Icsd 3 PDF

I
C
International
Classification of
S
Sleep Disorders
Third Edition
D
3
American Academy of Sleep Medicine
I
C
International
Classification of
S
Sleep Disorders
Third Edition
D
3
American Academy of Sleep Medicine
Copyright © 2014 American Academy of Sleep Medicine,
2510 North Frontage Road, Darien, IL 60561, U.S.A.
Copies of the manual are available from the American Academy of

Sleep Medicine in the U.S.A.
All rights reserved. Unless authorized in writing by the AASM, no portion

of this book may be reproduced or used in a manner inconsistent with
the copyright. This applies to unauthorized reproductions in any form,
including computer programs.
Correspondence regarding copyright permissions should be directed to the

Executive Director, American Academy of Sleep Medicine, 2510 North
Frontage Road, Darien, IL 60561, U.S.A. Translations to other languages
must be authorized by the American Academy of Sleep Medicine, U.S.A.
Recommended Citation
American Academy of Sleep Medicine. International classification of sleep

disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine, 2014.
International classification of sleep disorders, 3rd ed. American Academy of

Sleep Medicine. Includes bibliographies and index.
1. Sleep Disorders – Classification. 2. Sleep Disorders – Diagnosis
ISBN: 0991543416 (print)
ISBN: 0991543408 (online)

In memory of Peter Hauri, PhD
mentor, colleague and friend
Table of Contents
About the Editor............................................................................................8
Editor’s Notes................................................................................................9
Acknowledgments.......................................................................................10
Introduction..................................................................................................13
Insomnia.......................................................................................................19
Chronic Insomnia Disorder..................................................................................... 21
Short-Term Insomnia Disorder................................................................................ 41
Other Insomnia Disorder......................................................................................... 46
ISOLATED SYMPTOMS AND NORMAL VARIANTS
Excessive Time in Bed............................................................................................ 47
Short Sleeper.......................................................................................................... 47
Sleep Related Breathing Disorders...........................................................49

OBSTRUCTIVE SLEEP APNEA DISORDERS
Obstructive Sleep Apnea, Adult.............................................................................. 53
Obstructive Sleep Apnea, Pediatric........................................................................ 63
CENTRAL SLEEP APNEA SYNDROMES
Central Sleep Apnea with Cheyne-Stokes Breathing............................................. 69
Central Apnea Due to a Medical Disorder without Cheyne-Stokes Breathing........ 75
Central Sleep Apnea Due to High Altitude Periodic Breathing................................ 79
Central Sleep Apnea Due to a Medication or Substance........................................ 85
Primary Central Sleep Apnea................................................................................. 89
Primary Central Sleep Apnea of Infancy................................................................. 94
Primary Central Sleep Apnea of Prematurity.......................................................... 98
Treatment-Emergent Central Sleep Apnea........................................................... 102
SLEEP RELATED HYPOVENTILATION DISORDERS
Obesity Hypoventilation Syndrome....................................................................... 108
Congenital Central Alveolar Hypoventilation Syndrome....................................... 113
Late-Onset Central Hypoventilation with Hypothalamic Dysfunction.................... 118
Idiopathic Central Alveolar Hypoventilation.......................................................... 121
Sleep Related Hypoventilation Due to a Medication or Substance...................... 124
Sleep Related Hypoventilation Due to a Medical Disorder................................... 128
SLEEP RELATED HYPOXEMIA DISORDER
Sleep Related Hypoxemia.................................................................................... 134
5
Table of Contents

Snoring.................................................................................................................. 139
Catathrenia........................................................................................................... 141
Central Disorders of Hypersomnolence..................................................143

Narcolepsy Type 1................................................................................................ 146
Narcolepsy Type 2................................................................................................ 155
Idiopathic Hypersomnia........................................................................................ 161
Kleine-Levin Syndrome......................................................................................... 166
Hypersomnia Due to a Medical Disorder.............................................................. 171
Hypersomnia Due to a Medication or Substance................................................. 175
Hypersomnia Associated with a Psychiatric Disorder........................................... 179
Insufficient Sleep Syndrome................................................................................. 182
Long Sleeper........................................................................................................ 187
Circadian Rhythm Sleep-Wake Disorders...............................................189

Delayed Sleep-Wake Phase Disorder.................................................................. 191
Advanced Sleep-Wake Phase Disorder................................................................ 198
Irregular Sleep-Wake Rhythm Disorder................................................................ 204
Non-24-Hour Sleep-Wake Rhythm Disorder......................................................... 209
Shift Work Disorder............................................................................................... 215
Jet Lag Disorder.................................................................................................... 220
Circadian Sleep-Wake Disorder Not Otherwise Specified (NOS)......................... 224
Parasomnias..............................................................................................225
NREM-RELATED PARASOMNIAS
Disorders of Arousal (From NREM Sleep)............................................................ 228
Confusional Arousals............................................................................................ 229
Sleepwalking......................................................................................................... 229
Sleep Terrors......................................................................................................... 230
Sleep Related Eating Disorder............................................................................. 240
REM-RELATED PARASOMNIAS
REM Sleep Behavior Disorder.............................................................................. 246
Recurrent Isolated Sleep Paralysis....................................................................... 254
Nightmare Disorder............................................................................................... 257
OTHER PARASOMNIAS
Exploding Head Syndrome................................................................................... 264
Sleep Related Hallucinations................................................................................ 267
6
Table of Contents
Sleep Enuresis...................................................................................................... 270

Parasomnia Due to a Medical Disorder................................................................ 276
Parasomnia Due to a Medication or Substance................................................... 276
Parasomnia, Unspecified ..................................................................................... 278
Sleep Talking......................................................................................................... 279
Sleep Related Movement Disorders........................................................281

Restless Legs Syndrome...................................................................................... 282
Periodic Limb Movement Disorder........................................................................ 292
Sleep Related Leg Cramps................................................................................... 299
Sleep Related Bruxism......................................................................................... 303
Sleep Related Rhythmic Movement Disorder....................................................... 312
Benign Sleep Myoclonus of Infancy...................................................................... 317
Propriospinal Myoclonus at Sleep Onset.............................................................. 321
Sleep Related Movement Disorder Due to a Medical Disorder............................ 325
Sleep Related Movement Disorder Due to a Medication or Substance................ 326
Sleep Related Movement Disorder, Unspecified.................................................. 327
Excessive Fragmentary Myoclonus ..................................................................... 328
Hypnagogic Foot Tremor and Alternating Leg Muscle Activation......................... 330
Sleep Starts (Hypnic Jerks).................................................................................. 335
Other Sleep Disorder................................................................................339
Appendix A:
Sleep Related Medical and Neurological Disorders...............................341
Fatal Familial Insomnia......................................................................................... 342
Sleep Related Epilepsy......................................................................................... 345
Sleep Related Headaches.................................................................................... 350
Sleep Related Laryngospasm............................................................................... 355
Sleep Related Gastroesophageal Reflux.............................................................. 358
Sleep Related Myocardial Ischemia..................................................................... 363
Appendix B:
ICD-10-CM Coding for Substance-Induced Sleep Disorders.................369
Glossary.....................................................................................................371
Index...........................................................................................................377
7
About the Editor
Michael Sateia, MD, is Professor of
Psychiatry at the Geisel School of
Medicine at Dartmouth. He has served
in a variety of leadership capacities in
Sleep Medicine. He is Past-President
of the American Academy of Sleep
Medicine. Dr. Sateia was Associate
Editor for the Journal of Clinical Sleep
Medicine and chaired the Scientific
Program Committee of the Associated
Professional Sleep Societies. He was
a member of the Research Advisory
Board of the National Center on Sleep Disorders Research and held a five
year Academic Award from the National Heart, Lung, and Blood Institute.
He served on the Accreditation Council on Graduate Medical Education
Advisory Committee for Sleep Medicine and the American Board of Internal
Medicine Policy and Test Committee for Sleep Medicine. His editing respon-
sibilities have included the International Classification of Sleep Disorders,
2nd Edition; the comprehensive textbook, Sleep Medicine; and Insomnia:
Diagnosis and Treatment. In 2009 he received the Nathaniel Kleitman Award
from the American Academy of Sleep Medicine. He currently serves as task
force chair and editor for the International Classification of Sleep Disorders,
3rd Edition, and chair of the task force on the pharmacological management
of insomnia. He has authored numerous scientific articles in sleep medi-
cine, focused primarily on insomnia and professional education in sleep.
8
Editor’s Notes
Many people contributed to the development of this manual. The members of
the Task Force on ICSD-3, who also chaired individual work groups, devoted
countless hours and tireless dedication to the work, as did the members of
their respective work groups. Numerous reviewers also provided thoughtful
recommendations which served to improve the text. These individuals are
acknowledged individually on the following pages.
A number of staff members of the American Academy of Sleep Medicine
contributed to this work. Our field owes a particular debt of gratitude for the
diligence, dedication and determination of Ms. Carolyn Winter-Rosenberg,
Director of Coding and Compliance at the AASM, who oversaw all facets of
this project. Without her, this publication would not have been possible.
Special thanks are extended to the Board of Directors of the American
Academy of Sleep Medicine. My personal thanks go to Nancy Collop,
President of the AASM at the outset of the project. I would also like to thank
the following members of the board during the revision process who provided
their expertise and time in reviewing multiple drafts: Amy Aronsky, DO;
M. Safwan Badr, MD; Kelly Carden, MD; Ronald Chervin, MD, MS;
Nancy Collop, MD; Samuel Fleishman, MD; Timothy Morgenthaler, MD;
Susan Redline, MD; Ilene Rosen, MD; Steven Shea, PhD;
Patrick Strollo, Jr., MD; Nathaniel Watson, MD, MS; Terri Weaver, PhD, RN;
and Merrill Wise, MD.
The international review effort was coordinated by the World Sleep
Federation. Thanks goes to Clete Kushida, MD, PhD, President of the WSF
for his assistance in this facet. Charles Reynolds, MD, chair of the DSM-5
sleep disorders work group, served as a valuable liaison in our efforts to
maximize concordance between classification systems.
I would also like to thank David Neubauer, MD and Ruth Benca, MD, PhD
who provided expertise on psychiatric conditions, as well as Maria Carra, PhD
who assisted with the development of the Movement Disorders chapter.
Finally, we are grateful to our colleagues and families, whose patience,
support and understanding of the long hours required to bring this manual to
fruition often go unheralded, but are deeply appreciated.
Michael Sateia, MD, Editor
9
Acknowledgments
ICSD Revision Task Force
Michael Sateia, MD, Chair
Geisel School of Medicine at Dartmouth, Lebanon, NH
Richard Berry, MD
University of Florida Health Science Center, Gainesville, FL
Michel Cramer Bornemann, MD
HealthEast Care Systems of Minnesota, Maplewood, MN
Karl Doghramji, MD, Psychiatric Representative
Thomas Jefferson University, Philadelphia, PA
Jack Edinger, PhD
National Jewish Health, Denver, CO
Richard Ferber, MD, Pediatric Representative
Harvard Medical School, Boston, MA
Gerald Rosen, MD, Pediatric Representative
Children’s Hospital of Saint Paul, Saint Paul, MN
Michael Silber, MB, ChB
Mayo Clinic, Rochester, MN
Arthur Walters, MD
Vanderbilt University Medical Center, Nashville, TN
Phyllis Zee, MD, PhD
Northwestern University Medical School, Chicago, IL
10
Acknowledgments
ICSD Revision Workgroups

INSOMNIA HYPERSOMNOLENCE
Jack Edinger, PhD, Chair Michael Silber, MB, ChB, Chair

National Jewish Health, Denver, CO Mayo Clinic, Rochester, MN
Daniel Buysse, MD Isabelle Arnulf, MD
University of Pittsburg School of Medicine, Pittsburg, PA Hopital Pitie Salpetriere, Paris, France
Kenneth Lichstein, PhD Suresh Kotagal, MBBS, Pediatric Representative
University of Alabama, Tuscaloosa, AL Mayo Clinic, Rochester, MN
Jodi Mindell, PhD, Pediatric Representative Thomas Scammell, MD
Saint Joseph’s University, Philadelphia, PA Beth Israel Deaconess Medical Center, Boston, MA
Charles Morin, PhD Sebastiaan Overeem, MD, PhD
Universite Laval, Quebec, Canada Radboud University Nijmegen Medical
Center, Nijmegen, Netherlands
CIRCADIAN RHYTHM SLEEP
WAKE DISORDERS MOVEMENT DISORDERS
Phyllis Zee, MD, PhD, Chair Arthur Walters, MD, Chair

Northwestern University Medical School, Chicago, IL Vanderbilt University Medical Center, Nashville, TN
Judith Owens, MD, Pediatric Representative Ronald Chervin, MD, MS
Children’s National Medical Center, Washington, DC University of Michigan Health System, Ann Arbor, MI
Robert Auger, MD Stephen Duntley, MD
Mayo Clinic, Rochester, MN Critical Care Pulmonary and Sleep
Associates, Lakewood, CO
Makoto Uchiyama, MD, PhD
Nihon University School of Medicine, Tokyo, Japan Giles Lavigne, DMD, PhD
University of Montreal, Montreal, Canada
Kenneth Wright, PhD
University of Colorado, Boulder, CO Daniel Picchietti, MD, Pediatric Representative
Carle Foundation Hospital, Urbana, IL
James Wyatt, PhD
Rush University Medical Center, Chicago, IL Denise Sharon, MD, PhD
Tulane University School of Medicine, Destrehan, LA
Steven Lockley, PhD, Advisor
Harvard Medical School, Boston, MA Marco Zucconi, MD
San Raffaele Hospital, Milan, Italy
SLEEP RELATED BREATHING
DISORDERS APPENDIX A
Richard Berry, MD, Chair Members of the Movement

University of Florida Health Science Disorders Work Group
Center, Gainesville, FL
Sean Caples, DO
Teofilo Lee-Chiong, MD Mayo Clinic, Rochester, MN
National Jewish Health, Denver, CO
Susan Harding, MD
Carole Marcus, MBBCh, Pediatric Representative University of Alabama, Birmingham, AL
Children’s Hospital of Philadelphia, Philadelphia, PA
Stuart Quan, MD
Harvard Medical School, Boston, MA
PARASOMNIAS
Michel Cramer Bornemann, MD, Chair

HealthEast Care Systems of Minnesota, Maplewood, MN
Carlos Schenck, MD
Hennepin County Medical Center, Minneapolis, MN
Gerald Rosen, MD, Pediatric Representative
Children’s Hospital of Saint Paul, Saint Paul, MN
Mark Pressman, PhD
Lankenau Medical Center, Wynnewood, PA
11
Acknowledgments
International Society Reviewers Reviewers

ASIAN SLEEP RESEARCH SOCIETY Alon Avidan, MD
Masako Okawa, MD, PhD Richard Allen, PhD
Makoto Honda, MD, PhD Richard Bootzin, PhD
Yuhei Kayukawa, MD Christopher Drake, PhD
Yuichi Inoue, MD, PhD Umakanth Khatwa, MD
Sanjeev Kothare, MD
AUSTRALASIAN SLEEP ASSOCIATION
Lois Krahn, MD
Shantha Rajaratnam, PhD
Leon Lack, PhD
Leon Lack, PhD
Mark Mahowald, MD
Nick Antic, PhD
Raman Malhotra, MD
CANADIAN SLEEP SOCIETY William Ondo, MD
Charles Samuels, MD James Parish, MD
Atul Khullar, MD David Rapoport, MD
James MacFarlane, PhD Eve Rogers, MD
Manisha Witmans, MD Carol Rosen, MD
EUROPEAN SLEEP RESEARCH SOCIETY
Katherine Sharkey, PhD
Arthur Spielman, PhD
Claudio Bassetti, MD
Michael Thorpy, MD
Ludger Grote, MD, PhD
Dieter Reimann, PhD
FEDERATION OF LATIN AMERICAN AASM Staff
SLEEP SOCIETIES
Jerome Barrett,
Darwin Vizcarra, MD Executive Director
Stuart Franklin Escobar-Córdoba, MD, MFP, PhD Kathleen McCann,
Dalva Poyares, MD, PhD Assistant Executive Director
SLEEP RESEARCH SOCIETY Derek Claussen,
Graphic Design Manager
Ronald Szymusiak, PhD
Jon Wendling,
Kingman Strohl, MD Publications Production Editor
Phillip Gehrman, PhD
Jason Wilbanks,
Programmer
Carolyn Winter-Rosenberg,
Director of Coding and Compliance
Steve Van Hout,
Director of Information Technology
12
Introduction
Classification of disorders plays several key roles in medicine. The most familiar of
these is that is serves as a guide to clinicians in the identification of specific disease
states. In doing so, classification systems provide clinicians with important informa-
tion regarding numerous related factors including pathogenesis, prognosis, course, and
heritability. Moreover, therapeutic interventions are largely guided by the nosologi-
cal decisions made by clinicians. In turn, information accrued regarding therapeutic
response of these disease states is utilized to further refine the nosology. Classification
systems also serve to define the domain of a given discipline, a factor of particular
importance for fields such as sleep medicine which cut across many related special-
ties. Finally, by identifying areas of uncertainty and overlap among related patholo-
gies, these systems play a critical role in guiding future research agendas which will
enhance our knowledge and understanding of the clinical features, pathophysiology
and treatment response specific to each disorder.
Since its infancy 35 years ago, the field of sleep medicine has paid particular atten-
tion to the issue of classification, beginning with the 1979 American Sleep Disorders
Association’s Diagnostic Classification of Sleep and Arousal Disorders. Since that
time, as our knowledge and understanding of sleep disorders has grown, several differ-
ent structural approaches have been utilized in revisions of the classification system,
culminating in the International Classification of Sleep Disorders, 2nd Edition. The
organization of that edition, although not without its limitations, has proven effective
and user-friendly and has been maintained in the current revision.
Ideally, classification systems are based largely on pathophysiology. However, such an

approach is dependent on adequate knowledge concerning the various pathophysiol-
ogies of disease or disorder within a given discipline. As is the case with many diag-
nostic systems, our current knowledge and understanding of the pathophysiology of
many sleep disorders is inadequate. As a result, International Classification of Sleep
Disorders, 3rd Edition, not unlike its predecessors, employs a hybrid approach which
utilizes pathophysiology, where known, but also relies heavily on phenomenology and
organ system approaches. Despite these shortcomings, this approach is one that has
proven familiar and workable for sleep medicine clinicians.
Recognizing the need for currency and relevance in a rapidly evolving field, the
American Academy of Sleep Medicine Board of Directors approved a revision of
International Classification of Sleep Disorders, 2nd Edition in 2011. Following appoint-
ment of a chair/editor, a task force, consisting of individual work group chairs for each
13
Introduction
major division of the manual, was selected, along with two pediatric consultants. A
focus group of experts was convened in June 2011 to obtain input on major structural
and content issues. Based on this feedback, individual work groups then set about to
define the list of disorders to be included within their sections as well as proposed cri-
teria for each diagnosis. This process included comprehensive literature searches for
every potential diagnosis as well as for their major features. The draft diagnostic crite-
ria which emanated from this work were then reviewed and modified by the task force
(consisting of the work group chairs and pediatric advisors), as well as by the board
of the AASM. The edited criteria were then distributed to external peer reviewers with
expertise in the respective areas, as well as to international societies and membership
sections of the AASM for comment. These reviews were carefully considered and revi-
sions made based on this input. Subsequent to this, text revisions were begun and the
same review process and modifications were undertaken once text drafts were com-
pleted. Further modifications were made based on recommendations from the AASM
board before finalization of the edition. At all points in this process, efforts were made
to rely as heavily as possible on available and current scientific evidence. However,
due to the paucity of available evidence in many areas, decisions regarding the nosol-
ogy were often made by consensus of the work groups, task force, and reviewers.
Using ICSD-3
As noted above, the general structure of the current edition closely parallels that of the
second edition. The major clinical divisions remain unchanged. As with International
Classification of Sleep Disorders, 2nd Edition, pediatric diagnoses are fully integrated
into the major clinical diagnoses, with the exception of obstructive sleep apnea, pediatric.
Where pediatric presentations call for variation in the diagnostic criteria, those variations
are noted within the criteria section. In an effort to better identify those clinical features of
a disorder which are developmentally-specific, a text heading for Developmental Issues
has been added for each diagnosis. Specific ICD codes (9-CM and 10-CM) are listed at
the beginning of each diagnosis. Because of the complexities and differences between
International Classification of Sleep Disorders diagnoses and the ICD system, assign-
ment of codes is challenging. These issues are discussed further under Coding below.
Although classification systems are, by their nature, intended to define disorders in

the most specific terms possible, clinicians must recognize that there is inevitably
some degree of variability in presentation which may result in clinically significant
conditions which do not meet all specific criteria for a given diagnosis. Therefore,
some degree of judgment is necessary in the application of these criteria. Bearing this
exception in mind, all listed criteria should generally be met for establishment of a
given diagnosis, unless otherwise specified. Clinicians should note that most diagnoses
14
Introduction
within the International Classification of Sleep Disorders include a criterion, or cri-

teria, that connote clinical significance (i.e., disturbing symptoms, significant conse-
quences, distress or impairment in one or more functional realms). These criteria are
particularly important because, without them, many phenomena related to sleep-wake
do not rise to a level that requires clinical attention and treatment. Users should also
pay particular attention to the Notes section (where included), as these notes provide
essential definitions and details concerning application of the criteria.
Clinicians will note a number of significant content changes from the former edition.
The most apparent of these is the collapse of all previous chronic insomnia diagnoses
into a single chronic insomnia disorder diagnosis. The rationale for this is described
in the introductory section of Insomnia disorders. A separate diagnosis is retained for
short-term insomnia. Within the Central Disorders of Hypersomnolence section, the
nomenclature for narcolepsy has been changed to narcolepsy type 1 and type 2. This
modification is discussed in the introduction to that section. Users will also find several
new diagnoses within the Sleep Related Breathing Disorders. Within the Central
Sleep Apnea Syndromes, a diagnosis of treatment-emergent central sleep apnea now
appears. This term is preferred to the widely used term complex sleep apnea because
it describes a more specific and well-defined disorder in which the central apnea arises
in the context of positive airway pressure treatment for obstructive sleep apnea and
is not attributable to another cause. Central sleep apnea associated with other identi-
fiable etiologies such as Cheyne-Stokes breathing or substance-induced central sleep
apnea are not classified as treatment-emergent. Assigning a diagnosis of a sleep related
hypoventilation disorder requires demonstration of elevated PaCO2 (by direct measure
of arterial blood gas or, more commonly, by proxy measures such as end-tidal or trans-
cutaneous CO2 determination). The new diagnosis of sleep related hypoxemia disor-
der should be employed when there is sustained drop in SaO2 but PaCO2 has not been
measured. Within the parasomnia section, a single set of general criteria and a unified
text now describe disorders of arousal from non-rapid eye movement sleep, although
additional, specific criteria and separate coding are maintained for the diagnoses within
this section (i.e., confusional arousal, sleepwalking and sleep terror). Other, somewhat
less consequential additions, deletions and reassignment of diagnoses also appear in
this edition. International Classification of Sleep Disorders, 2nd Edition contained a
separate chapter for Isolated Symptoms and Normal Variants. A small number of these
were felt to qualify as formal diagnoses at this time and have been moved to relevant
sections. Other symptoms and variants appear at the conclusion of the chapter to which
they are most applicable (e.g., snoring to the Sleep Related Breathing Disorders, long
sleeper to Central Disorders of Hypersomnolence, and movement related variants to
the Sleep Related Movement Disorder section).
15
Introduction
A wealth of information regarding each diagnosis is contained within the separate text
headings within each diagnostic section. The outline below details some of the spe-
cific content to be found within each text heading. These terms are not indexed in the
hard copy version of this manual because they appear throughout the document. Users
should refer to the relevant text heading within a specific diagnosis for information
related to these terms:
Alternate Names Pathology and Pathophysiology

Diagnostic Criteria Objective Findings
Essential Features includes:
• Sleep logs
Associated Features • Actigraphy
Clinical and Pathophysiological • Questionnaires
Subtypes • Polysomnography
• Multiple sleep latency test
Demographics
• Neurological
includes:
◦◦ Electroencephalogram
• Prevalence
◦◦ Cerebrospinal fluid
• Gender bias
◦◦ Neuroimaging
• Racial / ethnic bias
◦◦ Electromyogram
• Cultural issues
◦◦ Autonomic
Predisposing and Precipitating • Endocrine
Factors • Genetic testing
includes: • Physical findings
• Risk factors • Respiratory
Familial Pattern ◦◦ Arterial blood gas
includes: ◦◦ Pulmonary function
• Genetics ◦◦ Ventilatory response
• Familial clusters • Cardiac
◦◦ Electrocardiogram
Onset, Course and Complications
◦◦ Echocardiogram
includes:
◦◦ Cardiac catheterization
• Medical
• Serum chemistry
• Neurological
• Psychiatric / social
Developmental Issues
includes:
• Pediatric
• Geriatric
16
Introduction
Relationship to Other Classification Systems

