of a pacifier at sleep onset may be beneficial positive predictive value of 97%); however, a negative oximetry
Avoid overheating of the infant (no more than one layer more than an does not rule out OSA. In a sleep center referred population, chil-
adult would wear) dren with a negative oximetry still had a 47% chance of OSA on
Regular prenatal care is recommended PSG [30]. Children can have severe OSA and maintain normal
oxygen saturations.
Smoke exposure, alcohol, and illicit drug use should be avoided during
Continuous positive airway pressure (CPAP) is also used to
and after pregnancy
treat OSA in children, particularly if there is significant residual
Infants should be immunized disease after adenotonsillectomy and/or the child is obese or has
Home cardiorespiratory monitors have not been shown to reduce the risk other medical comorbidities. While adherence can be a challenge,
of SIDS treatment of OSA with CPAP in children has been associated with
improvement in attention, sleepiness, behavior, and quality of life
Source data from Pediatrics, 128(5), Moon RY, SIDS and other sleep-related infant
deaths: expansion of recommendations for a safe infant sleeping environment, pp. 1030–9, [31]. There are published guidelines for manual titration in the
Copyright (2011), American Academy of Pediatrics. sleep laboratory [32,33].

There are alternative medical therapies to be used in children Behavioral methods that have been suggested include unmodi-
with mild OSA to avoid adenotonsillectomy or if residual mild OSA fied extinction (commonly referred to as the “cry-it-out” method)
persists after adenotonsillectomy. Leukotriene and glucocorticoid and extinction with parental presence. Both involve placing the
receptors have been shown to be present on adenoidal tissue, and child in bed without reacting to any behavior, no matter how long
treatment with both montelukast and intranasal steroids (intrana- the child is upset. This may not be well tolerated by the caregiver.
sal budesonide or fluticasone) has shown a decrease in AHI during Other methods include graduated extinction, whereby the car-
treatment that likely persists after the medication is discontinued egiver responds to the child over varying and increasing inter-
[34–38]. These medical therapies are likely beneficial in mild OSA vals. Delaying bedtime and removing the child from the bed have
(AHI < 5). Optimal treatment length has not been established, but also been suggested. The use of scheduled awakenings is another
at least 6 weeks is likely needed for benefit. These patients should method. The pattern of awakenings is established, then the parent
have close follow-up. awakens the child preemptively and the awakenings are faded over
time. No single behavioral intervention has been shown to be supe-
Central sleep apnea, sleep-related hypoventilation, rior to another [43,44]. Sleep hygiene also plays a role in behavioral
and sleep-related hypoxemia insomnia of childhood and should be addressed [46].
Less common forms of SDB in children include central sleep apnea
(CSA), sleep-related hypoventilation, and sleep-related hypoxemia. Restless legs syndrome (Willis–Ekbom disease)
There are no clear data on the frequency of CSA in children. If pre- The diagnosis of RLS (also now known as Willis–Ekbom disease,
sent, it may be associated with neurological issues such as Arnold– WED) in adults is made if the patient has an urge to move his or
Chiari malformation [39]. Children can also have CSA associated her legs, usually associated with an uncomfortable sensation that
with OSA that may resolve after adenotonsillectomy [40]. Brief is worsened by inactivity and partially relieved by movement. The
(<10 s) central apneas can be present in REM sleep or post-sigh/ symptoms are worse or only occur in the evening. In children,
post-arousal, and are likely normal if not associated with significant besides these diagnostic criteria, additional evidence is required to
oxygen saturation. Periodic breathing is also common in normal establish a diagnosis. This includes a description of the discomfort
infants [41]. in the child’s own words, such as “owwies ouchies, bugs crawling on
Sleep-related hypoventilation can occur in association with neu- the legs, …”. Since not all children are able to adequately describe
romuscular disorders due to weakness of the chest wall. It can also the discomfort and urge to move the limbs, at least two of the fol-
occur in other restrictive lung diseases such as scoliosis. A rare lowing should be present: sleep disturbance, a first -degree relative
form of sleep-related hypoventilation is seen with congenital cen- with RLS, elevated periodic limb movements of sleep (periodic
tral hypoventilation syndrome (CCHS), which is due to mutations limb movement index ≥ 5) on PSG [9]‌. The pediatric RLS diagnos-
in the PHOX2B gene and typically presents in infancy or early tic criteria have recently been updated [47]. The prevalence of RLS
childhood [42]. is about 1.9% in children and 2% in adolescents [4]. In a population
of patients referred to a sleep disorders center, the prevalence was
Insomnia found to be 5.9% [48].
Older children and adolescents can have psychophysiological RLS can impact sleep initiation and maintenance. There is an
insomnia similar to adults. Behavioral insomnia of childhood is spe- association with attention-deficit hyperactivity disorder (ADHD),
cific to infants, toddlers, and young children. It has been reported anxiety, and depression [4,49]. Initial treatment should focus on
in 20–30% of young children [43]. There are similarities with psy- improving sleep hygiene, having a consistent sleep–wake pattern,
chophysiological insomnia in that there are likely predisposing, getting sufficient sleep, and (if possible) eliminating exacerbat-
precipitating, and perpetuating factors; however, in behavioral ing factors such as caffeine, alcohol, nicotine, and medications
insomnia of childhood, the caregiver may be impacting these fac- such as sedating antihistamines, serotonergic antidepressants, and
tors and is the person verbalizing the impact of the insomnia to certain neuroleptics [49]. Oral iron has been shown to be effec-
the provider. There are two types of behavioral insomnia of child- tive in treating RLS in children, particularly if the serum ferritin
hood: sleep onset association disorder and limiting-setting disorder. is <50 μg/L [50,51]. Use of intravenous iron sucrose may be con-
Sleep onset association disorder is characterized by an extended sidered in patients who are unresponsive or intolerant to oral iron
process with special conditions to fall asleep, demanding or prob- [52]. A repeat serum ferritin should be obtained 3–4 months after
lematic sleep onset associations (eg, a need for rocking or patting), initiation of oral iron therapy. There are no FDA-approved medica-
delayed or disrupted sleep if associations are absent, and nighttime tions for RLS in children. In severe cases, medication can be used
awakenings that require intervention by the caregiver. The limit- with close follow-up for improvement and monitoring for side
setting type includes difficulty initiating or maintaining sleep, stall- effects. Clonidine, gabapentin, sedative–hypnotics, and dopamin-
ing or bedtime refusal at night, increased frequency of awakenings, ergics have all been suggested as possible pharmacological therapy
and insufficient or inappropriate limit setting by the caregiver [9]‌. in children [49].
Children with chronic medical problems and neurodevelopmen-
tal issues such as autism may be particularly vulnerable. The child Delayed sleep phase syndrome
should also be evaluated for comorbid sleep disorders such as RLS, Delayed sleep phase syndrome (DSPS) is defined as a delay in the
periodic limb movement disorder, and OSA. phase of the major sleep period compared with the desired wake
Anticipatory guidance/preventative care and a variety of behavio- time, with the chronic complaint of difficulty falling asleep and
ral treatments have been found to be effective treatments of behav- awakening at the desired times. If the individual is allowed to
ioral insomnia of childhood [43,44]. There are no FDA-approved choose his or her schedule, there is normal sleep quality and dura-
medications for childhood insomnia, and trials are limited [45]. tion for age [9]‌. A stable delay in the sleep period is demonstrated

in sleep logs or actigraphy. While this can occur at any age, this cataplexy. This may be related to central nervous system hypocre-
delay in preferred sleep time is a particular problem for adoles- tin deficiency [61]. There is a strong association of narcolepsy with
cents, and the prevalence of DSPS in this age group has been has cataplexy and HLA-DQB1*0602, although this haplotype is found
been reported at 7–16% [53,54]. This may be due to both social in up to 25% of the normal population and so assay per se is not
and biological factors [55]. Biological factors may include a genetic useful. In addition, cerebrospinal fluid (CSF) levels of hypocretin-1
component: for example, polymorphisms in the PER and CLOCK (also known as orexin A) are low or absent in most patients with
genes have been associated with DSPS [54]. Behavioral factors may narcolepsy with cataplexy [58]. The autoantigen tribbles homolog
include increased schoolwork, extracurricular activities, and jobs 2 (Trib2) has been found to be elevated in individuals with recent
that may also delay bedtime. Poor sleep hygiene with use of elec- onset of narcolepsy with cataplexy [62]. An association has also
tronic devices may also impact sleep. An early school start time been found between H1N1 influenza exposure and diagnosis of
may further contribute to sleep deprivation and daytime sleepi- narcolepsy with cataplexy [63].
ness. Adolescents should be screened for school avoidance and Diagnosis of narcolepsy is made using a combination of noc-
mood disorders. Diagnosis of DSPS is based on a careful history, turnal PSG and the multiple sleep latency test (MSLT). The PSG
with sleep logs and actigraphy used as adjunctive aids in diagnosis should be obtained on the night immediately preceding the MSLT
[56]. A typical pattern involves difficulty falling asleep (i.e, mid- [64]. One to two weeks of sleep logs and actigraphy prior to PSG
night or later) and difficulty arising for school during the week, and and MSLT are useful in documenting sleep wake patterns and ade-
“sleeping-in” to late morning/early afternoon at the weekend. PSG quate sleep for age. Children should be free of medications such
is only indicated if an additional sleep disorder (eg, OSA) is sus- as stimulants, hypnotics, anxiolytics, and antidepressants for 2–3
pected. When on vacation or summer break and allowed to revert weeks prior to sleep studies, as these agents can alter sleep archi-
to his or her natural pattern, the adolescent has no complaint of tecture, especially REM sleep. The most common medications in
sleepiness. children are stimulants and selective serotonin reuptake inhibi-
Treatment includes good sleep hygiene. Parental-set bedtimes tors (SSRIs). Guidelines for the MSLT in childhood have recently
have been shown to be beneficial to adolescent sleep [57]. Phase been published [64,65]. The MSLT is invalid prior to age of 5 years
advancing (shifting sleep onset time to an earlier hour) with adjunc- because napping is still physiological at this age. Most children with
tive use of melatonin (0.5 mg about 5–6 hours prior to the desired narcolepsy will have a mean sleep latency of <8 minutes with ≥2
bedtime) can be tried [56]. Bright light therapy (2500–10 000 lux) sleep onset REM periods (SOREMPs) [64]. Some children, how-
timed to be given after the nadir in core body temperature (typi- ever, may require repeat testing over time to make the diagnosis.
cally about 2 hours prior to the preferred wake time) may also help For children who are not eligible for MSLT because of age <5 years
advance the sleep phase. Once an earlier sleep onset time has been or the use of medications that cannot be safely stopped (eg, SSRIs),
established, behavioral adherence is key, as relapse to a later sleep testing for low CSF hypocretin levels is useful.
onset time can easily occur during vacations and holidays. Along The treatment of narcolepsy in children includes good sleep
with the above measures, phase advancing (moving backwards) the hygiene, maintaining regular sleep wake patterns, exercise, and
sleep onset time can be conducted in 15-minute increments every scheduled napping. This is rarely effective in isolation. There are
3–4 days. This is typically most effective if the desired bedtime is no FDA-approved medications for treatment of EDS or cataplexy
less than 3 hours from the actual bedtime. Phase delay (chrono- in children <16 years of age, so all medication use is off-label.
therapy) can be tried by shifting the bedtime forwards 3 hours Central stimulants are commonly needed. Methylphenidate in the
daily until the desired bedtime is reached. This is better suited if short-or long-acting form can be used, as can dextroampheta-
the actual sleep time is in the early morning hours. It also requires mine, modafinil, and armodafinil. Fluoxetine and venlafaxine can
vigilance in keeping the adolescent up until the new bedtime and be used for cataplexy. Sodium oxybate has also been reported to be
may require time off from school. Both melatonin and bright light beneficial in treating cataplexy in children [7,66,67]. The mainte-
therapy should be administered carefully, as inappropriate timing nance of wakefulness test (MWT) may be used to assess treatment
may worsen the phase delay [7,54]. efficacy [68].
Narcolepsy Parasomnias
Narcolepsy is characterized by excessive daytime sleepiness (EDS), Partial arousal parasomnias can arise from both NREM and REM
hypnagogic/hypnopompic hallucinations, sleep paralysis, and sleep. NREM parasomnias (i.e, sleepwalking, sleep terrors, and con-
cataplexy. It is a lifelong neurological disorder. Disrupted noctur- fusional arousals) are common in children owing to the increased
nal sleep is often present [9]‌. These symptoms are caused by an portion of the night spent in NREM 3 sleep, from which these
intrusion of REM sleep into wakefulness, together with an overall parasomnias typically arise. Children typically do not recollect the
dysregulation of the sleep and wake states [58]. Not all characteris- event. One study showed prevalences in children 2.5–6 years of
tics may be present in all children. In addition, a cataplexy history sleep terrors at 39.8% and sleep walking at 14.5% [2]‌. Because of
may be difficult to elicit, depending on age. This may contribute the predilection to arise out of NREM 3 sleep, these events typi-
to a reported delay in diagnosis from symptom onset of 10 years cally occur in the first third of the night. While parasomnias can be
or more [59]. Narcolepsy is increasingly recognized in the pediat- benign, there might be an increased risk of injury, such as during
ric population; however, diagnosis of narcolepsy in children may sleepwalking. Exacerbating factors include anxiety, OSA, and RLS,
still be delayed as a result of misdiagnosis [60]. Children may be as these disorders may trigger arousals that evolve into a parasom-
misdiagnosed with attention difficulties, mood disorders, and/ nia episode [69]. If the events described are atypical (highly stereo-
or behavioral problems. Increased prevalence of obesity and pre- typed with rhythmic motor behavior or occurring multiple times
cocious puberty has been observed in childhood narcolepsy with throughout the night), nocturnal seizures should be considered.

PSG is indicated in the diagnosis of parasomnias if the event is Table 49.4 Summary of sleep disorders found in specific populations
atypical or potentially injurious or there is a concern for seizures.
In this case, a 16-channel EEG montage should be utilized [64]. In Disorder Common sleep Evaluation/treatment
contrast to parasomnias, epileptiform events typically occur out of problems
N1 or N2 sleep [70]. The PSG should be examined for exacerbating
Trisomy 21 OSA PSG recommended prior to
factors such as OSA or periodic limb movements. Parents should (Down age 4 years; yearly screening
not attempt to awaken the child during the episode or discuss the syndrome) Adenotonsillectomy
event in the morning, as both may exacerbate the occurrence. For
CPAP
parasomnias that are disruptive or potentially injurious, a small
dose of a short-acting benzodiazepine such as clonazepam at bed- Autism Difficulty with Behavioral treatment for
time can be considered, with treatment continuing for 3–6 months spectrum sleep initiation and insomnia
and then slowly tapered [7]. disorder maintenance Melatonin
Parasomnias may also occur out of REM sleep. These include Angelman Difficulty with Identify circadian rhythm
nightmares and REM sleep behavior disorder (RBD). The presence syndrome sleep initiation and disorder if present
of nightmares has been associated with anxiety in children[71]. maintenance Behavioral treatment
While rare, the presence of RBD in children has been reported and Circadian rhythm of insomnia
may be related to conditions such as narcolepsy, structural brain- disorders Melatonin
stem lesions, use of SSRIs, and neurodevelopmental disorders such May require less sleep
as autism and Smith–Magenis syndrome [72]. than peers
Prader–Willi OSA (risk even greater PSG prior to initiation of GH
Sleep in specific populations syndrome on growth hormone) and yearly after
Certain populations of children have specific sleep disorders or CSA Treatment of SDB can include:
complaints that are unique to their disorder. This section highlights Hypoventilation ◆ Adenotonsillectomy
some sleep issues common to specific populations. A summary of EDS for OSA

◆ CPAP for OSA
the common sleep issues by population can be found in Table 49.4. SOREMPs
◆ Oxygen for CSA
Trisomy 21 ◆ Bilevel PAP for
Children with trisomy 21 (Down syndrome) show a higher preva- hypoventilation

lence of OSA than the general pediatric population, with rates Achondroplasia OSA Treatment of OSA:
reported at greater than 50% [73]. Children with trisomy 21 are ◆ Adenotonsillectomy
at risk for sleep disordered breathing as a result of clinical features ◆ CPAP
that include hypotonia, midface hypoplasia, relative macroglossia,
CSA (cervicomedullary Treatment of CSA:
posteriorly placed tongue, lymphoid hyperplasia, and being over- junction compression) ◆ Spinal cord decompression
weight [73]. Additional comorbidities such as congenital heart
Hypoventilation due to Treatment of hypoventilation:
disease, pulmonary hypertension, airway abnormalities, chronic
restrictive lung disease ◆ Bilevel PAP
lung disease, and scoliosis can be impacted by or can impact SDB.
Parental reports of sleep symptoms in this population may be OSA: obstructive sleep apnea; PSG: polysomnography; CSA: central sleep apnea;
unreliable. In a longitudinal study of children with trisomy 21, of CPAP: continuous positive airway pressure; PAP: positive airway pressure; SOREMPs: sleep
those whose parents reported no sleep concerns, 54% had abnor- onset REM periods.
mal sleep study results [74]. Unlike other children, the risk of OSA
in Down syndrome may not directly correlate with weight, owing in typically developing children, behavioral insomnia of childhood
to the added risk for upper airway collapse from hypotonia that is can be present. Behavioral deficits specific to ASD can contribute
typical of this disorder [75]. Children with trisomy 21 may sleep in to sleep disruption, including difficulty with emotional regulation,
unusual positions (eg, sitting ), which does not correlate with likeli- difficulty with transitions, and tendency to perseverate. Parental
hood of OSA [76]. Recent guidelines suggest referral to a pediatric communication about bedtime expectations may be more diffi-
sleep laboratory for PSG in all children with trisomy 21 prior to cult for the child with ASD to incorporate. They may not respond
the age of 4 years. Children should be screened yearly from the age typically to environmental clues [81]. Mood disorders such as anxi-
of 5 years up to 21 years for concern for SDB [77]. Because of the ety and depression can also affect sleep. Medications used to treat
inaccuracy of parental reporting in this population, a high index autism can further impact sleep [82]. The presence of comorbid
of suspicion for OSA should be present throughout the lifetime of epilepsy may also contribute to sleep disruption [83].
patients with trisomy 21. There may be biological reasons for sleep difficulties in ASD.
The major sleep-promoting neurotransmitter in the brain is γ-
Autism spectrum disorder aminobutyric acid (GABA). The GABAergic interneurons may
There is increased prevalence of a variety of sleep disorders in chil- be affected in ASD, causing disruption to this pathway [84,85].
dren with autism spectrum disorder (ASD), with parental report Abnormalities in melatonin have also been implicated, with low
as high as 50% to 80% [78–80], independent of intellectual abil- levels noted in children with ASD. This low level of melatonin
ity [80]. Of particular concern is difficulty with sleep initiation may negatively impact the percentage of NREM 3 sleep in these
and maintenance of which the causes are likely multifactorial. As children [86].

A practice pathway has been suggested for the treatment of Treatment of OSA should include evaluation for adenotonsillec-
insomnia in children with ASD [87]. After the impact of other tomy and CPAP therapy if indicated; those with PWS may be at
comorbidities and sleep disorders have been addressed, the recom- increased risk of residual OSA post-surgery [103]. In those with
mendation for first-line treatment includes behavioral interven- hypoventilation, bilevel PAP may be indicated. Oxygen has been
tions for insomnia. Melatonin is suggested as adjunctive therapy proposed for infants with central apnea and may improve the SDB
and has been shown to be safe, tolerable, and effective at low doses in addition to the hypoxemia [102]. Symptoms of SDB should be
(1–3 mg) [88]. Other pharmacological therapies should be reserved assessed at least yearly. PSG should be performed prior to initia-
for refractory cases, and there is limited evidence supporting their tion of growth hormone therapy, 6–10 weeks after initiation, and
use [87]. then yearly [100]. Growth hormone therapy may increase the risk
of OSA, particularly in the initial treatment phase, and may also
Angelman syndrome increase adenotonsillar hypertrophy [104–106]. There have been
Angelman syndrome is a genetic disorder with developmen- reports of sudden death associated with growth hormone therapy
tal delay, seizures, ataxia, speech delay, and a happy demeanor [107], but this correlation has not been definitively established.
[89]. An association with a notched delta pattern on EEG has Independent of SDB and obesity, individuals with PWS can have
been described [90]. Sleep problems are common and have been EDS that may be due to hypothalamic dysfunction[101]. This can
described in 20–80% of children with Angelman syndrome [89]. significantly disrupt quality of life. Increased nocturnal sleep and
The syndrome is caused by an abnormality in chromosome 15q11– behavioral problems may be present. SOREMPs can be observed,
q13 that causes lack of expression of ubiquitin protein ligase E3A as can cataplexy. Behavioral problems intrinsic to the disorder can
(UBE3A) [91]. This protein may also have an effect on circadian also contribute. Modafinil has been suggested as an effective treat-
rhythm, as shown by a Drosophila model of Angelman syndrome ment for enhancing alertness with minimal side effects [108].
[92]. Individuals with Angelman syndrome have been found to
have lower levels of nighttime serum melatonin than controls [93]. Achondroplasia
These factors may be a cause of the increased sleep complaints in There are over 100 different forms of dwarfism, of which achondro-
individuals with Angelman syndrome. Patients often have difficulty plasia is the most common. It is related to an autosomal dominant
with sleep initiation and maintenance and may require less sleep mutation in the fibroblast growth factor receptor 3 gene (FGFR3)
than typically developing peers. Circadian rhythm disorders have [109]. Individuals with achondroplasia are short-statured, with
also been described, including DSPS, free-running type and irregu- enlarged head, mid-face hypoplasia, long narrow trunk, short-
lar sleep–wake type [93]. Sleep disorders in this population have ened proximal limbs, and hypotonia. They are at risk for OSA from
been shown to impact parental stress [94]. The peak age for sleep their craniofacial abnormalities. Further, the skull base dysplasia
problems is between 2 and 6 years [94,95]; some children may have increases the risk for cervicomedullary junction compression and
improvement in their sleep as they become adolescents and adults CSA. Coexisting restrictive lung disease may add to the risk of
[96]. Key to treatment of children with Angelman syndrome are sleep-related hypoventilation, although this may be infrequent in
identification of circadian rhythm disorders if present, behavioral patients less than 3 years of age [110–114]. The prevalence of SDB
modification, and melatonin. Small clinical trials have shown that is unknown, but it occurs in 95% of preschool children with achon-
both behavioral interventions and melatonin up to 5 mg at bedtime droplasia, with the frequency of OSA being 10–35% [110]. The risk
can lead to improvement in sleep symptoms [97–99]. of obesity, and upper-airway muscle dysfunction due to jugular
foramen or hypoglossal canal stenosis, can also further increase
Prader–Willi syndrome the risk of SDB in an individual with achondroplasia [110]. Sudden
Individuals with Prader–Willi syndrome (PWS) have a risk of both unexpected death has been reported in achondroplasia, particu-
SDB and EDS independent of SDB. PWS is a genetic disorder that larly during infancy, and is thought to be due to the impact on
is due to a lack of expression of genes from the paternally inherited central respiratory drive of compression of the cervicomedullary
imprinted region of chromosome 15q11–q13 that causes neuro- junction [114]. In addition, infants with achondroplasia may have
cognitive deficits, hypothalamic dysfunction, and specific behav- a decreased arousal response overall, as well as a decreased arousal
iors. There is no gender preference. Infants with PWS present with response to SDB events, which can impact their risk of sudden
hypotonia, feeding difficulties, and failure to thrive. As individuals death [111]. PSG is recommended in the newborn period and sub-
with PWS develop, this changes into a pattern of hyperphagia and sequently based upon symptoms [114]. A high suspicion should be
obesity [100]. Individuals with PWS have many risk factors for SDB maintained for SDB throughout the individual’s lifetime. Treatment
and may develop OSA, alveolar hypoventilation, or central apnea. for SDB in achondroplasia may include surgical relief of spinal cord
Obesity, craniofacial features that include micrognathia, a small compression, adenotonsillectomy, and CPAP.
naso/oropharynx, and hypotonia can all contribute to their risk
of OSA. In addition, their obesity contributes to an increased load Future opportunities in pediatric
on relatively weak respiratory muscles and a risk of restrictive lung
disease, which can lead to alveolar hypoventilation. Scoliosis can
sleep medicine
also contribute. An abnormal response to both hypercapnia and Much has been learned about sleep in childhood, but many oppor-
hypoxia has been demonstrated in children with PWS. They may tunities remain for future research and exploration. This field
also have a failure of arousal with respiratory events. These factors would benefit from further prospective randomized controlled
may contribute to SDB and may be related to the hypothalamic dys- pharmacological trials. Many opportunities exist to further our
function seen in this disorder [101]. Increased central apneas have knowledge in the management and long-term consequences of
been observed in infants with PWS [102]. childhood sleep disorders. The assessment of arousals from sleep

needs further study, as both cortical and subcortical arousals need 21. Groswasser J, Simon T, Scaillet S, Franco P, Kahn A. Reduced arousals
to be included. Cyclic alternating patterns in the EEG also need to following obstructive apneas in infants sleeping prone. Pediatr Res
be considered as a marker for sleep fragmentation. The incorpo- 2001;49(3):402–6.
22. Franco P, Kato I, Richardson HL, et al. Arousal from sleep mechanisms
ration of metabolomics, proteomics, and molecular medicine into
in infants. Sleep Med 2010;11(7):603–14.
mainstream pediatric sleep medicine may also provide new insight 23. Trachtenberg FL, Haas EA, Kinney HC, Stanley C, Krous HF. Risk
into mechanisms and open up avenues for treatment. factor changes for sudden infant death syndrome after initiation of
Back-to-Sleep campaign. Pediatrics 2012;129(4):630–8.
24. Moon RY. SIDS and other sleep-related infant deaths: expansion of
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CHAPTER 50
Sleep in older adults
Rosalia Silvestri
Introduction difference in the constant routine notwithstanding consistent dif-

ferences between young and elderly subjects in the entrained con-
Several sleep modifications occur in elderly people, including ditions, probably due to diminished sensitivity or potency of the
EEG and circadian alterations and variations in the distribution normal zeitgebers.
of sleep stages (Box 50.1). The hypnogram of an elderly subject There seems to be a reduced circadian modulation of REM sleep
compared with that of a young adult (Fig. 50.1) shows increased and spindle frequency, with a phase advance relative to the circa-
wake after sleep onset (WASO), a steep decrease in the amount of dian melatonin profile.
slow-â•‰wave sleep (SWS) already in the first cycle, and, to a lesser Circadian alteration in the expression of the clock genes BMAL1,
extent, a decrease of REM sleep. REM density is also diminished CRY1, and PER1 [8]â•„are observed in elderly subjects with mild cog-
with increased REM fragmentation. Furthermore, there is a rise nitive impairment (MCI) and may represent a risk factor for MCI
in phase shifts/â•‰transitions and an increased number of arousals conversion to Alzheimer dementia (AD) [9].
throughout the night (Box 50.2), leading to a substantial total sleep Circadian alterations, including morning sleepiness and absence
time (TST) reduction, more pronounced as intermediate insom- of the afternoon dip, in MCI could represent early manifestations
nia. In addition, circadian and ultradian modifications also occur, of the behavioral and psychological signs of dementia (BPSD) and
leading to progressive phase advancement that may be erroneously early expression of later sundowning.
diagnosed as early morning insomnia. A polyphasic sleep rhythm On the other hand, although differences in performance after
with several naps occurring during the day time is linked to altered sleep deprivation (SD) often reflect genetic variances, with subjects
body temperature, showing an earlier acrophase and changes in possessing a longer version of PER3 showing a significant cogni-
endocrine rhythms including those of melatonin, growth hormone tive decline during SD around the circadian nadir, healthy older
(GH), thyroid-â•‰stimulating hormone (TSH), and cortisol [1]â•„. people usually tolerate SD better than younger subjects. This is
Sleep complaints of the elderly include nocturnal awakenings, probably due to a less-â•‰pronounced reduction of SWS compared
superficial and fragmented sleep, early awakening, and daytime with younger people [10]. There are also some gender differences
involuntary napping (Box 50.3). All of these alterations are often in sleep alterations that occur with age, which reflect the prevalence
more pronounced in community-â•‰dwelling and chronically hospi- of insomnia in women rather than in men. In fact, in women, sleep
talized or demented elderly people. Daytime somnolence is also efficiency (SE) declines and WASO and phase shift increase with
linked to loss of prefrontal cortex restoration during NREM sleep age compared with men, even if SWS reduction and flattening of
in aging [2]â•„. the slow-â•‰wave activity (SWA) decay curve occur in elderly women
Melatonin decreases with aging owing to neurodegeneration of 5 years later than in men [11]. Sleep circadian control has a greater
the suprachiasmatic nucleus (SCN) [3]â•„, as well as alterations of the role in women [12]. Therefore, manipulation of the circadian tim-
afferent cholinergic projections from the brainstem and nucleus ing system may offer more therapeutic approaches in women than
basalis of Meynert (NBM) [4]. in men to alleviate excessive daytime sleepiness (EDS) and insuf-
Most human studies suggest a decline in the amplitude of the ficient nighttime sleep.
circadian rhythm due to decreased amplitude of the endogenous Insomnia prevalence in older women, compared with men, con-
relationships between several physiological functions. Early studies firms the overall data regarding gender-â•‰related expression of insom-
by Czeisler et al. [5,6] and Monk [7]â•„in a constant routine proto- nia. In a meta-â•‰analysis of 29 studies, not only was the incidence of
col to avoid external confounding interference yielded contrasting insomnia considerately higher in women compared with men, but
results, suggesting a 90-â•‰minute phase advance with a 30% decrease gender differences in the population also showed that the overall
in amplitude of body temperature rhythm [6] or a less pronounced risk ratio of women to men (F:M) progressively increased from 1.28
in young adults (15–â•‰30 years old) to 1.73 in subjects over 65 years of
age [13]. Insomnia persistence appears to be both gender-â•‰and age-â•‰
Box 50.1â•‡ Sleep modifications in the elderly
related, with a decreased remission rate in subjects over the age of
65 [14]. Poor sleep is associated with poorer physical performance
◆ EEG alterations
and greater functional limitations in older women, significantly
◆ Sleep stages and cycle alterations affecting measures such as gait speed and grip strength [15].
◆ Circadian rhythm alterations Midlife insomnia has been a significant predictor of all cause-â•‰
mortality, with hazard ratio (HR) 2.74 (95% confidence interval

(a) Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
1 2 3 4 5 6 7 8
Hours of sleep
(b) Awake
REM
Stage 1
Stage 2
Stage 3
Stage 4
1 2 3 4 5 6 7 8
Hours of sleep
Fig. 50.1 Hypnograms of a (a) a young adult and (b) an elderly subject.
Box 50.2 Summary of major sleep alterations in older subjects In particular, AD patients show a progressive TST reduction in
parallel with the evolution of the neurodegenerative disease [20].
◆ ↓ S3–S4
Sleep is marked by several awakenings with psychomotor agitation
and restlessness. Physical and verbal aggression, including com-
◆ ↓ REM ↓ REM density plex hallucinations and vocalizations, obscene utterances, delirious
◆ ↑ REM fragmentation, ↑ WASO wandering, anxiety, rage, and fear usually starts in the late after-
noon. This aggression may last for the entire night, characterizing
◆ ↑ phase shifts, ↑ number of arousals
the so-called “sundowning” syndrome that affects up to 28% of
◆ ↑ naps patients [21].
EDS is also a prominent feature of demented patients, presenting
as a progressive increase in parallel with the advance of the disease
[22]. Most recent studies, however, show early EDS independently
Box 50.3 Sleep complaints of the elderly of previous night sleep, especially during the morning, with a loss
of normal vigilance rhythm [23]. Similarly, actigraphic studies
◆ Nocturnal awakenings (central insomnia) demonstrated a loss of physiological sleep propensity in the early
◆ Superficial sleep (↓ awareness of the environment) afternoon [24]. The loss of circadian rhythmicity in demented sub-
◆ Early
jects is evidenced by both melatonin and body temperature rhythm
awakening
alterations [3,25]. In fact, although the pineal gland is substantially
◆ Involuntary daytime napping intact in AD, the SCN is typically affected by early neurodegenera-
tion, even preclinically [26]. The rhythmic expression of BMAL1,
CRY1, and PER1 in the pineal gland appears to be both preclinically
(CI) 1.75–4.30), the mortality risk being high only for insomnia and clinically affected [8]‌, influencing the rhythmicity of cognitive
associated with short sleep duration, and stronger in men than in performances and accelerating the progression from MCI to AD.
women, although still significant in the latter. Recent evidence suggests a role for orexin (hypocretin, HCRT)
in driving amyloid plaque formation in AD. Experimental studies
indicate that sleep disruption leads to amyloid-beta (Aβ) deposi-
Sleep in elderly patients with dementia tion in mice, whereas, in the presence of an orexin antagonist or
BPSD, including sleep–wake rhythm alterations, anxiety, depres- in orexin gene knockout mice, the amount of amyloid deposition
sion, restlessness, and oral and sexual disinhibition, have a severe decreases in parallel with longer periods of both nocturnal and
and frequent (approximately 64%) impact on demented subjects diurnal sleep [27]. In humans, amyloid deposition relates more
and their families [16]. Among these, sleep disturbance represents a to sleep quality in terms of reduced SE rather than TST duration
major clinical problem and a consistent burden for caregivers, often [28]. There is a pathological interaction between Aβ42 and HCRT-
leading to patient hospitalization [17]. Among the noncognitive 1 levels, with higher cerebrospinal fluid (CSF) HCRT-1 levels in
symptoms, sleep disorders and nocturnal agitation in patients with early disease [29]. Moreover, sleep plays a scavenger role, not only
dementia are reported with a variable frequency of 19–54% [18,19]. promoting synaptic pruning, but also disposing of neurotoxins