Historically, there have been three major classifications systems for sleep disorders.
Although the International Classification of Sleep Disorders system has, for many
years, been the primary nosology for sleep medicine specialists, both the Diagnostic
and Statistical Manual of Mental Disorders (DSM) of the American Psychiatric
Association and the International Classification of Diseases (ICD) nosology of the
World Health Organization have also classified sleep disorders. Unfortunately, these
competing systems have differed significantly in structure and content over the years.
Development of DSM-5 was ongoing during the development of this manual and an
effort was undertaken to achieve the greatest degree of concordance possible between
these two systems, recognizing that the International Classification of Sleep Disorders
will inevitably contain a greater level of detail than DSM due to differences in their target
users. This goal was largely achieved although some differences will still exist. The
major change to the Insomnia section (i.e. establishment of a single chronic insomnia
disorder diagnosis) within this new system is paralleled in DSM-5. Central Disorders
of Hypersomnolence diagnoses are organized somewhat differently in the DSM clas-
sification than in this manual and narcolepsy criteria differ slightly. Circadian Rhythm
Sleep-Wake Disorder diagnoses are identical within the two systems with the exception
that DSM does not include a jet lag disorder. Sleep Related Breathing Disorders are
significantly more detailed within International Classification of Sleep Disorders than
DSM-5, although the organizational structures in this section are quite similar. Sleep
Related Movement Disorders and Parasomnias are likewise similar but with fewer
overall diagnoses within DSM-5.
With the publication of International Classification of Sleep Disorders, 2nd Edition, a

major effort to expand and reorganize sleep related diagnoses within ICD-9-CM was
undertaken. This effort resulted in the inclusion of many additional sleep related diag-
noses in ICD-9-CM (primarily within the Diseases of the Nervous System section).
The archaic distinction between “organic” and “non-organic” disorders has histori-
cally been a guiding principle of ICD, resulting in dissemination of sleep diagnoses to
both the neurological and mental disorder categories. Clinicians familiar with the ICD-
9-CM categories which have been employed since the most recent changes will find
general concordance between the assigned diagnostic codes found herein and the most
current version of ICD-9-CM. These ICD-9-CM codes for sleep disorders are essen-
tially carried over to ICD-10-CM. However, certain content revisions in International
Classification of Sleep Disorders, 3rd Edition (e.g., chronic insomnia) necessitates a
significant departure from the coding approach utilized in ICD-9-CM and International
Classification of Sleep Disorders, 2nd Edition. This is discussed further below.
17
Introduction
Coding
Diagnostic codes for the relevant ICD-9-CM and ICD-10-CM diagnoses can be found
at the beginning of each diagnosis section of the book. In the United States, the former
codes (ICD-9-CM) should be employed until the implementation date for ICD-10-CM
which, at the time of this writing, is to be no sooner than October 1, 2015. Following
that date, only the ICD-10-CM codes should be used. As already stated, clinicians
should recognize that there is not precise concordance between the assigned codes for
International Classification of Sleep Disorders, 3rd Edition diagnoses and the diagno-
ses listed within ICD. Changes to the International Classification of Sleep Disorders
classification system are not reflected in the ICD system for many years. Moreover, the
ICD classification of sleep disorders has historically been significantly less detailed
than ICSD (particularly for international users not employing the Clinical Modification
(CM) version used in the United States). Hence, clinicians will find many areas in
which assigned codes found in this manual do not correspond as closely as one would
like to ICD codes. Most notably, with the collapse of chronic insomnia diagnoses into
a single disorder in International Classification of Sleep Disorders, 3rd Edition, the
assigned codes for this diagnosis within International Classification of Sleep Disorders,
3rd Edition are 307.42 (ICD-9-CM) – “Nonorganic persistent disorder of initiating or
maintaining sleep” and F51.01 (ICD-10-CM) – “Primary insomnia.” A variety of other
insomnia diagnoses will continue to appear in the ICD system but, with the classifi-
cation and coding changes recommended herein, these become essentially defunct for
sleep medicine clinicians. In summary, the assigned codes in this edition represent
“best approximations” to the corresponding ICD codes, but some degree of discrep-
ancy between the systems will exist in a number of areas.
18
Insomnia
Chronic Insomnia Disorder............................................................................21
Short-Term Insomnia Disorder......................................................................41
Other Insomnia Disorder...............................................................................46
Isolated Symptoms and Normal Variants

Excessive Time in Bed..................................................................................47
Short Sleeper................................................................................................47
This section includes sleep disorders chiefly characterized by the complaint of insom-
nia. For the purpose of this manual, insomnia is defined as a persistent difficulty
with sleep initiation, duration, consolidation, or quality that occurs despite adequate
opportunity and circumstances for sleep, and results in some form of daytime impair-
ment. These three components of insomnia—persistent sleep difficulty, adequate
sleep opportunity, and associated daytime dysfunction—are collectively implied by
text references to the term insomnia. Among adults with insomnia, sleep complaints
most typically include difficulties initiating or maintaining sleep. Concerns about
lengthy periods of nocturnal wakefulness, insufficient amounts of nocturnal sleep, or
poor sleep quality often accompany these complaints. Individuals who report these
sleep related symptoms in the absence of daytime impairment are not regarded as
having an insomnia disorder that warrants clinical attention other than education and
reassurance. Insomnia among children is often reported by their caretakers and char-
acterized by bedtime resistance, frequent nighttime awakenings and/or an inability to
sleep independently. Regardless of the exact nature of the nocturnal sleep concerns,
daytime impairments are reported, presumably caused by the nighttime sleep diffi-
culties or by some common but unidentified mechanism during sleep and wakeful-
ness. Daytime symptoms typically include fatigue, decreased mood or irritability,
general malaise, and cognitive impairment. Among adults, chronic insomnia may
impair social or vocational functioning and reduce quality of life, whereas in chil-
dren it may lead to poor school performance, impaired attention, and behavioral
disturbance. In some patients, physical symptoms such as muscle tension, palpita-
tions, or headache may also be attributed to the insomnia. Others with more severe
forms of insomnia may be at increased risk for motor vehicle and work-site acci-
dents as well as psychiatric and cardiovascular disorders. Insomnia often accompa-
nies comorbid medical illnesses, mental disorders, and other sleep disorders. It may
also arise in association with the use, abuse, or exposure to certain substances. When
insomnia occurs comorbid to these conditions and is persistent and prominent, a sep-
arate insomnia diagnosis is warranted.
19
Insomnia
The insomnia nosology presented in this text represents a marked departure from
the previous International Classification of Sleep Disorders, 2nd Edition insomnia
classification system in terms of its conceptual framework and relative simplicity.
The previous insomnia nosology of the International Classification of Sleep Disorders
promoted the concept that insomnia can exist as a primary sleep disorder or arise as
a secondary form of sleep disturbance related to an underlying primary psychiatric,
medical, or substance abuse disorder. However, many symptoms and associated fea-
tures of so-called primary and secondary insomnias are overlapping, thus making
differentiation among such subtypes difficult, if not impossible. There is increas-
ing recognition that even when insomnia arises “secondary” to another condition,
it often develops an independent course over time and may remain as a clinically
significant condition, even if the so-called primary condition is adequately treated.
Evidence suggests that insomnia, if left untreated, may adversely affect the outcome
of these comorbid conditions. Moreover, it appears that treatment of the insomnia
may improve outcome of both the sleep disturbance and the comorbid conditions.
Given these observations, insomnia seems best viewed as a comorbid disorder that
warrants separate treatment attention.
In addition to the primary vs. secondary insomnia distinction, prior editions of the
International Classification of Sleep Disorders delineated multiple putative “primary
insomnia” diagnostic subtypes. Specifically, both the original 1990 version of the
International Classification of Sleep Disorders and the International Classification of
Sleep Disorders, 2nd Edition described primary insomnia subtypes such as psycho-
physiological insomnia, idiopathic insomnia, inadequate sleep hygiene, and paradox-
ical insomnia, as discrete diagnostic entities. Experience suggests that, in practice, it
is rare to encounter patients who meet the diagnostic criteria for exclusively one of
these subtypes. In fact, many of the diagnostic criteria delineated for these subtypes
represent generic characteristics (e.g., engaging in sleep-disruptive habits; underesti-
mation of sleep time, evidence of conditioned arousal) of insomnia, per se, and do not
facilitate discrimination among these subtypes or between these subtypes and those
presumed to have “secondary” forms of insomnia.
Both clinical experience and a growing body of empirical findings have shown
that the diagnostic distinctions advocated by previous versions of the International
Classification of Sleep Disorders are difficult to reliably ascertain and are of question-
able validity. In view of such considerations, the current manual abandons the previ-
ously employed complex and highly specific insomnia classification scheme described
by the original International Classification of Sleep Disorders and the 2nd Edition in
favor of a more global and defensible nosology.
20
Insomnia
The manual includes three diagnostic categories for insomnia: chronic insomnia
disorder, short-term insomnia disorder, and other insomnia disorder. These diag-
noses apply to patients with and without comorbidities regardless of whether those
comorbidities are viewed as potentially sleep disruptive. Chronic insomnia disorder is
characterized by chronic sleep onset and/or sleep maintenance complaints with asso-
ciated daytime impairment, and is reserved for individuals whose sleep difficulties
exceed minimal frequency and duration thresholds shown to be associated with clin-
ically significant morbidity outcomes. Short-term insomnia disorder is characterized
by sleep/wake difficulties that fail to meet the minimal frequency and duration criteria
of chronic insomnia disorder. Nonetheless, short-term insomnia disorder is associated
with clinically significant sleep dissatisfaction or waking impairment. Other insomnia
disorders should be assigned to those rare cases that fail to meet criteria for short-
term insomnia disorder, yet are thought to have sufficient symptoms of insomnia to
warrant clinical attention.
Chronic Insomnia Disorder

ICD-9-CM code: 307.42 ICD-10-CM code: F51.01
Alternate Names
Chronic insomnia, primary insomnia, secondary insomnia, comorbid insomnia, disor-
der of initiating and maintaining sleep, behavioral insomnia of childhood, sleep-onset
association disorder, limit-setting sleep disorder.
Diagnostic Criteria
Criteria A-F must be met
A. The patient reports, or the patient’s parent or caregiver observes, one or
more of the following:1
1. Difficulty initiating sleep.
2. Difficulty maintaining sleep.
3. Waking up earlier than desired.
4. Resistance to going to bed on appropriate schedule.
5. Difficulty sleeping without parent or caregiver intervention.
B. The patient reports, or the patient’s parent or caregiver observes, one or
more of the following related to the nighttime sleep difficulty:
1. Fatigue/malaise.
2. Attention, concentration, or memory impairment.
3. Impaired social, family, occupational, or academic performance.
21
Insomnia
4. Mood disturbance/irritability.
5. Daytime sleepiness.
6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression).
7. Reduced motivation/energy/initiative.
8. Proneness for errors/accidents.
9. Concerns about or dissatisfaction with sleep.
C. The reported sleep/wake complaints cannot be explained purely by
inadequate opportunity (i.e., enough time is allotted for sleep) or
inadequate circumstances (i.e., the environment is safe, dark, quiet, and
comfortable) for sleep.
D. The sleep disturbance and associated daytime symptoms occur at least
three times per week.
E. The sleep disturbance and associated daytime symptoms have been
present for at least three months.2
F. The sleep/wake difficulty is not better explained by another sleep disorder.
Notes
1. Reports of difficulties initiating sleep, difficulties maintaining sleep, or
waking up too early can be seen in all age groups. Resistance going to
bed on an appropriate schedule and difficulty sleeping without parent
or caregiver intervention is seen most commonly in children and older
adults who require the supervision of a caretaker due to a significant
level of functional impairment (e.g., those with dementia).
2. Some patients with chronic insomnia may show recurrent episodes
of sleep/wake difficulties lasting several weeks at a time over several
years, yet not meet the three-month duration criterion for any single
such episode. Nonetheless, these patients should be assigned a diagnosis
of chronic insomnia disorder, given the persistence of their intermittent
sleep difficulties over time.
3. Some patients who use hypnotic medications regularly may sleep well
and not meet the criteria for an insomnia disorder when they take such
medications. However, in the absence of such medications these same
patients may meet the above criteria. This diagnosis would apply to
those patients particularly if they present clinically and voice concerns
about their inability to sleep without their sleep medications.
4. Many comorbid conditions such as chronic pain disorders or gast
roesophageal reflux disease (GERD) may cause the sleep/wake complaints
delineated here. When such conditions are the sole cause of the sleep
difficulty, a separate insomnia diagnosis may not apply. However, in many
22
Insomnia
patients such conditions are chronic and are not the sole cause of sleep
difficulty. Key determining factors in the decision to invoke a separate
insomnia diagnosis include: “How much of the time does the sleep
difficulty arise as a result of factors directly attributable to the comorbid
condition (e.g., pain or GERD)?” or “Are there times that the sleep/wake
complaints occur in the absence of these factors?” “Have perpetuating
cognitive or behavioral factors (e.g., negative expectations, conditioned
arousal, sleep-disruptive habits) arisen, suggesting an autonomous aspect
to the ongoing insomnia?” If there is evidence that the patient’s sleep/
wake complaints are not solely caused by the medical condition, and those
sleep/wake complaints seem to merit separate treatment attention, then a
diagnosis of chronic insomnia disorder should be made.
Essential Features
The essential feature of chronic insomnia disorder is a frequent and persistent difficulty
initiating or maintaining sleep that results in general sleep dissatisfaction. The sleep
complaint is accompanied by distress about poor sleep and/or impairment in family,
social, vocational, academic, or other important areas of functioning. Furthermore,
the sleep disturbance and associated waking symptoms occur despite having adequate
time and circumstances each night to obtain necessary sleep. Chronic insomnia dis-
order can occur in isolation or comorbidly with a mental disorder, medical condition,
or substance use.
The sleep complaints that comprise chronic insomnia disorder may include difficul-
ties initiating sleep or difficulties maintaining sleep. The latter complaint may include
waking up during the night with difficulty returning to sleep or having a final awaken-
ing occurring too early, well before the desired rising time. Chronic insomnia disorder
may be characterized solely by sleep onset or sleep maintenance complaints or, more
commonly, by both types of complaints occurring together. Individuals’ sleep com-
plaints may also change over time such that those with solely sleep onset complaints
may subsequently develop sleep maintenance complaints and vice versa. Also, those
who present initially with mixed sleep onset and sleep maintenance difficulties may
later evidence one or the other of these difficulties but not both. Complaints about
poor-quality, unrefreshing, or nonrestorative sleep often accompany sleep onset and
sleep maintenance complaints, but do not suffice to define insomnia disorder when
occurring as the sole sleep complaint.
The degree of sleep disturbance required to assign a chronic insomnia disorder diag-
nosis is somewhat arbitrary in that it relies primarily on individuals’ subjective sleep
23
Insomnia
complaints. Moreover, the degree of sleep disturbance required to connote clinical

significance varies across age groups. Nonetheless, sleep onset latencies and periods
of wakefulness after sleep onset > 20 minutes generally connote clinically significant
sleep disturbances in children and young adults. In middle and older aged adults, onset
latencies and periods of wakefulness during sleep > 30 minutes typically connote clin-
ical significance. Complaints of early morning awakening are less well defined, but
typically entail the termination of sleep at least 30 minutes before the desired rising
time and a concomitant reduced total sleep time compared with the usual premorbid
sleep pattern. The exact time at which early morning awakenings occur may vary con-
siderably as a function of usual bedtimes. For example, a final awakening at 4:00 a.m.
is likely to connote clinical significance when the usual bedtime is 11:00 p.m. but not
when the usual bedtime occurs at 9:00 p.m.
Symptoms during wakefulness accompany the sleep difficulties and result in the
impairment of normal functioning. Common waking symptoms include fatigue;
reduced motivation; reduced concentration, attention, and memory functioning; and
irritability or reduced mood. Complaints of subjective daytime sleepiness are also
common, although, in contrast to patients with hypersomnolence conditions, many
with this complaint are not able to nap in the daytime and few show unintentional
sleep episodes. Reports of reduced performance at work or school or impaired social
functioning also are common. Some affected individuals attribute errors or accidents
at work to their sleep difficulties. Somatic symptoms such as headaches or gastrointes-
tinal dysfunction are occasionally attributed to the ongoing sleep difficulties as well.
The fatigue of insomnia sufferers is manifest mainly as a lack of energy and desire to
reduce or limit activity levels. This symptom should be differentiated from reports of
subjective sleepiness as well as from unintended sleep episodes. Insomnia sufferers
commonly report subjective sleepiness characterized by a sense of reduced alertness
and enhanced need or desire to sleep. However, they seldom fall asleep spontaneously
without intending to do so. Despite a desire to nap, many individuals with insomnia are
unable to do so. Frequent, unintentional daytime sleep episodes are more characteristic
of other types of sleep disorders such as sleep disordered breathing, narcolepsy, idio-
pathic hypersomnia, and the like.
In young children, difficulty falling asleep, staying asleep, or both are often the result of
inappropriate sleep associations or inadequate limit setting. Inappropriate sleep associ-
ations result from a child’s dependency on specific stimulation, objects, or settings for
initiating sleep or returning to sleep following an awakening; in the absence of these
conditions, sleep onset is significantly delayed. This manifestation usually presents as
24
Insomnia
frequent nighttime awakenings and/or nighttime fears or anxiety about sleeping alone.
The process of falling asleep is associated with a specific form of stimulation (e.g.,
rocking, watching television), object (e.g., bottle, excessive feedings), or setting (e.g.,
lighted room, parents remaining in the room, or child taken to parents’ bed). When
such conditions are absent, children with this disorder experience difficulty falling
asleep at bedtime and following normal nighttime arousals. If the conditions associ-
ated with falling asleep are reestablished, the child usually resumes sleep relatively
quickly. Because sleep-onset associations are highly prevalent in young children, the
phenomenon is defined as a disorder only if (1) the associations are highly problem-
atic or demanding (e.g., extended rocking, car rides); (2) sleep onset is significantly
delayed or sleep is otherwise disrupted in the absence of the associated conditions; and
(3) caregiver intervention is frequently required to aid the onset or resumption of sleep.
Limit-setting issues are characterized by bedtime stalling or bedtime refusal that is met
with and reinforced by inadequate limit setting by a caregiver. Sleep problems occur
when caregivers institute no or few limits or when limits are instituted inconsistently or
in an unpredictable manner. Limit-setting sleep problems may also result in prolonged
nocturnal awakenings, depending on caregiver response during the night.
It also should be noted that some children’s needs for specific conditions for sleeping
or their resistance to go to bed may reflect underlying anxiety or fears. Fear of sleep-
ing alone, being in the dark, or having nightmares may lead some children to demand
certain sleep promoting conditions (presence of parent in bedroom) or to repeatedly
delay their bedtimes.
Although transient and episodic forms of insomnia occur, the clinically significant
daytime consequences of insomnia and the longer term, more serious morbidity out-
comes most typically develop when the sleep difficulties occur at least three times per
week and persist for at least three months. For this reason, these frequency and dura-
tion criteria must be met for the assignment of a chronic insomnia disorder diagnosis.
However, it is recognized that more acute and episodic forms of insomnia may cause
significant distress and functional impairment and require clinical attention. Cases that
meet all criteria except the frequency or duration criteria for chronic insomnia disorder
should be assigned a diagnosis of short-term insomnia disorder.
Associated Features
Individuals with chronic insomnia disorder typically note feelings of reduced well-being
and general malaise during the day. In addition, excessive focus on and worry about ongoing
sleep difficulties and their associated daytime consequences are common. Thoughts about
ongoing sleep difficulties may occur through the day and may be amplified as bedtime
25
Insomnia
approaches. Frank performance anxiety about sleep is common. Although many with
insomnia may appear anxious and worry-prone, their anxiety and worry are often focused
mainly on their sleep difficulties. When anxiety and worry are more pervasive and not
solely focused on sleep problems, a comorbid anxiety disorder may be present. Many
with chronic insomnia disorder show a pattern of conditioned arousal in response to envi-
ronmental cues in their bedrooms or conscious efforts to initiate sleep. Such individuals
may fall asleep easily in settings outside of their bedrooms when not trying to sleep, but
show a pattern of cognitive and physiological arousal when lying down in their beds with
the intention to fall asleep. Some patients with this pattern may report sleeping better
when away from home than when at home. Unlike noncomplaining normal sleepers, indi-
viduals with chronic insomnia disorder often express conscious intentions and excessive
effort to sleep, only to find sleep difficult to initiate under such circumstances.
In children, the sleep disturbance may be accompanied by daytime behavioral prob-

lems and limit-setting difficulties during the day. In addition, the nighttime sleep distur-
bance often results in poor parental sleep and associated daytime impairment. Marital
conflicts regarding how to respond to or intervene with the ongoing sleep problem may
arise. Parents also may develop negative feelings toward the child who disrupts their
sleep and demands their attention during the night.
Clinical and Pathophysiological Subtypes

Various clinical and pathophysiological subtypes of insomnia have been described
in previous nosologies. Both the American Psychiatric Association’s Diagnostic and
Statistical Manual, 4th Edition, Text Revision (DSM-IV-TR) and the International
Classification of Sleep Disorders, 2nd Edition describe independently occurring or
primary forms of insomnia. Within DSM-IV-TR, the global term, primary insomnia,
is applied to all forms of insomnia that are not better explained by a coincident psychi-
atric, medical or substance use/abuse disorder. Within the International Classification
of Sleep Disorders, 2nd Edition system, multiple primary insomnia subtypes are delin-
eated. The specific primary insomnia subtypes listed in the previous International
Classification of Sleep Disorders, 2nd Edition include the following:
Psychophysiological insomnia is characterized primarily by heightened arousal and

learned sleep-preventing associations that result in a complaint of insomnia. Patients
presumed to have this type of insomnia often have sleep difficulty when trying to
sleep in their usual sleep setting at home but may fall asleep easily in a novel sleep
setting or when not trying to sleep. They also demonstrate excessive focus on and
worry about sleep and suffer from elevated levels of cognitive and somatic arousal,
particularly at bedtime.
26
Insomnia
Idiopathic insomnia is characterized by a longstanding complaint of sleep difficulties

with insidious onset occurring during infancy or early childhood. It is presumed to
arise in infancy or early childhood without discernible cause and to persist over time
without sustained periods of remission. Given its early onset, stability over time, and
lifelong course, this disorder is thought to arise from either genetically determined or
congenital aberrations in the sleep-inducing or arousal systems in the brain, or both.
No consistent genetic markers or neural pathology have been identified among those
presumed to suffer from this condition.
Paradoxical insomnia, which has previously been called sleep state misperception, is
described as a complaint of severe sleep disturbance without corroborative objective
evidence of the degree of sleep disturbance claimed. Those presumed to have this form
of sleep difficulty have a marked propensity to underestimate the amount of sleep they
actually are obtaining. In essence, they are thought to perceive much of the time they
actually sleep as wakefulness. Although many such patients routinely obtain norma-
tive amounts of sleep, as documented by standard polysomnographic measures, they
complain of the common sleep/wake symptoms of other insomnia disorders. Some
studies using neuroimaging or sleep electroencephalograph (EEG) spectral analysis
techniques have suggested that an altered sleep/wake arousal system in such individ-
uals may explain the apparent mismatch between their conventional objective sleep
measures and subjective sleep reports.
Inadequate sleep hygiene is presumed to result from or be sustained by daily living

activities that are inconsistent with the maintenance of good-quality sleep and
normal daytime alertness. Patients with this form of insomnia have ongoing sleep/
wake difficulties as a function of practices such as daytime napping, maintaining a
highly variable sleep/wake schedule, routinely using sleep-disruptive products (caf-
feine, tobacco, alcohol) too close to bedtime, engaging in mentally or physically acti-
vating or emotionally upsetting activities too close to bedtime, routinely using the
bed and bedroom for activities other than sleep, or failing to maintain a comfortable
environment for sleep.
Behavioral insomnia of childhood is presumed to result from improper sleep train-

ing or limit setting by parents or caretakers. Within this broader diagnosis, several
subtypes have been described. Sleep-onset association type is characterized by the
child’s dependency on specific stimulation, objects, or settings for initiating sleep or
returning to sleep following an awakening; in the absence of these conditions, sleep
onset is significantly delayed. Limit-setting type is characterized by bedtime stalling or
bedtime refusal that is the result of inadequate limit setting by a caregiver. A mixed type
27
Insomnia
characterized by features of sleep-onset association difficulties and bedtime resistance

represents a third subtype within this diagnostic category.
The DSM-IV-TR and International Classification of Sleep Disorders, 2nd Edition also
describe several so-called secondary insomnias, arising from co-occurring primary or
causative conditions. Among these are the following:
Insomnia due to (another) mental disorder is thought to be caused by or secondary

to a co-occurring psychiatric condition. Insomnia is a common complaint, particularly
among patients with mood disorders and anxiety disorders. Likewise, sleep distur-
bance is commonly seen in those with psychotic spectrum disorders and various Axis
II (personality) disorders. Among those individuals presumed to have insomnia due to
a mental disorder, insomnia has historically been regarded as a secondary symptom,
caused by the mental disorder itself.
Insomnia due to (a) medical condition is thought to be caused by or secondary to

a co-occurring medical condition. Like the mental disorders, many medical condi-
tions may have an ongoing insomnia complaint associated with them. In particular,
those conditions that cause some form of ongoing pain or discomfort, mobility lim-
itation, or breathing disturbance commonly have insomnia complaints accompanying
them. Among those individuals presumed to have insomnia due to a medical disor-
der, insomnia has historically been regarded as a secondary symptom, caused by the
medical disorder itself.
Insomnia due to drug or substance is thought to be caused by or secondary to use of