Chapter 50 sleep in older adults 471
by increasing the interstitial space, thereby favoring an increased types of insomnia complaints: sleep onset or maintenance prob-
exchange of CSF with interstitial fluid [30]. lems, and daytime emotional profiles (anxious or depressed sub-
There appear to be gender differences in the expression of orexin- jects with some kind of pain-related syndromes).
ergic mechanisms via dimorphic modulation of the HCRT-1 recep- Sedative antidepressants such as amitriptyline, trazodone, sertra-
tor driven by steroid hormones in females. This results in a more line, and mirtazapine can be safely used, with the caveat of pre-
pronounced gender-related sleep impairment [31]. scribing selective serotonin reuptake inhibitors (SSRIs) only in the
Gender differences have also been observed in the clinical epide- morning, given their known effect in fragmenting sleep and alter-
miology of AD, depending on the extent of the cognitive reserve, ing REM sleep and dreaming.
which is higher in men, and on the specificity of the affected brain Antihistamines should be avoided in elderly people because of
circuitry, with women showing higher cerebral blood flow and their anticholinergic properties and the risk for delirium, besides
connectivity in the parietal association cortices versus the visual the deleterious effects on sleep apnea, which is also a potential risk
and motor cortices in men [32]. Furthermore, environmental and for BDZ users. Typical (haloperidol and phenothiazines) or atypi-
behavioral aspects such as lifestyle, exercise and smoking affect cal antipsychotics (quetiapine and risperidone) are often used to
cognitive decline differently in the two genders [33]. control sundowning symptoms, delirium and agitation, whereas
The role of gender distribution of specific sleep disorders such as α2δ drugs, such as gabapentin and pregabalin, may prove helpful in
insomnia, sleep apnea and Willis–Ekbom disease/restless legs syn- controlling both anxiety and neuropathic pain.
drome (RLS) will be addressed in their respective sections. Melatonin is an endogenous night hormone influencing sleep
induction (MT1 receptor) as well as circadian rhythmicity and
Insomnia mood (MT2 receptor). It also exerts anti- inflammatory and
anti-cancer qualities by via the immune system (MT3 receptor).
Approximately 40% of the American adult population suffers from Melatonin diminishes progressively with age [44] and may be
occasional insomnia, and this is chronic in 15%, with women, older administered with different dosages and timing in the elderly either
adults, and depressed subjects being most at risk. Considering the to shorten sleep latency or to delay an anticipated sleep phase via
recent extension of life expectancy in Western countries, roughly morning administration [45]. Melatonin agonists such as ramelt-
17% of subjects 65 years or older are potentially at risk. The prev- eon have been used in the USA for long-term treatment of sleep
alence of insomnia ranges from 15% to 35% in elderly subjects onset insomnia [46], with improvement of latency to persistent
[34], prevailing in women, is highly comorbid with depression, sleep [47]. Antidepressants are of no use in the treatment of RLS-
and may be secondary to coexisting diseases [35]. This remains related insomnia and in fact may trigger RLS symptoms [48].
true for different geographic environments [36,37], with differing
gender specificity. Depression and chronic pain-related conditions
(eg, arthritis) are the comorbid disorders that are seen more fre- Excessive daytime sleepiness
quently in women, whereas cardiovascular and respiratory disor- EDS in the elderly stems from reduced SE without reduction in
ders are more prevalent in men. Sleep loss reduces not only quality overall sleep need. This can result from a specific sleep disorder (eg,
of life but also life expectancy [38], induces hypertension [39,40], obstructive sleep apnea syndrome (OSAS) or RLS) or from comor-
increases sustained sympathetic activity, alters cytokine activity, bid clinical conditions such as diabetes, hypertension, or chronic
and augments secretion of C-reactive protein (CRP), a marker of pain syndrome. Circadian alteration also induces sleep at inappro-
systemic inflammation. Furthermore, sleep loss also lowers the priate time, such as 7 pm (forbidden zone) or in the morning with
pain threshold, thus perpetuating the detrimental mechanism of elimination of postprandial dip.
insomnia. Chronic insomnia is an inherent tendency of aging, and
several therapeutic approaches, including cognitive–behavioral
therapy (CBT), may be attempted in cognitively fit older patients to Sleep disordered breathing in the elderly
treat short-and mid-term insomnia, often consolidating pharma- Sleep disordered breathing (SBD) in the elderly includes sev-
cological therapy [41,42]. The goal of insomnia-specific CBT is to eral nosological entities ranging from obstructive (OSA) or cen-
reassess realistic sleep needs and goals, encouraging sleep restric- tral (CSA) sleep apnea to chronic obstructive pulmonary disease
tion therapy and improving sleep hygiene through stimulus control (COPD), overlap syndrome, and CSA with periodic breath-
procedures. ing or Cheyne–Stokes respiration (CSR) in chronic heart failure
In addition, relaxation therapy has proven to be exquisitely help- (Table 50.1).
ful in tense or anxious patients. Mindfulness-based sleep therapy,
involving medication and a variety of relaxation techniques, is
particularly promising in chronic patients [43]. Pharmacological Table 50.1 SDB in the elderly
therapy includes the use of over-the-counter medicines, including
antioxidants, vitamins, valerian, and a variety of herbal products, Obstructive sleep apnea (OSA)
usually in combination with melatonin or prescription hypnotics.
Central sleep apnea (CSA)
The latter include benzodiazepines (BDZs: temazepam, estazolam,
and triazolam) and BDZ receptor agonists (zolpidem, zaleplon, Chronic obstructive pulmonary disease (COPD)
zopiclone, and eszopiclone). When choosing an agent, several fac- COPD + OSA (overlap syndrome)
tors should be considered, including the patient’s cognitive ability,
CSA with Cheyne–Stokes respiration (periodic breathing) (CSA–CSR) in
potential for abuse and dependence, and comorbid psychiatric/
chronic heart failure
organic illnesses. Short versus longer half-life will address different

In older populations aged 65–90 years, 81% suffered from Parasomnias

OSA with an apnea–hypopnea index (AHI) > 5 events/h (cut-
off value), but only 24% presented severe OSA with an AHI > 30 NREM parasomnias are exceedingly rare in elderly patients, with
events/h [49]. Elderly patients tend to have stable SDB that may some exceptions, such as patients with Parkinson disease (PD)
show improvement [50]. This could be due to reduced obesity and or diffuse Lewy body dementia (DLBD). Several complex REM
different fat distribution, in addition to different chemoreceptor and NREM sleep enactment behaviors [67], including REM sleep
responses. Depression, sleepiness, and cognitive impairment are behavior disorder (RBD), may occur in PD and DLBD patients.
more prominent in the elderly than in younger subjects. Gender RBD is often found in middle aged or elderly patients (see also
differences in SBD may disappear by old age. Voxel-based mor- Chapter 38 of this volume), who frequently become symptomatic of
phometry and fractional anisotropy may detect both the gray neurodegenerative rather than cryptogenic disease, the latter being
and white matter alterations induced by hypoxemia and sleep more common in younger age groups [68].
fragmentation in areas crucial to memory and executive func-
tions [51,52]. These changes are responsible for increased cog- Conclusions
nitive deterioration in OSA patients. The risk of falling in older
community-dwelling men may be due to OSA-related EDS and Sleep is profoundly altered in older adults in terms of its struc-
sleep disturbances [53]. ture and its circadian and ultradian control. These alterations may
There is an increased risk of developing cardiovascular disease herald later neurodegenerative processes, further modifying sleep
in older OSA patients [54], but carotid arteriosclerosis depends on consolidation. Both insomnia and EDS are highly prevalent in this
arterial stiffness [55]. Noninvasive continuous positive airway pres- age group, affecting these elderly people both cognitively and emo-
sure (CPAP) therapy improves sleepiness and reduces cardiovascu- tionally, besides constituting risk factors for cardiovascular diseases
lar mortality in elderly patients with OSA [56]. (including stroke) and cancer. Preventive efforts to address sleep
CSA alone significantly increases the risk of all-cause and cardio- disturbance before it adversely affect quality of life in this elderly
vascular mortality by more than twofold in community-dwelling population will be an important contribution.
elderly individuals [57], whereas OSA-related risks in the elderly
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CHAPTER 51
Sleep and its disorders

in women
Milena Pavlova
Reproductive hormones are among a variety of factors that influ- insomnia (without depression) and 86 age-â•‰and sex-â•‰matched con-
ence sleep and its disorders. As a result, some common sleep dis- trols and found no difference in frequency of objectively diagnosed
orders may have a different frequency, presentation, or treatment insomnia or subjective sleep complaints in women. They therefore
needs in women than in men. This chapter describes a number of hypothesized that the observed female predominance of insomnia
specific disorders. As these disorders are described in more detail symptoms may be due to the higher frequency of mood disorders
in the respective chapters elsewhere in the book, we will concen- or other comorbidities.
trate here on the characteristics that are unusual or demand specific A woman who reports insomnia should be evaluated care-
attention when treating women. fully for comorbid disorders, particularly depressive disorders.
A cross-â•‰sectional study from 10 countries reported that insomnia
Insomnia was present in most patients with depression. Other important
comorbidities include obstructive sleep apnea (OSA) and effects
Table 51.1 lists common presentations of insomnia, together with of medication. Insomnia is about twice as common in individu-
some that are potential emergencies and some that are rare syn- als who have a comorbid disorder [6]â•„. Specific comorbidities
dromes. Complaints of difficulty with sleep initiation and/â•‰or include heart disease, hypertension, stomach ulcers, migraine,
maintenance are common. Epidemiological reviews indicate that chronic obstructive pulmonary disease (COPD), asthma, and
worldwide, women of all age groups are more likely to report symp- arthritis, as well as menstrual problems. Effects of antidepres-
toms of insomnia [1–â•‰3]. The current International Classification sants (some reported to have insomnia as a side effect) and self-â•‰
of Sleep Disorders (ICSD-â•‰2) [4]â•„lists 11 disorders, at least 3 of medication with various over-â•‰the-â•‰counter substances, should
which are more common in women: insomnia due to mental dis- be considered as well (Table 51.2). Circadian rhythm disorders
order, psychophysiological insomnia, and presumably paradoxi- should also be considered, although there is no established sex
cal insomnia. Since depression is also more frequent in women, a predominance.
recent study was performed to evaluate whether insomnia is truly
more prevalent in women or is due to a confounding effect from Treatment
the higher rate of depressive symptoms. Voderholzer et al. [5] Treatment of insomnia should start with a careful review of poten-
performed polysomnography (PSG) on 86 patients with primary tial comorbidities and lifestyle factors, and this is particularly
important when treating women, for the following reasons:
Table 51.1â•‡Insomnia 1. Comorbidities are common, especially of mental health prob-

lems. Some comorbidities (eg, hyperthyroidism) require addi-
Common disorders Primary insomnia tional evaluations and early treatment.
Psychophysiological insomnia
Insomnia due to medication effects
Insomnia due to mental or medical disorders Table 51.2â•‡ Medications with potential sleep-â•‰disruptive effects
or as a symptom of another sleep disorder
Poor sleep hygiene Medication Cause of sleep disruption
Adjustment insomnia Headache medicines May contain caffeine
Circadian rhythm disorders leading to insomnia Steroids Primary stimulating effect
Potential emergencies Depression Wake-â•‰promoting medications (daytime)—â•‰ Residual stimulating effect
Medical disorders, endocrine abnormalities (thyroid, given for attention-â•‰deficit disorder, adjunct
other endocrine, cardiac, pulmonary, or others) treatment of depression, etc.
Rare syndromes Fatal familial insomnia Antidepressants (eg, selective serotonergic–â•‰
Paradoxical insomnia noradrenergic inhibitors)

2. Women of reproductive age may be considering pregnancy, and ◆ Treatmentincludes gradual schedule shifts, light therapy, and, in
many of the commonly used hypnotics are not safe for use in some cases, melatonin
pregnancy. ◆ Hypnotic medications may have a teratogenic risk.
3. Multiple substances may lead to insomnia. Simplifying the medica- ◆ Considerations of whether and when any pregnancy is
tion regimen and counseling the patient about the effects of over- planned should be brought up when evaluating women of
the-counter substances may be an efficient way to resolve insomnia reproductive age.
Insomnia is discussed in greater detail in the chapters in Section 5
Case of this volume.
A 24-year-old woman presented with complaints of difficulty initi- A particular challenge is the choice of a pharmacological agent
ating and maintaining sleep. She described onset in childhood and for women who are pregnant or considering pregnancy in the near
no obvious provoking factors. For some time, she had been using future. As can be seen in Tables 51.3 and 51.4, most prescription
zolpidem as needed with some success, but was considering po- medications used for the treatment of insomnia are not considered
tential long-term effects as well as future pregnancy, and wanted to safe in pregnancy. On the other hand, treatment of insomnia in the
know whether there are safer and/or nonpharmacological methods third trimester of pregnancy may decrease the risk of postpartum
to treat her symptoms. depression. A recent study by Khazaie et al. [7]‌examined the effect
On detailed questioning, she reported highly variable bed and of treating insomnia in 54 women randomly assigned to diphen-
wake times, with a tendency to be go to bed at about 3 am and wake hydramine, trazodone, or placebo, and found that both medications
up at about 11 am when on vacation or at weekends. During a work improved sleep. Moreover, depressive symptoms were reduced
week, she had to wake up at 7 am. Her difficulty falling asleep was at 2 and 6 weeks postpartum with both medications. Thus, care-
particularly pronounced on Sunday night. ful treatment of insomnia during pregnancy may have important
After a detailed discussion about the effects of a stable circadian implications for subsequent health. Generally, antihistamines
rhythm on sleep, she decided to attempt more stable wake and are considered safe in pregnancy [8], and the FDA has recently
bed times. Formal bright or blue light therapy was not used, but approved the use of doxylamine (Unisom; Diclegis when combined
she included a morning routine with an abundant ambient light with pyridoxine) for use in pregnant women. Although antihista-
exposure (morning jog), as well as an evening routine with lower mines are not typically the first-line treatment for insomnia, their
light levels. The initial steps were difficult and required discipline, relative safety makes them a potential pharmacological solution for
and she had mixed feelings about her success as it resulted in a pregnant women with insomnia who do not respond to nonphar-
somewhat less intense social life. She was encouraged, however, by macological measures.
finding out that she was more concentrated during the times when
she had to work, even though she had not appreciated any deficits Hypersomnia
before. After about 8 months of consistent effort, she had succeeded
in balancing her social life with a more regular sleep schedule, and When approaching a woman who presents with hypersomnia, it is
zolpidem was very rarely needed. paramount to consider comorbid conditions and the use of sedat-
ing substances. Primary disorders of sleep–wake regulation are
Teaching points relatively rare disorders (Table 51.5).
There is no known sex predominance of narcolepsy or idiopathic
◆ Circadian rhythm disturbances are a common cause of insomnia,
hypersomnia [4]‌. However, some of the rare hypersomnia syn-
especially in young women.
dromes have a sex predominance. Kleine–Levin syndrome is about
◆ Nonpharmacological treatments for insomnia are feasible in four times less common in women than in men. Recurrent hyper-
many cases. somnia in women may sometimes occur in a pattern, consistent
Table 51.3 Medications used to treat insomnia and corresponding pregnancy and lactation categories (classic hypnotics)
Medication Also known as Mechanism of action Half-life Pregnancy Lactation category

category
Clonazepam Klonopin Benzodiazepine 30–40 h D (FDA) Thomson: Infant risk cannot be ruled out
Lorazepam Ativan Benzodiazepine (Oral), about 12 h D (FDA) AAP: Drugs for which the effect on nursing
(mean) infants is unknown but may be of concern
Oxazepam Serax Benzodiazepine 5.7–10.9 h D (FDA) WHO: Compatible with breastfeeding
Thomson: Infant risk cannot be ruled out
Temazepam Restoril Benzodiazepine 3.5–18.4 h D (FDA) Thomson: Infant risk cannot be ruled out
Zaleplon Sonata GABA receptor agonist 1h C (FDA) Thomson: Infant risk is minimal
Zolpidem tartrate Ambien, GABAA receptor agonist Varies with formulation, C (FDA) Thomson: Infant risk is minimal
AmbienCR 2.5–2.8 h with
immediate-release
Edluar

Chapter 51 sleep and its disorders in women 477
Table 51.4 Medications used to treat insomnia and corresponding pregnancy and lactation categories (other)
Medication Also known as Mechanism of action Half-life Pregnancy category Lactation category
Trazodone Desyrel Related to potentiation of Immediate-release: 7 h C (FDA) Thomson: Infant
Desyrel Dividose serotonergic activity in the Extended-release: 10 h risk cannot be
CNS ruled out
Oleptro
Diphenhydramine Benadryl Histamine receptor blocker B (FDA)
Mirtazapine Remeron Enhance central noradrenergic 37 h (females) C (FDA) Thomson: Infant
and serotonergic activity risk cannot be
ruled out
Quetiapine Seroquel, Antagonist to serotonin Immediate-release: 6 h C (FDA) Thomson: Infant
Seroquel XR 5-HT1A and 5-HT2, dopamine Extended-release: 7 h risk cannot be
D1 and D2, histamine H1, and N-desalkylquetiapine, extended- ruled out
adrenergic α1 and α2 receptors. release tablet: 9–12 h
0.001), and menopause (p < 0.001). Women at high risk also had
Table 51.5 Hypersomnia
medical disorders more frequently.
Common disorders Poor sleep hygiene Some women with OSA do not present with the classic symp-
toms of loud snoring and hypersomnolence, yet may have a sig-
Obstructive sleep apnea
nificantly severe disease. Studies have found that women with
Hypersomnia dues to substance or to medical
OSA frequently report insomnia, morning headaches, fatigue, and
or psychiatric condition
mood disturbance [12]. On PSG, women may have more cluster-
Potential emergencies Depression ing of REM-related and positional events [13]. Particular attention
Medical disorders (consider hypothyroidism, should be paid to older women, as, even in asymptomatic individu-
toxic/metabolic encephalopathy, or central als, the frequency of sleep disordered breathing increases with age
nervous system infection) [14]. A particularly sharp increase in OSA frequency is seen after
Rare syndromes Menstrual-related hypersomnia menopause. In a study of 589 women evaluated with PSG, Young
Narcolepsy et al. [15] reported an odds ratio of 3.5 for OSA in postmenopausal
Idiopathic hypersomnia women, after controlling for age, smoking, body habitus, and other
Recurrent hypersomnia (Kleine–Levin syndrome confounding factors. OSA should be considered particularly in
in women) women who are overweight or obese, have micro-or retrognathia,
have polycystic ovary disease, or are menopausal. Identifying the
condition early may be important not only for symptom relief, but
also for preventative health reasons. At present, OSA is a recog-
with the menstrual cycle, a rare condition called menstrual-related nized risk factor for cardiovascular disease [16,17] and stroke [18].
hypersomnia This condition usually manifests in adolescence,
within the first months of menarche. Episodes usually last about Treatment
one week. Oral contraceptives may lead to prolonged remission The treatment of OSA depends on severity, presenting symptoms,
[9,10]. Hypersomnia is discussed in more detail in Section 4 of this and comorbid disorders. First-line treatment is considered con-
volume. tinuous positive airway pressure (CPAP), based on its effectiveness
from randomized controlled trials [19]. Alternatives include oral
Sleep disordered breathing, obstructive appliance treatments and surgical interventions. Another recently
sleep apnea developed nonsurgical treatment method uses an expiratory nasal
pressure device called Provent. OSA is discussed in more detail in
Although many clinicians consider sleep apnea a “man’s disease,” Chapter 16 of this volume.
sleep apnea symptoms are frequently reported by women as well.
Kapsimalis et al. [11] performed an analysis of 1254 women in the
United States, with an oversample of pregnant and postpartum Restless legs syndrome
women, using the Berlin Questionnaire, and found that 25% of the RLS is another sleep disorder that is more common in women.
participants reported symptoms that indicate a high risk for sleep The overall prevalence is 5–10% of the general population, and it
apnea syndrome. These women had common symptoms of OSA, is about 1.5 times more frequent in women [4]‌, and a recent popu-
such as habitual snoring (61%), observed apneas (7%), and day- lation study [20] reported an incidence of 1.7% per year. Use of
time sleepiness (24%). They also frequently reported sleep onset estrogen and history of obstructive lung disease were associated
insomnia (32%) or maintenance insomnia symptoms (19%) and with a significantly higher incidence of RLS, which, in turn, was
restless legs syndrome (RLS) symptoms (33%) or body movements associated with insomnia and increased sleepiness. More than half
(60%). The risk of OSA increased with age (p < 0.05), obesity (p < of the patients report a familial pattern. The symptoms may appear

without any apparent comorbidity (primary RLS) or in associa- Parasomnias

tion with anemia, renal disease, or pregnancy. About 80–90% of
patients with RLS have periodic limb movements of sleep (PLMS) Several parasomnias have a reported female predominance.
noted on a single-night PSG. Exploding head syndrome is a sensation of a sudden loud noise,
RLS is particularly common in pregnant women, possibly in rela- often described as cymbals, occasionally associated with a sense of
tion to decreased iron stores. In most of these cases, the symptoms a flashing light. Occasionally, the disorder may be associated with
abate after delivery, though in some rarer cases they may persist. a myoclonic jerk [4]‌and to some may be terrifying. PSG record-
ings indicated that most patients are actually in relaxed wakeful-
Treatment ness when the sensation occurred [23]. Women may also have a
There is a strong association of RLS and iron metabolism (dis- higher risk for sleep-related dissociative disorders and to some ex-
cussed in Chapter 24 of this volume), and the patient should have tent sleep-related hallucinations.
an evaluation of ferritin levels. In cases where ferritin is below 50 Some parasomnias have a different sex ratio in different age
ng/mL, iron supplementation should be considered. Some authors groups. Nocturnal enuresis in childhood is more common in boys.
have also reported a low folate level in pregnant women with RLS In older adults, however, enuresis has a female predominance [4]‌.
and a beneficial effect from folate supplementation. Nightmares have no established sex ratio in children, but among
In a woman of childbearing age, pharmacological treatment adults are more common in women. A study of sleep complaints
should consider pregnancy status. Table 51.6 shows the pregnancy/ of 2782 young adults suggested that women were more likely to
lactation category of commonly used agents. As most are not con- have nightmares, along with multiple awakenings [24]. In another
firmed harmless, in a woman who is pregnant it is best to start with study of 5622 subjects, nightmares were twice more commonly
nonpharmacological treatments [21]. Measurement of ferritin level reported by women, and were frequently associated with depres-
and replacement of iron, if appropriate, is indicated. Many advocate sive symptoms [25].
using more aggressive supplementation (until ferritin reaches 150 On the other hand, REM sleep behavior disorder (RBD) in asso-
ng/mL, not 100 ng/mL as in non-pregnant women). Gentle exercise ciation with violence is relatively uncommon in women [26]. There
and avoidance of caffeine may also be helpful. have been suggestions that women may have a less violent, and
For non-pregnant women, after an evaluation of ferritin, and po- thus much less visible, presentation. As a result, the disorder may
tential comorbid conditions, dopamine agonists are usually used be under-diagnosed in women.
as a starting treatment, starting at the lowest dose (0.125–0.25 mg With all parasomnias, an adequate differential diagnosis is
for pramipexole and 0.25–0.5 mg for ropinirole). Follow-up is indi- key (Table 51.7). Of particular importance is the need to distin-
cated to evaluate efficacy, as well as any side effects, some of which guish parasomnias from seizures, especially frontal lobe seizures
may not be recognized by the patient as such. For example, com- (which often occur from sleep), as often the behaviors may appear
pulsive behaviors are often not easily recognized by patients, but on similar.
a questionnaire 23% of patients treated with dopamine agonists for
RLS had compulsive eating, 10% compulsive shopping, and another Case
7% compulsive gambling [22]. In patients who do not respond, A 23-year-old woman with a recent diagnosis of depression pre-
gabapentin or in some instances opiates can be considered. sented to the sleep clinic with complaints suggestive of dream
Table 51.6 Medications used for the treatment of RLS and corresponding pregnancy and lactation categories
Medication Also known as Mechanism of action Pregnancy Lactation category

category
Acetaminophen Oxycodone: Acetaminophen: Thomson: Infant
(paracetamol)/ C (FDA) risk is minimal
oxycodone Oxycodone: Thomson: Infant risk
has been demonstrated
Carbidopa/levodopa Sinemet Levodopa: triatal dopaminergic neurotransmission C (FDA) WHO: Avoid breastfeeding if
is enhanced by exogenous supplementation of possible. May inhibit lactation.
dopamine through administration of dopamine’s Thomson: Infant risk cannot be
precursor, levodopa ruled out.
Carbidopa: Inhibits the peripheral decarboxylation
of levodopa
Gabapentin Neurontin, Gabarone Mechanism of action is unknown C (FDA) Thomson: Infant risk cannot be
ruled out
Pramipaxole. Mirapex, MirapexER Non-ergot dopamine agonist C (FDA) Thomson: Infant risk cannot be
ruled out
Ropinirole Requip, RequipXL Non-ergoline dopamine agonist C (FDA) Thomson: Infant risk cannot be
ruled out

Table 51.7 Parasomnia The childbearing woman—the effects

of the menstrual cycle
Common disorders Sleepwalking
Sleep is influenced by gonadal hormones. The circadian rhythm
REM sleep behavior disorder (RBD)
amplitude may vary with the menstrual cycle [28,29]. Generally,
Sleep-eating there is some blunting or decrease of the amplitude of multiple cir-
Other NREM parasomnias cadian regulated functions, including temperature, melatonin se-
Potential emergencies Undiagnosed seizures that have been cretion, and cortisol secretion, during the luteal phase. Specifically,
misdiagnosed as parasomnia during the mid-luteal phase, there is increase in the overall value of
Injuries from sleepwalking the core body temperature and a decrease in its circadian variation
amplitude, compared with the mid-follicular phase. There is also
Rare syndromes Recurrent isolated sleep paralysis
a reduction in REM sleep during the mid-luteal phase at the time
Exploding head syndrome
of the temperature minimum [30]. Stage 2 sleep may be signifi-
Rhythmic movement disorder cantly increased in the mid-luteal phase compared with the early
follicular phase.
The menstrual cycle may affect sleep. A relatively small study
enactment. She described variable behaviors that occurred in sleep from Baker et al. [31] examined the association between sleep
and also had some nightmares and sleep fragmentation. The events and the menstrual cycle in 26 healthy women with a mean age of
were particularly frequent around her menstrual period. Since she 21 years and reported a lower sleep quality over the 3 premenstrual
had also recently started treatment with a selective serotonin reup- days and 4 days during menstruation, compared with the mid-
take inhibitor (SSRI), it was concluded that she was most likely to follicular and early/mid-luteal phases.
have symptomatic RBD due to this medication. After a change in Menstrual disturbances affect sleep and the circadian rhythms
her depression treatment, the events became rarer and were not so in various ways. For example, slow-wave sleep was significantly
clearly associated with a dream, but did not stop, and sleep frag- increased and melatonin significantly decreased in a study of patients
mentation continued. Her mother also noted rare subtle, but with premenstrual dysphoric disorder compared with controls [32].
stereotypic 1-minute episodes of speech impairment. The patient Strine et al. [33] examined the associations of menstrual-related
was referred to a neurologist, who ordered a further evaluation problems with mental health and health behaviors. They included
with a PSG and requested sufficient EEG coverage to assess for an analysis of computer-assisted personal interviews from 11 648
the possibility of focal nocturnal seizures. The overnight technolo- women aged 18–55 years and found that 19% reported menstrual-
gist did not report any abnormal behaviors. The PSG revealed a related problems (eg, heavy bleeding, bothersome cramping, or pre-
20 s focal electrographic seizure, as well as very rare left temporal menstrual syndrome). These women were significantly more likely
interictal discharges. Review of the video at the time of the seizure than those without menstrual-related problems to report anxiety, de-
revealed only a brief turn in bed, which was not visually distin- pression, sleep problems, and pain. Women with menstrual-related
guishable from an arousal (i.e, without the supportive evidence problems were also significantly more likely to report feeling sad,
from EEG, the seizure would have been missed). A subsequent nervous, restless, hopeless, or worthless. Cigarette smoking, heavy
evaluation revealed a structural left-sided MRI abnormality that alcohol consumption, and being overweight or obese were also
likely served as a seizure focus. more frequently reported among women with menstrual-related
Teaching points problems than those without. The menstrual cycle may even affect
upper airway resistance as well [34]. Thus, sleep is affected by the
◆ Similarlyto insomnia, dysphoria, and other disorders, seizures
normal menstrual cycle and by menstrual disturbances, and these
can have a higher frequency around the menstrual period (cata-
effects are modified by lifestyle factors and comorbid conditions.
menial epilepsy).
Premenopausal women with an irregular menstrual cycle are
◆ Seizures should be carefully considered when evaluating a pa- reported to be more likely to report sleep difficulties [35]. These
tient with abnormal nocturnal behaviors. women also reported increased light sleep stages and awakenings.
◆ Adequate evaluation is key in determining the correct diagnosis. Premenstrual complaints were also reported more frequently by
women who had periodic limb movements or nocturnal desatur-
ation. Some evidence suggests that circadian disruption may in-
Sleep through different stages crease the risk of breast cancer [29]
of a woman’s life Teaching points
Sleep architecture is influenced by reproductive hormones. This is ◆ Gonadal hormones influence sleep.
reflected through many changes seen in relation to the menstrual
◆ During the luteal phase, there is “blunting” of the circadian signal
cycle, at different times of pregnancy, and in menopause.
of multiple hormones, including melatonin.
Childhood and adolescence ◆ Irregular menstrual cycles may be associated with more sleep
A study of 78 healthy children using logs and actigraphy reported difficulties.
that adolescent girls tend to sleep a little longer, but the evidence
is indirect [27]. Complaints of difficulty sleeping are slightly less Pregnancy
prevalent in girls than in boys [4]‌. The major differences in sleep Sleep normally evolves throughout the duration of pregnancy. In
disorder frequency are more evident later in life. a survey from a questionnaire administered to 325 women [36],

sleep duration increased during pregnancy, starting with early reported that menopausal status was not significantly associated
pregnancy, and decreased thereafter, being shortest during the first with sleep quality. In the subsequent analyses in an adjusted model,
3 months after delivery. However, during pregnancy, sleep became however, independent predictors of sleep quality were hot flashes
gradually more fragmented and restless. (p < 0.0001), depressive symptoms (Center for Epidemiological
Studies that use objective evaluation of sleep indicate changes Studies Depression Scale scores) (p < 0.0001), and levels of
in sleep architecture. A longitudinal study performed by Driver the reproductive hormone inhibin B (p = 0.05). Another large
et al. [37] consisted of serial PSGs performed in five healthy prim- community-based study performed in Taiwan [47] reported that
iparous women, starting in early pregnancy (8–16 weeks of ges- almost half of the participating middle-aged women felt dissatisfied
tational age), repeated every 2 months thereafter, and then again with their sleep and that these symptoms correlated strongly with
1 month after delivery. The authors reported an increase in the per- symptoms of depression and anxiety. A large cross-sectional study
centage of slow-wave sleep with advancing pregnancy, mostly after of 639 women (ages 45–54) reported an elevated depression rating
17 weeks of gestational age (36% in the last trimester versus 26% in score in association with frequent nocturnal hot flashes, irritability,
the first). A modestly shorter REM latency was noted during the and other menopausal symptoms such as vaginal discharge, as well
first and second trimesters, compared with the third (65 minutes as nausea, headaches, weakness, visual problems, muscle stiffness,
versus 79 minutes). In the third trimester, slow-wave sleep may be and incontinence [48].
decreased [38]. Frequent nighttime awakenings among menopausal women
Sleep deprivation has been linked to multiple adverse endocrine often appear as part of a cluster of symptoms that also include joint
consequences [39–41]. As a result, adverse pregnancy-related out- ache, hot flashes, mood changes, and concentration problems [49].
comes have been hypothesized. Further studies have posed the Other factors that contribute to insomnia include vulvovaginal at-
question whether circadian misalignment may increase the risk of rophy [50]. Surveys of the prevalence of various sleep symptoms
preeclampsia. Animal studies suggest that estradiol may modulate in menopause suggested that 56.6% of surveyed women suffered
not only sleep structure, but also recovery sleep [42]. from either insomnia or poor sleep quality, or both, and that these
A significant health concern is the potential association of poor were often associated with vasomotor symptoms, depressed mood,
sleep and adverse pregnancy outcomes. A study on maternal blood and anxiety [51]. Women presenting sleep disturbances had a two-
pressure reported a higher risk of pregnancy-induced hyperten- fold increase in the severity of menopausal symptoms (higher total
sion and preeclampsia with short and long sleep duration [43]. To Menopause Rating Scale (MRS) scores), and a six to eight times
examine whether sleep deprivation may increase the risk for preec- higher risk of impaired quality of life. Higher educational level
lampsia, preterm delivery, or other complications, Bonzini et al. was associated with fewer complaints of insomnia and better sleep
[44] performed a meta-analysis of 23 relevant studies and found a quality [51].
slightly increased risk of low birth weight with poor sleep. Of par-
ticular importance is the adequate diagnosis and treatment of any Treatment options
sleep disordered breathing. Some studies suggest that treatment of Symptomatic treatment of insomnia can be achieve with standard
any sleep apnea, when present, may reverse the risk of hypertension hypnotics. Various studies have reported efficacy of zolpidem at 10
and preeclampsia [45]. mg [52] and trazodone [53], as well as other frequently used medi-
cations, as already discussed under treatment of insomnia.
Teaching points The decision to use hormone replacement should be individual-
◆ Sleep normally changes during pregnancy. ized for the patient and depends on multiple factors. There may
◆ Poor sleep during pregnancy may increase the risk of hyperten- be beneficial effects of variable estrogen preparations on subjec-
sion and even preeclampsia. tive sleep [54,55]. There have also been reports that combined
estrogen–progestin regimens may lead to improved markers of
◆ Identification and treatment of common sleep disorders may im-
information processing and attention [56]. A recent randomized,
prove outcome.
double-blind, placebo-controlled study of either 300 mg of proges-
Menopause terone or placebo taken in the evening for 3 weeks indicated that,
objectively evaluated, sleep was improved [57]. Another study
Menopause itself probably does not change sleep as an independent reported improved hot flashes and sleep with a transdermal gel
factor. Young et al. [46] reported PSG-acquired sleep data from 589 containing 0.75 mg estradiol, which was well tolerated [58].
participants: premenopausal, perimenopausal, and postmeno- On the other hand, the use of estrogen replacement should be
pausal women. They reported that sleep quality was not worse in considered with caution because of its potential role in cerebrovas-
perimenopausal or postmenopausal women compared with pre- cular events [59]. Alternatives to medication may include nonphar-
menopausal women. On the contrary, postmenopausal woman had macological treatment such as psychotherapy, either alone or in
more deep sleep (16% versus 13% stages 3/4, p < 0.001) and sig- combination with hormone replacement therapy [60].
nificantly longer total sleep time (388 minutes versus 374 minutes,
p = 0.05). Menopausal status was moderately related to self-reported
dissatisfaction with sleep, but was not consistently associated with Summary
symptoms of insomnia or sleepiness. ◆ Sleep is affected by gonadal hormones.
Some of the common symptoms of menopause, such as hot
◆ Sleep complaints may vary with the menstrual cycle.
flashes, can disrupt sleep. A population-based cohort of 436
women from the USA, ages 35–47 years, who had regular men- ◆ Sleep may also change with the menstrual cycle, during preg-
strual cycles at enrollment and were followed for an 8-year period, nancy, and in menopause.

◆ Somesleep disorders are more common in women, while others 21. Aurora RN, Kristo D, Bista SR, et al. The treatment of restless legs syn-
may have a different presentation in women. drome and periodic limb movement disorder in adults—an update for
2012: practice parameters with an evidence-based systematic review
◆ Lifestyle
factors and comorbidities modify the effects of any
and meta-analyses. An American Academy of Sleep Medicine Clinical
menstrual irregularities on sleep. Practice Guideline. Sleep 2012;35:1039–62.
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nancy plans, especially when medications with potential terato- MH. Impulse control disorders with the use of dopaminergic agents in
restless legs syndrome: a case-control study. Sleep 2010;33(1):81–7.
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23. Sachs C, Svanborg E. The exploding head syndrome:
polysomnographic recordings and therapeutic suggestions. Sleep
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SECTION 12
Miscellaneous
sleep-â•‰related topics

CHAPTER 52
Violent parasomnias
and sleep forensics
Michel A. Cramer Bornemann and Mark R. Pressman
Introduction degree of aminergic and cholinergic neurochemical bias, central

nervous system (CNS) activation, and the degree of endogenous
Parasomnias are defined as unpleasant or undesirable physical v exogenous input. Under normal physiological conditions, which
events or experiential phenomena that occur during entry into include homeostatic drive and circadian rhythmicity, the process of
sleep, within sleep, or during arousals from sleep. They were ini- state declaration is maintained in a stable and predictable fashion
tially thought to represent a unitary phenomenon, often attrib- throughout a 24-â•‰hour period. However, as the components of sleep
uted to psychiatric disease. Indeed, the general public and popular frequently dissociate and oscillate, sleep and wake may be rendered
media continue to be enamored of the belief that the unconscious into a state that has not yet fully declared, thereby finding itself in
mind, in a state of either hypnosis or sleep, may reveal itself in a temporary unstable state of dissociation. Thus, sleep and wake, as
words, mental images, or behaviors although its meaning is kept well as the associated features of consciousness and unconscious-
at a distance from the conscious mind through repression. Various ness, are not dichotomous states, as they occur on a spectrum and
avenues for the interpretation of dreams have evolved based upon are evanescent. The admixture of wakefulness and NREM sleep
the premise that behaviors and/â•‰or experiences that arise from the explains confusional arousals (sleep-â•‰drunkenness), automatic
platform of sleep are the result of a breakdown of psychic censor- behaviors, or microsleeps [2]â•„. The admixture of wakefulness and
ship and may thereby provide insight into the machinations of the REM sleep explains cataplexy, wakeful dreaming, hypnagogic hal-
unconscious mind. Such “Dream Theory,” which may masquerade lucinations, lucid dreaming, and the persistence of motor activity
in subtle forms often involving the principle of “wish fulfillment,” during REM sleep (REM sleep behavior disorder, RBD) [3].
has been largely supplanted by testable as well as verifiable neu- The primary parasomnias are clinical phenomena that appear
roscientific constructs to account for parasomnias. Now, careful as the brain becomes reorganized across states and therefore are
clinical assessments, polysomnographic (PSG) studies, and refined particularly prone to occur during transitions between states. In
neurodiagnostic imaging have revealed that parasomnias are not view of (1) the large number of neural networks involving approxi-
a unitary phenomenon, but rather represent a large number of mately 100 billion neurons, neurotransmitters, and other state-â•‰
completely different conditions, most of which are diagnosable and determining substances that must be recruited synchronously for
treatable. Furthermore, most are not the manifestation of psychiat- full state declaration and (2) the frequent transitions among states
ric disorders and are far more prevalent than generally appreciated. during the wake–â•‰sleep cycle, it is surprising that errors in state dec-
Many parasomnias have the potential to compromise personal and laration do not occur more frequently than they do [2]â•„.
public safety, particularly those in close proximity to the afflicted, This chapter focuses on the acute violent, potentially harmful,
as a result of abrupt outward and potentially injurious behaviors and inappropriate, as well as asocial, behaviors associated with
that arise from the platform of sleep. sleep triggered by the two most common forms of primary paras-
The parasomnias may conveniently be categorized as “primary omnias (disorders of arousal and RBD), with a subsequent discus-
parasomnias” (disorders of the sleep states per se) or “secondary” sion of the forensic issues engendered by these parasomnias.
(disorders of other organ systems that interfere with the sleep pro-
cess). The primary parasomnias can be classified according to the
sleep state of origin: rapid eye movement (REM) sleep, non-â•‰rapid Disorders of arousal
eye movement (NREM) sleep, or miscellaneous (i.e., those involv- Disorders of arousal are NREM sleep parasomnias that occur on
ing but not respecting sleep state). The secondary parasomnias can a broad spectrum and include confusional arousals, sleepwalking,
be further classified by the organ system involved [1]â•„. and sleep terrors. The underlying pathophysiology is state disso-
The concept that sleep and wakefulness are not invariably ciation, whereby neither wake nor NREM has been completely
mutually exclusive states, and that the various state-â•‰determining declared. Simply stated, the brain is partially awake and partially in
variables of wakefulness, NREM sleep, and REM sleep may occur NREM sleep. The result of this mixed state of being is that the brain
simultaneously or oscillate rapidly, is the key to understanding pri- is awake enough to perform potentially very complex behaviors, yet
mary parasomnias. Recent advances in neurophysiology coupled asleep enough to not have conscious awareness.
with refined neurodiagnostic imaging modalities now reveal that Disorders of arousal share many common features. They tend
the three states are modulated by a host of influences, including the to arise from any stage of NREM sleep, most commonly from

486 Section 12 miscellaneous sleep-related topics
slow-wave sleep (SWS: stage N3, formerly stages 3 and 4 of NREM been suggested that sleep terrors may be the manifestation of
sleep), and therefore they usually occur in the first third of the sleep anomalous REM sleep admixed with NREM sleep [31].
cycle and hence rarely during naps. They are common in child-
hood, usually decreasing in frequency with increasing age [4]‌. Pathogenesis
Disorders of arousal may be associated with prior sleep depri- In addition to the phenomenon of state dissociation, in which two
vation, physical activity, or emotional stress. Medication-induced states of being overlap or occur simultaneously, there are likely
cases have been reported with sedative–hypnotics, neuroleptics, additional underlying physiological phenomena that contribute
minor tranquilizers, stimulants, and antihistamines, often in com- to the appearance of complex motor behaviors during sleep. These
bination with each other [4]‌. Contrary to popular opinion, there include locomotor centers, sleep inertia, and sleep state instability.
is no compelling evidence that overt alcohol intoxication serves to
Locomotor centers
trigger NREM parasomnias [5]. The recently published third edi-
tion of the International Classification of Sleep Disorders (ICSD- Locomotor centers (LMCs), present in multiple sites in the CNS,
3: the primary diagnostic, epidemiological, and coding resource for may play a role in the disorders of arousal, which represent motor
clinicians and researchers in somnology and Sleep Medicine, pro- activity that is dissociated from waking consciousness [32]. These
duced by the American Academy of Sleep Medicine, in association areas project to the central pattern generator of the spinal cord,
with the European Sleep Research Society, the Japanese Society of which itself is able to produce complex stepping movements in the
Sleep Research, and the Latin American Sleep Society) now states absence of supraspinal influence [33]. This accounts for the fact
unequivocally that “Sleepwalking should not be diagnosed in the that decorticate experimental and barnyard animals are capable of
presence of alcohol intoxication” [6]. performing very complex, integrated motor acts [34]. A biological
Recently, there have been numerous reports of extremely com- substrate is further supported by the similarity between spontane-
plex behaviors attributed to sedative–hypnotic agents, often result- ously occurring sleep terrors in humans and “sham rage” induced
ing in forensic issues [7–15]. In some women, disorders of arousal in animals [35–37]. Indeed, human neuropathology may result in
may be exacerbated by pregnancy or menstruation, whereas in oth- similar behaviors [38–42]. Dissociation of the LMCs from the par-
ers, disorders of arousal may be alleviated by pregnancy, suggesting ent state of NREM sleep would explain the presence of complex
hormonal influences [4]‌. Underlying predisposing, priming, and motor behavior seen in disorders of arousal. Spontaneous locomo-
precipitating factors have been thoroughly reviewed elsewhere [16]. tion following decerebration in cats clearly indicates that such cent-
Numerous other sleep disorders that result in arousals (obstruc- ers, if dysfunctional, release motor activity into the sleeping state
tive sleep apnea (OSA), nocturnal seizures, or periodic limb [43,44]. Single photon emission computed tomography (SPECT)
movements) may provoke these disorders [17]. Sleep disordered study involving an individual with sleep terrors suggested activa-
breathing (SDB) has been found to be more prevalent in both tion of thalamocingulate pathways with persistent deactivation of
children and adults with disorders of arousal. One recent study other thalamocortical arousal systems, resulting in a dissociation
found that sleep fragmentation induced by SDB is more com- between body sleep and mind sleep [45].
mon in adults with disorders of arousal than in normal subjects Sleep inertia
[18]. The combination of frequent arousals and sleep deprivation Sleep inertia (also termed sleep drunkenness) refers to a period of
seen in these other sleep disorders provides fertile ground for the impaired performance and reduced vigilance following awaken-
appearance of disorders of arousal. These represent a sleep disorder ing from the regular sleep episode or from a nap. This impairment
within a sleep disorder: the clinical event is a disorder of arousal, may be severe, last from minutes to hours, and be accompanied
but the true culprit is a different, unrelated sleep disorder. This by PSG-recorded microsleep episodes [46]. Support of a gradual
would explain the common clinical experience of improvement of disengagement from sleep to wakefulness comes from neurophysi-
disorders of arousal following identification and treatment of OSA ologic studies in animals and cerebral blood flow studies in humans
[19]. Conversely, effective treatment of OSA with nasal continuous [47–50]. There appears to be great inter-individual variability in
positive airway pressure (CPAP) may result in disorders of arousal, the extent and duration of sleep inertia, both following spontane-
presumably associated with deep NREM sleep rebound [20, 21]. ous awakening after the major sleep period and following naps.
Numerous studies have dispelled the myth that persistence of Sleep inertia likely plays a role in the susceptibility to disorders of
these behaviors beyond childhood or appearance in adulthood is arousal [47].
suggestive of underlying psychopathology [22–24]. In one study
in children, there was an association between disorders of arousal Sleep state instability
and anxiety [25]. Other studies have noted an elevated frequency The cyclic alternating pattern (CAP) may also play a role in the etiol-
of disorders of arousal in individuals diagnosed and treated for ogy of disorders of arousal [51]. CAP is a physiological component of
severe psychological disorders. However, there is no evidence NREM sleep and is functionally correlated with long-lasting arousal
of causation, and nocturnal wandering may be secondary to the oscillations. CAP is a measure of NREM instability with high level of
effects of highly sedating medications. These arousals may not be arousal oscillation [52]. More sophisticated monitoring techniques
the culmination of ongoing psychologically significant mentation, such as topographical EEG mapping suggest that there may be more
in that somnambulism can be induced in normal children by stand- delta EEG activity prior to the onset of sleep terrors [53]. There is no
ing them up during SWS, and sleep terrors can be precipitously difference in the macrostructural sleep parameters between patients
triggered in susceptible individuals by sounding a buzzer during with disorders of arousal and controls. However, patients with disor-
SWS [26–29]. ders of arousal have been found to have increases in CAP rate, in the
The mechanism of these disorders is not clear, but it is evident number of CAP cycles, and in arousals with EEG synchronization.
both genetic and environmental factors are involved [30]. It has An increase in sleep instability and in arousal oscillation is a typical

Chapter 52 violent parasomnias and sleep forensics 487
microstructural feature of SWS-related parasomnias and may play with diminished levels of consciousness and recall. SRED is often
a role in triggering abnormal motor episodes during sleep in these not associated with waking eating disorders and needs to be dis-
patients [54,55]. Microarousals preceded by EEG slow-wave syn- tinguished from the night-eating syndrome (NES), as the latter is
chronization during NREM sleep are more frequent in patients with characterized by morning anorexia, evening hyperphagia (while
sleepwalking and sleep terrors than in controls. This supports the awake), and insomnia and is associated with hypothalamic–
existence of an arousal disorder in these individuals [54]. Although pituitary axis abnormalities [69–71]. Nocturnal binging may be
some have reported hypersynchronous delta activity on PSGs of induced by benzodiazepine-class medications, and sleep-related
young adults with sleepwalking, this has not been the experience of eating has been associated with the administration of olanzapine
others [56,57]. EEG spectral analysis studies indicate that patients and non-benzodiazepine class medications, particularly zolpidem
with sleepwalking demonstrate instability of SWS, particularly in [11,12,72,73].
the early portion of the sleep period [58]. Impairment of efficiency The episodes of SRED are involuntary and exhibit seemingly
of inhibitory cortical circuits during wakefulness has also been “out of control” disinhibited unrestrained behaviors after an inter-
reported [59]. val of sleep, usually associated with partial arousals from sleep.
Subsequently, not uncommonly, there is partial recall, though the
Clinical features ability for recall is variable. Some patients cannot be easily brought
Disorders of arousal occur on a broad spectrum ranging from con- to full consciousness during an episode of eating, similar to conven-
fusional arousals, through somnambulism (sleepwalking), to sleep tional sleepwalking, and may have no recall of having eaten during
terrors (also termed pavor nocturnus and, erroneously, incubus the night. In contrast, some patients appear to exhibit consider-
or succubus). Some take the form of “specialized” behaviors (dis- able alertness during an episode, though impulse control remains
cussed later) such as sleep-related eating and sleep-related sexual absent, while maintaining substantial recall the following morning.
activity, executed without conscious awareness. A majority of individuals with SRED report a nightly frequency
of eating, which may occur several times in a given evening and
Confusional arousals
is not partial to any particular time during the sleep cycle. High-
These are often seen in children and are characterized by move-
caloric foods, often carbohydrates, are preferentially consumed.
ments in bed, occasionally thrashing about, or inconsolable cry-
Food items characteristically consumed during sleep-related eat-
ing [60]. “Sleep drunkenness” is probably a variation on this theme
ing are not typically consumed with preference during the daytime.
[61]. The prevalence of confusional arousals in adults is approxi-
Curiously, hunger and thirst are notably absent during episodes of
mately 4% [62].
compulsive eating with SRED. The episodes of eating may be expe-
Sleepwalking rienced as food-related enactment of a dream. Alcoholic beverages
Sleepwalking is prevalent in childhood (1–17%), peaking at 11– are almost never consumed. If an individual is confronted during
12 years of age, and is far more common in adults (nearly 4%) than an episode, the usual response is irritability and agitation.
is generally acknowledged [62–65]. Sleepwalking may be either Recurrent SRED has potential for a broad range of deleterious
calm or agitated, with varying degrees of complexity and duration. consequences, which may include (1) consumption of inedible
odd combinations of food or toxic substances (eg, buttered ciga-
Sleep terrors rettes, cat food, coffee grounds, or ammonia cleaning solutions);
The sleep terror is the most dramatic disorder of arousal. It is fre- (2) sleep-related injury (eg, blunt trauma or lacerations related to
quently initiated by a loud, blood-curdling scream associated with manipulation errors of kitchen utensils or heavy dishware; inter-
extreme panic, followed by prominent motor activity such as hit- nal or external burns associated with consuming/spilling hot foods
ting the wall, running around or out of the bedroom, even out of or beverages or inadvertent contact with stove burners; or poi-
the house, resulting in bodily injury or property damage. A uni- soning or internal injuries from ingesting toxic substances); and
versal feature is inconsolability. Although the victim appears to (3) adverse health consequences (obesity, hypercholesterolemia,
be awake, he or she usually misperceives the environment, and hypertriglyceridemia, destabilization of diabetes mellitus type 1 or
attempts at consolation are futile and may serve only to prolong 2, dental caries, or allergic reactions). Reactive depression may be
or even intensify the confusional state. Some degree of perception anticipated as a consequence of personal dejection and sense of fail-
may be evident—for example, running for and opening a door or ure over the apparent inability to control nocturnal eating. Formal
window. Complete amnesia for the activity is typical, but it may be sleep studies are indicated, as SRED may be the manifestation of
incomplete [26,66,67]. The intense endogenous arousal and exog- other sleep disorders such as restless legs syndrome (RLS, also now
enous unarousability constitute a curious paradox. As with sleep- known as Willis–Ekbom disease), periodic limb movements in
walking, sleep terrors are much more prevalent in adults than is sleep (PLMS), or OSA, all of which destabilize sleep and predispose
generally acknowledged (4–5%) [68]. Although usually benign, to arousal [66].
these behaviors may be violent, resulting in considerable injury to
the victim or others or damage to the environment, occasionally Sleep-related abnormal sexual behaviors
with forensic implications (see the discussion later in this chapter). Sleep-related abnormal sexual behaviors are now formally recog-
nized by ICSD-3. Sleep-related abnormal sexual behaviors are clas-
Specialized forms of disorders of arousal sified with the disorders of arousal (DOA) from NREM sleep. Of
Sleep-related eating disorder the subtypes of DOA, such sexualized behaviors are most often
Sleep-related eating disorder (SRED) is likely a specialized form associated with confusional arousals, but may be associated with
of disorder of arousal and consists of recurrent episodes of invol- other types of parasomnias, such as sleepwalking. This condi-
untary eating and drinking during arousals from sleep associated tion has been referred to by many terms in the medical literature

and popular media, including “Atypical sexual behavior during is of more than academic interest, as most of these conditions are
sleep,” “Sexual behavior in sleep,” “Sleep Sex,” and “Sexsomnia.” readily treatable. Emphasis must be placed on the types of studies
Inappropriate sexual behaviors occurring during the sleep state required; routine PSGs performed for conventional sleep disorders
without conscious awareness, presumably the results of an admix- are inadequate. In addition to the physiological parameters moni-
ture of wakefulness and sleep, have been reported [74]. A broad tored in the standard PSG, there must be an expanded EEG mon-
spectrum of such behaviors exist and may be expressed as sexual- tage and continuous audiovisual monitoring [56,80].
ized vocalizations or self-stimulatory/autoerotic touching, or may Observation by an experienced technologist is invaluable.
engage those who are in close proximity, such as a bed partner. The Multiple night studies may be required to capture an event.
persistence of these sexual behaviors may result in feelings of guilt, Interpretation should be made by a polysomnographer experi-
shame, or depression, and may lead to marital discord in some enced in these disorders. Sleep deprivation prior to formal PSG
cases [75]. study may increase the likelihood of capturing an event in the sleep
Despite the increased general awareness and formal clinical rec- laboratory [81]. Unattended studies have no role in the evaluation
ognition, much confusion remains about sleep-related abnormal of parasomnias [82]. Formal sleep studies are indicated to estab-
sexual behaviors, particularly as a multitude of medical, psychiat- lish a clinical diagnosis, but are of limited utility in forensic cases
ric, and toxic conditions may have similar features or may mimic (discussed later in this chapter). A negative study is not sufficient to
this condition [76]. Accurate diagnosis is not only essential as it rule out a diagnosis of a disorder of arousal, as PSG findings have
translates into an effective clinical management strategy with the both low specificity and low sensitivity. The diagnosis of a disorder
most favorable benefit-to-risk ratio, but also may have significant of arousal remains primarily a clinical diagnosis.
legal implications. For instance, the “Sleepwalking Defense” has
been well received by defense attorneys and has been success- Differential diagnosis
fully applied in the USA in cases of purported “sexsomnia,” result- Numerous other conditions may perfectly mimic the disorders
ing in a complete acquittal, as in State of Oregon v. James Kirchner of arousal. These include OSA, RBD, nocturnal seizures, psycho-
[77]. Cramer Bornemann presented at the APSS (the Associated genic dissociative disorders, malingering, or psychopathy [83–85].
Professional Sleep Societies) annual meeting in Minneapolis, NREM parasomnias may be particularly difficult to differentiate
Minnesota that over 33% of the more than 260 forensics cases sub- from nocturnal epileptic phenomena [86]. There may be an asso-
mitted between 2006 and 2013 for formal medico-legal review to a ciation between disorders of arousal and migraine headache [87],
sleep forensics consulting consortium were associated with charges neurofibromatosis type 1 [88], or Tourette syndrome [89,90]. In
of sexual assault for which a sleep-related abnormal sexual behavior children unable to verbalize, nocturnal cluster or migraine head-
was considered [78]. Despite the broad clinical acceptance of this aches may mimic sleep terrors [91]. OSA may be associated with
condition and some success in the court of law, many in the legal and even present as disorders of arousal [18,85,92].
community remain skeptical over the legitimacy of “sexsomnia,” as
demonstrated by a recent update put forth by the National Center Treatment
for the Prosecution of Child Abuse entitled Overcoming the Sleep Given the high prevalence of these disorders in normal individuals,
Disorder Defense [79]. In this regard, in the USA, Daubert or Frye formal sleep center evaluation should be confined to the situations
Hearings are not uncommon to attest to the legitimacy of sleep- listed above. Treatment is often not necessary. Reassurance of their
related abnormal sexual behaviors in the determination of admis- typically benign nature, lack of psychological significance, and the
sibility of potential testimony prior to the formal court room trial. tendency to diminish over time is often sufficient. Objective stud-
ies documenting medication efficacy are lacking. Tricyclic anti-
Diagnosis depressants and benzodiazepines may be effective and should be
Isolated, often bizarre, sleep-related events may be experienced by administered if the behaviors are dangerous to person or property
perfectly normal people, and most do not warrant further exten- or extremely disruptive to family members [61]. Paroxetine and
sive or expensive evaluation. The initial approach to the complaint trazodone have been reported to be effective in isolated cases of
of unusual sleep-related behavior is to determine whether further disorders of arousal [93,94]. Nonpharmacological treatment such
evaluation is necessary. The patient should be queried regarding the as psychotherapy [28], progressive relaxation [95], or hypnosis
exact nature of the events. Because many of these episodes may be [96] is recommended for long-term management. Anticipatory
associated with partial or complete amnesia, additional descriptive awakening has been reported to be effective in treating sleepwalk-
information from a bed partner or other observer may prove in- ing in children [97]. The avoidance of precipitants such as drugs
valuable. Home videotapes of the clinical event may be quite help- and sleep deprivation is also important. Sleep-related eating may
ful. In general, indications for formal evaluation of parasomnias respond to topiramate or dopaminergic agents [66]. Systematic
include behaviors that [1]‌: studies of pharmacological treatment of sleep-related abnormal
◆ are potentially violent or injurious; sexual behavior are lacking.
◆ are extremely disruptive to other household members;
◆ result
in the complaint of excessive daytime sleepiness;
Numerous physiologic phenomena occur during REM sleep and
◆ areassociated with medical, psychiatric, or neurological symp- fall into two categories: (1) tonic (appearing throughout a REM
toms or findings. period) and (2) phasic (occurring intermittently during a REM
Formal PSG studies, appropriately performed, will provide direct period). Tonic elements include electromyographic (EMG) sup-
or indirect diagnostic information in the majority of cases. This pression, low voltage desynchronized EEG, high arousal threshold,

hippocampal theta rhythm, elevated brain temperature, poikilo- [116]. However, Iranzo et al. performed 1H-MRS in 15 patients
thermia, olfactory bulb activity, and penile tumescence. Phasic ele- with idiopathic RBD to determine if midbrain or pontine teg-
ments include REMs, middle ear muscle activity (MEMA), tongue mentum abnormalities could be detected compared with matched
movements, periorbital integrated potentials (PIPs), somatic controls and did not find any significant metabolic disturbances,
muscle–limb twitches, variability of autonomic activity (cardiac including the choline/creatine ratio [117]. Despite this discrep-
and respiratory), and pontogeniculo-occipital (PGO) spikes. It is ancy, neuroimaging studies performed on patients with idiopathic
not known whether dreaming occurs tonically or phasically during RBD support the relationship between RBD and neurodegenera-
REM sleep [98]. tive disorders. Eisensehr et al. used [123I](N)-(3-iodopropene-2-
The tonic and phasic neurophysiological processes underly- yl)-2β-carbomethoxy-3β-(4-chlorophenyl)tropane (IPT)-SPECT,
ing each state can be variously dissociated and recombined across which reflects presynaptic dopaminergic transporter integrity, and
states [99]. For REM sleep, the processes that generally occur in [123I](S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2-pyrrolidinyl]
concert may also be seen in dissociated form—both experimentally methyl)benzamide (IBZM)-SPECT, which reflects postsynaptic
(eg, REM sleep-deprived animals with PGO spikes occurring in dopaminergic D2 receptor integrity, to investigate dopaminergic
NREM sleep and wakefulness) [100] and in human and animal dis- parameters in patients with RBD, Parkinson disease (PD), and con-
ease (narcolepsy). In narcolepsy, the best-understood dissociated trols [118]. They found that IPT uptake was highest in controls,
state, the sleep attacks, hypnagogic hallucinations, sleep paralysis, lower in patients with “subclinical” RBD, even lower in clinically
cataplexy, and automatic behavior each represent the intrusion or manifest RBD, and lowest yet in patients with PD. Muscle activity
persistence of one state of being into another—i.e, cataplexy may during REM sleep was independently associated with reduction of
be the inappropriate isolated intrusion of REM sleep atonia (REM striatal dopamine transporters. There was, however, no significant
atonia) into wakefulness, usually induced by an emotionally laden difference in IBZM uptake between the groups. These findings sug-
event [101,102]. gest that there is a continuum of reduced striatal dopamine trans-
The most common and best-studied REM sleep parasomnia is porters involved in the pathophysiological mechanisms causing
the RBD. In patients with RBD, somatic muscle atonia, one of the increased muscle activity during REM sleep in patients with “sub-
defining features of REM sleep, is absent, permitting the acting out clinical” RBD [119]. Positron emission tomography (PET) using
of dream mentation (or the dreaming out of fictive movements), dihydrotetrabenazine (DTBZ) was utilized by Albin et al. to com-
often with violent or injurious results [103]. pare findings in elderly subjects with idiopathic RBD with those
Ohayon et al. conducted a telephone survey using the Sleep- in similarly aged controls [120]. As these RBD subjects exhibited
EVAL expert system on 4972 individuals between the ages of 15 a reduction of striatal binding of DTBZ compared with controls,
and 100 years of age, which indicated an overall prevalence of vio- the results suggest a reduction in dopaminergic substantia nigra
lent behaviors in general during sleep of 2%, one-quarter of which neurons. This finding appears to be consistent with the hypothesis
were likely due to RBD, giving an overall prevalence of RBD of 0.5% that RBD reflects an evolving degenerative parkinsonian disor-
[104]. Another survey estimated the prevalence of REM sleep be- der reflective of the dysfunction of the pedunculopontine nucleus
havior to be 0.38% in elderly individuals [105]. (PPN) that is temporally coupled with basal ganglia dysfunction.
Currently, the most common cause of acute REM sleep without
Pathogenesis atonia and RBD may be iatrogenic. Acute RBD is almost always
The generalized atonia of REM sleep results from active inhibition induced by medications (most commonly tricyclic antidepressants,
of motor activity by pontine centers of the peri-locus coeruleus re- monoamine oxidase inhibitors, selective serotonin reuptake inhibi-
gion that exert an excitatory influence upon the reticularis magno- tors (SSRIs), or serotonin–norepinephrine reuptake inhibitors
cellularis nucleus of the medulla via the lateral tegmentoreticular (SNRIs)) or associated with withdrawal (alcohol, barbiturate, or
tract. The reticularis magnocellularis nucleus, in turn, hyperpolar- meprobamate) [103,121]. Excessive caffeine ingestion has also been
izes spinal motoneuron postsynaptic membranes via the ventrolat- implicated [122], as has chocolate ingestion [123]. The chronic
eral reticulospinal tract [106,107]. Loss of muscle tone during REM form is most often either idiopathic or associated with neurological
sleep in normal individuals is very complex and has been shown disorders. Each basic category of neurological disease (vascular,
to be due to a combination of activation of brainstem motor in- neoplastic, toxic/metabolic, infectious, degenerative, traumatic,
hibitory systems and inactivation of brainstem facilitatory systems congenital, and idiopathic) could be expected to result in RBD.
[108,109]. Normally, the atonia of REM sleep is briefly interrupted Box 52.1 lists reported associations with RBD [124]. A familial as-
by excitatory inputs that produce the rapid eye movements and the sociation has been documented [125]. Spontaneously occurring
muscle jerks and twitches characteristic of REM sleep [110–112]. idiopathic RBD has also been reported in dogs and cats [126,127].
REM atonia is felt to be mediated by glycine and may be influenced The overwhelming male predominance of RBD (not seen in
by medullary enkephalinergic neurons [113,14]. (The prevailing the associated neurodegenerative disorders) raises the intriguing
hypothesis that REM atonia is due to glycinergic inhibition has question of hormonal influences, as suggested in male-aggression
been questioned and modified [115].) studies in both animals and humans [128–130]. Another possible
Neuroimaging studies indicate dopaminergic abnormalities explanation for the male predominance is sex differences in brain
in RBD. Various types of neuroimaging studies in patients with development and aging [131–133]. There is evidence for a sex dif-
idiopathic RBD have been performed. Using proton magnetic ference in the effects of sex steroids on the development of the
resonance spectroscopy (1H-MRS), Miyamoto et al. detected an locus coeruleus in rats [134]. However, serum sex hormone levels
increase in the choline/creatine ratio in the pons of a 69-year-old are normal in idiopathic RBD or RBD associated with Parkinson
man with idiopathic RBD and interpreted these findings as dem- disease [135,136]. Recent studies suggest that RBD may be more
onstrating functional impairment on the cell membrane level common in women than previously thought [137,138].