or withdrawal from a drug or substance. Many forms of prescription and nonprescrip-
tion medications, street drugs, and other commonly used substances may produce sleep
disturbances either during periods of use or upon withdrawal. Given these effects,
insomnia complaints may arise either during periods when these substances are used
or following their discontinuance. Among those individuals presumed to have insom-
nia due to drug or substance, insomnia has historically been regarded as a secondary
symptom, caused by the drug or substance itself.
Despite the heuristic appeal of these various subtypes, it is often difficult to discrim-
inate among them in clinical practice. Many of the defining features of the so-called
primary insomnia subtypes such as conditioned arousal, poor sleep hygiene prac-
tices, and underestimation of sleep time are ubiquitous among insomnia sufferers,
per se, and are not specific to one subgroup. This is true whether the so-called
primary insomnia subtypes are considered in isolation or if all of the primary
28
Insomnia
and secondary subtypes mentioned are considered. There is substantial symptom

overlap both within the group of primary insomnias as well as among the primary
and secondary insomnias. Furthermore, many individuals with insomnia have mul-
tiple medical and psychiatric comorbidities, making it difficult to assign causation
to any single factor. As a result, discrimination among these subtypes has proven
difficult given their current definitions and available methods for their ascertain-
ment. Furthermore, it is not clear that insomnia is always the result of co-occur-
ring medical, mental, or substance use disorders. Often insomnia may precede the
onset of such conditions, and even when precipitated by such conditions, the insom-
nia may evolve and develop partial or total independence over time. In such cir-
cumstances, the term secondary insomnia seems inappropriate. Currently there is
limited understanding of mechanistic pathways in chronic insomnia, so it is not
possible to draw firm conclusions about the association or direction of causality
between insomnia and such co-occurring conditions. Furthermore, other than the
differing treatments required for distinctive comorbidities, efficacious treatments
for insomnia generally are similar across the range of insomnia subtypes. Finally,
research has provided very limited support for the reliability and validity of the
various specific subtypes discussed.
International Classification of Sleep Disorders, 2nd Edition additionally delineates

the separate pediatric diagnosis, behavioral insomnia of childhood, characterized by
sleep difficulties resulting from inappropriate sleep associations or inadequate limit
setting by parents or caretakers. Although perhaps more common in young children,
inappropriate sleep associations can occur in older age groups. For example, adults
with insomnia may report intolerance for quiet and dark settings and may not be able
to fall asleep unless the television is on. Similarly, it is not clear that limit-setting
issues are involved in the sleep difficulties of only young children. Such difficulties
also can manifest during adolescence as a function of volitionally delaying bedtimes.
Similarly, they may occur in older, cognitively impaired adults when their caretak-
ers allow liberal daytime napping that in turn results in disruptive awakenings and
night wandering. It is also clear that many of the features of sleep/wake dysfunc-
tion assigned to this childhood insomnia subtype overlap substantially with the global
insomnia disorder. Given these considerations, a separate childhood insomnia diagno-
sis is of questionable merit.
In addition to these various subtypes, a distinctive subtype of insomnia with objectively

short sleep duration has been recently described. This group is characterized by insom-
nia complaints, along with an objectively documented average sleep time less than
six hours per night and elevated morbidity risk. Because evidence in support of this
29
Insomnia
insomnia is currently limited, it is premature to delineate a separate insomnia category

for this presentation at this juncture.
Given all of these considerations, a more global and defensible approach has been
chosen for the diagnosis of those with chronic insomnia complaints. Specifically, the
single diagnosis of chronic insomnia disorder is provided for all patients who have per-
sistent and frequent insomnia complaints whether they occur in the presence or absence
of a potentially sleep-disruptive comorbid psychiatric illness, medical disorder, or
pattern of substance use.
Demographics
The full clinical syndrome of chronic insomnia disorder occurs in about 10% of the
population, but the prevalence of transient insomnia symptoms is much higher (30%
to 35% of the population). Chronic insomnia disorder is more common in women,
those with medical/psychiatric/substance disorders, and in people in lower socioeco-
nomic strata. It may occur at any age but is more commonly diagnosed in older adults,
most likely due to age-related deterioration in sleep continuity and increase in medical
comorbidities and medication use that increase insomnia risk.
Insomnia associated with requirements of parental/caregiver presence at bedtime

and/or during the night, along with insomnia due to limit-setting difficulties, are
estimated to occur in 10% to 30% of children, depending on the exact definitions
used. Certain subgroups of children, such as those suffering from chronic illnesses
or neurodevelopmental disorders, have a somewhat higher prevalence of insomnia
symptoms. Because children are not expected to sleep through the night with reg-
ularity until they are three to six months of age, six months is a reasonable age to
first consider a diagnosis of chronic insomnia disorder, unless the sleeplessness is
very marked at an earlier age. Furthermore, sleep-onset associations and limit-set-
ting problems are strongly associated with caregivers’ behaviors, bedtime interac-
tions, and culture. Thus, the interpretation of the nighttime awakenings and demands
for parental contact should be considered in the context of the family and culture.
Identification of sleep problems in children and adolescents are often based on spe-
cific cultural definitions. Studies on adolescents indicate prevalence rates of 3% to
12%, depending on the diagnostic criteria utilized, with higher frequency in girls than
boys after puberty.
Predisposing and Precipitating Factors

Individuals who have difficulty sleeping during stressful times or who report being
habitual light sleepers appear to have elevated propensity to develop chronic insomnia.
30
Insomnia
Prior transient episodes of poor sleep elevate the risk for subsequent development of a
chronic insomnia disorder. Job-related stress and factors such as death of a loved one,
divorce, a marked change in work schedule, job loss, and other major life changes are
often precipitating circumstances for chronic insomnia disorder. Personality factors
that produce anxious overconcern about health, general well-being, or daytime func-
tioning may serve as predisposing characteristics because individuals with chronic
insomnia disorder often display excessive preoccupation with daytime consequences
of insomnia, and they devote particular effort to what they presume are sleep-promot-
ing practices. A psychological style characterized by the repression and internalization
of disturbing affect is characteristic of those with chronic insomnia disorder and also
may represent a predisposing trait. Parents who have unrealistic sleep expectations for
their children may predispose them to insomnia by putting them in bed too early or
assigning them too much time in bed each night.
Comorbid psychiatric conditions, particularly mood and anxiety disorders, are asso-
ciated with increased risk for chronic insomnia disorder. Likewise, comorbid restless
legs syndrome or medical disorders such as GERD or those conditions that result in
chronic pain, breathing difficulties, or immobility also are associated with increased
risk for chronic insomnia disorder. A pattern of alcohol dependence/abuse as well as
the excessive use of caffeine or other stimulants may raise risk for chronic insomnia
disorder. Insomnia in children is often associated with difficult temperament, as well as
other comorbid medical and psychiatric conditions. Unstable home situations, safety
concerns and domestic abuse are likewise significant risk factors in both children and
adults. Caregiver and relationship factors are also important to consider. Furthermore,
parents of children with a current or past history of medical problems may have dif-
ficulty setting limits, whether because of guilt, a sense that the child is “vulnerable,”
or concerns about doing psychological harm. Environmental factors such as the child
sharing a room with a parent or with other siblings, the presence of extended family or
others in the home, and cramped living accommodations may contribute to negative
sleep-onset associations or poor limit setting.
Familial Patterns
The familial pattern of insomnia is not well documented. Nonetheless, the preva-
lence of insomnia is higher among monozygotic twins relative to dizygotic twins; it
is also higher in first-degree relatives than in the general population. The association
is stronger with mothers and daughters. The extent to which familial aggregation
represents shared genetic predisposition, shared environment, learned behavior (e.g.,
by observations of parental behavior), or a by-product of psychopathology remains
undetermined.
31
Insomnia
Onset, Course, and Complications

Onset may be insidious or acute. In the former case, individuals often report symptoms
of insomnia in early life or young adulthood. Onset of insomnia is often associated
with major life events (e.g., separation, death of a loved one), minor daily stressors, or
changes in sleep schedule.
The course of insomnia can be situational, recurrent, or persistent. The specific type
of sleep complaint may also change over time. Individuals who complain of diffi-
culty falling asleep at one time may later complain of difficulty maintaining sleep, and
vice versa. Although short-term insomnia often remits when the precipitating event
subsides or the individual adapts to it, sleep difficulties may also persist over time
even after the initial triggering factor has disappeared. When left untreated, insomnia
may persist and gradually lead to a vicious cycle of poor sleep, daytime impairments,
apprehension of insomnia, and further sleep disturbances. Among predisposed individ-
uals, insomnia can also follow an intermittent course, with recurrent episodes of sleep
difficulties associated with stressful life events. Even in persistent insomnia, there is
extensive night-to-night variability, with an occasional good night’s sleep intertwined
with several poor night’s sleep. Approximately 70% of individuals with insomnia at
a given time continue reporting insomnia a year later, and 50% still have insomnia
three years later. Complications of persistent insomnia include increased risks for
depression, hypertension, work disability, and prolonged use of prescription or over-
the-counter sleep aids.
Among children, chronic insomnia disorder may have its onset at any time during late
infancy through the childhood years. The course of chronic insomnia disorder in young
children varies and depends on the reasons for the sleeplessness. When limit-setting
factors and negative sleep associations resolve, sleep often improves. With age, inde-
pendence and privacy become more important, and sleep difficulties may decrease.
Complications may result from the consequent sleep loss and include irritability and
decreased attention and school performance. Increased family tensions and caregiver
sleep loss may also result. Some who develop insomnia during childhood may con-
tinue to suffer from chronic insomnia disorder into adulthood.
Developmental issues during childhood, such as separation anxiety and age/develop-
mental milestones, may predispose a child to developing sleep problems. For example,
limit-setting issues are often more common after the child is old enough to climb out of
the crib or is moved into a bed, has increased verbal skills, and desires greater indepen-
dence. Because children are not expected to sleep through the night with regularity until
32
Insomnia
they are three to six months of age, six months is a reasonable age to first consider a
diagnosis of insomnia disorder, unless the sleeplessness is very marked at an earlier age.
However, when sleep difficulties are persistent and pronounced in infants, underlying
medical causes should be considered (e.g., sleep disordered breathing, GERD, pain).
The specific symptoms of chronic insomnia disorder, as well as precipitating and per-
petuating factors, may vary across the adult age range. These changes may in part
reflect developmental changes across adulthood, such as the phase delay of endoge-
nous circadian rhythms in adolescence and young adulthood, and the phase advance
and increased number of awakenings often seen even among healthy older adults.
Epidemiological studies confirm that sleep onset difficulties and nonrestorative sleep
are most common among young adults with chronic insomnia disorder, whereas sleep
maintenance insomnia and early morning awakening are more common in middle-aged
and older adults. Objective daytime sleepiness is uncommon in younger adults with
insomnia, but more common in older adults. However, older adults may have less
sleep dissatisfaction than their younger counterparts, despite objectively worse sleep
continuity. Precipitating factors for chronic insomnia disorder may also change across
the adult age range, with medical and medication factors assuming a larger role in
older adults. Likewise, perpetuating factors may vary with the life circumstances of
adults of different ages. One common example is the option of older adults to spend
large amounts of time in bed after retirement, which may exacerbate the effects of age
on sleep continuity. Finally, medical disorders and symptoms (e.g., pain, dyspnea, and
impaired mobility) and medications often play a larger role in the insomnia of older
adults in comparison with younger adults. Hypnotic medications are disproportion-
ately prescribed to older adults, often with limited benefit and the potential for rebound
and withdrawal insomnia.
Pathology and Pathophysiology

Studies of the pathophysiology of chronic insomnia disorder have focused on one
or more dimensions of physiological hyperarousal during sleep and wakefulness.
These studies contrast groups of insomnia sufferers, typically those without sig-
nificant comorbidities, with healthy controls using a variety of physiological mea-
sures. Many of these studies are characterized by small sample sizes and lack of
replication. Collectively these studies suggest increased physiological arousal among
individuals with insomnia, characterized by measures such as increased heart rate,
altered heart rate variability, increased whole-body metabolic rate, elevated corti-
sol, adrenocorticotropic hormone, and CRF levels (particularly near sleep onset),
increased body temperature and increased high-frequency electroencephalographic
(EEG) activity during nonrapid eye movement (NREM) sleep. These studies imply
33
Insomnia
heightened activity of the sympathetic nervous system and hypothalamic-pitu-

itary-adrenal axis across sleep and wakefulness that is thought to perpetuate sleep/
wake dysfunction. Some evidence also suggests that physiological dysregulation
may be more evident in certain subgroups of individuals with insomnia (e.g., those
with extreme subjective-objective sleep discrepancies or those with insomnia and
short objective sleep duration). There is also some evidence that these findings may
not generalize to insomnia comorbid with mental disorders, which may have differ-
ent pathophysiological findings.
No discrete structural brain pathology can be identified in most individuals with insom-
nia. Patients with insomnia comorbid with neurological disorders such as stroke, brain
trauma, and multiple sclerosis may have identifiable brain lesions, but insomnia is
rarely their sole neurological symptom. Recent studies have provided conflicting evi-
dence regarding the finding of reduced hippocampal or anterior cingulate volume, with
most studies reporting negative findings.
Objective Findings
Although polysomnography is not indicated in the routine evaluation of insomnia,
it may be useful to rule out other sleep disorders (e.g., sleep-disordered breathing)
among some patients who appear to meet criteria for chronic insomnia disorder. In
the absence of other sleep disorders, results of polysomnographic sleep monitoring
of patients with chronic insomnia disorder may show increased sleep latency and/or
increased wake time after sleep onset coupled with reduced sleep efficiency in com-
parison with age-appropriate norms. Sleep onset latency or wake time after sleep onset
often exceeds 30 minutes, although one-hour to two-hour periods of wakefulness in
bed are not uncommon. A subset of patients shows reduced sleep duration of less than
six hours per night. Some patients show altered sleep architecture with an increase in
stage N1 sleep and a decrease in slow wave sleep. Patients with a pronounced condi-
tioned sleep difficulty in the home environment may show a reverse first-night effect
in the sleep laboratory (i.e., better sleep on the first vs. the second recording night).
However, some patients show normal sleep times and an absence of sleep onset or
sleep maintenance difficulties on standard polysomnographic (PSG) measures. Some
insomnia patients have alterations in power density measures of the sleep EEG when
compared with individuals without sleep complaints. Specifically, these patients often
show relatively greater power in the high frequency (beta and gamma ranges) band-
widths. Some reports have shown that elevated high-frequency power is characteris-
tic of insomnia patients with marked subjective-objective discrepancies in sleep mea-
sures, compared to insomnia patients with more obvious objective sleep disturbances
or individuals without sleep complaints.
34
Insomnia
Serial monitoring with PSG or actigraphy typically shows marked night-to-night vari-
ability in all sleep measures as well as in recorded bed and rising times. This variability
is typically greater than that of comparison groups of good sleepers.
Many patients with insomnia underestimate the actual sleep time shown by polysom-
nography, and some may provide sleep estimates that fall far short of actual PSG-
recorded sleep time. This latter group has previously been categorized as having
subjective insomnia, sleep state misperception, or paradoxical insomnia. In general,
patients with insomnia tend to underestimate sleep duration and overestimate sleep
latency and awakenings, whereas good sleepers tend to overestimate sleep duration
and underestimate sleep latency and awakenings relative to PSG. This subjective-ob-
jective mismatch may be related to physiological hyperarousal, and may be one of the
core features of insomnia.
Results of the Multiple Sleep Latency Test (MSLT) usually show normal daytime alert-
ness. In several studies, patients with insomnia have longer mean MSLT values than
control subjects, suggesting hyperalertness or hyperarousal. A minority of insomnia
patients, particularly older adults with insomnia, have reduced mean MSLT values
indicating increased sleepiness. Such a finding should prompt consideration of other
concurrent sleep disorders such as obstructive sleep apnea.
Young children typically show essentially normal sleep during PSG monitoring when
the caregiver is present and appropriate limits are set in the laboratory.
Although PSG and MSLT testing usually are not helpful in the establishment of an
insomnia disorder diagnosis, there are circumstances that may warrant such testing
with selected patients. PSG should be considered when there are reported symptoms
or bed partner observations of sleep disordered breathing or periodic limb movements
during sleep. Patients who present insomnia symptoms accompanied by excessive
daytime sleepiness may warrant PSG and MSLT testing, particularly if narcolepsy is
suspected. Patients who show acceptable adherence to trials of well-established insom-
nia therapies but fail to show adequate treatment response may benefit by PSG to rule
out a comorbid sleep disorder.
Finally, a small number of functional imaging studies have been conducted during
sleep and wakefulness in insomnia and control groups. These studies suggest region-
ally specific increases of relative glucose metabolism in insomnia compared to controls.
Specifically, these studies show smaller wake to NREM decreases of relative glucose
metabolism in sleep/wake-regulating regions including thalamus, upper brainstem,
35
Insomnia
anterior cingulate, and limbic cortex in insomnia patients. Self-reported and objective
sleep disruptions are related to increased relative metabolism in these regions. These
findings are similar to regional activation patterns during sleep in an animal model of
stress-induced insomnia. Other studies using nuclear magnetic resonance spectroscopy
have identified reduced gamma-aminobutyric acid (GABA) signaling in sleep-regu-
lating regions in insomnia that correlate with objective measure of sleep continuity.
Studies examining task-related changes in blood flow using blood oxygenation level
dependent functional magnetic resonance imaging (BOLD fMRI) paradigms have
shown reduced activation relative to baseline levels in individuals with insomnia when
compared to normal sleeping controls. Task-related activation changes in the direction
of “normalization” following cognitive behavioral treatment.
Differential Diagnosis
A chronic insomnia disorder that presents as difficulty initiating sleep should be differen-
tiated from delayed sleep-wake phase disorder. In the latter condition, sleep initiation is
consistently later than desired because the individual’s endogenous circadian rhythm is
delayed relative to the desired sleep schedule. Sleep-onset difficulties persist, and sleep
time is reduced whenever the individual chooses bedtimes and rising times that are too
early and out of phase with the endogenous circadian rhythm. However, patients with
delayed sleep-wake phase disorder are able to fall asleep with less difficulty, and sleep a
normal amount of time, when sleeping in phase with their delayed endogenous rhythm
by selecting late bed and rising times. By comparison, those with a chronic insomnia
disorder often feel sleepy at the desired bedtime but are unable to sleep regardless of the
timing of their bed and rise times. Furthermore, sleep problems tend to be more variable
on a night-to-night basis in insomnia disorder. Given the prevalence of delayed sleep-
wake phase disorder in teenagers and young adults, it is particularly important to con-
sider the possibility of this alternate or comorbid diagnosis when evaluating individuals
from these age groups presenting with sleep onset insomnia complaints.
A chronic insomnia disorder that presents as a difficulty maintaining sleep with pre-
mature morning rise times also should be differentiated from advanced sleep-wake
phase disorder. The latter tends to be more common in older adults than it is in younger
adults and children. Among those with an advanced sleep phase pattern, sleep initia-
tion is consistently earlier than desired because the individual’s endogenous circadian
rhythm is advanced relative to the desired sleep schedule. However, total sleep time is
adequate when the individual chooses early bed and rise times that coincide with the
advanced endogenous circadian rhythm. In contrast, those with chronic insomnia dis-
order may display sleep maintenance difficulties and early morning rise time regard-
less of the sleep schedule they select.
36
Insomnia
There can be some overlap between chronic insomnia disorder and both delayed and
advanced sleep-wake phase disorders. Patients with a delayed sleep pattern may
become chronically frustrated or anxious about their inability to initiate sleep at their
desired times, and this frustration or anxiety may continue to disrupt sleep and delay
sleep onset well beyond the sleep onset time promoted by the endogenous rhythm.
Early morning awakenings may similarly have arousing sleep disruptive effects in the
setting of an advanced sleep phase. In such circumstances both a circadian rhythm
sleep-wake disorder diagnosis and a chronic insomnia disorder diagnosis may apply
and should be assigned.
Chronic insomnia disorder should also be discriminated from situational sleep dif-
ficulties arising from sleep-disruptive environmental circumstances. A variety of
environmental factors including excessive noise or light and extreme temperatures
will disrupt the sleep of most individuals. Also, sleeping in an area where there is
imminent threat or danger to one’s safety can also be disruptive to sleep. Bed part-
ners who snore loudly, move excessively during sleep, or have parasomnias may
also disrupt one’s sleep. When an individual reports environmental circumstances
that would be regarded as disruptive to the sleep of most individuals, a chronic
insomnia disorder should not be assigned. Chronic insomnia disorder applies only
when the individual reports sleep difficulty in the context of sleep-conducive envi-
ronment circumstances or when the insomnia symptoms show some independence
from the environmental factors. When environmental circumstances are a primary
cause of sleep disturbance and associated consequences, a diagnosis of other sleep
disorder may be considered.
Chronic insomnia disorder should also be differentiated from patterns of chronic voli-
tional sleep restriction (insufficient sleep syndrome). Some individuals show excessive
daytime sleepiness, fatigue, and reduced sleep at night as a result of electing overly
demanding daytime schedules or by volitionally delaying sleep in order to engage
in desired recreational or social activities. However, when allowing themselves suffi-
cient time to sleep, they are able to initiate and maintain sleep easily and for a normal
duration. Those with chronic insomnia disorder tend to have excessive wake time
and reduced sleep time despite routinely allotting sufficient time to sleep. Moreover,
chronic insomnia disorder is not typically associated with excessive daytime sleepi-
ness and unintentional daytime sleep episodes, which are often observed in those with
patterns of volitional sleep restriction.
Insomnia symptoms may occur comorbid with another sleep disorder, such as sleep
apnea or restless legs syndrome. A chronic insomnia disorder diagnosis would apply
37
Insomnia
only when: (1) the insomnia symptoms show some independence in their onset or
variation over time from the other symptoms of the co-occurring sleep disorder; or
(2) when insomnia symptoms persist despite adequate treatment reflected by marked
symptom improvement in the coincident sleep disorder. A chronic insomnia disorder
diagnosis would not apply when effective treatment of the coincident sleep disorder
resolves the insomnia symptoms.
Among children, sleep difficulties may be present when the child has to sleep alone
in a separate room, but absent when the child is allowed to sleep with parents or when
a parent is present in the child’s bedroom. An absence of sleep difficulties under the
latter circumstances does not indicate the insomnia is resolved. Only when the child
is able to sleep consistently independently is there no longer an insomnia problem. In
some children, the persistence of sleep difficulties in the absence of parents may reflect
underlying conditions such as separation anxiety or an anxiety disorder.
In young children, sleep difficulties can be the result of medical issues, including gas-
troesophageal reflux, as well as developmental milestones, such as motoric, language,
and cognitive development. Children, adolescents, and adults may develop a chronic
insomnia disorder comorbid with a medical or psychiatric disorder. Insomnia symp-
toms may arise as a result of either another sleep disorder, a medical condition, or
a psychiatric disorder that has sleep-disruptive effects. A chronic insomnia disorder
diagnosis would apply when: (1) the insomnia symptoms show some independence in
their onset or variation over time from the other symptoms of the co-occurring sleep,
medical ,or psychiatric disorder; or (2) when insomnia symptoms persist despite ade-
quate treatment reflected by marked symptom improvement in the coincident sleep,
medical, or psychiatric disorder. Because insomnia symptoms often develop some
independence over time, a chronic insomnia disorder diagnosis usually will be war-
ranted when those symptoms are persistent in association with a chronic medical or
psychiatric disorder. A chronic insomnia disorder diagnosis would not apply when
effective treatment of the coincident sleep, medical, or psychiatric disorder resolves
the insomnia symptoms.
Unresolved Issues and Further Directions