his dreams. Most patients complain of sleep injury but rarely of

Box 52.1 Conditions associated with RBD
sleep disruption.
Amyotrophic lateral sclerosis In RBD patients, arousal from sleep to alertness and orientation
Autism is usually rapid and accompanied by complete dream recall (very
Brain stem parainfectious encephalitis (both RBD and unlike the confusional arousals observed in disorders of arousal
narcolepsy) such as sleepwalking or sleep terrors). After awakening, behavior
Cerebrovascular disease and social interactions are appropriate, mitigating against a NREM
Group A xeroderma pigmentosum sleep relationship, delirious states, or ictal/postictal phenomena,
Guillain–Barré syndrome but rather further supporting a REM sleep phenomenon. It should
Implantation of subthalamic stimulator for Parkinson disease be emphasized that the behaviors, although complex and violent,
(isolated event) are of briefer duration than those seen in disorders of arousal. In
Medication (particularly tricyclic antidepressants and SSRIs) some individuals, the clinical features contain elements of both
Möbius syndrome RBD and disorders of arousal (see the section on RBD variations
Machado–Joseph disease (spinocerebellar ataxia type 3) later in this chapter).
Multiple sclerosis A singular feature of the dream-enacted episodes in this group
Narcolepsy of patients is that customary dreams are generally not being played
Paraneoplastic (anti- Ma2) encephalitis (both RBD and out; rather, distinctly altered, stereotypical, repetitive, and “action-
narcolepsy) packed” dreams are put on display. The violence of the sleep-related
Parkinson disease associated with parkin mutations behavior is often discordant with the waking personality. The
Synucleinopathies (Parkinson disease, multiple system atrophy, increased aggressive dream content experienced by patients with
dementia with Lewy bodies, pure autonomic failure) RBD is not associated with increased daytime aggressiveness [143].
Tauopathies (Alzheimer disease, progressive supranuclear palsy, RBD and extrapyramidal disease
corticobasal degeneration)
As more patients with “idiopathic” RBD are carefully followed
Tourette syndrome
over time, it is becoming clear that the majority will eventually de-
Voltage-gated potassium channel antibody-associated limbic
velop neurodegenerative disorders, most notably the synucleinopa-
encephalitis
thies: PD, multiple system atrophy (including olivopontocerebellar
Adapted from Sleep Med Rev, 13(6), Mahowald, M.W. and C.H. Schenck, degeneration and the Shy–Drager syndrome), dementia with Lewy
The REM sleep behavior disorder odyssey, pp. 381–4, Copyright (2009), bodies, or pure autonomic failure. RBD may be the first manifest-
with permission from Elsevier. ation of these conditions and may precede any other manifest-
ation of the underlying neurodegenerative process by more than
10 years [144].
Systematic longitudinal study of patients with such neurological
Clinical features syndromes indicates that RBD and REM sleep without atonia may
The cases reported to date indicate strikingly similar clinical fea- be far more prevalent than previously suspected. Although the
tures [103]. The presenting complaint is often vigorous sleep prevalence of RBD in PD is unknown, subjective reports indicate
behaviors, usually accompanying incredibly vivid dreams. These that 25% of patients with PD have behaviors suggestive of RBD or
behaviors may result in repeated injury, including ecchymoses, lac- sleep-related injurious behaviors, and PSG studies found RBD in
erations, and fractures. Some of the self-protection measures taken up to 47% of patients with PD with sleep complaints [145–148].
by patients (tethering themselves to the bed, using sleeping bags In one large series of patients with multiple system atrophy, 90%
or pillow barricades, or sleeping on a mattress in an empty room) were found to have REM sleep without atonia and 69% had clinical
reveal the recurrent and serious nature of these episodes [139,140]. RBD [149], and in another, nearly half had RBD [150]. The pres-
The potential for injury to self or bed partner raises interesting ence of RBD may differentiate pure autonomic failure from mul-
and difficult forensic medicine issues [138]. RBD may have seri- tiple system atrophy with autonomic failure [151]. The finding of
ous psychological ramifications for the spouse: one woman threat- incidental Lewy bodies in one patient asymptomatic for PD sug-
ened suicide because her husband with RBD could not share their gests that this condition may explain idiopathic RBD in some older
bed [141]. patients [152]. The presentation of RBD and dementia is suggestive
Idiopathic RBD is commonly a chronic progressive disorder, with enough of dementia with Lewy bodies that RBD has been proposed
increasing complexity, intensity, and frequency of expressed behav- as one of the core diagnostic features of the latter [153]. The rela-
iors, but the symptoms may fluctuate over time [142]. Although tionship between neurodegenerative disorders and RBD has been
irregular jerking of the limbs may occur nightly, the major move- recently thoroughly reviewed [154].
ment episodes appear intermittently with a frequency minimum of The waking motor impairments of PD may improve or even nor-
once in 2 weeks to a maximum of four times nightly on 10 consecu- malize during REM sleep-related movements in PD–RBD patients.
tive nights. Observed somniloquy runs the spectrum from short In a study of 53 patients with PD–RBD who slept with bed partners,
and garbled to long-winded and clearly articulated. Angry speech 100% reported improvement of at least one of the following dur-
with shouting, but also laughter, can emerge. One patient appeared ing RBD episodes: faster, stronger or smoother movements; more
to have a dissociated RBD-lucid dream state in that he could carry intelligible, louder, or better-articulated speech; or normalization
on lengthy and coherent conversations with his wife and family of facial expression. Furthermore, 38% of bed partners reported
while dreaming and incorporate the conversational material into that movements were “much better” even in the most disabled PD

patients. The responsible mechanisms for these fascinating obser- Detailed PSG data in these patients have been reported else-
vations remain obscure [155]. where [98]. The overall sleep architecture is usually normal, with
the expected cycling of NREM and REM sleep. Most of the subjects
RBD and narcolepsy had excessive SWS for age. The conventional scoring parameters of
RBD may also be yet another manifestation of narcolepsy: it is Rechtschaffen and Kales [164] must be modified to allow for the
present in over half of patients with narcolepsy, may be an early persistence of EMG tone during epochs that are otherwise clearly
symptom in childhood narcolepsy, and may even be the present- REM sleep. In addition to the intermittent absence of atonia, there
ing symptom in narcolepsy [156–160]. Furthermore, tricyclic anti- are varying amounts of limb twitching (usually far in excess of that
depressants, monoamine oxidase inhibitors (MAOIs), SSRIs, and observed in normal REM sleep), gross body movements, and com-
SNRIs, prescribed to treat cataplexy, can trigger or exacerbate RBD plex, often violent behaviors that correlate with reported dream
in this population. The demographics (age and sex) of RBD in nar- mentation. A curious feature of the chin EMG and extremity move-
colepsy conform to those of narcolepsy, indicating that RBD in ments seen during the REM period is the variability of involvement
these patients is yet another manifestation of the state boundary and distribution. The submental EMG may be augmented without
dyscontrol seen in narcolepsy [158]. body movements or may be atonic despite flailing extremities. The
arms and legs often move independently, necessitating monitor-
Diagnosis ing of all limbs. Some patients demonstrated persistent (over the
Routine medical history-taking should include questions that span of several years) lateralization of limb EMG activity or also
screen for abnormal sleep movements and altered dreams, espe- predominant upper or lower extremity movements. Most patients
cially in older adults, patients of any age with acute or chronic CNS display prominent aperiodic movements of all extremities in every
disorders (particularly those who have neurological conditions that conceivable combination during all stages of NREM sleep. RBD
predispose to RBD such as PD or multiple system atrophy), and patients may also show conventional periodic movements of sleep
patients receiving psychoactive medications known to trigger RBD. usually involving the legs during both NREM and REM sleep,
The diagnosis of RBD may be suspected on clinical grounds, but infrequently associated with arousals. Prolonged periods of ape-
PSG confirmation is mandatory. The complaint of sleep-related riodic and periodic movements restricted to the arms were noted
injurious or violent behaviors should be taken very seriously. occasionally.
Reported injuries in our series include lacerations and fractures to The PSG marker of RBD is REM sleep without atonia (RWA)
the patient and/or bed partner. RBD has also resulted in subdural (Fig. 52.1). It must be remembered that RWA is a PSG observation
hematomas and other serious injuries [161–163]. and that RBD is a clinical syndrome of dream-enacting behavior
E1–M2
125 uv
E2–M2
125 uv
C3–M2
125 uv
C4–M1
125 uv
O1–M2
125 uv
O2–M1
125 uv
F4–M1
125 uv
Chin1–Chin2
125 uv
LEG/L-LEG/R
8 mv
ECG1-ECG2
4 mv
Fig. 52.1 Polysomnographic (PSG) example of REM sleep without atonia. This 2-minute epoch of REM sleep demonstrates prominent phasic anterior tibialis muscle
electromyography. Note the persistence of atonia in the submentalis electromyogram. This is the PSG marker of REM sleep without atonia (RWA). This pattern may be
seen in patients with or without a history of REM sleep behavior disorder (RBD). RWA in the absence of a history of RBD does not constitute RBD. The diagnosis of RBD
depends upon PSG-documented RWA coupled with a clinical history of dream-enacting behaviors. E1/E2: left/right outer canthus; M1/M2: left/right mastoid; C3/C4: left/
right central EEG; O1/O2: left/right occipital EEG; Chin: submentalis EMG; leg: anterior tibialis EMG; ECG: electrocardiogram.

associated with RWA. RWA often occurs without clinical symp- is strongly encouraged that such technicians be certified by the
toms and therefore, of itself, does not establish a diagnosis of RBD. American Board of Registered Polysomnographic Technologists
The diagnosis of RBD requires both the clinical history of dream- (RBPT).
enacting behavior coupled with the PSG finding of RWA. Some 4. As result of the association between RBD and narcolepsy, a mul-
cases of RWA may represent “preclinical” RBD, and RWA is most tiple sleep latency test (MSLT) is routinely administered the
commonly seen in association with medications, particularly SSRIs day following the overnight sleep study, particularly in younger
and SNRIs. patients [165].
Diagnostic criteria (ICSD-3) [6]‌ More extensive neurological evaluations, including multimodal
A. Repeated episodes of sleep-related vocalization and/or complex evoked potentials, brain imaging by magnetic resonance imaging
motor behaviors. (MRI) or computerized axial tomography (CAT), or comprehen-
B. These behaviors are documented by PSG to occur during REM sive neuropsychological testing by methods previously reported
sleep or, based on clinical history of dream enactment, are pre- [166] are indicated only if there is a suggestion of neurological dys-
sumed to occur during REM sleep. function by history or neurological examination.
C. PSG recording demonstrates REM sleep without atonia (RWA).
Differential diagnosis
D. The disturbance is not better explained by another sleep dis-
order, mental disorder, medication, or substance use. RBD can masquerade as many other conditions. Most conditions
in this differential diagnosis represented an initial clinical mis-
Notes related to RBD diagnostic criteria diagnosis in our series, leading to inappropriate and ineffective
1. This criterion can be fulfilled by observation of repetitive epi- treatment. The differential diagnosis of these disorders has been
sodes during a single night of video polysomnography. reviewed elsewhere [82]. It should be remembered that the clin-
ical event (arousal) may not be primary, but rather triggered by
2. The observed vocalizations or behaviors often correlate with another, underlying sleep disorder (eg, apnea leading to arousal
simultaneously occurring dream mentation, leading to the fre- leading to sleep terror). Nocturnal behaviors induced by OSA or
quent report of “acting out one’s dreams.” sleep-related seizures can perfectly mimic those of RBD [167–
3. The most current evidence-based data that are in accordance 169]. “Overlap” parasomnias (discussed later in this chapter) are
with AASM 30-s epoch scoring guidelines should be utilized. characterized by a clinical history suggestive of sleepwalking/
4. Upon awakening, the individual is typically awake, alert, co- sleep terrors with PSG features of motor disinhibition during
herent, and oriented. both REM and NREM sleep [170]. Nocturnal panic disorder is
poorly understood and requires more study. It is well established
5. On occasion, there may be patients with a typical clinical history that psychogenic dissociative disorders may arise predominately
of RBD with dream-enacting behaviors who also exhibit typical or exclusively from the sleep period [171]. Finally, our group has
RBD behaviors during video-PSG, but do not demonstrate suffi- seen extremely violent sleep-period behavior felt to represent
cient RWA, based on the current evidence-based data, to satisfy malingering [172].
the PSG criteria for diagnosing RBD. Such patients may be pro-
visionally diagnosed with RBD, based on clinical judgment. The
same rule applies when video-PSG is not readily available. Treatment
The acute form is self-limited following discontinuation of the
6. Medications may possibly unmask latent RBD with preexist-
offending medication or completion of withdrawal. About 90% of
ing RWA, according to current expert opinion. Therefore,
patients with chronic RBD respond well to clonazepam adminis-
medication-induced RBD can be diagnosed as RBD, using clin-
tered a half-hour prior to sleep time. The dose ranges from 0.5 to
ical judgment, pending future longitudinal studies.
2.0 mg, and there has been little, if any, tendency to develop tol-
The determination of what constitutes either excessive EMG aug- erance, dependence, abuse, or adverse sleep effects despite years
mentation, EMG twitching, or limb jerking requires both me- of continuous administration and efficacy [139,173]. Melatonin at
ticulous execution of standard recording techniques and an doses up to 12 mg at bedtime or pramipexole may also be effective
experienced polysomnographer. Studies remain ongoing to better [174–177]. Although tricyclic antidepressants may sometimes in-
quantify RWA. duce or potentiate RBD, imipramine has been reported effective in
We recommend that any patient suspected of having RBD three clonazepam-resistant cases [178]. Likewise, there are reports
undergo a systematic evaluation consisting of the following: of response to an SSRI (paroxetine) [179,180]. Carbamazepine has
1. A review of sleep/wake complaints (from patient and/or bed been effective in one case [181]. Levodopa may be effective, particu-
partner) larly in cases where RBD is the harbinger of PD [182]. There have
been anecdotal reports of response to gabapentin, MAOIs, done-
2. Neurological and psychiatric examinations
pezil, and clonidine [183,184]. In RBD associated with narcolepsy,
3. A sleep laboratory study that includes continuous videotaping the tricyclic antidepressants or MAOIs administered for cataplexy
of behavior during standard PSG monitoring of the electro- may be continued and clonazepam added [185]. The treatment
oculogram (EOG), EEG, EMG (chin, bilateral extensor digito- of medication-induced or PD-associated RBD is the same as for
rum, and anterior tibialis muscles), electrocardiogram (ECG), idiopathic RBD [186]. Pallidotomy has been effective in one case
and nasal air flow [164]. An experienced and formally trained of RBD associated with PD, whereas chronic bilateral subthalamic
technician makes written observations of ongoing behaviors. It stimulation was not [187–189]. An isolated episode, however, of

RBD has been reported immediately following left subthalamic Emergent concepts in cognitive
electrode implantation for the treatment of PD [190].
Underlying OSA should be ruled out before prescribing clon- neuroscience in understanding parasomnias
azepam [191]. Despite the often-dramatic clinical improvement The fact that violent or injurious behaviors may arise in the absence
with medications, the effect of clonazepam or melatonin on the of conscious wakefulness raises the crucial question of how such
PSG features of RBD is unimpressive. (Melatonin may restore some complex behaviors can occur. The widely held concept that the
of the tonic REM atonia, and clonazepam may reduce excessive brainstem and other more “primitive” neural structures primarily
phasic EMG activity during REM sleep—but clearly incompletely participate in elemental/vegetative rather than behavioral activities
[192,193].) This raises the possibility that these medications may is inaccurate: there is clear evidence that highly complex emotional
act preferentially upon the locomotor systems rather than those and motor behaviors may originate from these more primitive
affecting REM atonia [194]. structures, without involvement of more rostral neural structures.
The other essential therapeutic intervention concerns environ- Ethology is the study of whole patterns of animal behavior under
mental safety. Clonazepam is not an absolute guarantee: one pa- natural conditions in a manner that highlights the functions and
tient injured himself during a violent dream 1 year after initiating the evolutionary process of those patterns. With an ever-increasing
very satisfactory pharmacotherapy. There was no recurrence dur- physiological approach through the application of refined and ele-
ing the ensuing 5 months, even though the dose was not increased. gant laboratory research techniques to animal behavior, oppor-
Therefore, potentially dangerous objects, particularly firearms, tunities of cross-fertilization of neurobiology and ethology have
should be removed from the bedroom, cushions positioned around coalesced to develop neuroethology [198]. An important behavior
the bed, consideration given to placing the mattress upon the floor, type in ethology is the fixed action pattern (FAP), which is an in-
and windows protected. We anticipate some cases in which drug instinctive indivisible behavioral sequence that when initiated will
tolerance or ineffectiveness will lead to discontinuation, requiring run to full completion. FAPs are invariant and are produced by a
maximal environmental safety. neural network known as the innate releasing mechanism in re-
sponse to an external stimulus known as a sign stimulus. FAPs are
RBD variations ubiquitous in the animal kingdom and are seen from invertebrates
Parasomnia overlap syndrome to higher primates. Movements resulting in FAPs may be initiated
There is a subgroup of parasomnia patients with both clinical and by central pattern generators (CPGs), an anatomical entity well rec-
PSG features of both RBD and disorders of arousal (sleepwalking/ ognized by neurologists.
sleep terrors). These cases demonstrate motor–behavioral dyscon- Tassinari et al., in their neuroethological approach, recognized
trol extending across NREM and REM sleep and suggest the possi- that motor events related to certain epileptic seizures and paras-
bility of a unifying hypothesis for disorders of arousal and RBD. The omnias share very similar features suggestive of stereotyped in-
primary underlying feature is motor disinhibition during sleep— born FAPs perhaps initiated by CPGs [32]. Furthermore, Tassinari
when predominately during NREM sleep manifesting as disorders recognized CPGs as genetically determined neuronal aggregates
of arousal, and when predominately during REM sleep manifest- in the mesencephalon, pons, and spinal cord that from an evolu-
ing as RBD—with the parasomnia overlap syndrome occupying an tionary perspective were linked with innate primal behaviors es-
intermediate position, with features of both [170]. sential for survival (eg, feeding, locomotion, and reproduction). In
higher primates, CPGs are inhibited by the influence of neocor-
Agrypnia excitata tical control. It should be kept in mind that many of the CPGs are
This condition is characterized by generalized overactivity associ- located in the brainstem and in proximity to processes that govern
ated with loss of SWS, mental oneirism (inability to initiate and the wake, NREM sleep, and REM sleep transitions. Tassinari et al.
maintain sleep with wakeful dreaming), and marked motor and provide a neuroethological model whereby, despite diurnal neocor-
autonomic sympathetic activation seen in such diverse condi- tical inhibition, both epilepsy and sleep can lead to a temporary
tions as delirium tremens, Morvan fibrillary chorea, and fatal loss of control of the neo-mammalian cortex and thereby provide
familial insomnia [195]. Oneiric dementia is likely a related con- a pathway through a common arousal platform initiated by CPGs,
dition [196]. Agrypnia excitata is similar to “status dissociatus,” which in turn triggers these FAPs, resulting in the abrupt onset of
which may be the most extreme form of RBD, appearing to rep- bizarre motor and/or emotional expressions that are uncharacter-
resent the complete breakdown of state-determining boundaries. istic of the awake neocortical-mediated diurnal behaviors.
Clinically, patients with status dissociatus, by behavioral observa- In essence, the behaviors of primary sleep parasomnias are FAPs
tion, appear to be either awake or asleep; however, clinically, their that are mediated through CPGs, which may in turn result in serious
outward expression of sleep is very atypical, characterized by fre- injury to self or to others. Important, the victim is almost always
quent muscle twitching, vocalization, and reports of dream-like someone in proximity: victims are not “sought” out. The behaviors
mentation upon spontaneous or forced awakening. There are no associated with sleepwalking may be protracted, whereas those
PSG features of either conventional REM or NREM sleep; rather, associated with RBD tend to be very quick and brief. Sleepwalkers
there is a simultaneous admixture of elements of wakefulness, REM have their eyes open, allowing them to navigate complex paths;
sleep, and NREM sleep. “Sleep” may be perceived as “normal” and patients with RBD have their eyes closed, so they tend not to get
restorative by the patient despite the nearly continuous motor and very far before hitting something, which causes them to awaken.
verbal behaviors and absence of PSG-defined REM or NREM sleep. Upon awakening, sleepwalkers tend to be confused, disoriented,
Conditions associated with status dissociatus include protracted and unable to remember complex dream imagery, while those with
withdrawal from alcohol abuse, narcolepsy, olivopontocerebellar RBD are immediately awake, alert, and oriented, often with vivid
degeneration, and prior open heart surgery [197]. recall of a dream corresponding to the observed behavior.

Prevention of injury with medication and environmental safety management of many clinical conditions, including those found in
measures is most important. Sleeping in a room on the first floor sleep medicine.
or in the basement and alarming the room or dwelling are prudent Unfortunately, conflicts arise with escalating tension, as law
actions. It must be remembered that previously benign sleepwalk- in many ways is the polar opposite of neuroscience. Law usu-
ing episodes are no guarantee that a violent event may not occur ally requires dichotomies with an exacting all-or-none approach,
in the future. Moreover, medication is not failsafe. Last, once the whereas the modern scientist is comfortable describing nonstatic
individual has left the bedroom and steps out of the home, the com- systems in multiple intersecting dimensions. Courts reach deci-
promise in safety involves not just the individual patient but now sions savoring the adversarial bipartisan environment, while
the general public, and proactive measures should accordingly be much of science is consensus-driven and prepared with statistics
considered. on groups. Law covets tradition embodying centuries of thought
Individuals seeking medical attention for any type of injury and beliefs that resists change; science values rapidly accelerating
should be queried as to the circumstances of the event. Could the innovation. Last, law accepts cultural assumptions and common
car crash have been related to falling asleep at the wheel or to an sense that is largely based upon casual observation and unexam-
episode of sleep-driving? Could the fall down the stairs or out the ined conjecture.
window have occurred while sleepwalking? Inasmuch as sleep is an Advances in cognitive neuroscience have clearly established
anesthetic state, very painful injuries may not be appreciated until that consciousness (not unlike wakefulness and sleep) exists on a
awakening after completion of the behavior. Some fatal parasom- broad spectrum and certainly is not dichotomous. The element of
nias are undoubtedly deemed suicides, rather than correctly attrib- consciousness is an essential feature addressed in the courtroom
uted to an untoward tragic consequence of sleepwalking [199]. of every criminal case, placing neuroscientific principles at the
It should be noted that RBD and other parasomnias may appear core of criminal law. In many ways, the admixed states resulting
in the hospital setting. In one series of 20 patients experiencing from incomplete transitions between sleep and wakefulness are
parasomnias in intensive care units, 17 had RBD (3 developed RBD unique experiments in nature, providing the clinician scientist
during admission for neurological disorders, 1 was admitted as a a direct window into the evanescent spectrum of consciousness
consequence of RBD, and 13 displayed pre-existing RBD during with its associated expressions of human behavior. Thus, those
the course of hospitalization for other medical conditions) [200]. asked to become engaged in sleep forensics would appear to be
well poised at this intersection of law and neuroscience. But to be
Sleep forensics adequately equipped for the developing field of sleep forensics,
a medical expert called upon to investigate criminal allegations
Definition should not only be well versed in clinical sleep medicine but also
“The application of the principles and tools of neuroscience as applied be familiar with (1) the evolution of legal thought, (2) the neuro-
to Somnology and Sleep Medicine that have been widely accepted science of consciousness, (3) the clinical guidelines to assist in the
under international scientific peer-review to the investigation in
determination of purported acts of violence arising from sleep,
understanding unusual, irrational, and/or bizarre human behaviors
associated with alleged criminal behavior which is to undergo fur-
and (4) the guidelines for the role of sleep medicine in expert wit-
ther examination in a conflict resolution legal atmosphere and/or ness testimony. Such an approach not only will enhance the role
courtroom.” of the sleep medicine specialist as a resource to the legal commu-
nity, but will also begin to develop the framework for further re-
M. A. Cramer Bornemann
WORLDSLEEP 07, Fifth Congress of the WFSRSMS, search, particularly in parasomnias, and to facilitate the discourse
Cairns, Australia related to the social implications concerning advances in cogni-
tive neuroscience.
Introduction
Sleep disorders, most notably parasomnias, have become in- Evolution of legal thought
creasingly invoked as a legal defense to explain violent, reckless, The first appearance of the “sleepwalking defense” in an American
or asocial behaviors that have resulted in a broad spectrum of court of law came in Tirrell v Massachusetts in 1846 [201]. In the
criminal allegations. Sleep medicine professionals are often asked mid-to late-1800s, there were no plausible medical explanations
to render an opinion as to whether a given alleged criminal act to account for sleepwalking, let alone complex violent behaviors
could possibly have been committed during an admixed period of apparently arising from sleep that led to misfortune. Though such
wake/sleep, and therefore have been performed without conscious tragic circumstances resulting in death appear to be exceedingly
awareness and hence ultimately without culpability. Alternatively, rare, when presented to a court of law, as in HMS Advocate v Fraser
a prosecutor may request a medical expert opinion to combat an (1878) [202] and Fain v Commonwealth (1879) [203], a homicide
opposing counsel’s attempt to use a largely improbable, if not en- charge may be acquitted by defense pleas of a temporary “defect of
tirely bogus, sleepwalking defense as a means to secure a full ac- reason” or “disease of mind.”
quittal in a criminal case. The legal community’s perspective toward sleep began to shift in
Recent advances in neuroscience are providing clues regarding 1968 with Roger Broughton’s seminal publication characterizing
how our brains affect our minds and behaviors. Neuroscience has the relationship between somnambulism, nightmares, confusional
developed powerful tools to investigate the neural activity underly- states of arousal, and REM sleep [26]. By creating a clear demar-
ing elementary aspects of physiology and behavior, which has been cation between sleep disorders and other medical or psychiatric
extended to encompass research into memory, executive function, conditions, this appears to be the first scientific sleep-related pub-
and higher levels of cognition. Such innovative tools have also lication with direct legal implications—as supported by Regina v
been applied to understanding the pathophysiology, diagnosis, and Parks (1992) [204]. It was documented in this criminal case that

the defendant drove in the early morning hours to the house of his theories. The boundaries between our conscious and unconscious,
wife’s parents. Apparently while still sleepwalking, he was provoked as between wake and sleep, are permeable, dynamic, and interac-
to attack due to the in-laws’ physical contact; he attacked both of tive, and there is no valid scientific support for the sharp dichotomy
them with a kitchen knife, killing the mother and leaving the father that is currently held by the legal community. It is this model of
seriously injured [205]. The defendant was acquitted in a complete permeability, or state dissociation, that will also assist in the expla-
defense of all criminal charges, including homicide, in a court- nation of unusual, irrational, and/or bizarre human behaviors in
room jury trial; the rendering was eventually upheld by a landmark sleep forensics.
Supreme Court of Canada decision not to characterize sleepwalk- Violent sleep-related behaviors have been reviewed in the
ing as a mental health disorder. context of automatic behavior in general, with many well-
Regina v Park helped to usher the sleepwalking defense into the documented cases resulting from a wide variety of disorders
modern era, but the interface between law and science remains con- [208]. Conditions associated with sleep-period-related violence
tentious, due in part to conflicting philosophies, methodologies, fall into two major categories: neurological and psychiatric.
and goals. Nonetheless, there is now a greater degree of civic re- Behaviors arising from a primary neurological condition can be
sponsibility placed upon the field of sleep medicine, given the legal explained by applying conceptual approaches based upon models
community’s growing recognition of sleep’s broad implications on of evanescent consciousness, the overlapping physiology of clin-
behavior (or lack thereof) ranging from parasomnias, to cognitive ical disorders, and the platform of CPGs supported by semiotic
impairment related to sleep deprivation, to pharmaceutical tox- neuroethology.
icity, just to name a few. Thus, sleep forensics was born of the need Despite considerable attention in the popular media in the United
to address civic responsibility while appreciating that advances in States and the United Kingdom given to the association between al-
neuroscience have social implications. It thereby attempts to fa- cohol and sleepwalking, there are no compelling scientific research
cilitate discourse between the two disparate disciplines of law and data to support that alcohol intoxication, particularly that beyond
sleep medicine within currently held rules and regulations of the legal limits, will either prime or trigger such an admixture of states
legal system. such as sleepwalking or sleep-related abnormal sexual behaviors or
Anglo-American law has traditionally defined criminal offenses sexsomnia [5,209].
as requiring both an actus reus (guilty act) and a mens rea (guilty The application of sleep forensics is best based upon an adapt-
mind). The state (or prosecution) must prove both elements to se- able conceptual approach using the most current neuroscientific
cure a conviction. Regrettably, it has proven exceedingly difficult to and clinical principles, as opposed to a static condition that simply
establish either the precise meaning of these terms or the relation- lists or highlights clinical disorders and extrapolates associations
ships connecting them. Criminal law presumes that most human with criminal behavior. Such a dynamic approach would apply
behavior is voluntary and that individuals are consciously aware of current neuroscientific concepts of consciousness and sleep–wake
their acts. As voluntariness is to mens rea, consciousness is to vol- state dissociation to sleep medicine. As a result, to effectively trans-
untary conduct. late this information into the courtroom, attention must be given
to the controversy between dynamic neuroscientific principles of
Neuroscience of consciousness consciousness that contrast with static definitions put forth by the
A comprehensive review of the neuroscience of consciousness is US Model Penal Code. To assist in the determination of the puta-
well beyond the scope of this chapter. Consciousness is a term that tive role of an underlying sleep disorder in a specific violent act,
has varied and evolving meanings to neuroscientists, though in the guidelines should be proposed that are based upon international
legal realm its definition has held steadfast. In science, for example, clinical experience that have undergone peer-reviewed publication.
consciousness may be used to indicate whether or not an individual Last, the role of the sleep medicine specialist and recommendations
is in a conscious state, as in whether it has been altered, reduced, for expert witness qualifications and testimony should be addressed
or even lost. On the other hand, consciousness may be a trait or an to ensure that those who practice sleep forensics optimize dialogue
attribute of a psychological process, as in the ability to think, see, and maintain ethical behavior for the process of law to proceed
and feel consciously. With trait consciousness, further distinctions without hindrance.
may be made between conscious representations, which are usually Tassinari’s concept of the role of CPGs and FAPs provides a
phenomenal, and required conscious access. Unfortunately, a direct physiological explanation for parasomnias. As a neuroethological
objective marker for the neural basis of state and trait conscious- concept, it also sets a framework for future research by promot-
ness that is independent of an individual’s external expressions or ing a naturalistic approach through behavioral observation, includ-
behavior has yet to be determined. ing methodical data collection, to better understand the spectrum
There have been seismic shifts in cognitive neuroscience, which of parasomnias for which the duration and complexity of behav-
the legal system has yet to appreciate and incorporate into the legal iors remain ill defined. Last, this concept is particularly useful in
arena. Rather confusingly, the terms “conscious” and “unconscious” sleep forensics, as parasomnias and epileptic seizures tend to have
are still used in the lexicon of neuroscience, but the ideas and patterned stereotyped behaviors—without conscious awareness.
principles behind these terms have been substantially altered and When addressing criminal allegations and their potential associa-
continue to be refined, with one such example being Tononi’s infor- tion with sleep-related conditions, behavior pattern recognition
mation integration theory of consciousness [206,207]. Advances applying neuroethological concepts, indicative of process frac-
in neuroscience within the past 30 years support the existence of tionation and neurobehavioral investigative techniques, could be
a continuum of conscious and unconscious processes, and it has particularly beneficial and would be consistent with the direction
dispensed with Freudian-influenced psychoanalytic concepts and of current mainstream science.

Clinical guidelines to assist in the determination a sleep study. Provocation tests to trigger parasomnias by any
of purported violence arising from sleep intoxicants or mind-altering agents would appear to be ethic-
ally challenged until well-controlled validated research studies
The legal implications of automatic behavior have been discussed
have been performed.
and debated in both the medical and legal literature [210–213]. As
with non-sleep-related automatisms, the identification of a specific 10. Voluntary intoxication by alcohol, or other illicit mind-altering
underlying organic or psychiatric sleep/violence condition does intoxicants precludes the sleepwalking defense.
not establish causality for any given deed. Two questions accom- It should be emphasized that these guidelines are purely meant
pany each case of purported sleep-related violence: (1) directly to provide direction when beginning the review process to gauge
addressing mens rea, is it possible for behavior this complex to have whether or not a medicolegal case has merit for consideration of a
arisen in a mixed state of wakefulness and sleep without conscious- sleep disorder to be used as a possible defense. Once determined,
ness? And, (2) is that what happened at the time of the incident? the strength of the argument to either support or refute the defend-
The answer to the first is usually “yes.” The second can never be ant’s claim should be used alongside current neuroscientific models
determined with certainty after the fact. of consciousness and behavior and further sustained with the med-
To assist in the determination of the putative role of an under- ical expert’s wealth of specialized clinical experience.
lying sleep disorder in a specific violent act, the following clinical
guidelines have been proposed [104,214,215]: Role of the sleep medicine specialist
1. There should be reason by history to suspect a bona fide sleep Recent interest in the forensic aspects of parasomnias provides
disorder. Similar episodes, with benign or morbid outcome, sleep medicine professionals with an opportunity to educate and
should have occurred previously. (It must be remembered that assist the legal profession in cases of sleep-related violence. One
disorders of arousal may begin in adulthood.) infrequently used tactic to improve scientific testimony is to use
a court-appointed “impartial expert” [217]. When approached to
2. The duration of the action is usually brief (seconds), though
testify, volunteering to serve as a court-appointed expert, rather
action of longer duration (minutes) does not necessarily exclude
than one appointed by either the prosecution or defense, may en-
a sleep disorder or a sleep-related behavior.
courage this practice. Other proposed measures include the de-
3. The behavior is usually abrupt, immediate, impulsive, and velopment of a specific section in scientific journals dedicated to
senseless—without apparent motivation. Although ostensibly expert witness testimony extracted from public documents with
purposeful, it is completely inappropriate to the total situation, request for opinions and consensus statements from appropriate
out of (waking) character for the individual, and without evi- specialists, or the development of a library of circulating expert tes-
dence of premeditation. timony that could be used to discredit irresponsible professional
4. The victim is someone who merely happened to be present, usu- witnesses [217]. Good science is not determined by the credentials
ally in proximity, and who may have been the stimulus for the of the expert witness, but rather by scientific consensus [218], while
arousal. Sleepwalkers rarely, if ever, seek out victims [74,216]. admissibility in a court of law must also adhere to either the Frye or
Daubert standards for cases presented in the USA.
5. Immediately following return of consciousness, there is per-
To address the problem of junk science in the courtroom, many
plexity or horror, without any attempt to escape, conceal, or
professional societies are calling for and some have developed
cover up the action. There is evidence of lack of awareness on the
guidelines for expert witness qualifications and testimony. The
part of the individual during the event.
American Academy of Sleep Medicine’s stance on expert witness
6. There is usually some degree of amnesia for the event; however, testimony is to accept those opinions as held by the American
this amnesia need not be complete. Medical Association (AMA) in their 2004 Report of the Council
7. Sleep is an analgesic state. The sensory pathway for pain for the on Ethical and Judicial Affairs [219]. Similarly, influenced by both
most part is considered “off-line” during sleep. Consequently, American Academy of Neurology and the AMA, the following
pain associated with acts committed during disorders of arousal guidelines should serve as a compass [220–222]:
may not be perceived until awakening after the event. A. Expert witness qualifications
8. In the case of sleep terrors/sleepwalking or sleep inertia, the act: 1. Must have a current, valid, unrestricted medical or appropriate
psychology license.
A. May occur upon awakening (rarely immediately upon falling
asleep)—usually at least 1 hour after sleep onset. 2. Must be a Diplomat of the American Board of Sleep Medicine, or
have passed the American Board of Internal Medicine specialty
B. Occurs upon attempts to awaken the subject.
examination in sleep medicine.
C. Has been potentiated by sedative–hypnotic administration,
3. Membership in the Sleep Research Society is strongly encouraged.
or prior sleep deprivation.
4. Must be a recognized resource within the sleep medicine com-
9. PSG studies performed “after the fact” are of limited value in
munity and should have been actively involved in clinical prac-
determining whether a parasomnia accounted for the remote act
tice in a manner consistent with the requirement of the criminal
in question. Even capturing a parasomnia event during a sleep
case at the time of the event.
would indicate behavior at the time of the recording, not re-
motely. Furthermore, there is no scientific basis for attempting 5. Given the essential position of mens rea in criminal law and
to replicate conditions surrounding the event in question (sleep the pivotal role of levels of consciousness, must have significant
deprivation, or alcohol or other substance ingestion) during direct experience in either neurology and/or neuroscience.

B. Guidelines for expert testimony law. With this appreciation comes significant social responsibility.
1. Must be impartial: ultimate test for accuracy and impartiality is Applying process fractionation, much can be learned about con-
a willingness to prepare testimony that could be presented un- sciousness from sleep physiology, particularly in admixed states.
changed for use by either the plaintiff or the defendant. The growth of cognitive neuroscience will continue to change our
understanding of what it means to be human, and as a result jus-
2. Fees should relate to time and effort, not contingent upon the
tice will have to change in conformity with it. Last, the conceptual
outcome of the claim.
approach to sleep forensics encourages further research to define
3. Practitioner should be willing to submit such testimony for peer and characterize admixed states of wake/sleep and parasomnias, all
review. of which are beneficial in understanding the spectrum of complex
4. To establish consistency, the expert witness should make records human behavior. Close collaboration among basic neuroscientists,
from his or her previous expert witness testimony available to sleep medicine clinicians, and the legal community will facilitate
the attorneys and expert witnesses of both parties. the development of a commonly shared concept of consciousness
and culpability.
5. The expert witness must not become a partisan or advocate in
the legal proceeding.
It is not the role of the medical expert to win the case for his
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CHAPTER 53
Morbidity, mortality,
societal impact, and accident
in sleep disorders
Sergio Garbarino
Genetic and environmental factors Morbidity

across the human lifespan: etiology Sleep disorders and impairment in daytime functioning attributed
of primary sleep disorders to disturbed or poor quality sleep induce consistent decrements in
mood and cognitive abilities (concentration, memory, attention,
Sleep problems are common across the human lifespan from child- and vigilance), coupled with elevated levels of anxiety, fatigue, and
hood to adolescence and then adulthood [1]â•„. Similar types of sleep physical pain/â•‰discomfort, relative to normal sleepers [16].
disorders co-â•‰occur in the same family and often in association with Large survey and population-â•‰based studies further reveal a num-
emotional, behavioral, and health-â•‰related problems, as demon- ber of increased morbidity markers in those suffering from insom-
strated by twin studies, where sample shared environmental fac- nia, increased rates of healthcare utilization (physician visits and
tors, rather than genetics, play a role [2]. Moreover, the association medication prescriptions), and chronic health problems [17–â•‰19].
between sleep difficulties and depression is largely accounted for by Insomnia in older adults is of particular concern because it could
genetics [3]. increase the risk of injury, impaired quality of life, cognitive impair-
In addition, a prior sleep problem in a child is a risk factor for ment, depression, and metabolic syndrome. Insomnia is also asso-
the development of depressive symptoms [4]â•„, and the genetic ciated with a moderately increased risk for cardiovascular disease
background of insomnia seems to be shared with anxiety and (CVD) [20].
depression [5]. Snoring, sleep apnea, and obesity–â•‰hypoventilation syndrome
In adults, as in children, sleep problems are also often comor- (OHS) are common disorders that increase the risk of cardiovascu-
bid with emotional, behavioral, anxiety and depression, and other lar and cerebrovascular morbidity and mortality. Additional effects
health-â•‰related problems [6]â•„, owing to genetic and environmental of sleep disordered breathing (SDB) include reduced social func-
contributions. Genetic factors largely account for an association tion and quality of life. Because these disorders are chronic, they
between sleep disturbance and anxiety (74%) and between sleep may also have a deleterious effect on a patient’s employment status
disturbance and depression (58%) [7]. However, the genetic cor- and ability to work [21].
relation between daytime sleepiness and depression decreases after Many studies have identified a higher rate of comorbid medi-
accounting for activities of daily living, snoring, obesity, and history cal conditions associated with narcolepsy; consistently reported
of diabetes. Greater daytime sleepiness is associated with snoring comorbidity includes 15% restless legs syndrome (RLS) and 25%
and higher body mass index (BMI) [8]. Obesity is correlated with sleep apnea [22,23]; obesity, cognitive deficits, and psychiat-
insomnia and short sleep duration, determined largely by environ- ric disorders, especially depression [24] and anxiety [23,25,26].
mental factors and to an extent by some common genetic effects Additional medical conditions comorbid with narcolepsy include
[9,10]. In contrast, genetic factors largely account for evening types chronic pain, gastrointestinal disorders, hypercholesterolemia, and
and morning types (80% of phenotypic correlations) and for a pro- hypertension [25,26]. Many of these conditions impart a known
pensity to externalizing behaviors in those experiencing poor sleep increased mortality risk. Excessive daytime sleepiness (EDS) may
quality. Greater psychopathological symptoms and insomnia seem also be associated with an increased risk of suicidal ideation, espe-
to be associated with the shorter variant (the short allele instead of cially in the presence of depression.
the long allele) of the 5HTTLPR region of the serotonin transporter RLS can significantly impair sleep quality and quantity, with dif-
gene (SLC6A4) [11,12], but “long–â•‰long” homozygotes experienced ficulty initiating or maintaining sleep. Patients with moderate to
poorer sleep quality [13]. severe RLS reported short sleep times (5.2–â•‰5.4 hours per night)
Environmental factors (eg, low socioeconomic status, unemploy- and more sleep disturbance [27]. RLS sufferers have also reported
ment, low income, and negative life events) and negative lifestyle an increased frequency (two to five times) of sleep-â•‰related com-
factors (eg, a lack of exercise, smoking, and alcohol drinking) are plaints: not feeling refreshed upon awakening, headaches upon
associated with sleep problems in adults [14,15] (Fig. 53.1). awakening, and, during daytime, social isolation, depressed mood,

GENETIC
BACKGROUND ENVIRONMENTAL CONTRIBUTIONS
SLEEP DISORDERS
INCREASED
INCREASED
CANCER
IMPAIRED RISK OF CVD
PSYCHIATRIC COGNITIVE METABOLIC INCIDENCE
QUALITY OF MORBIDITY
DISORDERS IMPAIRMENT SYNDROME AND
LIFE AND
MORTALITY
MORTALITY
Impairment Obesity, diabetes Alteration

vitality, energy, for abnormal autonomic function,
Anxiety, Memory,
mental, social, adipogenesis, inflammatory and
depression, attention,
physical functions disturbed clock coagulatory
bipolar executive and
health gene expression, mediators,
disorder, visuoconstructive
comorbidities, reduced glucose hormonal profiles,
schizophrenia functions
functional tolerance and endothelial
capacities insulin sensitivity disfunction
REDUCED
INCREASED RISK OF ROAD HIGH SOCIAL
PERFORMANCE AT
ACCIDENT ECONOMIC IMPACT
WORK
Fig. 53.1 Correlation between sleep disturbances and genetic, environmental, and health-related factors.
difficulty in concentrating, and memory impairment [28]. Severe appears to be a cyclical relationship between sleep disturbance
RLS is known to be associated with sleep fragmentation, depres- and medical or psychiatric illness: insomnia predicts the develop-
sion, anxiety, obesity, obstructive sleep apnea (OSA), CVD, diabe- ment of a new depressive episode 1–3 years later and future clinical
tes, erectile dysfunction, and end-stage renal disease (ESRD) [29]. anxiety.
Individuals with RLS may also have difficulties in job performance Insomnia is one of the most common prodromal features of de-
and participating in social activities [30]. Impacts on next-day func- pression, with sleep symptoms preceding an episode of depression
tioning attributed to disturbed sleep due to RLS symptoms include in 40% of cases and with 90% of patients with major depression
activities of daily living (i.e, work and household chores), cogni- reporting sleep disturbances. A history of persistent insomnia is
tive functioning (i.e, lack of concentration, forgetfulness, mental also associated with a significantly increased risk of developing
tiredness, and decreased alertness), emotional functioning (i.e, a new depressive episode [32]. In a recent meta-analysis, non-
irritability and depressed mood), physical functioning (i.e, physical depressed people with insomnia were predicted to have a twofold
tiredness and decreased ability to perform active leisure activities), increased risk of developing depression compared with people with
energy, daytime sleepiness, and social functioning (i.e, negative no sleep difficulties [33]. Insomnia treatment improves mood and
effects on relationships and social activities/situations) [31]. depressive symptoms.
Sleep problems may also contribute to depressive symptom-
Psychiatric disorders and cognitive atology via their effect on brain structure, neurogenesis, and, in
particular, hippocampal function. Sleep restriction enhance neur-
impairment onal sensitivity to subsequent excitotoxic insults [34], increasing
Sleep disturbances exert a detrimental influence on the course of the brain’s vulnerability to neurotoxic challenges [35], with conse-
psychiatric illness and contribute to impaired function. Even when quent decreased bilateral hippocampal (bilateral) and gray matter
psychiatric disorders are successfully treated or stabilized, insom- volume in the left orbitofrontal cortex.
nia and other sleep disturbances often fail to remit. Insomnia fre- Sleep disturbance is a core feature of mood episodes in bipo-
quently co-occurs with a wide range of psychiatric disorders. There lar disorder. During periods of mania, the majority of patients

Chapter 53 morbidity, mortality, societal impact, and accident in sleep disorders 505
(69–99%) experience reduced need for sleep and shortened rapid Depressive symptoms have a major impact on quality of life [52].
eye movement (REM) sleep latency [36]. The rate of insomnia in High levels of depressive symptoms essentially expressed by fatigue
bipolar depression is very high, indeed nearly 100%, and the rate of affected 25% of children with narcolepsy, with girls older than
hypersomnia during the depressive phase of bipolar illness varies 10 years being especially vulnerable [53].
between 23% and 78%. Brain function is much more vulnerable to sleep loss in the morn-
Sleep disturbance is prevalent in schizophrenia, during both ing hours than during the wake maintenance zone in the evening
psychosis and remission. Sleep complaints include difficulty fall- hours. Performance at any given time is determined by an interac-
ing asleep, early morning awakening, awakening during the night, tion of the duration of the preceding wake episode (homeostatic
not sleeping soundly, and having increased time in bed. Sleep dis- factor), the chronic sleep debt carried by the individual, and the cir-
turbances have also been associated with exacerbated symptoms cadian phase (circadian factor) at the time of assessment. Circadian
in schizophrenia, particularly positive symptoms (eg, delusions, variation in performance is most evident when sleep loss is present
hallucinations, disorganized thinking, and behavior). Moreover, [54] (Fig. 53.2).
negative symptoms such as anhedonia, social withdrawal, loss
of motivation, and poor self-care are unrelated to insomnia
symptoms [36]. Cardiovascular disease
A recent study suggests clinically significant alterations in atten- Normal sleep continuity is considered to be important for the
tion and episodic memory in individuals with insomnia and sup- maintenance of cardiovascular, metabolic, and immune func-
ports a role for sleep disturbances (particularly sleep duration, tion, physiological homeostasis, and psychological balance. A re-
sleep fragmentation, and SDB) in the development of cognitive im- cent editorial has suggested that it is reasonable to include sleep
pairment [37,38]. disturbances among the top 10 potentially modifiable risk factors
EDS, mood changes, and cognitive impairments (especially in for CVD [55]. CVD, diabetes, and overweight/obesity are closely
attention, executive functioning, memory, and visuoconstructive linked conditions and are therefore considered together as “cardio-
abilities, with consequent reduction in quality of life) are the most metabolic diseases.” Many sociocultural and behavioral factors are
common daytime symptoms of OSA syndrome (OSAS) and SDB associated with increased cardiometabolic disease risk, including
[39–42]. lower socioeconomic status, deficient diet, and sedentary lifestyle.
Continuous positive airway pressure (CPAP) treatment for mod- Evidence from both experimental and epidemiological studies
erate and severe OSAS generally improves cognitive performance, indicates that decreased sleep duration or quality may be risk fac-
but some deficits may persist as impairment in executive and visuo- tors for cardiometabolic diseases.
constructive functioning [41,43,44]. Attention and vigilance gener- The association between poor sleep and CVD has been known
ally improve, while the effects of CPAP on memory are inconsistent for decades [56]. The links between insomnia, depression, and
[41,45]. It has been suggested that longer treatment times may be CVD show bidirectional associations, as also shown in longitudinal
required for specific cognitive changes to take effect [46]. studies [57]. A recent review suggests that extreme sleep duration,
A systematic review [47] of 44 studies showed that OSAS either short or long, is a risk factor independent of depression [58],
patients’ information processing speed was reduced in 50% of and insomnia is associated with CVD also after adjusting for de-
studies when compared with healthy controls. CPAP treatment pression. For women with at least one of the major symptoms (eg,
improved the processing speed marginally when compared with difficulty falling asleep, waking up during the night, waking up too
placebo or conservative treatment. OSAS severity is associated with early, or nonrestorative sleep), moderate to severe insomnia is an
delayed information processing speed and induces new deficits in independent risk factor for subsequent CVD: The fully adjusted
manual dexterity. Higher-level executive dysfunction in OSAS may hazard ratio (HR) was 1.4 for women and 1.3 for men with a cur-
be caused by impaired lower-level attentional processes, such as rent or former manual occupation [59]. The biological evidence
slowed information processing and decreased short-term memory supporting a possible pathway between insomnia and CVD is
span. Motor and processing speed performance was significantly based partly on alterations in autonomic functioning, inflamma-
impaired, correlating with oxygen desaturation. Hypoxemia and tory and coagulatory mediators, and hormonal profiles.
hypercapnia induced frontally related executive dysfunction. OSAS Several epidemiological studies have found significant associa-
patients’ working memory performance has been shown to be tions between insomnia and CVD markers, such as carotid intima–
affected by both executive and attentional deficits [48,49]. media thickness, cardiorespiratory fitness, and Framingham risk
Sleep disturbance (eg, insomnia) related to RLS has also been score. Difficulty in initiating sleep was associated with myocardial
found to compromise individuals’ ability to focus, memorize, and infarction or coronary death among women in the Framingham
ultimately to perform optimally at work or school, with alterations Study. Furthermore, delayed sleep could also lead to alterations in
in prefrontal cognitive tasks, mainly executive functions [50]. Sleep circadian rhythms, which are important for CVD pathogenesis.
deprivation also may increase irritability and hyperactivity, result- Difficulty in initiating sleep and nonrestorative sleep are associated
ing in problems in relationships with others and in normal life with a modestly higher risk of total mortality and CVD-specific
activities. mortality [20].
In patients with sleepiness due to narcolepsy, depression and psy- Other specific sleep disorders, particularly OSA, are also asso-
chiatric comorbidity, more than objective cognitive deficits, might ciated with cardiometabolic diseases. Sleep apnea can increase
play a role in the subjectively perceived attention deficits. When the risk of developing CVD (with an incidence rate of 2 per 100
counseling and treating patients with narcolepsy, clinicians should person-years) through a number of mechanisms: intermittent
pay attention to potential depression, because subjective cognitive hypoxia, sleep fragmentation, chronic sympathetic activation, and
complaints may not relate to objective cognitive impairments [51]. systemic inflammation [60]. The multivariable models identified

Physiological
sleep
Alertness
Circadian phase Sustained attention
Homeostatic factor Executive functions
High levels of
PERFORMANCE
Genotype
NO SLEEPINESS
SLEEPINESS
Alertness
Sustained attention
Executive functions
frontoparietal Low levels of
activation PERFORMANCE
Circadian phase
Homeostatic factor
Acute TSD or
ERRORS
chronic PSD
ACCIDENTS
Fig. 53.2 Schematic representation of the performance process: the response to sleepiness is genetically determined and conditioned by other factors. Sleepiness
influences our susceptibility to circadian variation (large circle) and reduces our level of alertness, sustained attention, and executive functions (small circle), with
increased risk of errors and accidents. TSD: total sleep deprivation.; PSD: partial sleep deprivation.
Reproduced from Garbarino et al [Eds], Sleepiness and Human Impact Assessment, Copyright (2014), with permission from Springer.
OSA-related factors as independent and significant predictors of a dose–response relationship between the severity of obstructive
the occurrence of CV events and all-cause mortality. The strong- SDB and the risk of serious adverse outcomes in stroke and TIA
est OSA-related predictor of CV events was the sleep time spent patients. In terms of CPAP treatment, a recent study showed how
with arterial oxygen saturation (SaO2) less than 90%, while the early nasal CPAP therapy has a positive effect on long-term survival
other factors included increased number of awakenings, increased in ischemic stroke patients and moderate–severe OSA [65].
mean heart rate, periodic leg movements, decreased total sleep
time (TST), or presence of EDS, which were significantly and inde- Diabetes
pendently associated with a 5–50% increased risk of development
of CVD by inducing endothelial dysfunction and sympathetic acti- According to the International Diabetes Federation, 382 mil-
vation. The significant association between apnea–hypopnea index lion people (8.3%) worldwide currently have diabetes. Glucose
(AHI) and the composite CV outcome was obtained only by uni- metabolism is one of numerous physiological functions governed
variate analyses [60]. by the circadian apparatus. Nowadays, disruption of circadian tim-
Severe OSA is significantly associated with an increased risk of ing mechanisms [66] is considered among the factors that play an
CVD, stroke, and all-cause mortality. A positive association with unequivocal role in increasing the risk of developing type 2 dia-
CVD was observed for moderate OSA. In contrast, this risk is not betes mellitus (T2DM), promoting pancreatic B-cell dysfunction,
significantly increased in patients with mild OSA [61]. abnormal adipogenesis, and absence of adequate insulin respon-
After adjustment for potential confounders, OSA severity is asso- siveness, with other factors being genetic susceptibility, excessive
ciated with higher levels of high-sensitivity troponin T in middle- food consumption or high calorie food intake, and a sedentary
aged to older individuals, suggesting that subclinical myocardial lifestyle. Sleep loss/disturbance induces circadian disturbances
injury caused by OSA may play a role in the subsequent risk of correlated with the onset of T2DM [67]: abnormal sleep times and
heart failure [62]. poor sleep quality are associated with low levels of glucose toler-
With regard to CPAP therapy, patients with worse oxygen desat- ance in humans. The distribution of glucose to all parts of the body
uration at night and CPAP adherence of less than 4 hours per night is organized by the molecular clock present in the liver [68]. Half of
showed a higher rate of hypertension or cardiovascular events than the nuclear receptors identified in the liver and in adipocytes exhibit
the control group [63]. a 24-hour periodicity. Important metabolic processes are dictated
SDB has been associated with a two-to threefold higher risk by the timing of food intake. Indeed, peripheral oscillator activity,
of incident stroke. In particular, OSA constitutes a risk factor for a mechanism by which circadian cycles are regulated in peripheral
cerebrovascular events, and it is frequently seen in patients with tissues, closely controls temporal processes in liver and pancreas.
both stroke and transient ischemic attack (TIA). OSA increases Moreover, desynchronization between the circadian period of adi-
sympathetic tone, inducing hypertension, which may be a predis- pocytes (the peripheral oscillator) and the circadian period of the
posing factor for stroke [64]. The evidence suggests that there is sleep–wake cycle (the suprachiasmatic nucleus) may play a central

role in reduced glucose tolerance. In the absence of circadian regu- depression, or underlying disease processes [74]. Strong evidence
lation, the ensuing desynchrony could induce a metabolic disorder exists linking short sleep duration with impairment of memory,
that, if sustained, could ultimately cause T2DM. The misalignment reduced immunity, risk to safety, and increased risks of obesity,
of clock functions may accelerate the development of T2DM. The diabetes, and hypertension or other CVD. There is evidence for
current evidence thus suggests that these processes have a recip- an associated between long sleep duration and obesity and depres-
rocal relationship, since an abnormal functioning of metabolism sion, but the evidence is unclear regarding a correlation between
promotes low expression of clock genes, while an impaired clock long sleep duration and diabetes, hypertension or other CVD, and
functioning can disrupt metabolic activity and alter adipogenesis, higher mortality [73,75].
body mass and obesity. The findings thus underscore the impor- Two meta-analyses have reported consistent increases in mortal-
tance of circadian regulation for normal metabolic functioning ity risk among short and long sleepers of approximately 10% and
and the fact that clock gene expression appears to be disturbed in 20–30%, respectively [76,77]. Conversely, a recent meta-analysis
T2DM [69]. cautions that it is premature to conclude, as previous reviews have,
Night light exposure, even at low levels, has been reported to alter that a robust, U-shaped association between sleep duration and
food timing and body mass accumulation in mice, thus suggesting mortality risk exists across populations [74].
that artificial lighting may be an important contributing factor to It is likely that sleep disturbances characterized by insomnia
the increased prevalence of metabolic disorders [70]. symptoms represent novel risk factors for mortality especially for
Shift work, insufficient sunlight exposure, sleep disturbances, men with difficulty initiating sleep and those with nonrestorative
late night eating, and nocturnal light exposure are all known to sleep. EDS has also been increasingly recognized as a major health
produce circadian clock disruption. Various surveys have docu- hazard and has been linked to an increased risk of all-cause mor-
mented the increased prevalence of T2DM in night-shift workers. tality. The increased risk was independent of a variety of risk fac-
This category of employees, whose work involves irregular sched- tors for mortality, including lifestyle factors and presence of several
ules and forced exposure to nocturnal lighting, show significant medical morbidities [20]. Insomnia has also been associated with
disruptions in sleep architecture and other markers of circadian incident depression, a risk factor for cardiovascular morbidity and
synchronization [71]. mortality. Thus, insomnia may increase mortality risk through
Impairment of clock functions can affect metabolic activities, effects on several biological pathways.
leading to reduced insulin sensitivity, impaired glucose metabo- Evidence exists for relationships between OSA and both all-cause
lism, obesity, and altered clock gene expression, and, together with mortality and various cardiovascular events, and available data sug-
the effects of timing of food, sleep/wake disruption, an impaired gest an association between mortality (all-cause and from CVD)
melatonin pathway, and exposure of nocturnal light, can cause and EDS [60]. The strongest OSA-related predictor of cardiovascu-
T2DM, and, by extension, threaten the survival of the organism. lar events seems to be the sleep time spent with SaO2 < 90%, but the
This can be seen in the high mortality rate associated with T2DM number of awakenings, mean heart rate, and presence of EDS are
in the human population [69]. significantly and independently associated with a 5–50% increased
Bed times and sleep restriction have been associated with reduced risk of development of the composite cardiovascular outcome, even
glucose tolerance and reduced insulin sensitivity, changes in after controlling for known CVD risk factors [60].
appetite-regulating hormones, including lower levels of leptin and Moderate–severe OSA is an independent risk factor for all-cause
increased levels of ghrelin, increased subjective appetite, increased mortality, cancer mortality, cancer incidence, and stroke [78].
caloric intake, particularly from fat, increased prevalence of obesity, In the US population, narcolepsy is associated with 1.5-fold
and higher BMI. Impaired sleep quality (as a consequence of either increase in all-cause mortality. Mortality rates increase with age,
reduced slow-wave sleep (SWS) or fragmented sleep) is associated but there is a peak in the relative mortality risk in the age groups
with reduced glucose tolerance and reduced insulin sensitivity. 25–34 and 35–44 years. At least some of the early mortality may be
Finally, increased blood pressure has been observed after a night a result of suicide, potentially resulting from the combination of
of sleep restriction. Taken together, these experimental studies sug- reduced health-related quality of life and comorbid depression [79].
gest that both sleep duration and reduced sleep quality are associ-
ated with over twice the risk of incident hypertension and adverse
cardiometabolic effects [72].
Sleep disorders and quality of life
There is a strong association between sleeping problems and
quality-of-life variables (eg, poor economic status, family and social
Mortality situations like divorce and separation, mental stress, and lifestyle).
Sleeping too little or too much impacts severely on health with According to Arber et al. [15], socioeconomic inequalities explain
a U-shaped association between short and long sleep duration, a major part of the gender-related differences in sleep problems.
and morbidity and even mortality risks across populations [73]. There is a pattern of increasing percentage confirming sleeping
Typically, short sleep duration is thought to increase mortality risk problems across worsening categories of economic, social, and
through adverse endocrinological, immunological, or metabolic family situations in all observed age groups, indicating a general,
effects, through the induction of chronic, low-grade inflamma- strong association between socioeconomic status and women’s
tion, or through increases in cortisol secretion or altered growth sleep. There is a significant association between perceived mental
hormone metabolism. Biological mechanisms proposed for the stress and poor sleep [80].
association between long sleep duration and mortality risk include Chronic insomnia has also been documented as negatively
increased sleep fragmentation, fatigue, changes in immune func- impacting several domains of health- related quality of life
tion, photoperiodic abnormalities, lack of physiological challenge, (HRQoL), not just the obvious ones, like vitality and energy, but