Much remains to be learned about the underlying pathophysiological pathways leading
to insomnia and whether insomnia should be classified as a unitary disorder or sub-
divided into several subtypes. Clearly, these issues are closely linked. Further studies
that clarify the pathophysiological pathways leading to insomnia ultimately will reveal
whether those meeting current criteria for chronic insomnia disorder suffer from a
single disease or multiple separate diseases with similar outward presentations.
38
Insomnia
A related unresolved issue is whether the current global classification promotes a generic
approach to insomnia therapy that ultimately fails to benefit some insomnia subgroups.
Perhaps this global classification scheme will overlook distinctive insomnia subtypes
with specific treatment needs that vary from the generic treatments typically provided.
Previous editions of the International Classification of Sleep Disorders allowed for the
assignment of an insomnia diagnosis to patients who present exclusively with com-
plaints of nonrestorative sleep; that is, patients who complain only of sleep that is
poor in quality or unrefreshing, in the absence of sleep-onset or sleep maintenance
complaints, could qualify for an insomnia diagnosis in previous versions of this nosol-
ogy. The current version of this nosology excludes such patients from the insomnia
diagnostic categories. This decision was based on several considerations. Most insom-
nia patients present with complaints of sleep initiation or maintenance difficulties.
Although a small subset of patients present with isolated complaints of nonrestorative
sleep, this complaint more commonly arises in association with other symptoms of
insomnia, or in conjunction with sleep disordered breathing, other sleep disorders or
certain chronic medical conditions (e.g., fibromyalgia or chronic fatigue syndrome).
Although various epidemiological studies have identified subgroups who are presumed
to have an insomnia disorder and present solely with a complaint that their sleep is non-
restorative or unrefreshing, such studies typically lack polysomnography that would be
needed to rule out other occult sleep disorders as a cause. Finally, nonrestorative sleep
remains a poorly defined construct that may reflect not only a type of sleep disturbance,
but also the daytime consequences of poor sleep such as fatigue and anergia. This con-
struct would benefit from further definitional efforts and research to explore its clinical
significance in the context of insomnia. Given these considerations, the isolated com-
plaint of nonrestorative sleep was not retained as part of the diagnostic definition of the
insomnia disorders delineated in this manual.
Bibliography
Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: a meta-analytic evaluation
of longitudinal epidemiological studies. J Affect Dis 2011;135;10–9.
Bastien CH, St-Jean G, Morin CM, Turcotte I, Carrier J. Chronic psychophysiological insomnia:
hyperarousal and/or inhibition deficits? An ERPs investigation. Sleep 2008;31:887–98.
Beaulieu-Bonneau S, LeBlanc M, Mérette C, Dauvilliers Y, Morin CM. Family history of insomnia in a
population-based sample. Sleep 2007;30:1739–45.
Billows M, Gradisar M, Dohnt H, Johnston A, McCappin S, Hudson J. Family disorganization, sleep
hygiene, and adolescent sleep disturbance. J Clin Child Adolesc Psychol 2009;38:745–52.
Bonnet MH, Arand DL. 24-hour metabolic rate in insomniacs and matched normal sleepers. Sleep
1995;18:581–8.
39
Insomnia
Bonnet MH, Arand DL. Heart rate variability in insomniacs and matched normal sleepers. Psychosom
Med 1998;60:610–5.
Bonnet MH, Arand DL. Hyperarousal and insomnia: State of the science. Sleep Med Rev 2010;14:9–15.
Buysse DJ, Angst J, Gamma A, Ajdacic V, Eich D, Rössler W. Prevalence, course, and comorbidity of
insomnia and depression in young adults. Sleep 2008;31:473–80.
Dohnt H, Gradisar M, Short MA. Insomnia and its symptoms in adolescents: comparing DSM-IV and
ICSD-II diagnostic criteria. J Clin Sleep Med 2012;8:295–9.
Edinger JD, Wyatt JK, Stepanski EJ, et al. Testing the reliability and validity of DSM-IV-TR and
ICSD-2 insomnia diagnoses: results of a multi-method/multi-trait analysis. Arch Gen Psychiatry
2011;68:992–1002.
Krystal AD, Edinger JD, Wohlgemuth WK, Marsh GR. Non-REM sleep EEG frequency spectral correlates
of sleep complaints in primary insomnia subtypes. Sleep 2002;25:630–40.
Lack LC, Wright HR. Treating chronobiological components of chronic insomnia. Sleep Med
2007;8:637–44.
Lichstein KL. Secondary insomnia. In: Lichstein KL, Morin CM, eds. Treatment of late-life insomnia.
Thousand Oaks, CA: Sage, 2000:297–319.
Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A. Behavioral treatment of bedtime problems and
night wakings in infants and young children. Sleep 2006;29:1263–76.
Mindell JA, Sadeh A, Wiegand B, How TH, Goh DY. Cross-cultural differences in infant and toddler
sleep. Sleep Med 2010;11:274–80.
Morgenthaler TI, Owens J, Alessi C, et al. Practice parameters for behavioral treatment of bedtime
problems and night wakings in infants and young children. Sleep 2006;29:1277–81.
Morin CM, Bélanger L, LeBlanc M, et al. The natural history of insomnia: a population-based 3-year
longitudinal study. Arch Intern Med 2009;169:447–53.
Nofzinger EA. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry
2004;161:2126–31.
Nofzinger EA, Nissen C, Germain A, et al. Regional cerebral metabolic correlates of WASO during sleep
in insomnia. J Clin Sleep Med 2006;2:316–22.
Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev
2002;6:97–111.
Ohayon MM, Caulet M, Lemoine P. Comorbidity of mental and insomnia disorders in the general
population. Compr Psychiatry 1998;39:185–97.
Ohayon MM, Roberts RE. Comparability of sleep disorders diagnoses using DSM-IV and ICSD
classifications with adolescents. Sleep 2001;24:920–5.
Perlis ML, Smith MT, Andrew PJ, Orff H, Giles DE. Beta/gamma EEG activity in patients with primary
and secondary insomnia and good sleeper controls. Sleep 2001;24:110–7.
Riemann D, Voderholzer U, Spiegelhalder K, et al. Chronic insomnia and MRI-measured hippocampal
volumes: A pilot study. Sleep 2007;30:955–8.
Riemann D, Spiegelhalder K, Feige B, et al. The hyperarousal model of insomnia: A review of the concept
and its evidence. Sleep Med Rev 2010;14:19–31.
Roberts RE, Roberts CR, Chan W. Persistence and change in symptoms of insomnia among adolescents.
Sleep 2008;31:177–84.
40
Insomnia
Sánchez-Ortuño MM, Carney CE, Edinger JD, Wyatt JK, Harris A. Moving beyond average values:
assessing the night-to-night instability of sleep and arousal in DSM-IV-TR insomnia subtypes. Sleep
2011;34:531–9.
Stepanski E, Zorick F, Roehrs T, Young D, Roth T. Daytime alertness in patients with chronic insomnia
compared with asymptomatic control subjects. Sleep 1988;11:54–60.
Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia with objective short sleep
duration is associated with a high risk for hypertension. Sleep 2009;32:491–7.
Winkelman JW, Buxton OM, Jensen JE, et al. Reduced brain GABA in primary insomnia: preliminary
data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep 2008;31:1499–506.
Winkelman JW, Benson KL, Buxton OM, et al. Lack of hippocampal volume differences in primary
insomnia and good sleeper controls: an MRI volumetric study at 3 Tesla. Sleep Med 2010;11:576–82.
Zhang J, Li AM, Kong AP, Lai KY, Tang NL, Wing YK. A community-based study of insomnia in Hong
Kong Chinese children: Prevalence, risk factors and familial aggregation. Sleep Med 2009;10:1040–6.
Short-Term Insomnia Disorder

Alternate Names
Acute insomnia, adjustment insomnia.
Diagnostic Criteria
Criteria A-E must be met
A. The patient reports, or the patient’s parent or caregiver observes, one or
more of the following:1
1. Difficulty initiating sleep.
2. Difficulty maintaining sleep.
3. Waking up earlier than desired.
4. Resistance to going to bed on appropriate schedule.
5. Difficulty sleeping without parent or caregiver intervention.
B. The patient reports, or the patient’s parent or caregiver observes, one or
more of the following related to the nighttime sleep difficulty:
1. Fatigue/malaise.
2. Attention, concentration, or memory impairment.
3. Impaired social, family, vocational, or academic performance.
4. Mood disturbance/irritability.
6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression).
7. Reduced motivation/energy/initiative.
8. Proneness for errors/accidents.
9. Concerns about or dissatisfaction with sleep.
41
Insomnia
C. The reported sleep/wake complaints cannot be explained purely by

inadequate opportunity (i.e., enough time is allotted for sleep) or
inadequate circumstances (i.e., the environment is safe, dark, quiet, and
comfortable) for sleep.
D. The sleep disturbance and associated daytime symptoms have been
present for less than three months.
E. The sleep/wake difficulty is not better explained by another sleep disorder.
Notes
1. Reports of difficulties initiating sleep, difficulties maintaining sleep, or
waking up too early can be seen in all age groups. Resistance going to
bed on an appropriate schedule and difficulty sleeping without parent
or caregiver intervention is seen most commonly in children and older
adults who require the supervision of a caretaker due to a significant
level of functional impairment (e.g., those with dementia).
2. Patients with short-term insomnia disorder may complain of sleep/
wake difficulties fewer than three times per week on average, yet
have clinically significant concerns about their symptoms and warrant
clinical attention.
3. Many conditions such as grief, acute pain, or other acute stressors are
quite often associated with poor sleep. When such conditions are the
sole cause of the sleep difficulty, a separate insomnia diagnosis may
not apply. The primary factor in determining application of a short-
term or adjustment insomnia diagnosis is the extent to which the sleep
disturbance becomes a significant focus for the individual and/or
warrants independent clinical attention.
Essential Features
The essential feature of short-term insomnia disorder is a short-term difficulty ini-
tiating or maintaining sleep that results in general sleep dissatisfaction. The sleep
complaint is accompanied by daytime distress about poor sleep or impairment in
family, social, occupational, academic, or other important areas of functioning.
Furthermore, the sleep disturbance and associated daytime symptoms occur despite
having adequate time and circumstances each night to obtain necessary sleep. Short-
term insomnia disorder can occur in isolation or comorbid with a mental disorder,
medical condition, or substance use. In many cases of short-term insomnia lasting
less than three months, there is an identifiable cause that serves as the precipitant. In
other cases, insomnia occurs episodically, often coincident to daytime stressors that
account for the insomnia.
42
Insomnia
As is the case for chronic insomnia disorder, sleep complaints that compose short-
term insomnia disorder may include difficulties initiating sleep or difficulties main-
taining sleep. The latter complaint may include waking up during the night with
difficulty returning to sleep or having a final awakening occurring too early, well
before the desired rising time. Short-term insomnia disorder may be character-
ized solely by sleep onset or sleep maintenance complaints or, more commonly,
by both types of complaints occurring together. Individuals’ sleep complaints may
vary such that sleep onset difficulties are apparent on some nights, whereas sleep
maintenance difficulties are present on other nights. Complaints about poor-quality,
unrefreshing, or nonrestorative sleep may accompany sleep onset and sleep mainte-
nance complaints, but do not meet the definition of this condition when they occur
in isolation.
Associated Features
Sleep disturbance is the primary feature of short-term insomnia disorder, but it is com-
monly accompanied by waking symptoms similar to those seen in chronic insomnia
disorder. Specific symptoms such as fatigue, impaired attention and concentration, poor
memory, irritability, and distress about poor sleep are common. When the insomnia
arises in reaction to a stressful life event, such as the loss of a loved one, major illness,
or divorce, the associated features may include anxiety, worry, ruminative thoughts,
sadness, or depression in relation to the specific stressor. If the individual uses alcohol,
illicit drugs, or medications for self-treatment, additional symptoms related to these
substances may be seen.

None.
Demographics
Short-term insomnia disorder can occur at any age. However, a short-term form of
insomnia may be difficult to establish in infants because it is often difficult to link
stressors to sleep disturbances in this age group. The exact prevalence of short-term
insomnia disorder is unknown. The one-year prevalence of short-term insomnia dis-
order among adults appears to be in the range of 15% to 20%. Like chronic insomnia
disorder, short-term insomnia disorder is more prevalent in women than in men, and
in older age groups.

Affected individuals may note a lifelong tendency toward light sleep or diffi-
culty sleeping during times of stress. A previous history of anxiety or depressive
43
Insomnia
symptoms and disorders also may predispose an individual to develop a short-

term insomnia disorder. In children, having a parent with insomnia or living in a
household lacking parental reinforcement of a consistent sleep/wake schedule may
be predisposing factors.
An acute, identifiable event or stressor usually precipitates this form of insomnia.

Common precipitating events include changes or disputes in interpersonal relation-
ships, occupational stress, personal losses, bereavement, diagnosis or onset of a new
medical condition, visiting or moving to a new location, or physical changes to the
usual sleep environment or schedule. Changes or stresses with a positive emotional
tone also may serve as precipitating events. In children or dependent adults, such
insomnia can arise when the caretaker makes abrupt changes in the child’s or adult’s
sleep routines or schedule. As is the case for chronic insomnia disorder, environ-
mental factors such as the child sharing a room with a parent or with other sib-
lings, the presence of extended family or others in the home, and cramped living
accommodations may contribute to negative sleep-onset associations or poor limit
setting in children.
Familial Patterns
Familial patterns are less well documented for cases of short-term insomnia disor-
der than they are for individuals meeting criteria for chronic insomnia disorder.
Nonetheless, the familial aggregation found for chronic insomnia disorders is expected
to also occur among individuals with more transient forms of insomnia. Data support
a greater genetic diathesis to psychophysiologic arousal among certain individuals in
response to stressors. This may, in turn, suggest a constitutional predisposition to short-
term or adjustment insomnia in such individuals.

Many individuals who develop short-term insomnia disorder experience remission
of their insomnia symptoms over time. This occurs as distress over the precipitating
event diminishes over time or in response to withdrawal of the stressor. However, a
portion of those who initially experience short-term insomnia may develop a more
chronic form of insomnia and subsequently meet criteria for chronic insomnia dis-
order. These individuals will then have the course and complications described for
chronic insomnia disorder.
As is the case for chronic insomnia disorder, short-term insomnia disorder would not
be considered until after a child reaches at least six months of age.
44
Insomnia
The propensity to experience sleep disturbance in response to stress may dispose young
and older individuals toward acute forms of insomnia. As is the case for chronic insomnia
disorder, sleep onset difficulties are most common among young adults with short-term
insomnia, whereas sleep maintenance complaints and early morning awakening are more
common in middle-aged and older adults. Objective daytime sleepiness is uncommon in
younger adults with short-term insomnia disorder, but is more common in older adults.
Balancing job and family stressors may contribute to intermittent short-term insomnia
problems in younger and middle-aged adults. In contrast, older, retired adults may have
short-term insomnia disorder related to exacerbations in comorbid chronic medical con-
ditions or due to loss of loved ones that commonly occurs with advancing age.

Research on the pathology and pathophysiology of short-term variants of insomnia
disorder is generally lacking because the majority of studies addressing this issue have
focused on samples with chronic insomnia disorders.
Short-term insomnia disorder shares many features with chronic insomnia disorder.
The primary difference between the two conditions is that short-term insomnia disor-
der does not meet the duration and frequency criteria required for the chronic insomnia
disorder diagnosis. Short-term insomnia disorder also should be distinguished from
circadian rhythm sleep-wake disorders resulting from rotating shift work or jet lag. In
the latter case, the sleep disturbance arises from a sleep-wake schedule alteration that
results in a mismatch between the endogenous circadian rhythm and the sleep-wake
schedule chosen—for example, having to sleep in the daytime rather than during the
nighttime. In the case of short-term insomnia disorder, no such mismatch exists; yet,
the individual demonstrates sleep onset or maintenance difficulties nonetheless.
Bibliography
Agnew HW Jr, Webb WB, Williams RL. The first night effect: an EEG study of sleep. Psychophysiology
1966;2:263–6.
Angst J, Vollrath M, Koch R, Dobler-Mikola A. The Zurich Study. VII. Insomnia: symptoms, classification
and prevalence. Eur Arch Psychiatry Clin Neurosci 1989;238:285–93.
Healey ES, Kales A, Monroe LJ, Bixler EO, Chamberlin K, Soldatos CR. Onset of insomnia: role of life-
stress events. Psychosom Med 1981;43:439–51.
Morin CM, Rodrigue S, Ivers H. Role of stress, arousal and coping skills in primary insomnia. Psychosom
Med 2003;65:259–67.
Roehrs T, Zorick F, Roth T. Transient and short-term insomnias. In: Krieger MH, Roth T, Dement WC,
eds. Principles and practice of sleep medicine, 3rd ed. Philadelphia: WB Saunders, 2000:624–32.
Tachibana H, Izumi T, Honda S, Takemoto TI. The prevalence and pattern of insomnia in Japanese
industrial workers: relationship between psychosocial stress and type of insomnia. Psychiatry Clin
Neurosci 1998;52:397–402.
45
Insomnia
Other Insomnia Disorder

This diagnosis is reserved for individuals who complain of difficulty initiating and
maintaining sleep and yet do not meet the full criteria for either chronic insomnia dis-
order or short-term insomnia disorder. In some cases, this diagnosis may be assigned
on a provisional basis when more information is needed to establish a diagnosis of
chronic insomnia disorder or short-term insomnia disorder. It is expected that this diag-
nosis will be used sparingly, given its nonspecific nature.
46
Insomnia
Excessive Time in Bed

Some individuals may present with isolated insomnia symptoms such as prolonged
sleep latencies or long periods of wakefulness during the night, yet not complain of
insomnia nor show daytime impairments. In children, this pattern may emerge when
parents or caregivers have unrealistic expectations for the child’s sleep needs and rou-
tinely allot too much time for the child to be in bed each night. In adults, this pattern
is perhaps most common in noncomplaining groups who routinely allot significantly
more time in bed than needed for sleep. For example, some individuals who are retired
from work or not currently employed may routinely spend excessive time in bed each
night and are not bothered by the expanded periods of wakefulness they routinely
experience. At present, epidemiological and laboratory studies are unable to ascertain
whether adverse health outcomes are more strongly associated with perceived sleep
difficulties/dissatisfaction or with particular objective indices of sleep duration, sleep
latency, and sleep continuity.
Short Sleeper
Some individuals routinely obtain less than six hours of sleep per night on average yet
have no sleep/wake complaints. Such individuals are considered to be normal short
sleepers if they have no complaints of sleep difficulties and show no obvious daytime
dysfunction. Among these individuals, the observed relatively low average sleep time
does not result from chronic volitional sleep restriction, as in the case of insufficient
sleep syndrome, but rather indicates a constitutional disposition for reduced sleep
requirement. The clinical significance of chronic short sleep duration, and the identifi-
cation of possible subtypes, remain open questions. Various studies have linked short
sleep duration with metabolic, cardiovascular, and other forms of medical morbidity.
However, these studies are typically unable to distinguish between individuals who
have short sleep in the context of insomnia or another sleep disorder, those who are
voluntarily restricting their sleep, and those who may have naturally short sleep. Short
sleep resulting from different causes may have different pathophysiological signifi-
cance. At present, those who demonstrate less than six hours of sleep per night should
not be assigned an insomnia diagnosis unless they also meet the criteria for one of the
insomnia disorder subtypes described herein.
47
Insomnia
Bibliography
Fernandez-Mendoza J, Calhoun S, Bixler EO, Pejovic S, Karataraki M, Liao D. Insomnia with objective
short sleep duration is associated with deficits in neuropsychological performance: a general population
study. Sleep 2010;33:459–65.
Hartmann E. Sleep requirement: long sleepers, short sleepers, variable sleepers, and insomniacs.
Psychosomatics 1973;14:95–103.
Ohayon MM, Caulet M, Guilleminault C. How a general population perceives its sleep and how this
relates to the complaint of insomnia. Sleep 1997;20:715–23.
Roehrs T, Zorick F, Roth T. Transient and short-term insomnias. In: Krieger MH, Roth T, Dement WC,
eds. Principles and practice of sleep medicine, 3rd ed. Philadelphia: WB Saunders, 2000:624–32.
Vgontzas AN, Liao D, Bixler EO, Chrousos GP, Vela-Bueno A. Insomnia with objective short sleep
duration is associated with a high risk for hypertension. Sleep 2009;32:491–7.
Webb WB, Friel J. Characteristics of “natural” long and short sleepers: a preliminary report. Psychol Rep
1970;27:63–6.
48
Sleep Related Breathing Disorders
Obstructive Sleep Apnea Disorders
Obstructive Sleep Apnea, Adult.....................................................................53
Obstructive Sleep Apnea, Pediatric...............................................................63
Central Sleep Apnea Syndromes

Central Sleep Apnea with Cheyne-Stokes Breathing....................................69
Central Apnea Due to a Medical Disorder without
Cheyne-Stokes Breathing.............................................................................75
Central Sleep Apnea Due to High Altitude Periodic Breathing......................79
Central Sleep Apnea Due to a Medication or Substance..............................85
Primary Central Sleep Apnea........................................................................89
Primary Central Sleep Apnea of Infancy.......................................................94
Primary Central Sleep Apnea of Prematurity.................................................98
Treatment-Emergent Central Sleep Apnea.................................................102
Sleep Related Hypoventilation Disorders

Obesity Hypoventilation Syndrome.............................................................108
Congenital Central Alveolar Hypoventilation Syndrome.............................. 113
Late-Onset Central Hypoventilation with Hypothalamic Dysfunction.......... 118
Idiopathic Central Alveolar Hypoventilation.................................................121
Sleep Related Hypoventilation Due to a Medication or Substance.............124
Sleep Related Hypoventilation Due to a Medical Disorder..........................128
Sleep Related Hypoxemia Disorder

Sleep Related Hypoxemia...........................................................................134

Snoring........................................................................................................139
Catathrenia..................................................................................................141
The sleep related breathing disorders are characterized by abnormalities of respi-

ration during sleep. In some of these disorders, respiration is also abnormal during
wakefulness. The disorders are grouped into obstructive sleep apnea (OSA) disorders,
central sleep apnea disorders, sleep related hypoventilation disorders, and sleep related
hypoxemia disorder. However, many patients will meet diagnostic criteria for more
than one of these groups. In particular, many patients have a combination of obstruc-
tive and central sleep apnea. Although a diagnosis is often based on which disorder
49
predominates, this may vary from night to night as well as over time in individual
patients. There is also overlap in pathophysiology, as some central apneas are associ-
ated with a closed upper airway and many obstructive apneas begin during a time of
falling ventilatory drive.
In the sections that follow, individual respiratory events (e.g., apneas, hypopneas, and
hypoventilation) are not defined; rather, reference is made to the most recent version of
the American Academy of Sleep Medicine (AASM) Manual for the Scoring of Sleep
and Associated Events for these definitions. The AASM Manual for the Scoring of
Sleep and Associated Events includes different scoring rules for adult and pediatric
individuals, definitions of obstructive and central apneas and hypopneas, and rules for
scoring Cheyne-Stokes breathing and hypoventilation.
The OSA disorders are separated into adult and pediatric categories, as the presenta-
tion, diagnostic criteria, course, and complications differ significantly. These disorders
are characterized by upper airway narrowing or closure during sleep while respiratory
effort continues (at least during some portion of the event). The use of out-of-cen-
ter sleep testing (OCST) with limited channels (electroencephalogram [EEG] is not
usually recorded) is now included in the diagnostic criteria for adult OSA.
The central sleep apnea syndromes are characterized by reduction or cessation of

airflow due to absent or reduced respiratory effort. Central apnea or hypopnea may
occur in a cyclical or intermittent fashion. Patients with central sleep apnea of various
etiologies may also exhibit OSA.
In primary central sleep apnea, the cause of the disorder is unknown (idiopathic). The
arterial partial pressure of carbon dioxide (PaCO2) during wake in these patients is
normal or low. Patients do not meet diagnostic criteria for other central sleep apnea dis-
orders. In central sleep apnea with Cheyne-Stokes breathing, there is a cyclical pattern
of crescendo-decrescendo respiration separated by central apneas or central hypopneas.
Most patients with this disorder have congestive heart failure (reduced or preserved
ejection fraction), although, less commonly, others exhibit this breathing pattern fol-
lowing stroke or in association with other neurological disorders. In high-altitude peri-
odic breathing, the disorder is associated with acute ascent to high altitude. Symptoms
must be present to establish the diagnosis of high-altitude periodic breathing, as this
breathing pattern is an expected finding after ascent to altitude. Central sleep apnea
due to medical or neurological condition (not Cheyne-Stokes) is usually due to a struc-
tural lesion in the central nervous system. These disorders should be excluded before
a diagnosis of primary central sleep apnea is made. In central sleep apnea due to drug
50
or substance, the patient demonstrates central apneas secondary to the effects of potent
opioids or other respiratory depressants on respiratory control centers.
Treatment-emergent central sleep apnea is a new addition to the International

Classification of Sleep Disorders. In this disorder, the patient exhibits predominantly
obstructive events during diagnostic sleep testing (e.g., obstructive or mixed apneas
and obstructive hypopneas), but central apneas or central hypopneas emerge or persist
on positive airway pressure treatment without a backup rate and are the predominant
residual breathing abnormality (i.e., obstructive events have resolved). A diagnosis of
treatment-emergent central sleep apnea is made when the central sleep apnea component
is not better explained by another diagnosis (i.e., another central sleep apnea disorder).
Sleep related hypoventilation disorders are characterized by an abnormal increase in

the arterial PCO2 (PaCO2) during sleep. Adult and pediatric hypoventilation disorders
are defined by different criteria. For adults, an increase in the arterial PCO2 (or sur-
rogate) to greater than 55 mm Hg for at least 10 minutes or an increase ≥ 10 mm Hg
above the awake value to a value of 50 mm Hg or greater for at least 10 minutes is
required. In pediatric patients, the PaCO2 (or surrogate) must be greater than 50 mm
Hg for greater than 25% of total sleep time.
In this edition of the International Classification of Sleep Disorders, there are a number
of changes in the classification of sleep related hypoventilation disorders. The obesity
hypoventilation syndrome is listed as a separate disorder given that it is both prevalent
and has distinct clinical characteristics. In contrast to other sleep related hypoventila-
tion disorders, a diagnosis of obesity hypoventilation syndrome requires documenta-
tion of awake (daytime) hypoventilation (PaCO2 > 45 mm Hg). For the other disorders
in this category, awake hypoventilation may or may not be present.
In the previous version of the International Classification of Sleep Disorders, a group

of disorders were listed under the category of sleep related hypoventilation/hypoxemia
disorders. In the International Classification of Sleep Disorders, 3rd Edition, disorders
manifesting hypoventilation are separated from disorders in which only a finding of
hypoxemia (arterial oxygen desaturation) during sleep is documented. Demonstrating
sleep related hypoventilation rather than simply hypoxemia has important diagnostic
and treatment consequences. Sleep related hypoxemia disorders are characterized by
sustained periods of significantly reduced oxyhemoglobin saturation during sleep. This
diagnostic category is used when sleep related hypoventilation is either not present or
the status is unknown. Sleep related hypoxemia can occur due to hypoventilation, ven-
tilation-perfusion mismatch, low partial pressure of oxygen, shunt, or a combination of
51
these factors. Many diverse etiologies can be associated with sleep related hypoxemia.
There are no longer separate diagnostic categories for the various types of medical
and neurological pathology that may contribute to hypoventilation or hypoxemia. In
the International Classification of Sleep Disorders, 2nd Edition, these included lower
airway obstruction, pulmonary parenchymal and vascular pathology, and neuromus-
cular and chest wall disorders. In the International Classification of Sleep Disorders,
3rd Edition, the specific pulmonary or neurological disorder should be diagnosed sep-
arately, in association with a diagnosis of sleep related hypoventilation due medical or
neurological condition or sleep related hypoxemia.
Bibliography
Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/occlusion during central sleep apnea.
J Appl Physiol 1995;78:1806–15.
Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM, Marcus CL and Vaughn BV for the American
Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, Version 2.0.3. www.aasmnet.org. Darien, IL:
American Academy of Sleep Medicine, 2014
Tkacova R, Niroumand M, Lorenzi-Filho G, Bradley TD. Overnight shift from obstructive to central
apneas in patients with heart failure: role of PCO2 and circulatory delay. Circulation 2001;103:238–43.
Tkacova R, Wang H, Bradley TD. Night-to-night alterations in sleep apnea type in patients with heart
failure. J Sleep Res 2006;15:321–8.
52
Obstructive Sleep Apnea Disorders
Obstructive Sleep Apnea, Adult

ICD-9-CM code: 327.23 ICD-10-CM code: G47.33
Alternate Names
OSA syndrome, sleep apnea, sleep apnea syndrome, obstructive apnea, sleep disor-
dered breathing, obstructive sleep apnea hypopnea syndrome.
The term upper airway resistance syndrome (UARS) is subsumed under this diagnosis
because the pathophysiology does not significantly differ from that of obstructive sleep
apnea. Use of the term Pickwickian syndrome is discouraged because not only has it
been applied to those with OSA, but also indiscriminately used to describe persons
who are only obese and those with obesity hypoventilation syndrome.
Diagnostic Criteria
(A and B) or C satisfy the criteria
A. The presence of one or more of the following:
1. The patient complains of sleepiness, nonrestorative sleep, fatigue, or
insomnia symptoms.
2. The patient wakes with breath holding, gasping, or choking.
3. The bed partner or other observer reports habitual snoring, breathing
interruptions, or both during the patient’s sleep.
4. The patient has been diagnosed with hypertension, a mood disorder,
cognitive dysfunction, coronary artery disease, stroke, congestive
heart failure, atrial fibrillation, or type 2 diabetes mellitus.
B. Polysomnography (PSG) or OCST1 demonstrates:
1. Five or more predominantly obstructive respiratory events2
(obstructive and mixed apneas, hypopneas, or respiratory effort
related arousals [RERAs])3 per hour of sleep during a PSG or per
hour of monitoring (OCST).1
OR
C. PSG or OCST1 demonstrates:
1. Fifteen or more predominantly obstructive respiratory events
(apneas, hypopneas, or RERAs)3 per hour of sleep during a PSG or
per hour of monitoring (OCST).1
53
Notes
1. OCST commonly underestimates the number of obstructive respiratory
events per hour as compared to PSG because actual sleep time,
as determined primarily by EEG, is often not recorded. The term
respiratory event index (REI) may be used to denote event frequency
based on monitoring time rather than total sleep time.
2. Respiratory events defined according the most recent version of the
AASM Manual for the Scoring of Sleep and Associated Events.
3. RERAs and hypopnea events based on arousals from sleep
cannot be scored using OCST because arousals by EEG criteria
cannot be identified.
Essential Features
OSA is characterized by repetitive episodes of complete (apnea) or partial (hypopnea)
upper airway obstruction occurring during sleep. These events often result in reduc-
tions in blood oxygen saturation and are usually terminated by brief arousals from
sleep. By definition, apneic and hypopneic events last a minimum of 10 seconds. Most
events are 10 to 30 seconds in duration but occasionally persist for one minute or
longer. Events can occur in any stage of sleep but more frequently occur in stages
N1, N2, and R sleep than in stage N3 sleep. Events are usually longer and associated
with more severe decreases in oxygen saturation when they occur in stage R sleep and
when the individual is sleeping supine. Oxygen saturation usually returns to baseline
values following resumption of normal breathing but may remain low if the apneic or
hypopneic events are very frequent and prolonged, or if there is underlying pulmonary
pathology. Snoring between apneas is typically reported by bed partners, as are wit-
nessed episodes of gasping or choking and body movements that disrupt sleep. Most
patients awaken in the morning feeling tired and unrefreshed regardless of the duration
of their time in bed. Apneas, hypopneas, and snoring may be exacerbated following
the ingestion of alcohol, use of sedating medications prior to sleep, or following an
increase in body weight.
Excessive sleepiness is a major presenting complaint in many but not all cases. The
sleepiness is most evident during relaxing or inactive situations. With extreme sleepi-
ness, sleep may occur while actively conversing, eating, walking, or driving. In women,
excessive sleepiness is a less prominent complaint. Additionally, reports of insomnia,
poor sleep quality, and fatigue are common, particularly among women. Quality of life
generally is adversely affected by unrefreshing sleep, sleepiness, and fatigue. Bed part-
ners may also report sleep disruption and associated consequences. The frequency of
apneas and hypopneas during sleep correlates poorly with daytime symptom severity
54
and impact on quality of life. In some cases, affected individuals will not endorse any
symptoms or confirm any bed partner observations.
Associated Features
Systemic hypertension is a common finding in patients with OSA. There is substan-
tial clinical and epidemiologic evidence implicating OSA as a significant risk factor
for development of systemic hypertension independent of other conditions such as
obesity and smoking. Additionally, OSA is frequently observed in patients with cor-
onary artery disease, atrial fibrillation, and stroke, and it may be an independent
risk factor for these conditions. OSA is also associated with type 2 diabetes, and
there are accumulating data to suggest that it is a risk factor for the development of
type 2 diabetes. Patients with severe disease may be at risk for developing pulmo-
nary hypertension and cor pulmonale, although this is usually seen only in patients
with daytime hypercapnia due to comorbid conditions such as morbid obesity or
chronic obstructive pulmonary disease (COPD). When OSA coexists with dilated
cardiomyopathy or ischemic heart disease, there may be worsening of the underly-
ing heart disease and predisposition to congestive heart failure. Gastroesophageal
reflux symptoms, nocturia, mood disturbance, and erectile dysfunction are some-
times reported in patients with OSA. The disorder can also be associated with the
following motor parasomnias: OSA-induced arousals from non-rapid eye movement
(NREM) sleep mimicking a primary disorder of arousal (confusional arousal, sleep-
walking, or sleep terrors); OSA-induced arousals from REM sleep mimicking REM
sleep behavior disorder; disorders of arousal from NREM associated with slow wave
sleep rebound during initiation of nasal continuous positive airway pressure (CPAP)
therapy of OSA; OSA-induced arousals linked with sleep related eating disorder;
and OSA-induced nocturnal seizures or cerebral anoxic attacks with prominent
motor activity.
Severity of OSA as determined by the frequency of apneas and hypopneas and/or

degree of oxygen desaturation correlates poorly with symptomatic sleepiness. Different
measures of sleepiness, including self-reported severity of sleepiness, commonly used
indices such as the Epworth Sleepiness Scale, and objective measures such as the
Multiple Sleep Latency Test (MSLT), are not strongly correlated and, thus, assessment
of sleepiness can be difficult and relatively unreliable. In addition, patients may adapt
to any level of sleepiness over time and fail to view it as a reportable problem. Bed
partner-observed breathing pauses and disruptive snoring may not always be accompa-
nied by patient complaints of sleepiness. Finally, it is important to note that sleepiness
is a condition with a number of possible etiologies and a range of manifestations (see
Differential Diagnosis).
55

Apneas and hypopneas are believed to have similar pathophysiology and consequences.
Therefore, from a clinical perspective, there is little importance in distinguishing
patients who have predominantly apnea from those who have predominantly hypopnea.
Occasionally, patients may demonstrate only REM-related apneas or hypopneas, but there
is no consensus to suggest that this is a distinct clinical or pathophysiological subtype.
Some patients have relatively few arterial oxygen desaturations but a significant
number of respiratory events characterized by narrowing of the upper airway result-
ing in brief arousals from sleep. Depending on the definition of hypopnea employed,
these events typically meet criteria for either hypopneas associated with arousal but no
desaturation, or for RERAs. When initially described, this latter group was said to have
UARS. Current data suggest that this condition represents simply a variant of OSA in
which obstructive events result in arousal but minimal arterial oxygen desaturation.
Patients with this condition commonly snore and report daytime sleepiness or fatigue.
However, there are some reports of patients with frequent respiratory arousals in the
absence of snoring. They tend to be less obese than individuals who have respiratory
event-associated arterial oxygen saturation. The prevalence of this group of patients is
unknown. When advanced technology is used to detect changes in airflow (as described
in the AASM Manual for the Scoring of Sleep and Associated Events), most of these
patients will be diagnosed as having OSA, as defined by the criteria listed above.
COPD and OSA frequently coexist, but there is no common pathophysiologic rela-
tionship. Nevertheless, individuals with both disorders have greater nocturnal oxygen
desaturation and daytime hypercapnia for the same degree of bronchial airflow obstruc-
tion, and greater risk of developing pulmonary hypertension and right heart failure.
The prevalence rate for having both conditions has been estimated to be 1%.
Demographics
OSA can occur in any age group. Estimates of prevalence are very dependent on how
sleep related respiratory events are defined, as well as their frequency and other criteria
used to define disease. Nevertheless, general population-based studies from a number
of countries indicate that OSA associated with daytime sleepiness occurs in 3% to
7% of adult men and 2% to 5% of adult women. However, because many individuals
with OSA do not endorse daytime sleepiness, the prevalence of the disease is likely
much higher. A major study yielded prevalence rates as high as 24% in men and 9%
in women using only an apnea-hypopnea index (AHI) criterion of ≥ 5/hour, although
addition of a daytime sleepiness criterion reduced these estimates to 4% in males and
2% in females.
56
The prevalence of OSA increases with age, although it appears to plateau in the elderly.
The ratio of OSA in men compared to women is approximately two to one. This dispar-
ity may decline in middle to older age as a result of a greater risk for OSA in women
after menopause.
OSA occurs in all racial and ethnic groups. In younger and elderly groups, but not
in middle-aged groups, OSA has been reported to be more prevalent in blacks than
whites. The prevalence of OSA in Asian patients is comparable to that of whites, despite
having a generally lower body mass index (BMI). Differences in craniofacial features
that predispose Asians to developing OSA are the likely explanation. Data comparing
OSA prevalence rates among Hispanics and Native Americans to other racial/ethnic
groups are sparse, although it is clear that OSA occurs commonly in these groups.

The major predisposing factor for OSA is excess body weight. It has been estimated
that ~60% of moderate to severe OSA is attributable to obesity. The risk of OSA
increases as the degree of additional weight increases, with an extremely high preva-
lence of OSA in people with morbid obesity. OSA patients with normal or below-nor-
mal body weight are more likely to have upper airway obstruction due to a localized
structural abnormality such as a maxillomandibular malformation or adenotonsillar
enlargement. Increasing neck circumference predicts higher AHIs; it is not, however,
independent of BMI. Instability in ventilatory control appears to increase risk of OSA.
Those patients with an exaggerated ventilatory response to a respiratory disturbance
have a greater propensity for obstructive events. Menopause is a risk factor for this
disorder in women, even after adjustment for age and BMI. However, use of hormone
replacement therapy may be protective. There are conflicting data concerning smoking
as a risk factor for OSA. Various abnormalities of the bony and soft tissue structures
of the head and neck may predispose the individual to having OSA. These may be
hereditary (e.g., mandibular size, mandibular position, palatal height) or acquired (e.g.,
enlarged adenoids and tonsils). Endocrine disorders such as acromegaly and hypothy-
roidism are risk factors for OSA. Adults and children with Down syndrome also have
a high prevalence of OSA. OSA is common in patients with some neurologic disorders
that affect peripheral muscles, such as myotonic dystrophy. OSA is likely made worse
following alcohol consumption or use of sedating medications before sleep and by
nocturnal nasal restriction or congestion due to abnormal morphology, rhinitis, or both.
Familial Patterns
OSA is a heritable condition as demonstrated by familial clustering of OSA patients.
First-degree relatives of OSA patients are twice as likely to have OSA in comparison
57
to those not affected. Clustering of symptoms that are associated with OSA such as
snoring, daytime sleepiness, and snorting or gasping also occurs. Heritability explains
approximately one third of the variation in the AHI, with a substantial proportion of the
heritability explained by obesity. Other inherited traits that might predispose an indi-
vidual to developing OSA include craniofacial morphology and ventilatory control.
Familial environmental factors such as physical activity and eating habits may play a
role as well. Nevertheless, genetic studies to date have not identified a unique gene or
genes responsible for OSA heritability.

As documented in longitudinal population studies, the severity of untreated OSA mea-
sured by the AHI tends to slowly progress over time. OSA becomes more severe in
patients whose BMI increases, but may improve with weight reduction. However, the
effect of weight gain on increasing OSA severity is greater than the impact of weight
loss on decreasing OSA severity. Moreover, the consequences of weight change are
more evident in men than women.
Substantial evidence implicates OSA as a risk factor for incident systemic hyper-
tension, coronary artery disease, congestive heart failure, stroke, and premature
mortality. Data suggest that these effects are more evident in men and middle-aged
individuals. In addition, there is accumulating evidence to suggest that OSA is a
risk factor for the development of type 2 diabetes mellitus independent of obesity.
Various arrhythmias are commonly observed in association with OSA. Evidence
suggests that OSA is particularly related to the onset and recurrence of atrial
fibrillation.
OSA may increase the severity of depression. Because of daytime sleepiness, func-
tional impairment occurs commonly as manifested by poor job performance, loss of
employment, impaired family relationships, and reduction in overall quality of life.
The risk of motor vehicle accidents is significantly increased among those with OSA.
OSA can occur in any age group, but in adults, prevalence accelerates between young
adulthood and middle age, with a plateau reached after approximately age 65 years.
Although OSA occurs in the elderly, it is commonly observed with few symptoms. In
addition, some evidence suggests that risk of cardiovascular disease related to OSA
may be less important in the elderly. This has raised the possibility that its presence
in this age group represents a distinct clinical variant. Pediatric OSA is discussed in a
separate section (below).
58

The pathophysiology underlying upper airway narrowing during sleep is multifactorial.
Patients with OSA commonly have reduced cross-sectional area of the upper airway
lumen due to either excessive bulk of soft tissues (tongue, soft palate, and lateral pha-
ryngeal walls) or craniofacial anatomy, or both. During inspiration, negative pressure
is generated in the lumen of the upper airway, promoting closure. However, pharyngeal
dilating muscles act to maintain patency. The activity of these muscles decreases with
sleep onset, but is normally adequate to maintain an open airway. In persons with OSA,
the activity of the pharyngeal dilating muscles becomes insufficient to prevent narrow-
ing and/or closure of the upper airway. This state-dependent change is the major con-
tributing factor leading to an obstructed upper airway. There is a further reduction in
tone and phasic activity of pharyngeal dilating muscles during REM sleep, particularly
in phasic REM, which likely contributes to apneas and hypopneas that are longer and
more pronounced. Decreased end-expiratory lung volume and falling ventilatory drive
associated with hypocapnia also predispose to upper airway narrowing or closure. In
the breaths leading up to obstructive apnea, end-expiratory upper airway caliber pro-
gressively decreases. Smaller end-expiratory lung volume may result in smaller upper
airway size due to decreased downward traction (tracheal tug). Some patients have
unstable ventilatory control (high loop gain) with resulting periods of hypocapnia that
may also contribute to upper airway narrowing.
The mechanisms of apnea/hypopnea termination are controversial. Event termination

may occur with or without an associated arousal. Some events may resolve with aug-
mentation of upper airway muscle tone from chemical (low PaO2, high PaCO2) and
mechanical (upper airway mechanoreceptors) stimuli, whereas others may depend on
a change of sleep state (arousal) at either a cortical or subcortical level. Cortical arous-
als are associated with changes detectable by EEG, whereas other changes of state
may be detectable only by direct or indirect measures of sympathetic tone. Even if
arousals are not required for termination of all obstructive events, sleep fragmentation
from arousals is nevertheless believed to be a significant cause of excessive daytime
sleepiness. Apneas and hypopneas typically last considerably longer in REM and, in
some patients, are only present in this sleep stage. The explanation for this finding is
unknown.
As an apnea or hypopnea event progresses, the patient gradually becomes more hypox-
emic; the degree of oxygen desaturation is dependent not only on the duration of the
event, but also on the patient’s baseline oxygen saturation and lung volume and the
presence of comorbid lung conditions. Slight hypercarbia also occurs during apneas
and hypopneas and is worse during REM sleep.
59
Accumulating evidence indicates that persons with OSA have elevated levels of circu-
lating inflammatory mediators related to repetitive episodes of oxygen desaturation and
increased sympathetic nervous system activity. Both of these findings may be import-
ant in the pathogenesis of hypertension and cardiovascular disease related to OSA.
Objective Findings
Obstructive apneas are documented by a cessation of airflow with ongoing respiratory
efforts during PSG or an OCST. When breathing effort is recorded with respiratory
inductance plethysmography, it typically shows paradoxical movement of the rib cage
and abdomen. If esophageal manometry is used, increasingly large swings between
inspiratory and expiratory efforts are observed. Obstructive hypopneas are a reduction
rather than a cessation of airflow with ongoing respiratory effort. Increasing respira-
tory effort with constant or reduced flow is indicative of increased upper airway resis-
tance. This state is most accurately identified with a quantitative measurement of flow
and esophageal manometry, although it can be inferred when there is obvious inspira-
tory airflow limitation (flattening of the inspiratory flow) on a nasal pressure recording.
Although patients with OSA have predominantly obstructive events, they may also
have variable amounts of central apneas. In some patients, these resolve with admin-
istration of positive airway pressure, whereas in others frequent central apneas either
persist or emerge, at least during the initial night of positive airway pressure treatment.
Oxygen saturation typically declines for a variable period of time following the onset
of an event (apnea or hypopnea), with the nadir usually occurring after normal breath-
ing resumes. The degree of oxygen desaturation may range from as little as 1% to 2%,
up to 30% to 40% or greater. If the baseline oxygen saturation is normal, there may
be no discernible drop in oxygen saturation despite evidence of airflow limitation fol-
lowed by arousal. As a result, some events associated with evidence of increased respi-
ratory effort (and/or flattening of inspiratory flow) and an arousal at event termination
may not meet diagnostic criteria for apnea or hypopnea. These events are defined as
RERAs. These events are presumed to have the same underlying pathophysiology as
obstructive apneas and hypopneas (upper airway obstruction) and are considered to be
as much of a risk factor for symptoms of unrefreshing sleep, daytime somnolence, and
fatigue as frank apnea or hypopnea.
The EEG may provide evidence of a brief arousal from sleep, and the submental electro-
myogram may demonstrate a burst of activity indicating upper airway dilating muscle
activation immediately preceding the resumption of normal breathing. Microphones
may record a sudden resumption of loud snoring. Obstructive apneas and hypopneas
may be accompanied by bradyarrhythmias, tachyarrhythmias, or both; however, the
60
prevalence of this finding in patients varies widely. At the time of arousals, there is
often a surge in both sympathetic nervous system activity and systemic blood pressure.
In contrast to patients with OSA, those with isolated snoring will not exhibit obstruc-
tive apneas, hypopneas, or RERAs on PSG or OCST and do not have other sleep symp-
toms attributable to breathing disturbance. However, because arousal-based hypopneas
and RERAs cannot be identified with OCST, OSA cannot be excluded if the OCST is
negative.
Patients with central sleep apnea have predominantly central rather than obstruc-
tive apneas, hypopneas, or RERAs as the primary finding on PSG or OCST. If mixed
apneas are predominant, a diagnosis of OSA should be made.
Patients with obesity hypoventilation syndrome will demonstrate daytime hypercap-

nia. Snoring may not be a prominent feature, although daytime sleepiness can occur.
Patients with sleep related hypoventilation disorders may show episodes of oxygen
desaturation without evidence of airflow obstruction on PSG or OCST. Confirmation
of nocturnal hypercapnia will be diagnostic. However, if obstructive apneas or hypo-
pneas are evident, a diagnosis of OSA should be made instead of, or in addition to, the
diagnosis of sleep related hypoventilation.
OSA must be differentiated from other causes of sleepiness such as narcolepsy, idio-
pathic hypersomnia, and insufficient sleep. These conditions often can be identified on
the basis of history, but PSG and/or MSLT may be required to confirm the diagnosis.
OSA should be distinguished from other causes of nocturnal dyspnea, such as noc-
turnal panic attacks, nocturnal gastroesophageal reflux, asthma, paroxysmal nocturnal
dyspnea from congestive heart failure, and nocturnal angina pectoris. In many cases,
absence of snoring and daytime sleepiness will be highly suggestive of etiologies other
than OSA. However, the absence of obstructive apneas, hypopneas, or RERAs on PSG
will definitively exclude OSA as the diagnosis.

Although substantial evidence implicates OSA as a risk factor for coronary artery
disease and stroke, it has not been clearly demonstrated that treatment mitigates this
risk. This is especially a concern for patients with mild OSA who are not hypersom-
nolent. The pathophysiologic mechanisms linking OSA to increased risk of coronary
artery disease, stroke, and hypertension require further investigation. Although there
61
is a clear association between OSA and type 2 diabetes mellitus, further studies are
needed to determine whether OSA is an independent risk factor and what mechanisms
are involved.
Bibliography
Berry RB, Brooks R, Gamaldo CE, Harding SM, Lloyd RM, Marcus CL and Vaughn BV for the American
Academy of Sleep Medicine. The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, Version 2.0.3. www.aasmnet.org. Darien, IL:
American Academy of Sleep Medicine, 2014
Berry RB. Dreaming about an open upper airway. Sleep 2006;29:429–30.
Budhiraja R, Budhiraja P, Quan SF. Sleep-disordered breathing and cardiovascular disorders. Respir Care
2010;55:1322–32.
Iber C, Ancoli-Israel S, Chesson AL, Quan SF; for the American Academy of Sleep Medicine. The AASM
manual for the scoring of sleep and associated events: rules, terminology and technical specifications.
1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
Pamidi S, Aronsohn RS, Tasali E. Obstructive sleep apnea: role in the risk and severity of diabetes. Best
Pract Res Clin Endocrinol Metab 2010;24:703–15.
Patel SR, Larkin EK, Redline S. Shared genetic basis for obstructive sleep apnea and adiposity measures.
Int J Obes (Lond) 2008;32:795–800.
Pepin JL, Guillot M, Tamisier R, Levy P. The upper airway resistance syndrome. Respiration
2012;83:559–66.
Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol 2005;99:1592–9.
Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:136–43.
White DP. Sleep apnea. Proc Am Thorac Soc 2006;3:124–8.
Younes M. Role of arousal in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med
2004;169:623–33.
Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing
among middle-aged adults. N Engl J Med 1993;328:1230–5.
Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health
perspective. Am J Respir Crit Care Med 2002;165:1217–39.
62
Obstructive Sleep Apnea, Pediatric

Alternate Names
Obstructive sleep apnea syndrome, sleep apnea, sleep apnea syndrome, obstructive
apnea, sleep disordered breathing, sleep hypopnea syndrome, obstructive hypoventila-
tion, and upper airway obstruction.
The term upper airway resistance syndrome (UARS) is subsumed under this diagnosis
because the pathophysiology does not significantly differ from that of OSA. Use of the
term Pickwickian syndrome is discouraged, as this term has been used loosely to cover
a constellation of conditions including OSA and central hypoventilation.
Diagnostic Criteria
Criteria A and B must be met
1. Snoring.
2. Labored, paradoxical, or obstructed breathing during the child’s
sleep.
3. Sleepiness, hyperactivity, behavioral problems, or learning problems.
B. PSG demonstrates one or both of the following:
1. One or more obstructive apneas, mixed apneas, or hypopneas, per
hour of sleep.1
OR
2. A pattern of obstructive hypoventilation, defined as at least 25%
of total sleep time with hypercapnia (PaCO2 > 50 mm Hg) in
association with one or more of the following:
a. Snoring.
b. Flattening of the inspiratory nasal pressure waveform.
c. Paradoxical thoracoabdominal motion.
Notes
1. Respiratory events defined according to the most recent version of the
Essential Features
Pediatric criteria for OSA apply to patients younger than 18 years. However, for the
purpose of PSG scoring, the AASM Manual for the Scoring of Sleep and Associated
Events states that adult diagnostic criteria may be used for patients aged 13 to 18 years.
63
Pediatric OSA is characterized by intermittent complete or partial obstruction (obstruc-

tive apnea or hypopnea); prolonged partial upper airway obstruction; or both prolonged
and intermittent obstructions that disrupt normal ventilation during sleep, normal sleep
patterns, or both. Children with OSA may demonstrate several breathing patterns
during sleep. Some children have cyclic episodes of obstructive apnea, similar to that of
adults with the syndrome. However, some patients, particularly younger children, have
a pattern of obstructive hypoventilation, which consists of long periods of persistent
partial upper airway obstruction associated with hypercapnia, arterial oxygen desatu-
ration, or both. Some children may manifest a pattern of UARS similar to that seen
in adults, including snoring without identifiable airflow obstruction and increasingly
negative esophageal pressure swings and cyclic arousals. In children, upper airway
obstruction occurs predominantly during REM sleep. Children often do not have cor-
tical arousals in response to the upper airway obstruction, although they may have
movement or autonomic arousals. Perhaps as a result of this higher arousal threshold,
sleep architecture is usually normal, with normal amounts of slow wave sleep. Even
short obstructive apneas may be associated with severe hypoxemia because children
have a lower functional residual capacity and a higher metabolic rate than adults.
Most children with OSA present with a history of snoring and difficulty breathing
during sleep. Snoring is usually loud and may be punctuated by pauses and gasps,
with associated movements or arousal from sleep. However, some patients, particu-
larly infants and those with neuromuscular weakness, may not snore. Patients with
obstructive hypoventilation often have continuous snoring without pauses or arous-
als. Children have a very compliant rib cage. As a result, paradoxical breathing is a
prominent sign in these patients (note that paradoxical breathing during REM sleep
is a normal phenomenon in young children up to at least age three years). A pectus
excavatum may be present. Thoracic retractions may be present. Children may sleep in
unusual positions, such as seated or with their neck hyperextended. Diaphoresis may
be observed. Morning headaches may also occur. Many parents of children with OSA
are so concerned about their child’s breathing that they sleep with their child or stimu-
late their child to terminate the apneas.
Excessive daytime sleepiness may be present, especially in older children and adoles-
cents, but is seen less commonly in children than in adults with OSA. Developmental,
behavioral, and learning issues are frequently present. These may include attention
problems, hyperactivity, moodiness, irritability, and impaired academic performance.
64
Associated Features
Hypoxemia and hypercapnia are often present during sleep and may be severe. A prom-
inent sinus arrhythmia is often seen, although other arrhythmias are rare. Secondary
enuresis may occur. Breathing during wakefulness is normal, although mouth breath-
ing secondary to adenoidal hypertrophy may be present. Other nonspecific daytime
symptoms related to adenotonsillar hypertrophy, such as frequent upper respiratory
tract infections or dysphagia, may occur. Although studies have shown that children
with OSA generally have larger tonsils and adenoidal tissue than do other children, the
size of the tonsils and adenoidal tissue does not predict disease in individual patients.