also extending to other aspects of mental, social, and physical func- strategies that enable patients to cope with the impact of the disease
tioning [16,81]. Successfully improving sleep, using both phar- later in life when they are in their peak productivity [79].
macological and nonpharmacological interventions, can lead to
significant improvements in domains of HRQoL [16]. Sleep disorders and performance at work
Several large surveys have also reported a graded trend with in-
The relationship between work performance and sleep quality is
somnia severity; such associations continue to hold after control-
reciprocal and potentially complex. Occupational injuries are a
ling for both physical and mental health comorbidities [82–84].
major problem worldwide. The prevalence of sleep problems var-
Insomnia impacts on quality of life differently according to
ies in the working population, ranging from approximately 18% in
age: the “young” category (ages 30–49), had significantly lower
Europe to 23% in the US [98]. Thus, work schedules and occupa-
scores on all domains of the 36-Item Short Form Health Survey
tional demands can act as precipitating and perpetuating factors
(SF-36); the middle category (50–69 years) showed impairment on
in the development of insomnia [99]. Insomnia-related impaired
all but two domains (emotional role limitation and physical role
work performance continues to represent a significant cost bur-
limitation); and the elderly category was significantly impaired in
den on the individual worker, healthcare systems and employ-
four out of eight domains (pain, vitality, mental health, and physical
ers (typically, absenteeism). Large survey and population-based
functioning) relative to reference values [85].
studies further reveal a number of increased morbidity mark-
Comparing those with insomnia and normal sleepers under
ers in those suffering from insomnia, including increased work
six main domains (energy level, pain, sleep, social isolation, emo-
absenteeism, reduced work productivity, and greater frequency
tional reactions, and physical abilities), individuals with insomnia
of accidents [101–102]. Such impairments may be compounded
had significant impairment [86], considering five validated catego-
by co-occurring illness. However, workplace studies controlling
ries: physical role; energy and will to do things; cognitive (concen-
for both mental and physical comorbidities still reveal significant
tration, attention, and memory); social (relationships with others);
negative effects of insomnia on objective data (eg, absenteeism),
and psychological well-being [87].
self-reported work efficiency [101], work disability pension claims
RLS impairs HRQoL [88]. In a recent study including a large co-
[103], and overall loss in productivity [104]. Workers reporting
hort in the US, RLS symptoms and other sleep complains were lon-
insomnia symptoms experience a subjective reduction in work-
gitudinally associated with lower future physical function in elderly
place productivity that appears to be related to symptom sever-
population. The authors found a level of disability significantly
ity and may develop incrementally over time [99]. The majority
higher among those with RLS than among those without [30].
of studies have reported significantly increased absenteeism, the
The development of specific pathophysiological conditions
levels of which have also been associated with the severity of the
associated with impaired locomotion or spontaneous locomotor-
insomnia symptoms [105]). The National Sleep Foundation sur-
like movements such as RLS seems to involve the central pattern
vey [106] found that the risk of accidents and injuries at work was
generator, a network of spinal neurons. Poorer sleep quality, pres-
significantly higher among those reporting a sleep latency of more
ence of insomnia, or EDS can predict greater disability independ-
than 30 minutes.
ent of RLS symptoms and are associated with poorer physical
The prevalence of sleep disorders and of EDS is higher in shift
function [30].
workers than in non-shift workers [107–111]. The association be-
EDS and altered circadian rhythms may affect quality of life
tween sleep disorders and shift work is bidirectional. Shift work
directly, particularly in relation to functional capacity, health, and
induces some sleep complaints such as insomnia, poor sleep quality,
sensation of well-being [89]. Sleep apnea is the most common cause
and daytime sleepiness. On the other hand, underlying sleep dis-
of excessive sleepiness, which leads to significant impairments in
orders decrease workers’ capabilities to adapt with shift working
quality of life and cognitive performance, especially if it is associ-
and increase the number of accidents at work [107–109,112–114].
ated with obesity [90,91]. The decrease in vitality, social function-
Insomnia and low sleep quality had the highest correlation with the
ing, and emotional dimensions is significantly related to diurnal
incidence of negative occupational impacts [111].
sleepiness and impaired alertness [90]. Quality of life scores were
Workers with sleep problems had a 1.62 times greater risk of
reported to be lower in 40–60% of obese populations [92], with
being injured at work compared with workers without sleep prob-
an impairment linearly related to BMI and improving after weight
lems. Moreover, each aspect of the sleep problem significantly
loss. Sleepy non-physically active subjects and group with severe
increased the risk for work injuries, with the largest effects being
apnea had impaired quality of life associated with EDS, a decrease
seen for the use of sleep medication and for breathing-related sleep
in quality of sleep, a reduction in sleep efficiency, increased stages
problems. Approximately 13% of work injuries could be attributed
I and II sleep, and reduced stage III and REM sleep compared with
to sleep problems [98].
the control group. Nocturnal hypoxemia is a commonly cited caus-
ative factor for abnormal sleep patterns with adverse consequences
on both physical and mental health [93,94]. Sleep disorders and road safety
Narcolepsy is a chronic disease often requiring lifelong medi- Every day, more than 3000 people die in motor vehicle crashes
cal treatment, which may have a profound impact on function- around the world—amounting to more than 1.3 million motor-
ing, quality of life, and healthcare costs [95]. Moreover, a recent vehicle-related deaths worldwide each year—and between 20 mil-
study on the societal effects of narcolepsy reported a substantial lion and 50 million more are injured and often left disabled for life
economic burden resulting from high healthcare costs and reduced [115]. Human error is found in 90% of accidents [116], with the
income observed up to 11 years before diagnosis [79,96]. However, main human factors being fatigue and sleepiness [113,117,118].
it has also been reported that HRQoL tends to improve over time Several reviews have reported that OSA, insomnia, hyper-
in patients with narcolepsy [97], perhaps as a result of adaptation somnias, and sleepiness increased the risk of work-related

traffic accidents in commercial drivers. In general, sleep prob-

Box 53.1 Commission Directive 2014/85/EU of 1 July 2014
lems cause a two- to sevenfold increased risk of traffic acci- amending Directive 2006/126/EC of the European Parliament
dents. According to the European statistics on accidents at work and of the Council on Driving Licences
(ESAW), road traffic accidents constituted 9.6% of all accidents
at work in 2007 [119]. Article 2
Studies on the relationship between sleep disorders and road
◆ 1. Member States shall adopt and publish, by 31 December
accidents are impressive. An Australian study observed that
2015 at the latest, the laws, regulations and administrative
approximately 50% of injured motor drivers surviving a vehicle
provisions necessary to comply with this Directive. They shall
collision had at least one sleep-related risk factor [120]. In a large
forthwith communicate to the Commission the text of those
cohort of regular highway drivers, 16.9% complained of at least
provisions.
one sleep disorder, with 5.2% reporting OSAS, 9.3% insomnia, and
0.1% narcolepsy and hypersomnia; 8.9% of drivers reported expe- ◆ They shall apply those provisions from 31 December 2015.
riencing at least once a month an episode of sleepiness at the wheel ◆ When Member States adopt those provisions, they shall con-
so severe that they had to stop driving. One-third of the drivers tain a reference to this Directive or be accompanied by such a
(31.1%) reported near-miss accidents (50% being sleep-related), reference on the occasion of their official publication. Member
7.2% reported a driving accident in the past year, and 5.8% of these States shall determine how such reference is to be made.
driving accidents were sleep-related [121].
Insomnia is responsible for EDS in 12–15% of adults. EDS as Annex
a consequence of insomnia might increase accident risk, but the 2. In Annex III to Directive 2006/
126/EC, Section 11
risk of insomnia symptoms appears to be differentially associated (“NEUROLOGICAL DISEASES”) is replaced by the following:
with motor-vehicle and non-motor-vehicle accidents. Moreover,
the strong association between hypnotics and road traffic accidents Obstructive sleep apnoea syndrome
is under debate. Insomnia symptoms significantly elevate accident ◆ 11.2. In the following paragraphs, a moderate obstructive sleep
risk in the workplace, though the extent to which such accident risk apnoea syndrome corresponds to a number of apnoeas and
is influenced by the concomitant use of hypnotic drugs is less clear hypopnoeas per hour (Apnoea–Hypopnoea Index) between
[99]. Insomnia and insomnia symptoms can negatively impact the 15 and 29 and a severe obstructive sleep apnoea syndrome cor-
efficiency of daytime psychomotor performance. responds to an Apnoea–Hypopnoea Index of 30 or more, both
OSAS is probably the most studied pathology with respect to associated with excessive daytime sleepiness.
traffic and workplace accidents [122]. It results in complaints of
◆ 11.3. Applicants or drivers in whom a moderate or severe ob-
severe daytime sleepiness [123], and, most importantly, many suf-
ferers report sleep-related crashes or near-miss incidents. Several structive sleep apnoea syndrome is suspected shall be referred
studies in the last 20 years have shown a clear positive relationship for further authorised medical advice before a driving licence
between OSAS and traffic accidents [124–139]. is issued or renewed. They may be advised not to drive until
The most important study regarding driving accidents and OSAS confirmation of the diagnosis.
is be the case–control investigation by Teran-Santos et al. [140], ◆ 11.4. Driving licences may be issued to applicants or drivers
which compared apneics with controls to evaluate the accident risk with moderate or severe obstructive sleep apnoea syndrome
related to nocturnal breathing disorder. Compared with controls, who show adequate control of their condition and compliance
apneics having an AHI ≥10 had an odds ratio of 6.3 (95% confi- with appropriate treatment and improvement of sleepiness, if
dence interval 2.40–16.02) for experiencing a traffic crash. This re- any, confirmed by authorised medical opinion.
lationship remained significant after adjustment for the potential ◆ 11.5. Applicants or drivers with moderate or severe obstructive
confounders of alcohol consumption, visual-refraction disorders, sleep apnoea syndrome under treatment shall be subject to a
BMI, years of driving, driver age, traffic accident history, medica- periodic medical review, at intervals not exceeding three years
tions causing drowsiness, and sleep schedule. Many other studies for drivers of group 1 and one year for drivers of group 2, with a
have confirmed the increased accident risk associated with OSAS view to establish the level of compliance with the treatment, the
in noncommercial drivers [118,141,142]. Furthermore, many stud- need for continuing the treatment and continued good vigilance.
ies have also shown that OSAS plays an important role in road acci-
dents of professional drivers [124,143–145]. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.
194.01.0010.01.ENG
From the point of view of legislation, in Europe since 2014, there
has been a historic change in the regulation of driving licenses and
OSAS: see Box 53.1.
There are too few sufficiently large studies to determine with Even though periodic limb movements of sleep (PLMS) and RLS
confidence the actual magnitude of risk posed by narcolepsy for can give rise to severe excessive daytime sleepiness and fatigue,
nodding-off driving accidents [128]. The proportion of patients these disorders have yet to be properly evaluated for the risk each
with sleep-related accidents was reported highest in narcoleptics possesses for driving crashes. In a small sample of patients suffer-
[139]. Other studies showed a significant decrement in the mean ing from either PLMS or RLS, about 16% of the subjects had been
level of attention and vigilant scores plus substantial inconsist- involved in traffic crashes [139]. Thus, it is impossible to conclude
ency of cognitive performance of narcoleptics in simulated driving from this quite small sample-sized study the actual risk attributed
assessment studies [146,147]. to each of these sleep disorders.

9. Watson NF, Goldberg J, Arguelles L, Buchwald D. Genetic and

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CHAPTER 54
Sleep at high altitude and

during space travel
Yvonne Nussbaumer-â•‰Ochsner and Konrad E. Bloch
Introduction Sleep at high altitude in healthy subjects

Both at high altitude and during space travel, humans are exposed According to a common belief, sleep in newcomers at high altitude
to unusual environmental conditions like hypobaric hypoxia and is not as refreshing as near sea level. This assumption has, however,
microgravity, respectively, that may directly or indirectly affect sleep only recently been corroborated by scientific evidence. For exam-
and wakefulness functions. Exposures to altitude and space exert ple, a study using the Groeningen Sleep Quality Questionnaire
quite dissimilar physical stimuli that elicit distinct physiological in 100 tourists arriving in a ski resort at 3500 m revealed that 46
responses. Nevertheless, a mountaineer climbing in remote high- perceived poor sleep quality in their first night at altitude [2]â•„. As
lands and an astronaut travelling through space may experience subjective perception of sleep quality correlates poorly with objec-
sleep difficulties through similar mechanisms. The challenge of tive measures of sleep duration and structure, it is important to
prolonged physical exertion, disruption of the regular sleep–â•‰wake consider studies using objective measurement methods when
rhythm, noise, uncomfortable temperature and sleeping conditions, assessing the effect of altitude on sleep [3]. Few studies have used
the excitement of participating in an extraordinary mission, hope of polysomnography (PSG), the gold standard for objectively record-
great achievements, and fear of life-â•‰threatening failure may all con- ing sleep at altitude. This limitation is most likely due to logistic
tribute to sleep difficulties in mountain climbing and space travel. difficulties and the lack of electricity in remote mountain facili-
Illnesses specific to hypoxia at high altitude or to microgravity in ties. A systematic literature search on studies evaluating the effect
space may additionally interfere with refreshing sleep and perfor- of altitude on sleep based on objective measurements (either PSG
mance during wakefulness. Both healthy persons and subjects with or actimetry) revealed only three randomized, controlled studies
a particular susceptibility or a pre-â•‰existing disease may be affected.
In this chapter, the effects of high altitude and space travel on
Altitude (in 1000 ft)
sleep will be reviewed. While conclusions on sleep at high altitude
0 5 10 15 20 25 30
are supported by data from an increasing number of observational 800
and randomized, controlled studies, the few case reports on sleep in Sea level
space published to date provide only limited insights. Zurich
140
700
Sleep at high altitude

Barometric pressure (mmHg)
120
600
Inspired PO2 (mmHg)

With increasing altitude, barometric pressure falls exponentially Airplane cabin pressure
(Fig. 54.1). As a consequence, the inspired and arterial partial pres- at cruising altitude 100
sures of oxygen decrease. This has a profound influence on virtu- 500
La Paz
ally all organ systems [1]â•„. With prolonged exposure to altitude,
80
compensatory mechanisms, termed acclimatization, take place 400 Mont Blanc
that mitigate some of the adverse effects. For example, the hypoxic
stimulation of ventilation at altitude and the increased ventila- 60
tory sensitivity to hypoxia and hypercapnia increase the arterial 300
oxygen partial pressure. In addition, erythropoiesis and a shift in
Mount Everest 40
the hemoglobin–â•‰oxygen dissociation curve related to respiratory
200
alkalosis enhance the oxygen-â•‰carrying capacity of arterial blood. 0 1 2 3 4 5 6 7 8 9
However, depending on individual susceptibility, speed of ascent, Altitude (in 1000 m)
and altitude reached, the adaptation may be inappropriate, leading
Fig. 54.1â•‡ Nonlinear fall of barometric pressure and the estimated inspiratory
to excessive instability of respiratory control with pronounced peri-
oxygen partial pressure with increasing altitude.
odic breathing and high-â•‰altitude-â•‰related illness that induce sleep Reproduced from Nussbaumer-â•‰Ochsner Y, Bloch KE, Air travel and altitude. In: Ayres JG,
disturbances. These conditions will be discussed later in this chap- Harrison RM, Nichols GL, Maynard RL, [eds], Environmental Medicine, pp. 547–â•‰561, Copyright
ter, after a review of studies on the effect of altitude on sleep. (2010), with permission from CRC Press.

(a) (b)
120 10
†† ††
100
PVT response speed (1/s)

8
80
AHI (1/h)
60 6
† †
40
4
20
0 2
Night 1 Night 2 Night 1 Night 2 Night 1 Night 2 Night 1 Night 2
490 m 1630 m 2590 m 490 m 1630 m 2590 m
(c) (d)
100
Mean nocturnal oxygen saturation (%)
50
† †
NREM stages 3 and 4 (% TST)

†† †† ††
95 40
30
90
20
85
10
80 0
Night 1 Night 2 Night 1 Night 2 Night 1 Night 2 Night 1 Night 2
490 m 1630 m 2590 m 490 m 1630 m 2590 m
Fig. 54.2 Results of sleep and vigilance studies obtained in 51 healthy men living below 800 m during a sojourn at 1630 and 2590 m for 2 days each: (a) apnea–hypopnea
index (AHI); (b) psychomotor vigilance test response speed; (c) mean nocturnal oxygen saturation; (d) slow-wave sleep (NREM sleep stages 3 and 4 as percentage of
total sleep time). Horizontal lines, boxes, and whiskers represent the median, quartiles, and 10th and 90th percentiles, respectively; individual values beyond this range are
displayed by asterisks. † indicates p < 0.05 versus 490 m; †† indicates p < 0.05 versus 490 and 1630 m.
Reproduced from Sleep, 36(12), Latshang TD, Lo Cascio CM, Stowhas AC et al., Are nocturnal breathing, sleep, and cognitive performance impaired at moderate altitude (1,630–2,590 m)?,
pp. 1969–1976, Copyright (2013), with permission from Associated Professional Sleep Societies, LLC.
[4–6], including a total of 76 subjects, of these 51 participated in 3 and 4) (Fig. 54.2) [4]. This was corroborated by quantitative EEG
one of these studies [4]. In addition, five case–control studies [7– analyses demonstrating a reduction in slow-wave activity correlat-
11] (including a total of 135 subjects) and 28 uncontrolled obser- ing with periodic breathing that emerged at 1630 and 2590 m (Fig.
vational studies [3,5,12–37] (including a total of 302 subjects) 54.3) [47,48]. The alterations in sleep structure were not associated
were identified and analyzed in detail. Field studies performed in with impaired performance in a battery of cognitive and psycho-
the mountains [4,7–9,14,18,22,23,28,30,34,35] were differentiated motor tests applied to the subjects in the morning after sleeping at
from studies simulating altitude by use of normobaric hypoxia altitude (Fig. 54.2) [4]. In studies performed in healthy mountain-
(low inspired oxygen fraction) [21,31] or by hypobaric hypoxia eers at higher altitude (4559 m), the reduction in slow wave-sleep
(using a decompression chamber) [5,6,19,20,24,27]. Studies were (SWS) was more pronounced than in the cited study at 2590 m, and
further classified according to the range of altitudes at which they subjects experienced a reduced sleep efficiency and more frequent
were conducted: n = 8 at moderate altitude (1500–2500 m) [4– arousals compared with baseline measurements at 490 m (Fig. 54.4)
6,15,26,28,31,34], n = 27 at high altitude (2501–4500 m) [4,5,8– [49]. While other studies performed at altitudes of 4500 m or more
14,16–18,21,23–29,33,34,37– 41], and n = 12 at very high altitude [19,20,22,50] confirmed an increased sleep fragmentation, no trend
(> 4500 m) [3,7,9,15,19,20,22,28,32,34–36]. This classification was of increasing arousals was observed in studies performed at alti-
chosen based on the prevalence of acute mountain sickness. Very tudes below 3200 m [7,23,31]. Notably, there was a major discrep-
limited information on sleep of highlanders living permanently at ancy between subjective and objective assessment of sleep at high
high altitude is available [42–46]. altitude, as shown by a comparison of subjective estimates of sleep
In a randomized crossover trial in 51 healthy young men, we latency with corresponding PSG measurements (Fig. 54.5) [3].
found that sleep structure was significantly altered already at Whether acclimatization improves sleep quality at altitude has not
an altitude of 1630 m and even more so at 2590 m [4]‌. The main been conclusively studied, although one report suggests that this is
changes consisted of a slight reduction in deep sleep (NREM stages indeed the case [50]. We have identified only two reports on sleep

Chapter 54 sleep at high altitude and in space travel 517
F3A2 C3A2
1.2
490 m
1.15 1630 m N1
1630 m N2
1.1 2590 m N1
2590 m N2
1.05
Relative power density
0.95
0.9
0.85
0.8
0.75
30
20
F-values
10
0
0 5 10 15 20 25 0 5 10 15 20 25
Frequency (Hz) Frequency (Hz)
Fig. 54.3 (See colour plate section) Relative NREM sleep EEG power density spectra at moderate altitude recorded in healthy subjects. Upper panels: Spectra at altitude
(1630 and 2590 m, N1 (first night) and N2 (second night)) are plotted relative to baseline sleep (490 m; line at 1). Significant differences (p < 0.05) between baseline and
altitude are indicated by “+” (n = 44). Frequency resolution: 0.2 Hz. Lower panels: F-values of the frequency bins with significant p-values for factor Condition (490 m N1,
1630 m N1, 1630 m N2, 2590 m N1 and 2590 m N2) of mixed model ANOVA with factors Condition and Order. F3A2: frontal derivation; C3A2: central derivation.
Reproduced from PLoS One, 8(10), Stadelmann K, Latshang TD, Lo Cascio CM et al., Quantitative changes in the sleep EEG at moderate altitude (1630 m and 2590 m), pp. e76945 Copyright
(2013), with permission from PLoS under Creative Commons License 4.0.
in children at altitude. In these studies, actigraphic recordings sug- periods of hyperventilation alternating with central apneas or
gested a more restless sleep in unacclimatized prepubertal children hypopneas (Fig. 54.6). Exposure to hypoxia induces an immediate
aged 11–12 years at 3560 m [8] and in preverbal children aged 3–33 increase in ventilation (hypoxic ventilatory response) and venti-
months at 3109 m [26] compared with sea level. latory sensitivity to hypoxia and hypercapnia increases with ac-
When evaluating the available literature on sleep at altitude, it climatization [51]. Hyperventilation with hypocapnia is therefore
becomes evident that the studies are heterogeneous, encompassing typically observed in newcomers at altitude. Once the arterial par-
different study protocols and settings that do not always allow a tial pressure of carbon dioxide (PaCO2) falls below a certain level,
generalization of the results to the vast number of tourists travelling called the apneic threshold, ventilation ceases until PaCO2 rises
to altitude. Subjects are mostly selected from among healthy, highly again owing to metabolic activity. The resulting breathing pattern,
trained mountaineers, athletes, or soldiers. The study settings vary characterized by waxing and waning of ventilation with periods
greatly even within the same investigation, and the sample size is of apnea/hypopnea alternating with hyperpnea, is called periodic
often inadequate. With these limitations and taking the more ro- breathing. It is a prominent characteristic of sleep at high altitude,
bust evidence from a few recent randomized or controlled stud- but it may even occur during wakefulness and exercise at altitude
ies into particular consideration, one may cautiously conclude that [52]. The apneic phases of periodic breathing may be perceived as a
with increasing altitude, there is a trend for reduced SWS and sleep distressing sense of suffocation followed by gasping for air in a few
efficiency and increasing sleep fragmentation (Fig. 54.4). deep breaths.
Propensity for periodic breathing is increased during NREM
High-altitude periodic breathing during sleep sleep compared with wakefulness because of the absence of the sta-
High-altitude sleep disturbances are linked to periodic breathing, bilizing effect of the tonic “wakefulness drive” [53]. Furthermore,
an oscillating pattern of waxing and waning of ventilation with the reduced background drive to breathe during NREM sleep

(a)
Awake
S1
S2 SpO2 NR3&4
490 m NR1&2
S3 96% REM
S4
REM
22:00 23:00 24:00 22:00 01:00 02:00 03:00 04:00 05:00 Awake
(b)
Awake
S1
4559 m S2 NR3&4
SpO2
1st night REM NR1&2
S3 67%
S4
REM
Awake
22:00 23:00 24:00 22:00 01:00 02:00 03:00 04:00 05:00
(c)
Awake
S1
S2 SpO2 NR3&4
4559 m
71% REM NR1&2
3rd night S3
S4
REM
22:00 23:00 24:00 22:00 01:00 02:00 03:00 04:00 05:00 Awake
Fig. 54.4 Effects of short-term acclimatization to high altitude on sleep in healthy subjects. The hypnogram obtained in a subject during a night at 490 m (a) shows a normal
distribution of sleep stages and several NREM/REM sleep cycles. In contrast, the hypnogram recorded during the 1st night at 4559 m (b) reveals predominantly superficial
sleep stages with frequent awakenings, very rare deep sleep stages 3 and 4, and no REM sleep. The hypnogram from the 3rd night at 4559 m (c) reveals a partial restoration of
normal sleep architecture. The right panels qualitatively summarize the trends of alterations in sleep structure at high altitude. The mean nocturnal oxygen saturation (SpO2)
and the distribution of sleep stages are represented in the pie charts. The outer circles of each panel represent the time in bed, the white area is the time spent awake and the
pie chart area reflects total sleep time comprising NREM stages 1–4 (NR1&2: superficial stages; NR3&4: slow-wave or deep sleep stages) and REM sleep.
Adapted from High Alt Med Biol, 12(3), Nussbaumer-Ochsner Y, Schuepfer N, Siebenmann C, Maggiorini M, Bloch KE, High altitude sleep disturbances monitored by actigraphy and
polysomnography, pp. 229–236, Copyright (2011), Mary Ann Liebert, Inc. publishers; Nussbaumer-Ochsner Y, Bloch KE, Sleep, In: Swenson ER, Bärtsch P [eds], High Altitude: Human Adaptation to
Hypoxia, pp. 325–339, Copyright (2014), Springer.
60
* * * * * related to a reduced hypercapnic and hypoxic ventilatory response
compared with wakefulness is associated with hypercapnia [54,55].
50
This reduces the amount of hyperventilation required to cross the
apneic threshold because of the hyperbolic shape of the isometa-
Sleep latency (min)
40
bolic line reflecting the relationship between alveolar ventilation
and alveolar partial pressure of carbon dioxide (PACO2) relation-
30
ship (Fig. 54.7) [56].
Most studies reveal an increasing prevalence of periodic
20
breathing with increasing altitude and hypoxemia. It is observed
already at 1630 m with great inter-individual variation in preva-
10
lence (Fig. 54.2) [4]‌. The reported number of periodic breathing
cycles with central apnea/hypopnea is associated with an altitude-
0
490 m 4559 m dependent decrease in oxygen saturation and ranges from 10
Night 1 Night 2 Night 3 Night 4
events/h at a simulated altitude of 2650 m [57] to as much as 254
events/h at 7620 m [20]. Correspondingly, with increasing altitude,
Fig. 54.5 Sleep latencies estimated subjectively (white bars) significantly exceed the fraction of the night spent with periodic breathing increased
the corresponding values measured by PSG (green bars) in mountaineers studied from 34–58% at 4559 m [8,9] to 68% at 5050 m [22,58], to 73–75%
at 4559 m (*p < 0.05). Bars and vertical lines represent medians and quartile at 7620–8050 m [21,59]. Periodic breathing may be associated with
ranges; the upper quartile in night 3 was 120 minutes.
short awakenings or brief arousals that result in fragmented, non-
Reproduced from High Alt Med Biol, 12(3), Nussbaumer-Ochsner Y, Schuepfer N,
Siebenmann C, Maggiorini M, Bloch KE, High altitude sleep disturbances monitored by actigraphy
restorative sleep. In one study, up to 52% of nocturnal arousals were
and polysomnography, pp. 229–236, Copyright (2011), Mary Ann Liebert, Inc. publishers. associated with periodic breathing cycles, suggesting an important

but not exclusive role of periodic breathing in causing sleep disrup-

Volume
sum
tion at altitude [19]. In more recent field studies [3,4,34,50], the
correlation of arousals and periodic breathing during exposure to
1L
Volume rib hypoxia was less consistent (Fig. 54.8) than in the cited hypobaric
cage chamber study [19]. Of note, there may be a mutual interaction
1L among arousals and periodic breathing, since periodic breath-
Volume
abdomen
ing may induce arousals, and they may in turn promote periodic
breathing due to changes in ventilatory control during the sleep–
20
V′E (L/min) wakefulness transition.
0 Research on ventilatory adaptation to high altitude has been
140
Heart nearly exclusively focused on adults. Only one study investigated
rate (1/min)
50
the nocturnal breathing pattern in prepubertal children aged 10–
90 11 years in comparison with adults [8]‌. Pairs of children with their
SpO (%) fathers underwent PSG studies at the Jungfrau Joch (3450 m) in
50 3 min
Switzerland after rapid ascent by train. It was found that despite a
Fig. 54.6 Nocturnal polygraphic recording obtained at 6850 m in a 29-year-old similar degree of nocturnal hypoxemia (mean nocturnal oxygen
woman. The channels are the respiratory inductive plethysmographic sum, rib saturation of 85% versus 84%) and hypocapnia (mean of 32 versus
cage and abdominal volumes, minute ventilation (V′E), heart rate, and oxygen 32 mmHg), children had less periodic breathing than adults (32.5
saturation (SpO2). In the first part of the 3-minute recording, breathing is regular. versus 54.1 periodic breathing cycles/h in the first night at 3450 m,
Subsequently, periodic breathing is triggered by a large breath (sigh or gasp). This p < 0.05). This was related to a lower apneic threshold for CO2, a
results in oscillations of oxygen saturation from 64% to 71%.
Reproduced from Am J Respir Crit Care Med, 182(4), Bloch KE, Latshang TD, Turk AJ et al.,
greater CO2 reserve, and a shorter circulation time in children pro-
Nocturnal periodic breathing during acclimatization at very high altitude at Mount Muztagh moting a more stable control of breathing compared to adults [8].
Ata (7,546 m), pp. 562–568, Copyright (2010), with permission from American Thoracic Society. There is only little information on the effect of ventilatory
acclimatization on periodic breathing at altitude. In a field study
250 performed at 4559 m in 16 mountaineers, ventilation initially
increased to almost one and a half of the value at lowland owing
to an increase in both tidal volume and breath rate [49]. Over the
200 +32% course of 4 days, minute ventilation slightly decreased, and this
+21%
was associated with a gradual increase in arterial oxygen saturation
(SpO2) while end-tidal partial pressure of carbon dioxide (PETCO2)
V′A, % V′A 490 m
150
100 100
#
490 m 80 *
50 *
4559 m, night 1
Number of events/h
3.6 3.2 4559 m, night 3 60

0
20 25 30 35 40 45 50
PACO2 (mmHg) 40
Fig. 54.7 Based on recordings in healthy mountaineers at 4559 m, determinants *

of periodic breathing are illustrated here in a diagram of alveolar ventilation (V′A) 20
versus alveolar partial pressure of carbon dioxide (PACO2, which is represented by
the end-tidal PCO2 as a surrogate). Assuming an increase in the metabolic rate on *
the 1st and 3rd night at 4559 m compared with the low-altitude baseline at 490 m, 0
the corresponding isometabolic lines are displaced by 25% and 10%, respectively. The 490 m 1st night 3rd night
eupneic PCO2 during stable breathing dropped from 40 mmHg at 490 m to 32 and 4559 m 4559 m
26 mmHg, respectively, on the 1st and 3rd nights at 4559 m. This was associated with Apnea–hypopnea-related arousal index
a decrease in the corresponding apnea threshold from 28 to 22 mmHg (PACO2 at Apnea–hypopnea index
V′A = 0). The increase in the slope of the line connecting the eupneic PCO2 with the
apnea threshold suggested an increase in the ventilatory sensitivity to hypocapnia Fig. 54.8 Data from sleep studies performed in healthy mountaineers at 4559 m.
in the 3rd compared with the 1st night (from 3.2 to 3.6 L/mmHg). Correspondingly, Medians and quartile ranges (bars, vertical lines) of the apnea–hypopnea index
the displacement of the eupneic PCO2 to the left on the isometabolic line increased (AHI) and the apnea–hypopnea-related arousals index at 490 m and on the 1st
the overshoot in V′A required to drive the PCO2 from the eupneic level to the apnea and the 3rd night at 4559 m are shown. Only 11% and 4% of apneas/hypopneas
threshold (from +21 to +32%). These changes were associated with a reduction in were followed by an arousal during the 1st and 3rd night, respectively. *p < 0.05
the AHI on the 3rd compared with the 1st night at 4559 m. versus 490 m, #p < 0.05 versus 1st night at 4559 m.
Reproduced from Sleep, 35(10), Nussbaumer-Ochsner Y, Schuepfer N, Ursprung J, Siebenmann Source data from Sleep, 35(10), Nussbaumer-Ochsner Y, Schuepfer N, Ursprung J,
C, Maggiorini M, Bloch KE, Sleep and breathing in high altitude pulmonary edema susceptible Siebenmann C, Maggiorini M, Bloch KE, Sleep and breathing in high altitude pulmonary
subjects at 4,559 meters, pp. 1413–1421, Copyright (2012), with permission from Associated edema susceptible subjects at 4,559 meters, pp. 1413–1421, Copyright (2012), Associated
Professional Sleep Societies, LLC. Professional Sleep Societies, LLC.