Clinical presentations include OSA, obstructive hypoventilation, and recurrent arousal
associated with increased respiratory effort (RERAs).
Demographics
The prevalence in children has been estimated at 1% to 4%, but the prevalence may
currently be higher due to the pediatric obesity epidemic. The prevalence in infants
and adolescents is unknown. In prepubertal children, the disease occurs equally among
boys and girls; in adolescents, data suggest the prevalence may be higher in males.
There appears to be a higher prevalence in black children than white children; the prev-
alence in other ethnic groups is unknown. The disease can occur at any age, from the
neonatal period to adolescence, but in otherwise healthy children it is most common in
the preschool age (in association with adenotonsillar hypertrophy) and in adolescents
(in association with obesity).

Adenotonsillar hypertrophy and obesity are the most common predisposing/precip-
itating factors. Children with craniofacial abnormalities, particularly micrognathia
or midfacial hypoplasia, are at risk. Those with Down syndrome are particularly at
risk for having OSA. Children with neuromuscular diseases often have upper airway
muscle weakness, which predisposes to airway collapse. Children with cerebral palsy
may be predisposed to OSA because of spasticity, weakness, or incoordination of the
upper airway muscles. Infants with gastroesophageal reflux may develop OSA due to
upper airway edema or laryngospasm. Other medical conditions such as mucopoly-
saccharidosis and sickle cell disease may predispose to OSA. Pharyngeal flap oper-
ations, typically performed to improve speech quality in patients with cleft palate,
can result in OSA. Environmental tobacco smoke exposure has been associated with
snoring and OSA.
65
Familial Patterns
There is evidence for an increased risk of OSA in children with affected family
members. Potential mechanisms for familial aggregation include heritability of pre-
disposing skeletal, soft tissue, body habitus, or respiratory control characteristics.
However, the relative roles of genetic factors versus environmental factors have not
been determined.

The exact course of pediatric OSA has not been well studied. Symptoms typically
begin within the first few years of life, although the disease may not be diagnosed
until many years later. The natural course of untreated OSA is not known. A few
short-term studies suggest that some children with mild disease may improve, or
conversely, have worsening of the condition; long-term studies are not available.
Complications are frequent and may be severe. In early childhood, OSA can cause
growth failure, especially when associated with a comorbid genetic or craniofacial
disorder. Cognitive and behavioral complications are common and may include
developmental delay, poor school performance, attention deficit hyperactivity dis-
order, inattention and impairment in concentration, and aggressive behavior. Rarely,
cases of severe asphyxial brain damage, seizures, and coma have been reported.
Cardiovascular complications include pulmonary hypertension, cor pulmonale, and
systemic hypertension.
Developmental issues are reviewed within individual sections.

In children, as in adults, OSA results from a combination of abnormal neuromuscular
control and anatomical narrowing of the collapsible (supracartilaginous) portion of the
upper airway. During wakefulness, the patient with OSA compensates by augmenting
upper airway muscle tone to dilate the upper airway; thus, obstructive apnea does not
occur. During sleep, there is a decrease in ventilatory drive and in neuromuscular tone,
facilitating upper airway collapse. The resultant recurrent hypoxemia, hypercapnia,
and sleep disruption may lead to neurobehavioral, cardiovascular, and growth abnor-
malities. Childhood OSA has also been associated with metabolic and inflammatory
abnormalities.
In most children who are otherwise healthy, upper airway narrowing is primarily due
to adenotonsillar hypertrophy. Pediatric OSA also occurs in association with obesity,
which is becoming increasingly prevalent. Other causes for upper airway narrowing
66
include craniofacial anomalies, particularly those involving midface hypoplasia or

micrognathia/retrognathia. In addition, children with decreased upper airway muscle
tone or abnormal upper airway muscle function, such as children with muscular dys-
trophy or cerebral palsy, are at increased risk for OSA.
Objective Findings
PSG demonstrates obstructive and mixed apneas, hypopneas, or periods of obstructive
hypoventilation. In children, obstructive apneas lasting two respiratory cycles or longer
are scored. In contrast to adults with OSA, EEG arousals may or may not be present fol-
lowing apneas, especially in young children, although subcortical/autonomic arousals
(as manifested by body movements, tachycardia, or measurements of pulse transit time
or arterial tonometry) may occur. Possibly as a result of the higher arousal threshold,
sleep architecture is usually preserved. Apneas and hypopneas occur primarily during
REM sleep, and breathing may be totally normal during NREM sleep. Obstructive
events are frequently associated with desaturation and hypercapnia. Evaluation of the
upper airway by endoscopy, radiography, computed tomographic scans, or magnetic
resonance imaging studies may show large tonsils and adenoidal tissue and a narrow
upper airway, although these tests are not performed routinely. Echocardiography may
show evidence of right, left, or biventricular hypertrophy.
Pediatric OSA must be differentiated from isolated snoring. Children with snoring but
without observed apnea, labored breathing during sleep, daytime behavioral issues,
sleepiness, or other symptoms of OSA may not require further laboratory investigation.
However, children who have snoring and symptoms of OSA need evaluation to deter-
mine whether they have isolated snoring or OSA (N.B. this distinction cannot reliably
be made clinically but should be based on PSG). Children with primary snoring do not
have apneas, gas exchange abnormalities, or frequent arousals on PSG. Central sleep
apnea can be differentiated from OSA by the lack of chest or abdominal wall move-
ment associated with the central apneas. Mixed apneas may be seen and are included
in the diagnosis of OSA. Children with fixed upper airway obstruction due to struc-
tural abnormalities tend to obstruct both awake and asleep, and have stridor rather
than snoring. OSA in children must be distinguished from nonobstructive alveolar
hypoventilation. Children with lung or chest wall disease may have desaturation and
hypercapnia during sleep. It may be difficult to separate nonobstructive hypoventila-
tion and desaturation from OSA, especially because the two conditions may coexist.
In general, children with nonobstructive hypoventilation will not snore and will not
have paradoxical inward rib cage motion during inspiration, although the latter may
be present in children with neuromuscular disease. OSA must be differentiated from
67
other causes of sleepiness such as narcolepsy, idiopathic hypersomnia, and insufficient

sleep. Sleep related epilepsy may mimic obstructive apnea during sleep and may be
indistinguishable from OSA without the appropriate EEG monitoring, especially in
infants who may have only subtle motor components of seizures.

There is a need for further research in many aspects of pediatric OSA. Although studies
of prevalence have been performed in the past, the prevalence has probably increased
in recent years due to the increasing prevalence of childhood obesity. Further data
regarding the prevalence in infants and adolescents is needed. The natural course of
the disease, the optimal techniques for monitoring patients during PSG, the effects of
mild OSA, and the threshold necessitating treatment require further study. The role of
genetic, ethnic, and anatomic factors in the pathophysiology of childhood OSA also
requires further study.
Bibliography
Arens R, Marcus CL. Pathophysiology of upper airway obstruction: a developmental perspective. Sleep
2004;27:997–1019.
Arens R, McDonough JM, Costarino AT, et al. Magnetic resonance imaging of the upper airway structure
in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2001;164:698–703.
Marcus CL, Brooks LJ, Davidson Ward S, et al.; American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea syndrome: technical report. American Academy of
Pediatrics. Pediatrics 2012;130:e714–55.
Marcus CL, Brooks LJ, Draper K, Gozal D, et al.; American Academy of Pediatrics. Diagnosis and
management of childhood obstructive sleep apnea syndrome: clinical practice guideline. American
Academy of Pediatrics. Pediatrics 2012;130:576–84.
Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered
breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care
Med 1999;159:1527–32.
68
Central Sleep Apnea Syndromes
Central Sleep Apnea with Cheyne-Stokes Breathing

ICD-9-CM code: 786.04 ICD-10-CM code: R06.3
Alternate Names
Cheyne-Stokes respiration.
Diagnostic Criteria
(A or B) + C + D satisfy the criteria
1. Sleepiness.
2. Difficulty initiating or maintaining sleep, frequent awakenings, or
nonrestorative sleep.
3. Awakening short of breath.
4. Snoring.
5. Witnessed apneas.
B. The presence of atrial fibrillation/flutter, congestive heart failure, or a
neurological disorder.
C. PSG (during diagnostic or positive airway pressure titration) shows all
of the following:
1. Five or more central apneas and/or central hypopneas per hour of
sleep.1
2. The total number of central apneas and/or central hypopneas is >
50% of the total number of apneas and hypopneas.2
3. The pattern of ventilation meets criteria for Cheyne-Stokes
breathing (CSB).1
D. The disorder is not better explained by another current sleep disorder,
medication use (e.g., opioids), or substance use disorder.
Notes
1. As defined by the most recent version of the AASM Manual for the
Scoring of Sleep and Associated Events.
2. If criterion C2 is not met, CSB can be listed as a polysomnographic
finding.
3. A diagnosis of central sleep apnea (CSA) with CSB does not exclude a
diagnosis of OSA.
69
Essential Features
CSA-CSB is characterized by recurrent central apneas or central hypopneas alternat-
ing with a respiratory phase exhibiting a crescendo-decrescendo pattern of flow (or
tidal volume). The longer cycle length (> 40 seconds; typically 45 to 60 seconds)
distinguishes CSB from other central sleep apnea types. The vast majority of patients
with CSA-CSB have either systolic or diastolic heart failure. In systolic heart failure
the cycle length is longer (longer respiratory phase) than in patients with diastolic
heart failure, and there is often a delay in the nadir of the associated oxygen desatu-
ration. Patients with CSA-CSB have normal or low daytime arterial PCO2 (PaCO2).
Some patients with heart failure have a mixture of obstructive and central apneas with
more central apneas in the later part of the night or when the patient is placed on posi-
tive airway pressure (PAP). A diagnosis of CSA-CSB requires that events be predom-
inantly central apneas and hypopneas with an average frequency of at least 5/hour
during a diagnostic PSG or either the diagnostic or therapeutic portion of a split-night
study. For patients with a mixture of OSA and CSA-CSB, the central apneas may
appear only after elimination of obstruction on positive airway pressure. In patient
with CSA-CSB, arousal from sleep tends to occur at the zenith of respiratory effort
between contiguous central apneas or hypopneas. This can result in sleep fragmen-
tation. However, patients may complain of disturbed nocturnal sleep or nocturnal
dyspnea rather than daytime sleepiness.
Associated Features
Presenting features of CSB pattern during sleep may include excessive daytime sleep-
iness, insomnia, or nocturnal dyspnea. Because many patients with CSA-CSB have
known heart failure, their complaints of frequent awakenings or disturbed sleep may be
falsely assumed to be entirely secondary to heart failure. Because studies have shown
that approximately 60% of patients with heart failure have some form of sleep apnea, a
high index of suspicion is indicated. A CSB pattern can also occur during wakefulness
and can be observed at bedside or in the clinic. Some studies suggest that the pres-
ence of CSA-CSB during wakefulness is associated with a worse prognosis. Although
heart failure is the major cause of CSA-CSB, recent studies suggest that it can be
noted after stroke. CSA-CSB can rarely present in an idiopathic form or be associated
with renal failure.
As in other forms of CSA, apneas and hypopneas are associated with absent or reduced
ventilatory effort, respectively, due to diminished central respiratory drive. Of inter-
est, a longer respiratory phase between apneas is associated with a longer circulation
time and delay in the saturation nadir. The CSB breathing pattern is characteristically
observed during stages N1 and N2 and usually resolves or is attenuated during REM
70
sleep. In patients with both OSA and CSA-CSB, the relative amount of central and
obstructive apnea can vary over time or even within the same night.

Some patients have combined OSA and CSA, and the CSA-CSB may not manifest
until the patient is placed on positive airway pressure treatment. These patients are
considered to have both OSA and CSA with CSB. Patients with systolic or diastolic
heart failure may have CSB, but the cycle length is longer in those with systolic dys-
function. Patients with neurological disorders may have CSB, but the characteristic
cycle length is less well described.
Demographics
CSA with CSB generally is seen in subjects older than 60 years. The prevalence of this
breathing disorder in the setting of chronic congestive heart failure has been reported
to be 25% to 40%, depending on how patients are divided into those with predomi-
nant OSA and those with CSA. In patients with heart failure there is a striking male
predominance in the occurrence of CSA-CSB. Of interest, the use of β-blockers and
angiotensin-converting enzyme inhibitors for treatment of congestive heart failure has
not decreased the prevalence of CSA-CSB. Some form of sleep apnea is reported in
50% to 70% of patients following stroke, depending on the AHI cutoff used for diagno-
sis. Although OSA predominates, central sleep apnea is also common especially in the
first few days following stroke. CSA-CSB has been reported to occur in 26% to 50%
of patients in the acute period following stroke.

The most important predisposing factors are the presence of congestive heart failure,
stroke, and possibly renal failure. Within the heart failure population, risk factors for
CSB pattern during sleep include male sex, age older than 60 years, the presence of
atrial fibrillation, and daytime hypocapnia (i.e., awake PaCO2 of 38 mm Hg or less). In
general, greater pulmonary congestion (higher left ventricular end-diastolic pressure)
predicts lower PaCO2. Some studies suggest that CSA-CSB occurs more commonly in
the supine position. Although renal failure is often listed as a possible cause of CSA-
CSB, there is scant literature documenting this association.
Familial Patterns
Not applicable or known.
71

There are no definitive data concerning the onset. However, because it is seen in the
setting of congestive heart failure, stroke, and possibly renal failure, CSA with CSB
most likely has its onset following the development of one of these illnesses. In the
setting of systolic congestive heart failure, it is associated with a poor prognosis, as
indicated by a greater adjusted relative risk for mortality-cardiac transplantation com-
pared to patients without CSB. These data suggest that CSB pattern during sleep par-
ticipates in the pathophysiology and progression of heart failure. Its clinical signifi-
cance in the setting of stroke or other neurological disorders remains less certain. In
some patients with CSA after stroke, the pattern can transition to one of OSA. The
presence of obstructive apnea following stroke has been found to be associated with a
worse prognosis.
Although there are reports of CSB in children, the condition is extremely rare in this
age group. Of interest, one study of patients with congestive heart failure across all
age groups found CSB to be absent in children but present in 40% of the adult patients
with congestive heart failure. A limitation of the study was that only ten children with
congestive heart failure were studied.

CSA with CSB generally arises because of instability in the respiratory control system.
A high ventilatory drive and delay in chemoreceptor response to changes of PaCO2 and
PaO2 (due to increased circulation time) are likely the major factors. This breathing
disorder tends to occur in individuals with a chronically low PaCO2 when awake and
asleep. Hyperventilation occurs due to an increase in the responsiveness of the periph-
eral and central chemoreceptors. The increased responsiveness is believed to be due to
both increased sympathetic tone and stimulation of vagal irritant receptors in the lungs
by pulmonary congestion. The PaCO2 in individuals with CSB pattern and heart failure
is closer to their apneic threshold than in those without CSB pattern (primarily due to
a smaller sleep related rise in PaCO2 in those with CSB), so that even modest increases
in ventilation can drive PaCO2 below the apneic threshold. The most common trigger
factor for central apnea is an arousal from sleep, which abruptly augments ventilation
and drives PaCO2 below the apneic threshold.
The crescendo-decrescendo pattern of tidal volume results from prolonged lung-to-che-

moreceptor circulatory delay, such that changes in PaCO2 in the lung are trans-
mitted only very slowly to the chemoreceptors, resulting in a gradual buildup and
falloff of ventilatory stimulation. The length of the cycle is directly proportional to
72
lung-to-chemoreceptor circulation time and inversely proportional to cardiac output.

Accordingly, whereas the length of the ventilatory-apneic cycle in primary CSA is
typically shorter than 40 seconds, in CSB pattern it is almost invariably longer than 40
seconds (usually 45-90 seconds). One study of patients with varying degrees of heart
failure found a considerably shorter cycle time in patients with normal ejection frac-
tion (e.g., diastolic heart failure). The pathophysiology of CSB pattern in the setting
of stroke and renal failure has not been examined in any detail. However, apneas in
association with these medical disorders are believed to be due to a reduction in PaCO2
below the apneic threshold. In individuals with renal failure, pulmonary congestion
(volume overload) may play a role in stimulating hyperventilation.
Objective Findings
The polysomnographic hallmarks of CSB pattern are recurrent central apneas and
central hypopneas alternating with ventilatory periods having a prolonged crescen-
do-decrescendo pattern of airflow (tidal volume). CSB pattern typically occurs at the
transition from wakefulness to NREM sleep and during stages N1 and N2. It tends to
dissipate in stages N3 and R. In stage N3 sleep the sleeping PaCO2 is higher (further
above the apneic threshold). During REM sleep the hypoxic and hypercapnic ventila-
tory responses are lower, thereby reducing the tendency for an overshoot in ventilation
which may drive PaCO2 below the apneic threshold.
Arousals are frequently seen in association with CSB and are typically noted at or near
the zenith in respiratory effort (or airflow), although can occur at or near the onset of
the respiratory phase pattern. In contrast, arousals tend to occur at apnea termination in
other CSA disorders. As noted above, a longer respiratory phase (and cycle length) is
associated with lower cardiac output and longer circulation time.
Central hypopnea, rather than apnea, can occur at the nadir in respiratory effort in
patients with CSB and have been included in calculation of the central AHI in a sub-
stantial number of investigations. Central hypopneas are characterized by the absence
of snoring, flattening in the nasal pressure or PAP device flow signal, and thoracoab-
dominal paradox.
Central apneas and central hypopneas are usually accompanied by modest oxyhemo-
globin desaturation; arterial oxygen saturation seldom falls below 80% to 85%. The
combination of oxygen desaturation and arousals from sleep leads to sleep fragmenta-
tion with reduced amounts of stage N3 sleep. Additionally, PaCO2 less than 40 mm Hg
is typically observed during wakefulness. In patients with both obstructive and central
apneas, the proportion of central apneas tends to increase over the night, and this is
73
associated with a fall in the sleeping PaCO2. The lower sleeping PaCO2 is thought to be
due to an increase in pulmonary congestion during the night with stimulation of juxta-
capillary (J) receptors in the lung interstitium and a subsequent increase in ventilatory
drive. As noted above, some patients have more CSA-CSB in the supine position.
Primary CSA can usually be distinguished from CSB pattern by the absence of a history
of heart failure, stroke, or renal failure and by the absence of a crescendo-decrescendo
breathing pattern between central apneas. The cycle length (apnea + ventilatory phase)
in primary CSA is typically less than 40 seconds. High-altitude periodic breathing
only occurs at high altitude and is not associated with heart failure, stroke, or renal
failure. Patients with CSA due to drug or substance have a history of use of this type of
medication, and an ataxic breathing pattern may be present. If patients with CSA asso-
ciated with opioids manifest periodic breathing, the respiratory phase does not have a
crescendo-decrescendo pattern and the cycle length is shorter. Patients with CSA due to
a medical or neurological disease without Cheyne-Stokes will have central apnea that
does not have Cheyne-Stokes morphology, as the name implies. Sleep related hypoven-
tilation and hypoxemic syndromes can be readily distinguished from CSA-CSB by
documentation of an awake PaCO2 > 45 mm Hg and/or sleep related hypoventilation.
Patients with CSA-CSB usually have an awake PaCO2 < 40 mm Hg. In patients with
sleep related hypoventilation disorders, some central apneas may be present, but these
events do not have a Cheyne-Stokes morphology. Additionally, oxygen desaturation in
sleep related hypoventilation syndromes is generally more pronounced during REM
sleep. OSA is distinguished by the presence of respiratory efforts during apneas. A few
central apneas or hypopneas at sleep onset or during REM sleep are normal, especially
in elderly subjects. These cease once sleep becomes stable.

The pathophysiology and clinical significance of CSB pattern have not yet been eluci-
dated in the setting of stroke and renal failure. Less is also known about the importance
of CSB in patients with heart failure with a normal ejection fraction.
Bibliography
Dowdell WT, Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting as sleep apnea syndrome.
Clinical and polysomnographic features. Am Rev Respir Dis 1990;141:871–9.
Hall M, Xie A, Rutherford R, Ando S, Floras J, Bradley T. Cycle length of periodic breathing in patients
with and without heart failure. Am J Respir Crit Care Med 1996;154:376–81.
Lanfranchi P, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in
chronic heart failure. Circulation 1999;99:1435–40.
74
MacDonald M, Fang J, Pittman SD, White DP, Malhotra A. The current prevalence of sleep disordered
breathing in congestive heart failure patients treated with beta-blockers. J Clin Sleep Med 2008;4:38–42.
Naughton M, Benard D, Tam A, Rutherford R, Bradley T. The role of hyperventilation in the pathogenesis
of central sleep apnea in patients with congestive heart failure. Am Rev Respir Dis 1993;148:330–8.
Peer A, Lorber A, Suraiya S, Malhotra A, Pillar G. The occurrence of Cheyne-Stokes respiration in
congestive heart failure: the effect of age. Front Psychiatry 2010;1:133.
Pressman MR, Benz RL, Schleifer CR, Peterson DD. Sleep disordered breathing in ESRD: acute beneficial
effects of treatment with nasal continuous positive airway pressure. Kidney Int 1993;43:1134–9.
Sahlin C, Svanborg E, Stenlund H, Franklin KA. Cheyne-Stokes respiration and supine dependency. Eur
Respir J 2005;25:829–33.
Sin D, Fitzgerald F, Parker J, Newton G, Floras J, Bradley T. Risk factors for central and obstructive
sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med
1999;160:1101–6.
Sin DD, Logan AG, Fitzgerald FS, et al. Effects of continuous positive airway pressure on cardiovascular
outcomes in Heart failure patients with and without Cheyne-Stokes Respiration. Circulation
2000;102:61–6.
Wedewardt J, Bitter T, Prinz C, Faber L, Horstkotte D, Oldenburg O. Cheyne-Stokes respiration in heart
failure: cycle length is dependent on left ventricular ejection fraction. Sleep Med 2010;11:137–42.
Xie A, Skatrud J, Puleo D, Rahko P, Dempsey J. Apnea-hypopnea threshold for CO2 in patients with
congestive heart failure. Am J Respir Crit Care Med 2002;165:1245–50.
Central Apnea Due to a Medical Disorder without

Cheyne-Stokes Breathing
Alternate Names
Diagnostic Criteria
Criteria A-C must be met
A. The presence of one or more of the following1:
1. Sleepiness.
4. Snoring.
B. PSG shows all of the following:
1. Five or more central apneas and/or central hypopneas per hour of
sleep.2
75
2. The number of central apneas and/or central hypopneas is > 50% of

the total number of apneas and hypopneas.
3. Absence of CSB.2
C. The disorder occurs as a consequence of a medical or neurological
disorder but is not due to medication use or substance use.
Notes
1. In infants and young children, symptoms are supportive but not
required.
3. Sleep related hypoventilation is not required but may be present. If the
patient meets criteria for both sleep related hypoventilation and CSA
due to medical or neurological condition not Cheyne-Stokes, both
diagnoses can be made.
4. In some patients other abnormalities of breathing such as ataxic
breathing may be prominent.
5. A diagnosis of central apnea due to a medical disorder without CSB
does not exclude a diagnosis of OSA.
Essential Features
CSA that is attributed to a medical or neurological condition (and does not have the
pattern of CSB) is classified here. The majority of these patients have brainstem lesions
of developmental, vascular, neoplastic, degenerative, demyelinating, or traumatic origin.
Associated Features
Patients generally present with sleep fragmentation, excessive daytime sleepiness, or
insomnia. Other signs and symptoms that are often, but not invariably, present include
snoring, witnessed apnea, and awakening with shortness of breath. The presentation
varies with the cause of central apnea and may include neurological findings.