remained stable. However, the apnea–hypopnea index (AHI) fur- Table 54.1 Altitude-related illnesses
ther increased from 60.9/h to 86.5/h. In a hypobaric chamber
study simulating an altitude of 4200 m in 7 healthy men, ventila- Condition Time of Main manifestations and
tion increased over the course of 4 days, associated with progres- exposure diagnostic criteria
sive hypocapnia and gradually improved arterial oxygen saturation
Acute mountain Hours to Headache, loss of appetite, insomnia,
[17]. Changes were similar in wakefulness, NREM sleep, and REM sickness (AMS) days fatigue
sleep, suggesting that suprapontine influences were not essential for
the acclimatization to chronic hypoxia, despite the marked influ- High-altitude cerebral Hours to Severe headache, ataxia, confusion,
edema (HACE) days loss of consciousness
ence of the sleep/wakefulness state on the stability of ventilatory
control. Periodic breathing was not reported in the cited study [17], High-altitude Days Dyspnea, cough with eventually
but other investigations have revealed variable results in this regard pulmonary edema blood-tinged sputum, cyanosis,
during acclimatization. While some authors reported a decrease in (HAPE) exercise intolerance, pulmonary
hypertension
the prevalence of periodic breathing over the course of 7 days at
4300 m [51], others found no significant change during 6 days at High-altitude Years Dyspnea, exercise intolerance, right
3200 m [23] or even an increase during 28 days at 5050 m [22]. In pulmonary heart failure. Mean pulmonary artery
34 mountaineers ascending Mount Muztagh Ata, periodic breath- hypertension (HAPH), pressure (mPAP) >30 mmHg or
ing increased during acclimatization over the course of more than or cardiac chronic systolic pulmonary artery pressure
mountain sickness (sPAP) >50 mmHg at altitude of
2 weeks at altitudes between 3730 and 6850 m, despite improving
residence; absence of excessive
arterial oxygen saturation consistent with a progressive increase in erythrocytosis (hemoglobin
the loop gain of the respiratory control system [58]. concentration <19 g/dL in women,
<21 g/dL in men)
Sleep in subjects affected by altitude-related illness
Chronic mountain Years Headache, dizziness, dyspnea, sleep
Altitude-related illnesses may exert a major impact on sleep sickness, Monge disturbances, fatigue. Excessive
through the associated symptoms and excessive hypoxemia. A disease (CMS) erythrocytosis (hemoglobin
summary of the different forms is provided in Table 54.1. Acute concentration ≥19 g/dL in women,
forms include acute mountain sickness (AMS), high-altitude cere- ≥21 g/dL in men). In some patients,
bral edema (HACE), and high-altitude pulmonary edema (HAPE). pulmonary hypertension, right heart
Chronic forms include chronic mountain sickness (CMS, Monge failure, hypoventilation
disease), and high-altitude pulmonary hypertension (HAPH). Subacute mountain Weeks to Dyspnea, exercise intolerance,
AMS is the most common form of high-altitude-related illness, sickness, or adult months pulmonary hypertension, right heart
affecting 10–40% of lowlanders ascending rapidly to moderate and infantile forms failure
altitudes (3000 m) and 40–60% ascending to altitudes between of cardiac subacute
4000 and 5000 m [60,61]. The diagnosis relies on the presence of mountain sickness
headache, sleep disturbance, and other typical symptoms in the (CSMS)
appropriate setting (Table 54.2). Obviously, headache, the cardinal Source data from N Engl J Med, 369(17), Bartsch P, Swenson ER, Acute high-altitude
symptom of AMS, and other AMS symptoms, including stomach illnesses, pp. 1666–67, Copyright (2013), Massachusetts Medical Society.
upset, might affect sleep quality at altitude. Insomnia is there-
fore commonly reported by mountaineers suffering from AMS,
and it is one of the symptoms evaluated by the Lake Louise AMS impaired diffusing capacity [64]. Subjects affected by HAPE expe-
Questionnaire (Table 54.2). As already mentioned, lowlanders rience severe sleep disruption and pronounced periodic breathing
arriving at 3500 m commonly reported sleep disturbances during [3]‌. Nifedipine or dexamethasone administered prophylactically
their first night at altitude, and this was most prominent in those may prevent HAPE.
suffering from symptoms of AMS [2]‌. Correspondingly, unaccli- Only a few studies have investigated sleep disturbances in high-
matized mountaineers suffering from AMS at 4590 m (Capanna landers affected by chronic altitude-related illness [42,46]. Among
Regina Margherita, Mt. Rosa) perceived their sleep quality as poor, Kyrgyz highlanders with HAPH studied at their altitude of resi-
and actigraphy confirmed pronounced nocturnal restlessness [49]. dence (3250 m), SWS was reduced compared with healthy high-
These symptoms were partially relieved with acclimatization for landers and the prevalence of sleep apnea was increased. This
2 days. Untreated AMS may progress to HACE, a life-threaten- suggested a potential role of sleep apnea in predisposing to elevated
ing condition characterized by severe headache (often resistant to pulmonary artery pressure [42].
painkillers), ataxia and progressive impairment of consciousness.
Evacuation to a lower altitude, supplemental oxygen, and dexa-
Effect of altitude in lowlanders with pre-existing
methasone may be lifesaving. sleep and breathing disorders
HAPE is a noncardiogenic form of pulmonary edema devel- In lowlanders suffering from the obstructive sleep apnea (OSA) syn-
oping in otherwise healthy, susceptible subjects within 2–5 days drome who discontinued their continuous positive airway pressure
after rapid ascent to altitudes over 3000 m [62]. With an estimated (CPAP) therapy during a sojourn at 1860 and 2590 m, we observed
prevalence of 3–5% at 4559 m, HAPE is much less common than pronounced hypoxemia and exacerbated sleep-related breathing
AMS [63]. The main clinical manifestations of HAPE are dysp- disturbances due to frequent central apneas/hypopneas (Fig. 54.9)
nea, cough, and reduced exercise tolerance associated with severe [65]. This was associated with sleep-related cerebral hypoxia as
hypoxemia, a restrictive pattern of pulmonary function, and an monitored by near-infrared spectroscopy (Fig. 54.10) [66]. During

Table 54.2 Lake Louise Score Questions and Rating associated with leg edema [65]. Subsequent randomized placebo-
controlled trials revealed that combined treatment with CPAP
Self-report 1. Headache 0 None using computer-controlled variable mask pressure and aceta-
(by mountaineer) 1 Mild zolamide provided improved oxygenation and optimal control of
2 Moderate breathing disturbances in sleep apnea patients at altitude [67,68].
3 Severe, incapacitating In patients with chronic obstructive pulmonary disease (COPD),
sleep is commonly disturbed near sea level [69] owing to dyspnea,
2. Gastrointestinal 0 None
cough, coexistent sleep-related breathing disorders, and other fac-
symptoms 1 Poor appetite or nausea tors that are yet incompletely understood. In a randomized con-
2 Moderate nausea or trolled study, we observed that COPD patients with moderate to
vomiting severe impairment in pulmonary function at 490 m (i.e, GOLD
3 Severe nausea or vomiting, grade 2–3) developed considerable nocturnal hypoxemia and se-
incapacitating vere high-altitude periodic breathing associated with sleep distur-
3. Fatigue and/or 0 None bances during the first night at 2590 m [70].
weakness 1 Mild
Prevention and treatment of sleep
2 Moderate
disturbances at altitude
3 Severe, incapacitating
Sleep disturbances at altitude can be mitigated by following a few
4. Dizziness/ 0 None basic rules. By selecting a gradual ascent to altitude, acclimatization
lightheadedness 1 Mild may improve oxygenation and hence altitude tolerance. In addition,
2 Moderate the risk of altitude-related illness is reduced. According to recom-
3 Severe, incapacitating mendations for healthy subjects, the ascent rate at altitudes above
5. Difficulty 0 Slept as usual 3000 m should not exceed 300 m/24 h, and sleeping altitude should
sleeping 1 Did not sleep as well
be selected as low as possible to avoid excessive nocturnal hypox-
as usual emia [71]. The use of drugs might also improve altitude tolerance.
2 Woke up many times, poor
However, the potential advantages and disadvantages of pharmaco-
night sleep logical therapy should be carefully considered, and its use should be
3 Could not sleep at all
restricted to mountaineers who suffer from altitude-related illness
or severe sleep problems. Several drugs used to prevent and treat
Clinical 6. Change in 0 None high-altitude-related illness (AMS, HACE, or HAPE), including
assessment mental status 1 Lethargy lassitude acetazolamide, dexamethasone, and nifedipine, may also improve
(by investigator)
2 Disoriented/confused sleep. In the following subsections, several treatment options are
3 Stupor/semi-consciousness discussed.
4 Coma Oxygen
7. Ataxia (heel-to- 0 None Using supplemental oxygen counteracts the effect of hypobaric
toe walking) 1 Maneuvers to maintain hypoxia and is a rational way to treat altitude-related illnesses and
balance thereby improve sleep quality. Raising the oxygen concentration
2 Steps off line at a given high altitude by 1% increases the inspired oxygen par-
3 Falls down tial pressure to a degree corresponding to an altitude reduction of
4 Cannot stand approximately 300 m [72]. Raising the fraction of inspired oxygen
(FiO2) in the sleeping room at 3800 m by 3% using oxygen concen-
8. Peripheral 0 None
trators increased nocturnal oxygen saturation, reduced the amount
edema 1 Peripheral edema at one of periodic breathing, and improved subjective sleep quality and
location
some tests of cognitive daytime performance [73,74]. Unfortunately,
2 Peripheral edema at two or oxygen is often not available in remote mountain areas.
more locations
Carbonic anhydrase inhibitors
The sum of the scores of self-rating (questions 1–5) and clinical assessment
(questions 6–8) is the Lake Louise Score. A score > 3 points on the AMS Self- The carbonic anhydrase inhibitor acetazolamide has been exten-
Reported Questionnaire in the presence of headache—while at an altitude > sively tested and found to be an effective drug for the preven-
2500 m—constitutes AMS. A sum score > 4 indicates clinically relevant acute tion and treatment of AMS [75]. Acetazolamide stimulates renal
mountain sickness (AMS) bicarbonate excretion, thereby inducing metabolic acidosis. This
counteracts the hypoxia-induced respiratory alkalosis and stimu-
Source data from Sutton JR, Coates G, Huston CS, [eds], The Lake Louise acute mountain
sickness scoring system. Hypoxia and molecular medicine: proceedings of the 8th
lates ventilation through augmenting the hypercapnic ventilatory
international hypoxia symposium, Copyright (1993), Queen City Press. response. Acetazolamide improves nocturnal oxygen saturation and
reduces high-altitude periodic breathing [76–78]. In a randomized
comparison with theophylline, acetazolamide was equally effective
daytime, driving simulator tests revealed impaired performance in normalizing periodic breathing at 3454 m but provided a higher
at 2590 m compared with 490 m baseline, and patients showed an nocturnal oxygen saturation [25]. In another study performed in
increase in blood pressure, cardiac arrhythmias, and weight gain mountaineers suffering from sleep disturbances at 3450 m, there

(a) 490 m (b) 2590 m

C3A2
LEOG
REOG
EMG
Pnas
Sum
Ribcage
Abdomen
EMGdiaL
EMDdiaR
100
SpO2 (%)
80
60
HR (1/min)
35
0 20 40 60 80 100 120 140 0 20 40 60 80 100 120 140
Time (s) Time (s)
(c)
2590 m, night 2 77 **
2590 m, night 1 **
85
1860 m, night 2 68 *
1860 m, night 1 62 *
490 m 45
80 60 40 20 0 20 40 60 80
Obstructive Apnea–hypopnea/h Central
Fig. 54.9 The effect of altitude travel in patients with untreated obstructive sleep apnea syndrome was investigated in a randomized study [65]. (a, b) Polysomnographic
recordings in one patient with predominantly obstructive apneas at 490 m (a) and central apneas at 2590 m (b). (c) Sleep-related breathing disturbances at 490 m and
on the 1st and 2nd night at 1860 and 2590 m, respectively, in the entire group of 34 untreated patients with obstructive sleep apnea syndrome. The bars and horizontal
lines represent median values and quartile ranges of obstructive and central apnea–hypopnea indices. At higher altitudes, the total apnea–hypopnea index increased
significantly, related to the emergence of central apnea/hypopnea during NREM sleep. *p < 0.01 versus 490 m; **p < 0.01 versus 490 m and versus 1860 m.
was no difference between acetazolamide (125 mg) and temazepam disturbances was considerable, acetazolamide was superior to no
(7.5 mg) concerning oxygen saturation, percent periodic breath- therapy at all and may therefore be recommended for OSA patients
ing, and actigraphic measures of sleep [79]. However, subjective at altitude if CPAP therapy is not feasible. An even better and nearly
sleep quality was significantly better in the group receiving temaz- optimal control of breathing disturbances was achieved in another
epam. Because acetazolamide acts as a diuretic, subjects on aceta- randomized trial with combined treatment by acetazolamide and
zolamide complained significantly more about nightly awakenings auto-adjusting CPAP [67].
due to urination. Apart from polyuria (8–55%), other frequent
side effects of acetazolamide comprise acral paresthesias (35–90%) Dexamethasone
and unpleasant taste (4–14%) [80]. In otherwise-untreated OSA Dexamethasone is a potent drug that prevents and effectively treats
patients travelling to 1680 and 2590 m, we found that acetazola- AMS and prevents HAPE in susceptible subjects [81]. Moreover,
mide (250 mg bid) improved oxygenation, nocturnal breathing disin a recent study in HAPE-susceptible subjects ascending from
turbances, and sleep quality, and it prevented an excessive blood lowlands to 4559 m within 24 hours, we found that dexametha-
pressure rise [68]. Even though the amount of residual breathing sone (4 mg bid) taken before ascent improved nocturnal oxygen

(a)
490 m
100
90
80
CTO, SpO2 (%)

70
60
50
40
30
22:00:00 23:00:00 00:00:00 01:00:00 02:00:00 03:00:00 04:00:00 05:00:00
(b) 2590 m
100
90
80
CTO, SpO2 (%)
70
60
50
40
30
22:00:00 23:00:00 00:00:00 01:00:00 02:00:00 03:00:00 04:00:00 05:00:00
(c)
Cycle time
Nasal cannula
pressure (au)
100
SpO2 (%) 90 S1
80 S2
70
CTO (%) 60
C1
C2
50
1
HHb (au)
0
O2Hb (au)
–1
CtHb (au) 0 H2
–1
H1
04:45:00 04:46:00 04:47:00 04:48:00
Fig. 54.10 Recordings of cerebral oxygenation by near-infrared spectroscopy (NIRS) in a patient with untreated obstructive sleep apnea syndrome at 490 m and on
the 1st night at 2590 m. (a, b) Entire nights (7.5 hours) with large swings of finger pulse oximetry (SpO2), and more moderate swings of cerebral tissue oxygen saturation
(CTO) that depart from lower baseline levels. (c) A 3-minute episode of the recording at 2590 m. Nasal cannula pressure swings show several apnea/hyperpnea cycles
and corresponding changes in SpO2, CTO, oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), and total cerebral hemoglobin (CtHb). Variables listed in
Table 54.2 are marked: SpO2 baseline (S1); SpO2 nadir (S2); SpO2 desaturation amplitude = difference in amplitude S1 − S2; SpO2 desaturation time to nadir = difference
in time S2 − S1; CTO baseline (C1); CTO nadir (C2); CTO desaturation amplitude = difference in amplitude C1 − C2; CTO desaturation time to nadir = difference in time
C2 − C1; CtHb rise in amplitude = H2-H1; CtHb time from CTO drop to CtHb peak = difference in time H2 − C1.
Reproduced from Chest, 146(2), Ulrich S, Nussbaumer-Ochsner Y, Vasic I et al., Cerebral oxygenation in patients with obstructive sleep apnea. Effects of hypoxia at altitude and of acetzolamide,
pp. 299–308, Copyright (2014), with permission from Elsevier.

saturation and increased the amount of SWS at 4559 m [50]. The may further impair sleep quality. The relevance of sleep problems
powerful action of the drug in the prevention and the treatment during space missions is highlighted by common in-flight use of
of AMS—and thereby also improving sleep—seems to outweigh sleep medication. During 79 US Space Shuttle missions, involving
by far the potential sleep-disturbing effects, which are not well 219 person-flights, the use of any medication was recorded in 94%
established [82]. [89]. Of these medications, 47% were for space motion sickness and
45% for sleep disturbances, with smaller percentages of analgesics
Theophylline
or anti-inflammatory agents. The most commonly used hypnotics
Theophylline reduces nocturnal periodic breathing [25], but does were temazepam (67% of all sleep medications), followed by zolpi-
not show any beneficial effects on oxygen saturation and sleep dem (10%), triazolam (10%) and flurazepam (7.5%). In contrast
structure [83]. It may exert its action by an increase in ventilatory to medication against space motion sickness, which was mainly
drive and in cardiac output, but the mechanisms have not been used at the beginning of the mission, sleep medications were taken
studied in detail. Theophylline has a narrow therapeutic window, throughout the mission duration.
shows interactions with many other drugs, and promotes cardiac A detailed analysis of the effects of space flight on sleep is ham-
arrhythmia. It is therefore not recommended as a standard treat- pered by the lack of conclusive studies. Most of what is currently
ment of high-altitude periodic breathing. known about sleep, circadian rhythms, and work–rest schedules in
Hypnotics space is based on anecdotal reports originating from log books and
Several randomized placebo-controlled trials have evaluated the interviews with astronauts, plus a few observational studies. The
effect of benzodiazepines and non-benzodiazepine hypnotics in first experiments were performed in monkeys and revealed that
subjects at simulated or real altitude [15,24,27,30,84,85]. Contrary sleep was remarkably fragmented and unusually brief in duration
to some negative expectations, neither the benzodiazepine temaze- [90–92]. In the following discussion, only human studies performed
pam nor the non-benzodiazepine hypnotics zolpidem and zaleplon during real space travel are considered [93–96], since simulations
had adverse effects on oxygen saturation and ventilation, but they (water immersion and head-down rest) may not appropriately
were effective in improving sleep quality at altitude and, in some reflect the complex physical, physiological, and psychological
studies, even next-day performance [24,27,30,84,85]. Therefore, effects of real space flight [97–99]. We identified seven observa-
the cited hypnotics may be used cautiously to treat insomnia in tional studies including a total of 21 astronauts evaluating sleep
mountaineers at moderate altitude (up to 4000 m) in a safe setting in space using electrophysiological monitoring [93–96,100–102].
where resting in a state of reduced arousability is not considered to In one of these studies, the effect of microgravity on breathing dur-
represent an unacceptable risk. Since zaleplon has a relatively short ing sleep was evaluated in five astronauts [103].
half-life (1 h) compared with zolpidem (2.4 h), it might be particu- In 1974, Frost et al. reported on sleep studies in 2 astronauts liv-
larly suitable for use in the mountains. In mountaineers sleeping in ing in space for 28 (Skaylab II) and 59 days (Skylab III) [93]. Data
exposed camps, the use of hypnotics is discouraged because of the from 9 of 12 and from 18 of 20 attempted sleep recordings during
potential danger associated with a potential paradoxical reaction Skylab II and III missions, respectively, were available for analy-
or impaired arousability. Further studies on sleep and treatment of sis. During the Skylab II mission, the mean in-flight sleep duration
its disturbances at altitude have been systematically reviewed [86]. was shorter (6.04 h) than the sleep duration before departure (6.9
h), which was related to a shorter resting time. During the Skylab
III mission, sleep times did not differ significantly from preflight
Sleep in space travel baseline. No major changes in sleep stages were noted. Post-flight
Given the necessity and opportunity of performing interplan- changes concerned mostly REM sleep, with an increase from 18.5%
etary spaceflights, the effects of microgravity and other associated to 25% in Skylab II and from 13% to 22% in Skylab III. Gundel and
physical effects on human sleep have become of increasing inter- colleagues performed PSG together with body temperature record-
est. Restorative sleep is essential for maintaining optimal alertness ings as a marker of the circadian rhythm in four astronauts aboard
and neurobehavioral functioning over the course of long-lasting, the Russian Mir station [95]. Analysis of recordings did not reveal
demanding space missions. Reduction of the gravitational force to significant changes in any of the sleep parameters. Monk et al. stud-
less than 1g (microgravity) may induce space motion sickness. The ied four astronauts during a 17-days Space Shuttle mission [96]. For
symptoms are similar to those of terrestrial motion sickness and operational reasons, there were changes in bedtime and wake time
comprise headache, malaise, disorientation, nausea, and vomiting throughout the flight, but these were distributed equally through-
usually lasting for not more than 2–3 days [87]. Space missions are out the mission, leading to a phase advance of 25 minutes per day
associated with sleep restriction and disruption and with distur- with a strict schedule of a 23.58-hour day and an 8-hour sleep
bances of the circadian rhythm, especially if the mission requires opportunity. No hypnotics were used during the whole mission.
very long and irregular shifts. Various physiological functions (eg, Sleep time was reduced from an average of 392 minutes to 353 min-
hormone secretion, body temperature, and sleep rhythm) exhibit a utes in early flight and to 375 minutes in late flight, with a marked
circadian periodicity with a cycle length of approximately 24 hours. reduction in SWS. No difference in sleep architecture in late flight
Space flight may alter this circadian rhythm, causing profound compared with early flight periods was found. Similar results were
disturbances in physiological functions. Thus, during a 520-day obtained on board the Mir orbiting station in four subjects living
ground simulation of a Mars mission in six subjects, disturbances of up to 241 days in space. The durations of SWS and REM sleep did
sleep quality, sleep–wake periodicity, and timing recorded by actig- not change, and the cyclic structure of sleep persisted [101].
raphy suggested inadequate circadian entrainment [88]. Sleeping The only randomized trial performed in space was conducted
in an unusual, noisy, and uncomfortably warm environment, con- during Space Shuttle missions STS-90 and STS-95 [100,103]. In
fined to a sleeping bag, and the excitement and stress of the flight a double-blind placebo-controlled crossover design [100], 0.3 mg

melatonin was administered on alternate nights in five subjects 11. Julian CG, Vargas E, Gonzales M, et al. Sleep-disordered breathing and
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295
Index
A anorexia nervosa 453 BMAL1 4, 38

acetazolamide 402, 521–2 antidepressants 10, 127, 189, 192–3, 330, 378, body temperature regulation 8, 44–5, 292–3
acetylcholine neurons 25 444, 445 borderline personality disorder 453
achondroplasia 465 antiepileptics 287 botulism 305
acid maltase deficiency 305 antihistamines 193 bradycardia 46
acid reflux 415–16 antihypertensives 140 brain-derived neurotrophic factor 37
acquired immunodeficiency syndrome 138 anti-MA2 antibodies 349 brain tumors 137
acromegaly 139, 423 antipsychotics 193–4, 452 breathing
actigraphy 85–7, 90 antispasmodics 140 at altitude 517–20
acute cardiovascular syndromes 430 anxiety disorders 123, 182, 445–8 autonomic control 292
acute mountain sickness 520 apnea–hypopnea index 78–9, 109, 146, 159 pacemaker 45
adaptive servo-ventilation 159, 160, 162–3, 168, apnea scoring 76 periodic 517–20
169, 171, 172, 402–3 apolipoprotein E (APOE4) 369 respiratory monitoring 57–8, 68,
Addison’s disease 424 apparent life-threatening event 460 75–8, 147–50
adenosine 50 arboviruses 138 bright light therapy 206, 210, 217, 218, 221, 463
adenosinergic system 36 armodafinil 126, 208–9 bruxism 92, 113, 230–2
adolescent sleep 11, 479 arousal disorders 113, 383–8, 495–8 bugle pressures 307
adrenaline neurons 24 arterial blood gases 307 bulimia nervosa 453
advanced sleep phase disorder 13, 216–17 ascending reticular activating system 3
African trypanosomiasis 138–9 asthma 409 C
age-related changes in sleep 11–12, 255, 347, atrial fibrillation 269 caffeine 127, 140, 208, 210–11
459, 469–72, 479 autism spectrum disorder 464–5 cancer-related fatigue 360
agrypnia excitata syndrome 293, 347, 493 autoimmune disease 125, 137, 347, 360 cannabis 140, 453
AIDS 138 automatic behavior 121 carbamazepine 287
airflow monitoring 58, 75–6, 147–9 autonomic dysfunction 267, 291–8, 350 carbon dioxide monitoring 76
alarm clock headache 315, 320 autonomic nervous system 43–4, 291–2 carbonic anhydrase inhibitors 521–2
alcohol and alcoholism 140, 452–3 awakening epilepsy 281 cardiac arrhythmias 296
aldosterone 49–50 awakening headache 313, 435 cardiac disease 153, 360, 395–405
α2δ ligands 241, 242 cardiac function 46
alpha activity 73 B cardiac output 46
alpha agonists 430 Babinski’s response 43 cardiac transplantation 402, 404
alternating leg muscle activation 91, 114, 229 baroreflex 291–2 cardiopulmonary disease 359–60
altitude-related illness 520 baroreflex sensitivity 293 cardiovascular disease 398, 505–6
alveolar hypoventilation syndromes 167–8 Basic Language Morningness Scale 218 cardiovascular reflex tests 293
Alzheimer disease 138, 255–7, 348, 350, 470–1 behavioral insomnia of childhood 462 cardiovascular system 46–7
American Academy of Sleep Medicine (AASM) behavioral therapy 126, 134, 194–8 cataplectic facies 121
guidelines benign epilepsy with centrotemporal spikes 283 cataplexy 19–21, 121–2
actigraphy 86 benign sleep myoclonus of infancy 113 catecholamine systems 24–5
multiple sleep latency test 82 benzodiazepine receptor agonists catechol-O-methyltransferase 36
periodic limb movement scoring 89 (z-drugs) 189–91, 210, 444 cellphones 108
polysomnography 55–6 benzodiazepines 189–91, 210, 287, 430, 524 central nervous system
amphetamines bilevel positive airway pressure 159, 162, arousal scoring 74–5
shift workers 208 172, 308 changes in sleep 43
withdrawal 140 binary units 61 central pattern generators 493, 495
amyloid plaques 470 biofeedback 197–8 central sleep apnea
amyotrophic lateral sclerosis 302–3, 359 bipolar derivation 59–60 Cheyne–Stokes breathing 168, 397
anemia 360 bipolar disorder 451–2, 504–5 children 460, 462
Angelman syndrome 465 bits 61 clinical findings 153, 395, 397
angiotensin I/II 49–50 blindness 216, 219, 350 drug-induced 168–9
anoneira 333, 334–5 blood pressure 46–7, 161–2, 291–2, 420 elderly 472
anoneirognosis 338 dippers 47, 292 heart failure 153, 399–400
530
530 index
central sleep apnea (cont.) cognitive therapy 197 neuroimaging 336–8

ICSD-3 criteria 112 Columbian Jet Lag Scale 210 reality confusion 338
non-hypercapnic 167 common mode rejection 58–9 reward activation model 340
oxygen therapy 402 complex sleep apnea syndrome 170–1 driving 508–9
pathophysiology 167–8, 398–9 computer use 108 drug dreams 339, 340
phrenic nerve stimulation 403 COMT 36 drug-induced conditions
positive airway pressure therapy 162, 168, confusional arousals 384–5, 487 central sleep apnea 168–9
171, 402–3 congenital central alveolar hypoventilation hypersomnia 139–40
primary 169–70 syndrome 172, 295–6, 462 in ICU 430
primary of infancy 460 congenital muscular dystrophies 305 sleep problems in MS 329
scoring 76 congenital myasthenic syndrome 305 substance abuse 140, 168–9, 453
substance use 168–9 consciousness 7, 495 Duchenne muscular dystrophy 303
treatment emergent 170–1 continuous positive airway pressure 159, duodenal ulcer 415
treatment options 402–3 161–2, 163–4, 168, 171, 172, 266–7, 308, dynamic occlusion 147
cerebral blood flow 47 400–1, 402, 425–6, 445, 447, 461, 505
Charcot–Wilbrand syndrome 333–4 coronary artery disease 398 E
Cheyne–Stokes breathing 168, 397, 402–3, 472 corticobasal degeneration 258 eating disorders
childhood epilepsy with occipital corticosteroids 329 anorexia and bulimia 453
paroxysms 283 corticotropin 423, 424 night eating syndrome 113, 388, 423–4, 487
children 459–66 corticotropin-releasing hormone 423, 424 sleep-related 113, 387–8, 487
apparent life-threatening event 460 cortisol 48, 49, 423, 424 ecstasy 453
central sleep apnea 460, 462 cosinor analysis 86 elderly 12, 45, 255, 367–70, 469–72
confusional arousals 384 costs of sleep disorders 181–2, 510 electrical interference (50/60 Hz) 58, 60, 63
delayed sleep phase syndrome 462–3 Creutzfeldt–Jakob disease 37–8 electrical status epilepticus during sleep 283–4
development of sleep 11–12, 459, 479 critical closing pressure 146–7 electrocardiogram 57, 65, 67
free-running sleep disorder 220 critical illness 429–30 electrodes 56–7, 71–2
infant sleep position 461 Cushing’s disease 424–5 electroencephalography
insomnia 462 cyclical alternating pattern 10, 486 biofeedback therapy 197–8
narcolepsy 463 cytokines 50 consciousness 7
narcolepsy with cataplexy 121, 127 cyclic alternating pattern 10, 486
obstructive sleep apnea 461–2 D NREM sleep 3, 9–10
parasomnias 463–4 deep sleep 9 periodic limb movements during
restless legs syndrome 462 deep vein thrombosis 410 sleep 229
sleep disordered breathing 461–2 delayed sleep phase disorder 13, 134, 217–18, polysomnography 56, 59–60, 72, 73
sleep-related hypoventilation 462 446, 462–3 REM sleep 3, 10
sleep-related hypoxemia 462 delirium in ICU 429 signal derivation 59–60
stroke and sleep apnea 267 delta activity 73 sleep stage scoring 73–4
sudden infant death syndrome 460, 461 dementia 470–1 speeding 75
chin EMG 56–7, 72 frontotemporal 350 wakefulness 3
chromosomal abnormalities 139 with Lewy bodies 257–8, 348, 379 electromyography 10, 56–7, 72
chronic anemia 360 see also Alzheimer disease biofeedback 197
chronic fatigue syndrome 134, 361 depression 123, 182, 328, 443–5, 504 electronic devices 108
chronic kidney disease 360, 419–21 dermatomyositis 305 electro-oculography 56, 72
chronic mountain sickness 520 detrusor-dependent enuresis 389 Elpenor syndrome 384
chronic obstructive pulmonary disease 359–60, developmental aspects of sleep 11–12, 459, 479 encephalitis 138
409, 410, 472, 521 dexamethasone 522, 524 encephalopathy 347
chronic renal insufficiency 360, 419–21 dexmedetomidine 430 endocrine disorders 139, 423–7
chronic widespread musculoskeletal dextroamphetamine 126 endocrine system 48–50
pain 434 diabetes 139, 162, 426, 506–7 end-stage renal disease 360, 419–21
chronotherapy 463 Diagnostic and Statistical Manual of Mental energy drinks 208
circadian dysrhythmia 349–50 Disorders (DSM-V) 109–10 environmental factors 125, 427, 503
circadian rhythm 4, 13 dialysis patients 360, 419–21 epidemic encephalitis 138
circadian rhythm sleep–wake disorders diaphragm pacing stimulation 309 epilepsy 279–88
215–16 dihydroergotamine 318 antiepileptic drugs 287
DSM-V criteria 109 dim light melatonin onset 206 benign with centrotemporal spikes 283
ICSD-3 criteria 113 dippers 47, 292 childhood with occipital paroxysms 283
post-traumatic 325 diuresis-dependent enuresis 389 disturbed sleep 350
stroke 271, 273 dopamine agonists 140, 241, 242, 247, epileptic encephalopathy with continuous
Circadin 192 248–9, 250 spikes and waves during slow sleep 283–4
circulatory system 46–7 dopaminergic system 24–5, 36, 98, 229, 239– excessive daytime sleepiness 138, 286
clarithromycin 135, 137 40, 339, 340, 345, 489 grand mal seizures on wakening 281
classification systems 109–15 dopamine transporter 36 juvenile myoclonic 281–2
CLOCK 4, 38 dorsal paragigantocellular nucleus 16 nocturnal frontal lobe 284–5
clomipramine 127 Down syndrome 139, 464 obstructive sleep apnea 286
clonazepam 378 dream delusions 122 parasomnias 285–6
clozapine 452 dreaming 333–40 REM sleep behavior disorder 286
cluster headache 313, 314, 315, 319–20 deficits 333–6 sleep disorders and 285–6
cocaine 140, 453 excess 338–9 sleep-related hypermotor 285
cognitive–behavioral therapy 218, 240, 444 motivational theories 340 sudden unexpected death 288
cognitive function 8, 357, 367–70, 505 neurochemistry 339 vagus nerve stimulation 287–8
1 53
index 531
epileptic encephalopathy with continuous free-running sleep disorder 219–21 ICSD-3 criteria 112–13
spikes and waves during slow sleep 283–4 frontotemporal dementia 350 idiopathic 113, 131–5, 338
epinephrine neurons 24 Functional Outcomes of Sleep medical disorders 137–9, 270–1, 348–9
epochs 61, 72 Questionnaire 152 medication and substance use 139–40
Epstein–Barr virus 138 psychiatric disorders 140
Epworth Sleepiness Scale 82, 152, 205 G women 476–7
ergot alkaloids 318 GABAergic neurons 15–16, 25–9, 37 hypertension 182, 420
esophageal function 47–8 gabapentin 287 hyperthyroidism 426
esophagitis 415–16 gain 60 hypnagogic foot tremor 91, 113–14, 232
estradiol 427 gastric acid secretion 47–8, 415 hypnagogic hallucinations 122
ethology 493 gastric motility 48 hypnagogic hypersynchrony 12
ethosuximide 287 gastroesophageal reflux disease 47–8, 415–16 hypnic headache 315, 320
EURO-QOL 152 gastrointestinal function 47–8, 415–17 hypnogram 9
excessive daytime sleepiness genetics of sleep 5, 33–9 hypnotics 189–91, 208, 210, 524
chronic kidney disease 420 gepants 318 hypocretin (orexin) 5, 29–30, 38, 123, 125,
dementia 470 ghrelin 423–4 346, 470
elderly 471 glutamatergic neurons 15, 25–9 hypoglossal nerve stimulation 401–2
epilepsy 138, 286 glycogenoses 139 hypopnea scoring 76–8
migraine 316 glymphatic system 8–9 hypotension 420
narcolepsy 119–20 gonadal hormones 426–7 hypothalamic–pituitary–adrenocortical
Parkinson disease 137, 247–9 gonadotropin-releasing hormone 49 system 423, 424–6
pharmacotherapy 126–7 gonadotropins 49 hypothalamic–pituitary–somatotropic
post-traumatic 325 grand mal seizures on wakening 281 system 423–4
quality of life 508 ground electrode 57 hypothalamus 16–17, 23, 314, 315, 346
excessive fragmentary myoclonus 91, growth hormone 48–9, 423–4 hypothyroidism 139, 360, 426
113–14, 229 growth hormone-releasing hormone 423 hypoventilation syndromes
excessive quantity of sleep 131 Guillain–Barré syndrome 138, 359 alveolar 167–8
excitatory postsynaptic potentials 44 congenital central alveolar 172, 295–6, 462
exercise therapy 206, 240 H obesity 171–2
expert witnesses 496–7 hallucinations 113, 122, 338
expiratory pressure relief 163–4 headache 313–21, 434–5 I
exploding head syndrome 113, 317, 321, alarm clock 315, 320 ICU patients 429
390, 478 on awakening 313, 435 image rehearsal therapy 447
cluster 313, 314, 315, 319–20 imipramine 127
F hypnic 315, 320 immune system 50; see also autoimmune
faciomandibular myoclonus 92, 231 medication-overuse 317–19 disease
facioscapulohumeral muscular migraine 313, 314, 315, 316, 317–19, 435 immunoglobulin G 133
dystrophy 305 nocturnal 313 immunomodulation 127–8, 329
familial advanced sleep phase REM-locked 317 indomethacin 321
disorder 34, 216–17 sleep apnea 316–17, 320, 435 inductance plethysmography belts 58, 149
familial studies 34–5 tension-type 317, 320–1, 435 infantile spasms 283
fatal familial insomnia 37, 293–5, 338, 347 head injury 306, 347 infection 50, 125, 138–9
fatigue 355–61 head jerks 92 infectious mononucleosis 138
cancer-related 360 heartburn 415–16 inflammatory myopathies 305
central 356 heart disease 153, 360, 395–405 influenza vaccination 125
chronic fatigue syndrome 134, 361 heart rate 43–4, 46, 293 inhibitory postsynaptic potentials 44
chronic renal disease 420 heart transplantation 402, 404 Innsbruck Questionnaire 378
cognitive 357 hemodialysis 360, 419–21 insomnia
comorbidity 357 hepatitis B 138 assessment and evaluation 180–1
definition 355–6 high-altitude 515–24 cardiovascular disease 505
excessive daytime sleepiness high-altitude cerebral edema 520 children 462
differentiation 121, 122 high-altitude pulmonary edema 520 chronic renal disease 420
hemodialysis 420 high-altitude pulmonary hypertension 520 contemporary models of 182–4
medical conditions 359–60 high-frequency leg movements 91 costs 181–2
neurological disorders 357–9 histamine neurons 25 daytime impairment 181
pathophysiology 356 histamine-3 receptor antagonists 127, 135 defining features 177
peripheral 356 HIV 138 depression 182, 443–4, 504
psychiatric disorders 360 HLA typing 124, 125, 135, 330 DSM-V criteria 109, 177
sleep disorders 357 hormone replacement therapy 480 elderly 469–70, 471
Fatigue Severity Scale 355 hormones 8, 48–50, 423–7 fatal familial 37, 293–5, 338, 347
fibromyalgia 434 Horne–Östberg Morningness–Eveningness fatigue 357
filters 55, 60 Questionnaire 216, 218 general health effects 181–2
fixed action patterns 493, 495 human immunodeficiency virus 138 genetic factors 179–80
flip-flop switch model 3, 314 Hunter–Cheyne–Stokes breathing 168, 397, heart failure 404–5
fluid overload 420–1 402–3, 472 ICSD-3 criteria 110, 112, 177
flumazenil 135 Huntington disease 258, 348, 350 industrialization 108
follicle-stimulating hormone 49 hypercapnia 301 integrative psychobiological model 183–4
forced oscillation technique 150 hypersomnia migraine 316
forced vital capacity 301, 307 differential diagnosis 81 morbidity 181–2
forensics 494–7 DSM-V criteria 109 mortality risk 507
532
532 index
insomnia (cont.) leg EMG 57 multiple sclerosis 138, 327–31, 349, 357–8