None. Some of the common medical and neurological disorders causing central apnea
not associated with CSB are listed in Pathology and Pathophysiology (below).
Demographics
The prevalence and demographics of this disorder vary with the underlying etiology.
Patients with Chiari malformation (CM) can present in infancy or childhood, but the
most common age of presentation is 20 to 40 years. Patients with stroke tend to be older.
76

Because of the heterogeneity of etiologies in this type of CSA, predisposing and pre-
cipitating factors are variable. In CM there is herniation of a portion of the brainstem
through the foramen magnum. In CM type 1, a portion of the cerebellar tonsils herni-
ate. CSA in these patients is believed to occur due to impaired function of ventilatory
control centers in the brainstem.
Familial Patterns
None known.

These factors vary as well with the different etiologies. In CM the presentation is typi-
cally age 20 to 40 years of age but can occur in infants and children. With the increased
use of magnetic resonance imaging (MRI), cases are often diagnosed before symptoms
are severe. The CSA following a cerebrovascular accident (CVA) is abrupt in onset.
In patients exhibiting both central and obstructive apnea, the central apneas tend to
resolve with time. Some post-CVA patients with central apneas have central apnea
with CSB, whereas in others the CSA does not have a pattern consistent with CSB. The
central apneas can lead to sleep fragmentation, yielding either hypersomnolence or
insomnia or both. There is little evidence that these apneas or their associated hypoxia
and hypercapnia lead to pulmonary hypertension, cor pulmonale, or other adverse car-
diovascular consequences.
Not known.

CSA is caused by failure of the ventilatory control centers to initiate ventilatory effort.
The abnormality is due to dysfunction of central ventilatory control centers. The pres-
ence of sleep may unmask ventilatory control abnormalities with the loss of the wake-
fulness stimulus. Sleep related hypoventilation and/or daytime hypoventilation may
coexist with CSA due to medical or neurological disorder, not CSB, in which case both
diagnoses can be made.
A number of causes of CSA due to medical or neurological disorders–not Cheyne-

Stokes—have been described. Patients with CM exhibit obstructive, central, or a
mixture of obstructive and central apneas. Some patient exhibit nocturnal hypoventi-
lation but rarely daytime hypoventilation. CSA and/or OSA can be the initial presenta-
tion of the disorder. Symptoms include headache (especially with laughter, coughing,
77
or exertion), neck pain, and vertigo. An MRI is diagnostic of the condition and should
be considered as part of the evaluation of all patients without an obvious cause of
central apnea.
Brainstem neoplasm can present with central apnea not of the Cheyne-Stokes type.
Patients with a recent cerebrovascular accident show a high incidence of sleep disor-
dered breathing. Although obstructive apnea is more common, central apnea may be
noted initially after a cerebrovascular accident. Some patients exhibit a pattern of CSB,
whereas in others periodic breathing without the characteristic CSB pattern is present.
Patients with multiple system atrophy may also present with CSA that does not have
a CSB pattern.
Objective Findings
The polysomnogram of the patient with CSA due to medical or neurological condi-
tion—not CSB—demonstrate recurrent (five or more per hour) central apneas and/or
central hypopneas. The central apneas and hypopneas meet criteria for these events as
defined by the most recent version of the AASM Manual for the Scoring of Sleep and
Associated Events. Runs of recurrent central apneas separated by periods of ventilation
may occur. The interevent respiratory phase is typically brief with a maximum of five
breaths. The central apneas do not have the pattern of CSB.
Patients with CSA due to medical or neurological disorder—not CSB—should be dif-
ferentiated from primary CSA, in which no known cause is identified. As the name
implies, patients with a pattern of CSB should be classified as such. Patients with
central nervous system neoplasms may have a central hypoventilation syndrome with
sleep related hypoventilation with or without an increase in daytime PaCO2.

With the possible exception of poststroke central apnea, the disorders classified here
are thought to be relatively rare. The presenting symptoms may not be a sleep related
complaint. Except for those associated with CM and poststroke CSA, the disorders are
not well characterized.
Bibliography
Cormican LJ, Higgins AC, Davidson R, et al. Multi system atrophy presenting as central sleep apnea. Eur
Respir J 2004;24:323–5.
Dauvilliers Y, Stal V, Abril B, et al. Chiari malformation and sleep related breathing disorders. J Neurol
Neurosurg Psychiatry 2007;78:1344–8.
78
Fernández AA, Guerrero AI, Martínez MI, et al. Malformations of the craniocervical junction (Chiari type
I and syringomyelia: classification, diagnosis and treatment). BMC Musculoskelet Disord 2009 Dec
17;10 Suppl 1.
Parra O, Arboix A, Bechich S, et al. Time course of sleep-related breathing disorders in first-ever stroke or
transient ischemic attack. Am J Respir Crit Care Med 2000;161:375–80.
Siccoli MM, Valko PO, Hermann DM, Bassetti CL. Central periodic breathing during sleep in 74 patients
with acute ischemic stroke—neurogenic and cardiogenic factors. J Neurol 2008;255:1687–92.
Central Sleep Apnea Due to High Altitude Periodic

Breathing
Alternate Names
None.
Diagnostic Criteria
Criteria A-D must be met
A. Recent ascent to high altitude.1
B. The presence of one or more of the following:2
1. Sleepiness.
3. Awakening with shortness of breath or morning headache.
4. Witnessed apnea.
C. The symptoms are clinically attributable to high-altitude periodic
breathing or PSG, if performed, demonstrates recurrent central apneas
or hypopneas primarily during NREM sleep at a frequency of ≥ 5/hour.
medical or neurological disorder, medication use (e.g., narcotics), or
substance use disorders.
Notes
1. Typically at least 2,500 meters (8,202 feet), although some individuals
may exhibit the disorder at altitudes as low as 1,500 meters.
2. Periodic breathing is a common response to altitude. Associated symptoms
are required to make the diagnosis of a disorder. There is no level of the
central AHI separating a normal and abnormal response to high altitude.
3. A diagnosis of CSA due to high-altitude period breathing does not
exclude a diagnosis of OSA.
79
Essential Features
High-altitude periodic breathing is characterized by alternating periods of central apnea
and hyperpnea associated with recent ascent to high altitude. The pattern of periodic
breathing is an expected response to ascent to elevation. Only those individuals who
manifest related symptoms, as described below, are diagnosed with this disorder. The
cycle length of this respiratory pattern is commonly less than 40 seconds and often as
short as 12 to 20 seconds. The percentage of individuals exhibiting periodic breathing
during sleep increases at higher altitudes. Approximately 25% exhibit periodic breath-
ing at 2,500 meters (8,202 feet), and virtually 100% demonstrate periodic breathing
at 4,000 m (13,123 feet). Periodic breathing has been described at altitudes as low as
1,500 meters (4,900 feet). Chronic exposure to altitude above 2,500 meters has also
been associated with periodic breathing in some studies.
Associated Features
At altitude, individuals may complain of frequent awakenings, poor-quality sleep, and
a sense of dyspnea. These symptoms will often improve with time at moderate altitude
but may persist at extreme altitude. Alterations in sleep associated with ascent to alti-
tude include a reduction in stage N3 sleep and increased arousal frequency. Total sleep
time and the amount of REM sleep are either unchanged or decreased. Of note, the
degree of both subjective and objective impairment of sleep quality was not correlated
with the severity of periodic breathing in a number of studies.

None known.
Demographics
The demographics of high-altitude periodic breathing are not known. High-altitude
periodic breathing tends to occur in individuals with a high hypoxic and probably
hypercapnic ventilatory response. Because men generally have higher chemorespon-
siveness than women, high-altitude periodic breathing may be more common in men
than in women. As stated above, periodic breathing will occur in virtually anyone
ascending to higher than 4,000 meters and in some individuals at lower altitudes. The
latter group probably comprises individuals with increased hypoxic chemoresponsive-
ness. In one study, individuals both with and without periodic breathing at altitude had
alterations in sleep architecture. Those with periodic breathing had a greater arousal
index, although their sleep architecture was otherwise not significantly different from
individuals who did not develop periodic breathing.
80

The only known predisposing factor for the development of high-altitude periodic
breathing is increased ventilatory chemoresponsiveness, primarily hypoxic ventila-
tory responsiveness. A high hypoxic ventilatory response will lead to increased hyper-
ventilation on ascent to altitude. This hyperventilation leads to hypocapnic alkalosis
that, during sleep, inhibits ventilation. Thus, repetitive cycles of apnea and hyperpnea
develop during NREM sleep. The obvious precipitating factor for the development of
this periodic breathing is ascent to altitude. The more rapid the ascent, the more likely
periodic breathing is to develop.
Familial Patterns
Some data suggest that ventilatory chemoresponsiveness is directly inherited. Because
elevated hypoxic responsiveness is a predisposing variable in the development of
high-altitude periodic breathing, it would seem likely that there would be a familial
pattern in the development of this respiratory abnormality. However, there are no data
addressing this issue.

This respiratory pattern will generally be evident during sleep immediately after ascent
to altitude. This depends to some extent on the rapidity of the ascent, the elevation,
and individual predisposition. However, it will be present most often on the first night
at altitude. At moderate altitude, the breathing pattern may become more regular over
time, although at extreme altitude it is likely to persist. One recent study found that
the amount of periodic breathing continued to increase over three days to two weeks
of acclimatization. Studies of adaptation to altitude suggest that sleep quality may
improve despite further increases in periodic breathing. It has been hypothesized that
hypoxia itself may have an important role in disturbing sleep architecture. Thus, sleep
and symptoms may improve during acclimatization to altitude even if the amount of
periodic breathing actually increases.
The complications of high-altitude periodic breathing, which are generally limited to

disrupted sleep on the initial nights at altitude, include frequent awakenings, often
with shortness of breath or a sensation of suffocation that may lead to fatigue or sleep-
iness on the following day. There is no clear association between periodic breathing
and other altitude syndromes (high-altitude pulmonary edema, acute mountain sick-
ness, and high-altitude cerebral edema). In fact, periodic breathing is a marker of high
hypoxic responsiveness, which generally yields improved oxygenation at altitude and
a reduced frequency of the maladaptive syndromes.
81
Relatively little is known about differences between children and adults concerning
periodic breathing at altitude. One study did compare breathing in children and their
fathers. The children revealed reduced nocturnal oxygen saturation and associated
hyperventilation at high altitude similar to the adults, but their breathing pattern was
more stable. The investigators hypothesized that children may have a lower apnea
threshold for CO2 than adults.

High-altitude periodic breathing is believed to be a product of the hyperventilation
induced by the hypobaric hypoxia encountered at altitude. At 2,500 meters the atmo-
spheric pressure is approximately 570 mm Hg and the ideal alveolar PO2 around 55
mm Hg (depending on the level of PaCO2). Actual arterial PO2 values will be lower,
especially during sleep. The hypoxic ventilatory response shows a steep increase in
ventilation when the arterial PO2 level drops below 55 mm Hg. The increases in venti-
lation associated with hypoxemia result in hypocapnic alkalosis. Because PaCO2 is the
principal stimulus to respiration during NREM sleep, a low PaCO2 can yield a loss or
reduction in respiratory drive, resulting in central apnea or hypopnea. The greater the
ventilatory response to hypoxia, the greater the fall in PaCO2. Thus, individuals with
brisk hypoxic responses more commonly tend to demonstrate this respiratory pattern.
Over the course of the apnea, the PaO2 falls and PaCO2 rises, eventually stimulating a
resumption of ventilation. However, after several large breaths, the PaCO2 again falls
below the apnea threshold, initiating another pause in breathing. This cycle is then
repeated over the course of the night. Of note, the respiratory pattern is often improved
during REM sleep with reduced cycling. This is likely due to the decreased hypoxic
and hypercapnic responsiveness characteristic of REM sleep. Of interest, in one study
the hypoxic ventilatory response continued to increase up to seven days after ascent
to altitude. This resulted in a lower PaCO2 and higher PaO2. The reduction in peri-
odic breathing in some individuals with adaptation to altitude despite a greater venti-
latory response to hypoxemia may be due to a lowering of the apneic threshold. Other
studies have found that the amount of periodic breathing continues to increase over
three days to two weeks of acclimatization despite improvements in oxygen saturation.
The increase in both periodic breathing and oxygen saturation is thought to be due to
increased controller gain of the respiratory system.
A number of studies have found that the impairment of sleep architecture does not
correlate with the degree of periodic breathing. One study found that the amount of
periodic breathing was greater on the third night at altitude compared to the first night.
However, both the nocturnal oxygen saturation and amount of stage N3 also increased
82
on the third night compared to the first night. It has been hypothesized that hypoxia
rather than periodic breathing might be the major factor disturbing sleep.
Objective Findings
The PSG of individuals with high-altitude periodic breathing demonstrates recur-
rent central apneas with a cycle time of less than 40 seconds, and typically around 20
seconds. There is some degree of associated arterial oxygen desaturation. The apneas
are short, generally 8 to 10 seconds in duration. In one study, the apnea duration was
around 8 seconds (7 to 9 seconds) in children and approximately 12 seconds (10-14
seconds) in adults.
The cycle length is commonly less than 40 seconds. This breathing pattern occurs only
during NREM sleep with more rhythmic respiration during REM sleep. Because this
breathing pattern is a physiologic adaptation to altitude, there is no specific number
of apneas per hour of sleep that is considered normal or abnormal. The apneas and
associated hyperpnea can lead to recurrent arousals from sleep, which often increase
stages N1 and N2 sleep while reducing stage N3 sleep. REM sleep (stage R) duration
is generally preserved, as is total sleep time. As noted above, some studies have found
a reduction in total sleep time and stage R as well as stage N3. Of interest, the arousal
index was only around 25% of the AHI in some investigations.
High-altitude periodic breathing should be distinguished from other SRBDs. The
major distinguishing factor is, of course, recent ascent to high altitude. An individual
with OSA will likely continue to have this nocturnal respiratory problem at altitude.
Altitude might even exacerbate the OSA. Patients with chronic mountain sickness
demonstrate relative hypoventilation at altitude (i.e., breathe less than is encoun-
tered in normal individuals at similar altitude) such that they are more hypoxic than
normal individuals who have a greater ventilatory response to the same ambient
hypoxia. During sleep, these individuals often demonstrate further arterial oxygen
desaturation. Some of the individuals will demonstrate apneas or periodic breathing.
A diagnosis of chronic mountain sickness does not imply that periodic breathing is
present. However, periodic breathing may be more common in these patients than
previously appreciated.

Recent studies suggest that hypoxemia rather than the amount of periodic breathing
may be the major factor impairing sleep quality. Further studies relating changes in
sleep and periodic breathing at altitude are needed.
83
Bibliography
Anholm J, Powles A, Downey R, et al. Operation Everest II: arterial oxygen saturation and sleep at
extreme simulated altitude. Am Rev Respir Dis 1992;145:817–26.
Bloch KE, Latshand TD, Turk AJ, et al. Nocturnal periodic breathing during acclimatization at very high
altitude at Mount Muztach Ata (7,546 m). Am J Respir Crit Care Med 2010;182:562–8.
Burgess, K.R., Lucas, S.J., Shepherd, K.L., et al. Worsening of central sleep apnea at high altitude—a role
for cerebrovascular function. J Appl Physiol 2013; 114: 1021–8.
Coote JH, Tsang G, Baker A, Stone B. Respiratory changes and structure of sleep in young high-altitude
dwellers in the Andes of Peru. Eur J Appl Physiol 1993;66:249–53.
Goldberg S, Schoene R, Haynor D, et al. Brain tissue pH and ventilatory acclimatization to high altitude.
J Appl Physiol 1992;72:58–63.
Johnson P, Edwards N, Burgess KR, Sullivan CE. Sleep architecture changes during a trek from 1400 to
500 m in the Nepal Himalaya. J Sleep Res 2010;19:148–56.
Kohler M, Kriemler S, Wilhelm EM, Brunner-LaRocca H, Zehnder M, Bloch KE. Children at high altitude
have less nocturnal periodic breathing than adults. Eur Respir J 2008;32:189–97.
Lahiri S, Barnard P. Role of arterial chemoreflex in breathing during sleep at high altitude. Prog Clin Biol
Res 1983;136:75–85.
Lahiri S, Meret K, Sherpa M. Dependence of high altitude sleep apnea on ventilatory sensitivity to
hypoxia. Respir Physiol 1983;52:281–301.
Lombardi C, Meriggi P, Agostoni P, et al. Highcare Investigators. High-altitude hypoxia and periodic
breathing during sleep: gender-related differences. J Sleep Res 2013; 22:322–30.
Nickol AH, Leverment J, Richards P, et al. Temazepam at high altitude reduces periodic breathing
without impairing next-day performance: a randomized cross-over double-blind study. J Sleep Res
2006;15:445–54.
Nussbaumer-Ochsner Y, Ursprung J, Siebenmann C, Maggiorini M, Bloch KE. Effect of short-term
acclimatization to high altitude on sleep and nocturnal breathing. Sleep 2012;35:419–23.
Schoene R. Control of ventilation in climbers to extreme altitude. J Appl Physiol 1982;53:886–90.
Waggener TB, Brusil PJ, Kronauer RE, Gabel RA, Inbar GF. Strength and cycle time of high-altitude
ventilatory patterns in unacclimatized humans. J Appl Physiol 1984;56:576–81.
White D, Gleeson K, Pickett C, Rannels A, Cymerman A, Weil J. Altitude acclimatization: influence on
periodic breathing and chemoresponsiveness during sleep. J Appl Physiol 1987;63:401–12.
84
Central Sleep Apnea Due to a Medication or

Substance
Alternate Names
Narcotic or opioid induced central sleep apnea.
Diagnostic Criteria
A. The patient is taking an opioid or other respiratory depressant.
B. The presence of one or more of the following:
1. Sleepiness.
4. Snoring.
C. PSG (diagnostic or on positive airway pressure) shows all of the
following:
1. Five or more central apneas and/or central hypopneas1 per hour of
sleep (PSG).
3. Absence of CSB.1
D. The disorder occurs as a consequence of an opioid or other respiratory
depressant.
E. The disorder is not better explained by another current sleep disorder.
Notes
2. Ataxic breathing (irregular variations in respiratory cycle time and tidal
volume) may be noted.
3. Nocturnal and/or daytime hypoventilation may be present but are not
required. If sleep related hypoventilation is present, a diagnosis of sleep
related hypoventilation due to medication or substance use can be made as
well as a diagnosis of central sleep apnea due to a medication or substance.
4. A diagnosis of CSA due to a medicationor substance does not exclude a
diagnosis of OSA.
85
Essential Features
Users of potent long-acting opioids may have central apneas during sleep. The most
common offending drug is methadone. However, the condition has also been described
in patients taking long-acting forms of morphine or oxycodone as well as individu-
als being treated with fentanyl patches or continuous narcotic infusions. Suboxone (a
combination of buprenorphine and naloxone) is often used for treatment of patients
with narcotic dependence and pain and can also cause drug-induced central apnea. The
description of this population is complicated by the fact that many of the affected indi-
viduals may be using multiple drugs (prescribed or illicit) that affect sleep and breathing.
Associated Features
Breathing abnormalities associated with these drugs are not restricted to central apneas
and may also include hypoventilation and OSA with prolonged respiratory events. In
fact, many patients present with a combination of both OSA and CSA. Patients who
have nocturnal hypoventilation may have normal or increased daytime PaCO2. In most
patients with daytime hypoventilation, the PaCO2 is only mildly increased (46-50
mm Hg). Patients with drug-induced central apnea who are being treated for chronic
pain often report significant daytime sleepiness. Due to the sedating effects of opioid
medications, the sleepiness may not substantially improve even if the central apnea
is treated successfully. However, one study of patients on chronic methadone mainte-
nance found the average Epworth Sleepiness Scale score to be within normal range.
In these patients, who manifested only mild to moderate OSA (average AHI about 18/
hour), the degree of sleepiness correlated with a depression index. A case series of
patients treated with opioids for chronic pain found AHI values above 30/hour (up to
100/hour) and moderate to severe sleepiness. In this group, 50% to 80% of respiratory
events were central apneas. Sleepiness that is disproportionately high in comparison to
the severity of the AHI (and in some cases, at least partially unresponsive to treatment)
is likely due to the direct sedative effects of the narcotic medication itself.

None known.
Demographics
There are no known sex, racial, or ethnic differences. The prevalence of this disorder
is not known, although limited data suggest that it occurs commonly in those being
treated with opioids for chronic pain.
86

Use of a potent long-acting narcotic is the major causative factor. If patients are suc-
cessfully withdrawn from the offending medication, the central apnea may resolve.
Familial Patterns

This disorder is typically seen after opioids have been used for at least two months. An
increased risk of death has been reported with the use of potent narcotics. There has
been a large increase in deaths associated with methadone due to the increasing use of
this medication for chronic pain. Many of these deaths occur during sleep.
Information regarding the presentation of this disorder in children is limited. CSA due to
opioid medications has been described in children being treated for pain due to cancer.

The presumed pathophysiology for the development of these varied breathing abnor-
malities during sleep is the respiratory depression that occurs through action of the
drugs on the µ-receptors on the ventral surface of the medulla. Studies have demon-
strated depression of the awake hypercapnic ventilatory drive; however, it often
improves after five to eight months of continued drug use. In one study the hypoxic
ventilatory drive never fully normalized. Another study of patients on chronic meth-
adone maintenance found that the hypoxic ventilatory drive is increased compared to
that of control subjects. In this study the hypercapnic ventilatory response was reduced
in comparison with that of controls who were not taking opioids. The difference was
not due to a lower tidal volume but rather reduced respiratory rate. Differences in
technique or patient population may explain the divergent findings. The cause of the
ataxic breathing in patients on opiates is not known. However, one study of patients
on chronic opioids found that the incidence of ataxic breathing increased with the total
narcotic dose.
Objective Findings
The drug-induced central apneas may occur as a form of periodic breathing with runs
of central apneas separated by a short ventilatory phase (2 to 4 breaths) or intermittent
and sporadic central apneas. The underlying breathing pattern may show a slow respi-
ratory rate or an ataxic breathing pattern. The term ataxic breathing is sometimes used
as a synonym of Biot breathing, although definitions of the latter term vary widely.
87
Ataxic breathing is characterized by an irregular breathing rhythm as well as irregular

depth of breathing (tidal volume). Obstructive breathing events are also common in
patients taking potent opioids and a diagnosis of both OSA and CSA is often appro-
priate. Prolonged obstructive apneas with severe arterial desaturation may be noted.
The drug-induced central apneas occur mainly during NREM sleep and, in patients
without coexistent obstructive apnea, the AHI may be much lower during REM than
during NREM sleep. Patients also tend to have a low arousal index and increased stage
N3 sleep. Unlike other forms of central apnea, drug-induced central apneas may occur
during stage N3 sleep.
This condition is best distinguished from other types of central sleep apnea by the
patient’s ongoing use of long-acting opioids. Other SRBDs may be present and may
complicate PSG findings.