multiple sclerosis 327–9 leg movements in sleep 89–91 multiple sleep latency test 81–4, 123, 205
natural history 179 Lennox–Gastaut syndrome 283 multiple system atrophy 138, 379
neurocognitive model 183 levodopa 241 multisystem disease 139
neuroimaging 99–101 levothyroxine 135 Munich Chronotype Questionnaire 216, 218
neurological conditions 347–8 light sleep 9 muscular dystrophy
non-pharmacological limb-girdle muscular dystrophy 305 congenital 305
interventions 194–8, 444 limit-setting disorder 462 Duchenne 303
pain 433 limits of entrainment 216 facioscapulohumeral 305
Parkinson disease 250, 348 linkage analysis 34–5 limb-girdle 305
pharmacotherapy 189–94, 198 lithium 137 myasthenia gravis 304–5, 359
polysomnography 180 locomotor centers 486 myotonic dystrophy 138, 303–4, 349, 359
post-traumatic 325 long sleeper 12, 113, 134
prevalence 177–8 loop gain 167, 398–9 N
psychobiological inhibition/ loss of state boundary control 124–5 napping 207, 348, 436
attention–intention–effort model 183 Lou Gehrig’s disease 302–3, 359 narcolepsy
psychological and behavioral lung transplantation 409 cataplexy, see narcolepsy with cataplexy
interventions 194–8, 444 luteinizing hormone 49 without cataplexy 119, 247–8
pulmonary disorders 409 lysosomal storage disorder 139 children 463
quality of life 507–8 cognitive function 505
restless legs syndrome 348 M dream/reality confusion 338
risk factors 179 maintenance of wakefulness test 81–4 DSM-V criteria 109
road safety 509 major depressive disorder 443–5 fatigue 357
schizophrenia 452 mandibular advancement devices 154–5, 401 ICSD-3 criteria 112
shift work 205 mania 451–2, 504–5 idiopathic hypersomnia
sleep maintenance 250, 348 maxillomandibular osteotomy 401 differentiation 133–4
sleep misperception 180 maximum expiratory pressure 307 migraine 316
sleep onset 45, 347–8 maximum inspiratory pressure 307 mortality risk 507
stroke 269–70 Mayo Sleep Questionnaire 378 multiple sclerosis 330
3-P model 182–3 mazindol 126, 134 neuroimaging 98–9
women 475–6 MDMA 453 orexin system 5
work performance 508 mean sleep latency 82, 84 Parkinson disease 247–8
Insomnia Severity Index 205 mechanical ventilation 308–9, 429, 430 quality of life 508
insufficient sleep syndrome 113, 140 medication-overuse headache 317–19 REM sleep behavior disorder and 19,
insulin 426 melanin concentrating hormone 30 123, 491
insulin resistance 162 melanopsin 4 road safety 509
intensive care units 429–30 melatonin 13, 48, 315, 346, 471 secondary 348–9
intensive sleep retraining 196–7 melatonin agonists 191–2, 210, 471 type 1 and 2 107, 112, 119, 123
interferon alpha 50 melatonin therapy 134, 191–2, 206, 208, 210, narcolepsy with cataplexy 119–28
interferon-β1 329 217, 218, 220, 221–2, 287, 378, 463 autonomic dysfunction 296–7
interleukin-6 50 memory 4–5, 8, 123 behavioral modification 126
International Classification of Sleep Disorders menopause 45, 480 children 121, 127
(ICSD-3) 109, 110–14 menstruation comorbidity 122–3
intestinal motility 416 hypersomnia 477 diagnosis 123–4
intraoral devices 154–5, 401 Kleine–Levin syndrome 136 differential diagnosis 124
invasive mechanical ventilation 308–9 migraine 318 environmental triggers 125
iron supplements 242, 462, 478 sleep during 479 epidemiology 119
irregular sleep–wake rhythm disorder 221–2 metabolic disorders 139, 305, 359 genetic predisposition 125
irreminiscence 333, 334, 335 metabolic syndrome 162, 267 ICSD-3 criteria 123
irritable bowel syndrome 416–17 metabolism 8, 47 network dysfunction 19–21
isolated phrenic neuropathy 305–6 3,4-methylenedioxymethamphetamine 453 neurobiology 19–21
methylphenidate 126 pathophysiology 124–5
J migraine 313, 314, 315, 316, 317–19, 435 pharmacotherapy 126–8
JEM sleep 73 migrating motor complex 48, 416 risk factors 125
jet lag 45, 209–11, 216, 427 mild cognitive impairment 469 symptoms 119–22
juvenile myoclonic epilepsy 281–2 mindfulness meditation training 197 treatment 125–8
minute ventilation 46 nasal air pressure transducer 58, 76, 149
K mitochondrial myopathies 305 neck myoclonus during sleep 92
Karolinska Sleepiness Scale 82, 205 mixed apneas 76, 78 network model of REM sleep 17
K-complexes 10, 11–12, 73, 459 modafinil 126, 134, 155, 208–9, 330 neurodegeneration 137–8, 255–9, 348, 350,
kidney disease 360, 419–21 Monge disease 520 379–80, 490–1
Kleine–Levin syndrome 101, 113, 135–7, 338 monoamine neurons 16, 25 neurological disorders 137–8, 345–51, 357–9
monoamine oxidase 36 neuromodulation 318–19, 320
L morbidity risks 181–2, 503–4 neuromuscular disorders 138, 301–9, 349, 359
lactation, medication use 476, 477, 478 mortality risks 507 neuromuscular junction disorders 304–5, 359
Lambert–Eaton myasthenic syndrome 305 Morvan’s syndrome 347 neuromyelitis optica 349
lamotrigine 287 motivational theories of dreaming 340 newborn sleep 11, 459
Landau–Kleffner syndrome 284 motor neuron disease 302–3, 359 nicotine 412
lasmiditan 318 motor vehicle accidents 508–9 Niemann–Pick disease 139
laughter-induced cataplexy 121 mouth pressures 307 night eating syndrome 113, 388, 423–4, 487
legal issues 494–7 mucopolysaccharidoses 139 nightmares 109, 113, 338–9, 447, 478
53
index 533
nocturia 249–50, 328 stroke 263–9, 398, 506 pavor nocturnus 385–6

nocturnal enuresis 35, 478 surgical treatment 155 PCO2 reserve 398
nocturnal frontal lobe epilepsy 284–5 tongue muscles 46 pediatrics, see children
nocturnal headache 313 weight loss 154 PER3 38
nocturnal hypoventilation 302, 307, 349 women 477 periaqueductal gray 16, 314
nocturnal leg cramps 230 obstructive sleep apnea syndrome period control 215
nocturnal myoclonus 227 acromegaly 423 periodic breathing 517–20
nocturnal panic attacks 339, 447–8 altitude effects 520–1 Periodicity Index 228
non-entrained type/non-24-hour sleep autonomic dysfunction 296 periodic limb movement disorder 113, 227–30
disorder 219–21 cognitive function 505 periodic limb movements 89–90, 227
noninvasive ventilation 302–3, 308, 309 driving licenses 509 periodic limb movements during sleep
non-periodic leg movements 89 DSM-V criteria 109 actigraphy 87, 90
non-REM sleep, see NREM sleep hypothalamic–pituitary–adrenocortical antidepressants 445
nonrestorative sleep 433 system 425 clinical relevance 229
non-steroidal anti-inflammatory drugs 140 ICSD-3 criteria 112 differential diagnosis 229
noradrenaline (norepinephrine) neurons 24–5 idiopathic hypersomnia differentiation 133 EEG 229
Norrie disease 139 neuroimaging 97–8 epidemiology 227
NREM parasomnias 113, 286, 383–8, presentation 395 heart failure 404
463–4, 472 traffic accidents 509 hemodialysis 419
NREM sleep occipital nerve stimulation 319, 320 multiple sclerosis 328–9
autonomic control 43, 292 oneiric stupor 293 narcolepsy with cataplexy and 122
blood pressure 46 opioids 140, 168–9, 241, 397, 430, 453 pathophysiology 229
cardiac function 46 orexin (hypocretin) 5, 29–30, 38, 123, 125, polysomnography 228
cerebral blood flow 47 346, 470 restless legs syndrome 238
CNS changes 43 orofacial myofunctional therapy 107 road safety 509
cyclic alternating pattern 10 overlap syndrome 359, 410, 472 scoring 89–90
EEG 3, 9–10 oxidative phosphorylation disorders 305 stroke 274–5
epileptic activity 279, 281 oximetry 58, 68, 76, 307 treatment 229–30
genetic control 33 oxygen therapy 309, 402, 521 periodic limb movements of
metabolism 47 wakefulness 89, 227
muscle hypotonia 44 P periodic paralyses 359
neuroanatomy 347 pain 327–8, 433–7 peripheral nervous system 44
neuroimaging 97 panic attacks 123, 339, 447–8 peripheral vascular resistance 47
normal architecture 9 paradoxical intention 197 pharyngeal collapsibility 146–7
respiration 46 paradoxical sleep, see REM sleep phase advancement therapy 463
stages (N1, N2 and N3) 9–10, 73 parasitic disease 138–9 phase control 215
thermoregulation 45 parasomnia overlap syndrome 376, 493 phase delay therapy 463
NREM sleep arousal disorder 109 parasomnias phase response curve 215
nucleus tractus solitarius 43 children 463–4 phenobarbital 287
Nyquist theorem 61 cognitive neuroscience of 493–4 phenytoin 287
DSM-V criteria 109 phrenic nerve stimulation 403
O elderly 472 phrenic neuropathy 305–6
obesity 107, 122, 154, 398, 424 epilepsy 285–6 physical exercise 206, 240
obesity hypoventilation syndrome 171–2 heritability 34 piezoelectric belts 58
obsessive–compulsive disorder 445–6 ICSD-3 criteria 113 pitolisant 127, 135
obstructive sleep apnea 145–56 migraine 316 Pittsburgh Sleep Quality Index 205
cardiovascular disease 398, 505–6 narcolepsy with cataplexy and 123 pleiosomnia, post-traumatic 325
children 461–2 NREM 113, 286, 383–8, 463–4, 472 PLMS Index 228, 238
clinical findings 150–3 other 113, 388–90 polio 306, 358
CPAP therapy 161–2, 163–4, 266–7, 400–1, REM 113, 464 polymyositis 305
425–6, 445, 447, 461, 505 sleep forensics 494–7 polysomnography 55–70
depression 444–5 violent 485–94 analog-to-digital conversion 61
elderly 472 women 478–9 artifacts 55, 63–8
epilepsy 286 parasympathetic system 43, 291 data processing 78–9
fatigue 357 Parkinson disease 245–51 definition 55
management 153 circadian dysrhythmia 350 development of 55
mandibular advancement devices 154–5, 401 dopamine agonist therapy 247, 248–9, 250 digital data display 60
mortality risk 507 dream/reality confusion 338 digital filters 55, 60
multiple sclerosis 329–30 excessive daytime sleepiness 137, 247–9 ECG 57, 65, 67
narcolepsy with cataplexy and 122 fatigue 358 EEG 56, 59–60, 72, 73
non-CPAP treatment 153–5, 401–2 hypersomnia 348 electrical interference (50/60 Hz) 58, 60, 63
overlap syndrome 359, 410, 472 insomnia 250, 348 electrical safety 63
Parkinson disease 249 narcolepsy 247–8 electrodes 56–7, 71–2
pathophysiology 46, 146–7, 397–8 nocturia 249–50 EMG 56–7, 72
pharmacotherapy 155 pre-motor 249 EOG 56, 72
positional 267 REM sleep behavior disorder 249, 339, epochs 61, 72
post-traumatic stress disorder 447 379, 490–1 filters 55, 60
postural treatment 154 sleep disordered breathing 249 gain 60
prevalence 395 paroxysmal hemicrania 317, 321 indications 55–6
pulmonary disorders 409–10 patent foramen ovale 269 insomnia 180
scoring 76 pathological wakefulness 429 monitoring patients 63
534
534 index
polysomnography (cont.) process S 4, 346 autonomic dysfunction 297–8

movement artifacts 67 progressive muscle relaxation 197 clinical features 490–1
muscle artifact 63–5 progressive supranuclear palsy 258 diagnosis 375–6
noise 63 prolactin 49, 426 differential diagnosis 376, 492
oximetry 58, 68, 76 propriospinal myoclonus at sleep onset 92, disease associations 378–9
PAP flow sensors 58 113, 229 dreaming 339
patient/equipment interface 56–7 proximal myotonic myopathy 303 DSM-V criteria 109
periodic limb movements during sleep 228 Prozac eyes 10 elderly 472
polarity verification 59 psychiatric disorders 140, 360, 443–8, epidemiology 375
popping artifact 66 451–3, 504–5 epilepsy 286
recording parameters 56 psychobiological models 183–4 ICSD-3 criteria 113, 492
referential derivation 59–60 psychological interventions 194–8 multiple sclerosis 330
REM sleep behavior disorder 376–7 pulmonary artery pressure 47 narcolepsy and 19, 123, 491
respiration artifacts 66 pulmonary capillary wedge pressure 399 network dysfunction 17–19
respiratory monitoring 57–8, 68, 75–8 pulmonary disorders 409–12 neurodegeneration 379–80, 490–1
scoring 72–5 pulmonary embolism 410 neuroimaging 99
sensitivity 60 pulmonary function tests 307 Parkinson disease 249, 339, 379, 490–1
signal derivations 59–60 pulmonary hypertension 410 pathophysiology 378–9, 489
signal processing 58–9 pulmonary rehabilitation 412 polysomnography 376–7
slow-frequency artifact 65–7 pulse oximetry 58, 68, 76, 307 risk factors 375
sweat artifact 65 pulse transit time 150 scoring 93
system reference 61, 67–8 screening 377–8
timescale 61 Q stroke 273–4
polyvinylidene fluoride sensors 58 quality of life 507–8 treatment 378, 492–3
Pompe disease 139, 305 QUEBEC 152 women 478
pontine brainstem lesions 335–6 quinine sulfate 230 REM Sleep Behavior Disorder
positive airway pressure therapy 159–64 Questionnaire–Hong Kong 378
adaptive servo-ventilation 159, 160, 162–3, R REM Sleep Behavior Disorder Screening
168, 169, 171, 172, 402–3 ramelteon 192, 210, 471 Questionnaire 249, 378
adherence and compliance 163–4 rapid eye movement sleep, see REM sleep REM Sleep Behavior Disorder Severity
autotitrating CPAP 161, 164 RBD Severity Scale 93–4 Scale 249
bilevel 159, 162, 172, 308 recurrent isolated sleep paralysis 113 REM Sleep Behavior Disorder Single Question
clinical results 161–3 referential derivation 59–60 Score 378
cognition and 370 relaxation training 197 renal disease 360, 419–21
continuous 159, 161–2, 163–4, 168, 171, 172, REM atonia 10, 44, 376–7, 378, 489 renal function 48
266–7, 308, 400–1, 402, 425–6, 445, 447, REM behavioral events 377 renin 425–6
461, 505 REM-locked headache 317 renin–angiotensin–aldosterone system 49–50
devices and interfaces 160–1 REM sleep residual volume 301
elderly 367, 370 atonia 10, 44, 376–7, 378, 489 respiratory disturbance index 146
expiratory PAP 159 without atonia 93 respiratory effort 76
expiratory pressure relief 163–4 autonomic control 43, 292 respiratory-effort-related arousal 78,
heated humidification 163 blood pressure 46 146, 147–8
initiation 161 cardiac function 46 respiratory failure 430
inspiratory PAP 159 cerebral blood flow 47 respiratory gases 76
modifiable pressure settings 163 circulatory system 46, 47 respiratory inductive plethysmography
physiological mechanisms 159–60 CNS changes 43 bands 58, 149
side effects 163 dissociation phenomenon 127 respiratory monitoring 57–8, 68, 75–8,
posterior hypothalamic neurostimulation 320 EEG 3, 10 147–50
post-polio syndrome 306, 358 epilepsy 279 respiratory muscle weakness 301
post-traumatic fatigue 358 generation of REMs 97 respiratory system 45–6
post-traumatic sleep disorders 138, 325–6, metabolism 47 restless legs syndrome 107–8, 237–42
349, 435 network model 17 antidepressants 445
post-traumatic stress disorder 446–7 neuroanatomy 347 children 462
postural treatment 154 neurobiology 15–21, 347 clinical aspects 237–9
Prader–Willi syndrome 139, 465 neurochemistry 339 cognitive function 505
pramipexole 140 neuroimaging 97 diagnostic criteria 237–9
prefrontal leucotomy 335 neuromuscular disorders 302 DSM-V criteria 109, 239
pregabalin 241 normal architecture 9 early-onset 237
pregnancy parasomnias 113, 464 elderly 472
medication use 476, 477, 478 phasic 10, 74 epidemiology 237
restless legs syndrome 478 reciprocal interaction model 3 fatigue 357
sleep during 479–80 respiration 46, 302 genetics 34–5, 239
primary central sleep apnea 169–70 stages 10, 73–4 hemodialysis 419
of infancy 460 stroke 268 ICSD-3 criteria 113, 239
primary nocturnal enuresis 35 thermoregulation 45 insomnia 348
primidone 287 tonic 10, 74 iron deficiency 98, 240
prion protein 37–8 REM sleep atonia index 93 iron supplements 242, 462, 478
problem-solving therapy 197 REM sleep behavior disorder 375–81, 488–93 late-onset 237
process C 4, 346 antidepressants 445 migraine 316
53
index 535
multiple sclerosis 328–9 sleep apnea–hypopnea syndrome 146, 154, space travel 524–5
neuroimaging 98 155–6, 430 sphingolipidoses 139
periodic leg movements during sleep 238 sleep attacks 120 spinal cord injury 306, 350
pharmacotherapy 241–2 sleep bruxism 92, 113, 230–2 spinal muscular atrophy 306–7
physiopathology 239–40 sleep disordered breathing spinocerebellar ataxia 259
pregnancy 478 children 461–2 split-night study 161
pulmonary disorders 412 elderly 367–70, 471–2 sporadic inclusion-body myositis 305
quality of life 508 multiple sclerosis 329–30 stages of sleep 9–10, 73–4
road safety 509 neuromuscular disorders 301–9 Standard Shiftwork Index 206
sleep disturbance 239 Parkinson disease 249 Stanford Sleepiness Scale 82
stroke 274–5 pathogenesis 46 state boundary control 124–5
treatment 240–2 post-traumatic stress disorder 447 status cataplecticus 121
uremic 419 women 477 status dissociatus 259, 493
women 477–8 see also sleep-related breathing disorders Steinert disease 303
reticular formation 23 sleep drunkenness 384, 486, 487 stimulants 126, 134, 208–9, 330
revisualization deficiency 333, 334, 335 sleep enuresis 113, 388–90 withdrawal 140
reward activation model 340 sleep forensics 494–7 stimulus control therapy 196
rhythmic foot movement 232 sleep fragmentation 122 stroke 263–75
rhythmic masticatory muscle activity 92, sleep hygiene education 198 circadian rhythm sleep disorders 271, 273
230, 231 sleep inertia 384–5, 486 fatigue after 358
rhythmic movement disorder 92–3, 113, 232 sleepiness, state/trait 81–2 hypersomnia 137, 270–1
road safety 508–9 sleepiness scales 81–2, 152, 205 insomnia 269–70
ropinirole 140 sleeping sickness 138–9 obstructive sleep apnea 263–9, 398, 506
Rosenthal syndrome 338 sleep instability 486–7 REM sleep behavior disorder 273–4
sleep latency 82, 84 sleep-related breathing disorders 263–9,
S sleep medicine 7, 107 398, 506
safety issues sleep onset association disorder 462 sleep-related movement disorders 274–5
polysomnography 63 sleep onset REM period (SOREMP) 82 sublaterodorsal tegmental nucleus 15
sleep disorders 508–9 sleep paralysis 122 substance abuse 140, 168–9, 453
sampling rate 61 sleep-related abnormal sexual sudden infant death syndrome 460, 461
sarcoidosis 139 behavior 387, 487–8 sudden onset of sleep 247
sawtooth waves 10 sleep-related breathing disorders sudden unexpected death in epilepsy 288
schizophrenia 452, 505 definitions 146 sundowning 256, 273, 470
scoliosis 303 heart disease 395–403 supine vital capacity nasal inspiratory
sedative-induced hypersomnia 140 hemodialysis 419–20 pressure 307
sensitivity 60 ICSD-3 criteria 112 suprachiasmatic nucleus 4, 13, 38, 44, 346
sensorimotor rhythm feedback 197–8 pulmonary disorders 409–12 suvorexant 5
sepsis 429–30 stroke 263–9, 398, 506 sympathetic system 43, 291
serotonergic system 25, 36–7, 315 traumatic brain injury 325 synucleinopathies 99, 249, 297–8, 378,
serotonin transporter 37 see also sleep disordered breathing 379–80, 490–1
sexsomnia 387, 487–8 sleep-related eating disorders 113, 387–8, 487 systemic lupus erythematosus 139, 360
shift work 45, 203–9, 216, 357, 427, 507, 508 sleep-related faciomandibular system reference 61, 67–8
short-sleepers 12 myoclonus 92, 231
sickle cell disease 267 sleep-related hallucinations 113 T
signal derivations 59–60 sleep-related hypermotor epilepsy 285 temperature regulation 8, 44–5, 292–3
signal processing 58–9 sleep-related hypoventilation 302, 410–11, 462 temporomandibular disorders 434
sign stimulus 493 sleep-related hypoxemia 302, 411–12, 462 tension-type headache 317, 320–1, 435
Sjögren syndrome 360 sleep-related leg cramps 113 testosterone 49, 427
sleep sleep-related movement disorders 227–33 thalamic infarction 347, 349
age-related changes 11–12, 255, 347, 459, ICSD-3 criteria 113–14 theophylline 402, 524
469–72, 479 post-traumatic 325 thermistors 58, 75–6, 148
definition 7 scoring movements 89–94 thermocouples 58, 75–6, 148
deprivation 8 stroke 274–5 thermoregulation 8, 44–5, 292–3
developmental changes 11–12, 459, 479 sleep restriction therapy 196 theta activity 73
duration and mortality risk 507 sleep scoring 72–5 theta electroencephalography feedback 197–8
function 4–5, 8–9 sleepsex 387, 487–8 3-P model 182–3
genetics of 5, 33–9 sleep spindles 10, 11, 73, 97, 459 thyroid stimulating hormone 49
neuroanatomy 23, 345–7 sleep starts 229 tiagabine 287
neurochemistry 23–30, 339 sleep-talking 113 tick-borne encephalitis 138
neuroimaging 97 sleep terrors 339, 385–6, 487 tidal volume 46
neurophysiology 23–30 sleepwalking 386–7, 487 tobacco 412
normal amount 12 sleepwalking defense 488, 494–5 tonsillectomy 401
normal architecture 9–10 slow-wave sleep 9, 73, 97 tracé alternant 459
physiological changes in 43–50 Smith–Magenis syndrome 139 tracé discontinue 459
scoring 72–5 smoking (cessation) 412 tracheostomy 308–9
stages 9–10 snoring 264, 313 traffic accidents 508–9
staging rules 73–4 social phobia 123 transcranial magnetic stimulation 337, 356
subjective quality 33–4 sodium oxybate 126–7, 134 transient ischaemic attacks 265
sleep apnea headache 316–17, 320, 435 somnambulistic sexual behavior 387, 487–8 transplant patients 402, 404, 409
536
536 index
traumatic brain injury 138, 325–6, 349, uremic toxicity 420 W

358, 435 urine production 48 wakefulness
treatment emergent central apnea 170–1 EEG 3
triptans 318 V neuroanatomy 23, 345–6
trisomy 21 139, 464 vagotomy 415 neurochemistry and neurophysiology
Trypanosoma brucei 138–9 vagus nerve stimulation 287–8 23–30
tumour necrosis factor-α 37, 50 valerian 194 staging 73
twin studies 33–4 valproate 137, 287 West syndrome 283
type 1 diabetes 426 vasopressors 430 Willis–Ekbom disease, see restless legs
type 2 diabetes 139, 162, 506–7 ventral tegmental area 339 syndrome
ventrolateral periaqueductal gray 16, 314 women 475–81
U ventrolateral preoptic area 346 work performance 508
upper airway collapsibility 146–7 vigabatrin 287
upper airway resistance syndrome 78, viral infections 138 Z
145–6, 147–8 vital capacity 301, 307 z-drugs 189–91, 210, 444

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Oxford Textbooks in Clinical Neurology

5-​HT 5-​hydroxytryptamine (serotonin) BIPN bilateral isolated phrenic neuropathy

IPAP inspiratory positive airway pressure NDRI norepinephrine (noradrenaline)–​dopamine

PLMW periodic leg/​limb movements during wakefulness SCN suprachiasmatic nucleus

TTH tension-​type headache VNS vagus nerve stimulation

Introduction to basic science

4 Section 1 basic science

As described by Borbély, sleep is modeled by the homeostatic

gal DR cadian oscillation of BMAL1 is regulated by the orphan nuclear

Chapter 1 introduction to basic science 5

subsequent transfer of short-​term memories to longer-​term stor- References

6 Section 1 basic science

An overview of sleep medicine

8 Section 1 basic science

Table 2.2 Physiological criteria for wakefulness and sleep

Criterion Awake NREM sleep REM sleep

Chapter 2 an overview of sleep medicine: history, definition, sleep patterns, and architecture 9

10 Section 1 basic science

Chapter 2 an overview of sleep medicine: history, definition, sleep patterns, and architecture 11

there is usually nocturnal sleep consolidation by the age of 1 year.

12 Section 1 basic science

Chapter 2 an overview of sleep medicine: history, definition, sleep patterns, and architecture 13

1 secretion is coupled to SWS. It is also well known that plasma levels

1 example, there is a natural tendency toward a delayed sleep phase

14 Section 1 basic science

16 Section 1 basic science

Chapter 3 neurobiology of rem sleep 17

18 Section 1 basic science

W/PS-on neurons W-on neurons PS-on neurons Inhibitory pathways

SWS-on neurons PS-off neurons Excitatory pathways

Paradoxical (REM) sleep

SWS-on neurons PS-off neurons Excitatory pathways

Chapter 3 neurobiology of rem sleep 19

Idiopathic RBD CORTICAL

Degenerating neurons W-on neurons PS-on neurons Inhibitory pathways

20 Section 1 basic science

W/PS-on neurons W-on neurons PS-on neurons Inhibitory pathways

W/PS-on neurons PS-off neurons Excitatory pathways

Chapter 3 neurobiology of rem sleep 21

22 Section 1 basic science

24 Section 1 basic science

Fast EEG (W & REM):

Slow EEG (SWS):

Cortical activation (W/REM): Glu CB

Chapter 4 neuroanatomical, neurochemical, and neurophysiological bases of waking and sleeping 25

26 Section 1 basic science

8 neurons is positively correlated with EMG activity. They are thus

Chapter 4 neuroanatomical, neurochemical, and neurophysiological bases of waking and sleeping 27

SWS-max: Nb+/GAD+ neuron (BF) W-max: Nb+/VGluT2+ neuron (SubLDT)

PS-max: Nb+/VGluT2+ neuron (LDT) PS-max: Nb+/GAD+ neuron (SubLDT)

Chapter 4 neuroanatomical, neurochemical, and neurophysiological bases of waking and sleeping 29

and subcortical forebrain. The alternating activity of different Orexin neurons

W-max: Orexin neuron (PH) PS-max: MCH neuron (PH)

30 Section 1 basic science

Chapter 4 neuroanatomical, neurochemical, and neurophysiological bases of waking and sleeping 31

32 Section 1 basic science

The genetics of sleep

34 Section 1 basic science

Chapter 5 the genetics of sleep 35

5-HT 5-hydroxytryptamine (serotonin) BIPN bilateral isolated phrenic neuropathy

IPAP inspiratory positive airway pressure NDRI norepinephrine (noradrenaline)–dopamine

PLMW periodic leg/limb movements during wakefulness SCN suprachiasmatic nucleus

TTH tension-type headache VNS vagus nerve stimulation

subsequent transfer of short-term memories to longer-term stor- References

Gene Modification Affected phenotype/trait References

Fig. 7.1 The International 10/20 System of electrode placement (top view).