Further study is needed to determine risk factors and pathogenesis for development of
these sleep disordered breathing patterns in users of long-acting opioids. It has been
hypothesized that these sleep disordered breathing patterns may play a role in the unex-
plained increased mortality in this population. This also requires further study.
Bibliography
Alattar MA, Scharf SM. Opioid-associated central sleep apnea: a case series. Sleep Breath 2009;13:201–6.
Centers for Disease Control and Prevention (CDC). Vital signs: risk for overdose from methadone used for
pain relief—United States, 1999-2010. MMWR Morb Mortal Wkly Rep 2012;61:493–7.
Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term
opioid therapy. Chest 2003;123:632–9.
Guilleminault C, Cao M, Yue HJ, Chawla P. Obstructive sleep apnea and chronic opioid use. Lung
2010;188:459–68.
Ramar K. Reversal of sleep-disordered breathing with opioid withdrawal. Pain Pract 2009;9:394–8.
Santiago TV, Pugliese AC, Edelman NH. Control of breathing during methadone addiction. Am J Med
1977;62:347–54.
Shook JE, Watkins WD, Camporesi EM. Differential roles of opioid receptors in respiration, respiratory
disease, and opiate-induced respiratory depression. Am Rev Respir Dis 1990;142:895–909.
Teichtahl H, Prodromidis A, Miller B, Cherry G, Kronborg I. Sleep-disordered breathing in stable
methadone programme patients: a pilot study. Addiction 2001;96:395–403.
Teichtahl H, Wang D, Cunnington D. Ventilatory responses to hypoxia and hypercapnia in stable
methadone treatment patients. Chest 2005;128:1339–47.
Walker JM, Farney RJ, Rhondeau SM. Chronic opioid use is a risk factor for the development of central
sleep apnea and ataxic breathing. J Clin Sleep Med 2007; 3:455–61.
88
Wang D, Teichtahl H, Goodman C, Drummer O, Grunstein RR, Kronborg I. Subjective daytime sleepiness
and daytime function in patients on stable methadone maintenance treatment: possible mechanisms. J
Clin Sleep Med 2008;4:557–62.
Primary Central Sleep Apnea

Alternate Names
Idiopathic central sleep apnea.
Diagnostic Criteria
A. The presence of at least one of the following1:
1. Sleepiness.
4. Snoring.
B. PSG demonstrates all of the following:
1. Five or more central apneas and/or central hypopneas2 per hour of
sleep (PSG).
3. Absence of CSB.2
C. There is no evidence of daytime or nocturnal hypoventilation.
medical or neurologic disorder, medication use, or substance use
disorder.
Notes
1. In children, daytime symptoms may not be evident.
Essential Features
Primary CSA is of unknown etiology (idiopathic) and is characterized by recurrent
central apneas, defined as a cessation of airflow during sleep associated with an absence
of respiratory effort. Airflow and respiratory effort cease simultaneously in a repetitive
89
fashion over the course of the night. This recurrent cessation and resumption of venti-
lation can lead to sleep fragmentation, yielding excessive daytime sleepiness, frequent
nocturnal awakenings, or both. Thus, patients may present with symptoms of hyper-
somnolence or insomnia. Patients with primary CSA tend to have low normal arterial
PaCO2 during wakefulness (less than 40 mm Hg). Patients with a known medical or
neurological disorder that is believed to cause central apneas are classified elsewhere.
Associated Features
Patients generally present with excessive daytime sleepiness, sleep fragmentation, or
insomnia. Other signs and symptoms that are often, but not invariably, present include
snoring, witnessed apnea, and awakening with shortness of breath.

The disorder is rare, precluding identification of any definite subtypes.
Demographics
Not known. Most studies suggest this disorder is rare, most common in middle-aged
to elderly individuals, and more frequent in men than women, although not all studies
support this sex bias.

CSA in these patients occurs because the arterial PCO2 (PaCO2) drops below the hypo-
capnic apnea threshold (HAT). During wakefulness, drops in PaCO2 do not result in
apnea. However, during sleep, when the PaCO2 drops below the HAT, respiratory
effort ceases. For most patients, the HAT is within a few mm Hg of the awake PaCO2.
Any factors that narrow the gap between the sleeping PaCO2 and the HAT predispose
to central apnea. A high ventilatory response to CO2 seems to be a major predisposing
factor in the development of primary CSA. This can lead to the instability in venti-
latory control that characterizes the disorder. Frequent arousal from sleep can also
predispose to the development of central apneas, as ventilatory control is somewhat
unstable at sleep-wake transitions. Increased ventilation associated with arousal can
result in a PaCO2 below the HAT after the return to sleep. Because ventilatory drive is
lower during REM than NREM sleep, hypocapnic central apnea is much less common
during that sleep stage. Two other variables have been discussed as possible predispos-
ing factors, although their true role in the development of this syndrome is uncertain.
First, frequent arousal or awakening due to low arousal threshold or sleep maintenance
insomnia have been reported to lead to an increase in central apneas. Because ventila-
tory control can be somewhat unstable in the normal wake-sleep transition with occa-
sional central apneas being observed in otherwise normal individuals, any disorder
90
that interrupts sleep may worsen CSA. Some studies have suggested a worsening of
primary CSA in the supine position, but this has been more clearly documented in
patients with CSB.
Familial Patterns
Some data suggest that ventilatory chemoresponsiveness is directly inherited. Because
elevated CO2 responsiveness is a predisposing variable in the development of idio-
pathic CSA, it would seem likely that there would be a familial pattern in the develop-
ment of this respiratory abnormality. However, there are no data addressing this issue.

Not known. The apneas can lead to sleep fragmentation, yielding either hypersomno-
lence or insomnia. There is little evidence that these apneas or their associated hypoxia
and hypercapnia lead to pulmonary hypertension, cor pulmonale, or other adverse car-
diovascular consequences.
Criteria for apnea of infancy and apnea of prematurity are detailed elsewhere and it
should be noted that central apnea is defined somewhat differently in infants and chil-
dren than in adults. Central apneas that are brief (< 20 seconds in duration) and not
associated with desaturation or arousal are commonly observed in both premature and
term infants.
In adults, population studies report an increase in the occurrence of central apnea with
increasing age, especially in men.

Primary CSA is caused by instability of the respiratory control system in the transition
from wakefulness to sleep and less commonly during stable NREM sleep. Central
apnea in patients with primary CSA most often occurs during stages N1 and N2 sleep
and is rare during stages N3 and R sleep. Central apneas tend to occur in individuals
with a high or increased ventilatory responsiveness to CO2. Arterial PCO2 levels below
the hypocapnic apnea threshold lead to a cessation in ventilatory effort and, therefore,
a central apnea. Individuals with high CO2 ventilatory responsiveness tend to have
lower PaCO2 levels (both daytime and sleep) and a lower gradient between the sleep-
ing PaCO2 and the apneic threshold. Hence, a smaller increase in ventilation is required
to reach this apnea threshold and inhibit ventilation. Individuals with high chemore-
sponsiveness also hyperventilate more in response to small changes in arterial PaCO2.
This again often drives the PaCO2 below the apnea threshold, yielding a cessation
91
of ventilation. However, not all factors that cause greater ventilatory drive have the
same effect. Studies suggest that although hypoxemia increases chemoresponsiveness
to PaCO2, the gap between the PaCO2 and the apneic threshold is smaller (predispos-
ing to central apnea). Metabolic acidosis and nonhypoxic chemoreceptor stimulants
tend to decrease HAT more than they decrease the sleeping PaCO2, resulting in a larger
gap between the HAT and the sleeping PaCO2 and lower likelihood of central apnea.
Metabolic alkalosis tends to increase HAT as well as decrease ventilatory responsive-
ness, yielding a smaller gap between the HAT and sleeping PaCO2.
Objective Findings
The PSG of the patient with primary CSA demonstrates more than five central apneas
and/or central hypopneas per hour of sleep. The central apneas and central hypopneas
meet criteria for these respiratory events in adults or children as defined by the most
recent version of the AASM Manual for the Scoring of Sleep and Associated Events.
Published studies of patients with primary CSA have required that > 50% to 85%
of respiratory events be central apneas. Periodic breathing characterized by episodes
of recurrent central apneas separated by periods of ventilation may occur. The inter-
event respiratory phase is typically brief with a maximum of five breaths. The venti-
latory phase between central apneas does not have the crescendo-decrescendo pattern
of CSB breathing. Central apneas commonly lead to mild arterial oxygen desaturation,
although more severe desaturation can occur. Central apneas may also lead to arousal
from sleep, causing fragmentation and yielding increased stages N1 and N2 sleep at
the expense of stage N3 sleep. As noted above, central apneas in these patients are less
common during REM sleep. In summary, respiration, arterial oxygenation, and sleep
architecture are affected by this disorder. Additionally, an arterial PaCO2 less than 40
mm Hg is typically observed during wakefulness. These patients do not exhibit sleep
related hypoventilation.
Normal individuals may have a few central apneas in the wake-sleep transition.
However, once stable sleep is achieved, these apneas should cease. Normal individuals
should not have more than five central apneas per hour of sleep.
Primary CSA must be distinguished from other sleep related breathing disorders. Some
patients with predominantly OSA will have central apneas during diagnostic or positive
airway pressure titration studies. These apneas tend to resolve immediately or over
time on positive airway pressure treatment. The pattern of central apneas in primary
CSA differs from that of CSA with CSB. Primary CSA lacks the crescendo-decrescendo
pattern of respiration between contiguous central apneas noted in patients with CSA
92
with CSB. The cycle length is longer in CSB (greater than 40 seconds and typically
45 to 90 seconds). The longer cycle length in CSB versus primary CSA is due to a
longer respiratory phase between central apneas. In primary CSA, the apnea is often
terminated abruptly by a large breath, and there are usually no more that 4 to 5 breaths
between apneas. Furthermore, most patients with Cheyne-Stokes respiration will have
a history of congestive heart failure or a neurological disorder. Patients with central
apnea due to substance use, particularly potent long-acting narcotics, may exhibit
periodic breathing with central apneas, but the pattern of ventilation between apneas
does not have a crescendo-decrescendo pattern and the cycle length is shorter than 40
seconds. In addition, the underlying pattern of breathing is often ataxic (irregular varia-
tions in cycle length and tidal volume) and a low respiratory rate may be noted. Unlike
primary CSA, central apneas can occur during stage N3 in patients taking opioids.
Patients with CSA due to medical or neurological conditions not of the Cheyne-Stokes
pattern often have a history of a known neurological disorder (recent cerebrovascular
accident) but in others a high index of suspicion for an underlying disorder is indi-
cated. For example, patients with Chiari malformation may present in adulthood with
unexplained central apneas and relatively few other symptoms. Thus, primary CSA is
a diagnosis based on careful exclusion of other causes of CSA.
In sleep related hypoventilation and hypoxemic syndromes, patients have normal or

increased daytime arterial PCO2 (PaCO2) with the onset or worsening of hypoven-
tilation during sleep. Daytime hypoventilation is defined as a PaCO2 > 45 mm Hg.
Patient with primary CSA usually have an awake PaCO2 < 40 mm Hg. The causes
of sleep related hypoventilation include abnormalities in ventilatory control, neuro-
muscular disease, parenchymal lung disease, or restrictive chest wall disorders. PSG
in these patients may reveal a few central apneas, but the predominant pattern is one
of reduced tidal volume (shallow pattern of breathing), often without a compensatory
increase in respiratory rate. There is usually significant oxygen desaturation secondary
to hypoventilation and/or ventilation perfusion mismatch. Patients with parenchymal
lung disease, neuromuscular disease, or chest wall disorders typically have abnormal
pulmonary function tests and the most severe arterial oxygen desaturation typically
occurs during REM sleep.

Although primary CSA is believed to be a relatively rare disorder, additional prevalence
data are needed. The pathophysiology of this disorder remains unclear. Specifically, the
relative roles of instability in sleep state (low arousal threshold, delayed transition from
wake to stable sleep) and respiratory control instability (elevated hypercapnic ventila-
tory response) require further elucidation.
93
Bibliography
Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence of sleep-
disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608–13.
Bradley T, McNicholas W, Rutherford R, Popkin J, Zamel N, Phillipson E. Clinical and physiological
heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis 1986;134:217–21.
Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below eupnoea
as a determinant of ventilatory stability in sleep. J Physiol 2004;560:1–11.
Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: Pathophysiology and treatment. Chest
2007;131:595–607.
Hall MJ, Xie A, Rutherford R, Ando S, Floras JS, Bradley TD. Cycle length of periodic breathing in
patients with and without heart failure. Am J Respir Crit Care Med 1996;154:376–81.
White D, Zwillich C, Pickett C, Douglas N, Findley L, Weil J. Central sleep apnea: improvement with
acetazolamide therapy. Arch Intern Med 1982;142:1816–9.
Xie A, Rankin F, Rutherford R, Bradley TD. Effects of inhaled CO2 and added dead space on idiopathic
central sleep apnea. J Appl Physiol 1997;82:918–26.
Xie A, Rutherford R, Rankin F, Wong B, Bradley T. Hypocapnia and increased ventilatory responsiveness
in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 1995;152:1950–5.
Xie A, Wong B, Phillipson E, Slutsky A, Bradley T. Interaction of hyperventilation and arousal in the
pathogenesis of idiopathic central sleep apnea. Am J Respir Crit Care Med 1994;150:489–95.
Primary Central Sleep Apnea of Infancy

ICD-9-CM code: 770.81 ICD-10-CM code: P28.3
Alternate Names
Infant sleep apnea, apnea of infancy, primary sleep apnea of the newborn.
Inappropriate terms for primary central sleep apnea of the newborn include near-miss
sudden infant death syndrome (SIDS), near-SIDS, aborted SIDS, and aborted crib
death; these terms imply a causal relationship between apnea and SIDS that is not
supported by extensive research. Likewise, the term “apparent life-threatening event
(ALTE)” should not be used. Although some infants with primary sleep apnea present
with an ALTE, there are many other causes of ALTE, and some children with sleep
apnea do not have ALTE.
Diagnostic Criteria
A. Apnea or cyanosis is noted by an observer or an episode of sleep related
central apnea or desaturation is detected by monitoring.
B. The infant has a conceptional age of at least 37 weeks.
94
C. PSG or alternative monitoring such as hospital or home apnea

monitoring shows either:
1. Recurrent, prolonged (> 20 seconds duration) central apneas.1
2. Periodic breathing2 for ≥ 5% of total sleep time.
D. The disorder is not better explained by another sleep disorder, medical
or neurological disorder, or medication.
Notes
1. Normative data concerning the number of prolonged central apneas per
hour are not well established.
3. Short (< 20 seconds) central apneas associated with significant
desaturation are more likely to be a sign of decreased pulmonary reserve
than of central nervous system pathology.
4. Definitive determination of the central nature of apneas requires
simultaneous monitoring of airflow and respiratory effort. Obstructive
and mixed apneas may also be present, but central apneas are
predominant.
Essential Features
Primary CSA of infancy is characterized by prolonged, predominantly central apneas in
children of at least 37 weeks conceptional age. These events are typically associated with
physiological compromise (hypoxemia, bradycardia), or the need for intervention such
as stimulation or resuscitation. Obstructive and/or mixed apneas or hypopneas may also
be seen, although central events are the predominant finding. It is a disorder of respira-
tory control that can be either a developmental problem associated with immaturity of
the brainstem respiratory centers or secondary to other medical conditions that produce
apnea by mechanisms such as direct depression of central respiratory control. Apnea in
the neonate or infant may be exacerbated or precipitated by a variety of medical condi-
tions, such as anemia, infection, hypoxemia, metabolic disturbances, gastroesophageal
reflux, substances, or anesthesia, which must be recognized and treated to stabilize the
apnea. If another medical condition appears to be the cause rather than an exacerbating
factor for the CSA, then the condition should be classified as CSA due to a medical or
neurological condition, or CSA due to a medication or substance.
Despite the heterogeneity of infant risk groups and underlying pathophysiology, most
studies report a progressive decrease in frequency of apneas and risk of symptomatic
apnea secondary to other medical conditions after the early weeks of life.
95
Associated Features
Infants may present with an ALTE (defined by a National Institutes of Health
Development Conference as “an episode that is frightening to the observer, and that
is characterized by some combination of apnea [central or occasionally obstructive],
color change, marked change in muscle tone, choking or gagging. In some cases, the
observer fears that the infant has died”). Many infants with primary CSA of infancy
will not have an ALTE, and many ALTEs are not associated with apnea. Primary CSA
of infancy is state dependent, and the frequency of respiratory events increases during
active (REM) sleep. Paradoxical chest wall movements are common during active sleep
in infants and may cause a fall in arterial oxygen saturation because of ventilation or
perfusion defects associated with a decrease in functional residual capacity. Underlying
comorbidities (for example, chronic lung disease or abnormal neurological status) can
predispose the infant to having a more severe or prolonged course for apnea. Note that
a small upper airway will exaggerate the obstructive elements of this disorder.

Not applicable.
Demographics
Less than 0.5% of full-term newborns experience symptomatic apnea. Studies have
shown that during the first six months of life, 2% of healthy full-term infants will
experience at least one apnea event lasting 30 seconds or longer or an apnea that lasts
at least 20 seconds and is associated with a heart rate less than 60 beats per minute.
Apnea of infancy occurs equally in males and females, and in infants of all races and
ethnic groups.

Many factors may precipitate apneic episodes, including gastroesophageal reflux, intra-
cranial pathology, substances, anesthesia, metabolic disorders, impaired oxygenation,
and infection (including sepsis, meningitis, respiratory syncytial virus infections, and
pertussis). Infection with respiratory syncytial virus, in particular, can increase the fre-
quency and the duration of apneas.
Familial Patterns
None known.

Onset is usually in the first weeks or months of life. Some infants may be diagnosed by
nursing observations or routine monitoring soon after birth. Older infants may present
96
with an ALTE or may have failure to thrive. The prognosis is generally good, with res-
olution of apnea over the first few years of life and no residual sequelae. The presence
of persistent severe apnea may be an indication of an underlying medical condition and
should prompt further evaluation. Patients with persistent severe apnea may develop
sequelae related to hypoxic events.
This is a condition of infancy that normally improves over time.

Physiological factors contributing to apnea are related to immaturity of respiratory
control. These include developmental alterations in central drive, chemoreceptor or
mechanoreceptor responses, and upper airway reflexes. Precipitating factors for wors-
ening apnea include gastroesophageal reflux, intracranial pathology, substances, anes-
thesia, metabolic disturbances, impaired oxygenation, and infection.
Objective Findings
Apnea is predominantly central, but obstructive and mixed apneas may occur. Apneas
are seen most frequently during REM sleep. Other diagnostic tests, such as a full EEG
or evaluation for reflux, may be appropriate in individual cases.
Primary CSA of infancy should be distinguished from the normal respiratory pauses
that occur during sleep. Normative respiratory data from several large studies show
that healthy asymptomatic infants commonly have central respiratory pauses, either
as isolated events (particularly during REM sleep) or after sigh breaths or movements.
Primary CSA of infancy should be distinguished from the popular clinical term, ALTE,
which is not a specific diagnosis but an ill-defined constellation of parent-reported
apnea symptoms that range in severity from benign to life threatening.
Recurrent, severe infant sleep apnea is usually due to other comorbid conditions,
such as gastroesophageal reflux, metabolic disease, or unrecognized neurological
conditions such as seizures, brainstem malformation, or neurodegenerative condi-
tion; thus an evaluation for these conditions should be performed. Another diagnos-
tic consideration is a form of child abuse (Munchausen syndrome by proxy) mani-
fest as imposed upper airway obstruction or attempted suffocation. Primary CSA of
infancy should be disassociated from the postmortem diagnosis of SIDS. Although
a small percentage of SIDS victims experience apnea symptoms prior to death,
97
primary apnea in the newborn or infant has not been established as an independent
risk factor for SIDS.

Infancy is a developmental period normally characterized by instability of control of
breathing; thus, defining what is abnormal is a diagnostic challenge. Further research
is needed into the mechanisms of ventilatory control development in the infant and the
pathophysiologic factors resulting in infant apnea.
Bibliography
American Academy of Pediatrics. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics
2003;111:914–7.
Hunt CE, Hufford DR, Bourguignon C, Oess MA. Home documented monitoring of cardiorespiratory
pattern and oxygen saturation in healthy infants. Pediatr Res 1996;39:216–22.
National Institutes of Health Consensus Development Conference on Infantile Apnea and Home
Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987;79:292–9.
Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors:
Comparison of healthy infants with those at increased risk for SIDS. JAMA 2001;285:2199–207.
Southall DP, Plunkett MC, Banks MW, Falkov AF, Samuels MP. Covert video recordings of life-
threatening child abuse: lessons for child protection. Pediatrics 1997;100:735–60.
Primary Central Sleep Apnea of Prematurity

ICD-9-CM code: 770.82 ICD-10-CM code: P28.4
Alternate Names
Apnea of prematurity.
Diagnostic Criteria
A. Apnea or cyanosis is noted by an observer, or an episode of sleep related
central apnea, desaturation, or bradycardia is detected by hospital
monitoring in the postnatal period.
B. The infant has a conceptional age less than 37 weeks at the time of onset
of symptoms.
C. PSG or alternative monitoring such as hospital or home apnea
monitoring shows either:
1. Recurrent prolonged (> 20 seconds duration) central apneas.1
2. Periodic breathing2 for ≥ 5% of total sleep time.
98
D. The disorder is not better explained by another sleep disorder, medical

or neurological disorder, or medication.
Notes
1. Normative data concerning the number of prolonged central apneas per
hour are not well established.
3. Short (< 20 seconds) central apneas associated with significant
desaturation are more likely to be a sign of decreased pulmonary reserve
than of central nervous system pathology.
4. Obstructive and mixed apneas may also be present, but central apneas
are predominant.
Essential Features
Apnea is very common in preterm infants, and the prevalence varies inversely with ges-
tational age. In the preterm infant, sleep apnea can be anticipated, is primarily related
to immaturity, and may require supportive ventilatory and pharmacologic treatment.
The condition will improve with maturation unless extenuating conditions, such as
hypoxemia due to chronic lung disease or gastroesophageal reflux, are present. Apneas
are predominantly central, but mixed or obstructive apneas or hypopneas may be seen.
The events are typically associated with physiological compromise (hypoxemia, bra-
dycardia) or the need for intervention such as stimulation or resuscitation.
Associated Features
Apnea in the preterm infant is commonly associated with bradycardia. Primary CSA
of prematurity is state dependent, and the frequency of respiratory events increases
during active (REM) sleep. Paradoxical chest wall movements are common during
active sleep in neonates and may cause a fall in arterial oxygen saturation because of
ventilation or perfusion defects associated with a decrease in functional residual capac-
ity. Underlying comorbidities (for example, chronic lung disease or abnormal neuro-
logical status) can predispose the infant to having a more severe or prolonged course
for apnea. Note that a small upper airway will exaggerate the obstructive elements of
this disorder.

None known.
99
Demographics
The prevalence of apnea of prematurity varies inversely with conceptional age. In
studies, approximately 25% percent of infants who weigh less than 2,500 g at birth
and 84% of infants under 1,000 g may experience symptomatic apnea during the neo-
natal period. Ninety-two percent of preterm infants will be symptom free by 37 weeks
postconceptional age, and 98% by 40 weeks after conception, with resolution in most
infants by 43 weeks postconception. Apnea of prematurity occurs equally in males and
females, and in infants of all races and ethnic groups.

Developmental delay in respiratory control associated with premature birth is the
major predisposing condition. Diverse factors are known to precipitate development
of apneic episodes in predisposed preterm infants. These include thermal instability,
gastroesophageal reflux, intracranial pathology, substances, anesthesia, metabolic
disorders, impaired oxygenation, and infection. Infection with respiratory syncytial
virus can increase the frequency and the duration of apneas in predisposed infants.
OSA associated with upper airway abnormalities can present as apnea of prematurity.
Persistence of apnea after 43 weeks conceptional age should raise suspicion of addi-
tional etiologic factors.
Familial Patterns
None known.

In preterm infants, apnea is rare on day one of life, and its presence usually signals
another illness. More typical onset occurs between the second and seventh days. Apnea
of prematurity usually ceases by 37 weeks conceptional age but may persist for several
weeks beyond term, especially in infants born before 28 weeks postconception; apnea
beyond 43 weeks postconception is rare. Adverse outcomes for former preterm infants
are more closely related to the prenatal or neonatal course, associated comorbidities,
and environmental factors than to the apnea of prematurity per se. For most children,
long-term outcomes for uncomplicated apnea of prematurity are excellent. However,
the prognosis for infants with persistent recurrent apnea spells requiring frequent
resuscitation is more guarded and depends on the cause of the apnea and associated
comorbidities.
This is a condition related to prematurity that normally improves over time.
100

Physiological factors contributing to apnea are related to immaturity of respiratory
control. These include developmental alterations in central drive, chemoreceptor or
mechanoreceptor responses, and upper airway reflexes. Precipitating factors for wors-
ening apnea in preterm infants include thermal instability, gastroesophageal reflux,
intracranial pathology, substances, anesthesia, metabolic disturbances, impaired oxy-
genation, and infection.
Objective Findings
Most premature neonates are diagnosed with apnea of prematurity based on cardio-
respiratory monitoring in the neonatal intensive care unit, rather than by PSG. When
PSG is performed, central apneas are often shown to have a mixed component, with
mixed apneas accounting for 50% to 75% of apneas in small premature infants; studies
suggest that obstructive-type events account for 10% to 20% of events; and pure central
events, 10% to 25%. Periodic breathing may be present.
Apnea of prematurity should be distinguished from normal, physiologic respiratory
pauses that occur during sleep in infants. Studies have shown that healthy asymptom-
atic infants commonly have brief (< 20 second) central respiratory pauses, either as
isolated events (particularly during REM sleep) or after sigh breaths or movements (in
which case the apneas may be longer). These infants are typically asymptomatic, with
no changes in color or muscle tone.
The differential diagnosis is long and includes apnea secondary to severe gastroesoph-
ageal reflux, central nervous system malformations or hemorrhage, seizures, sepsis,
and rarely primary cardiac arrhythmias. Comorbid conditions should be suspected
whenever apneas are severe or continue beyond 43 weeks gestation.

The mechanisms underlying physiologic maturation of ventilatory control are not well
understood. Further research is required to determine which infants are at greatest risk
for severe apnea.
Bibliography
American Academy of Pediatrics. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics
2003;111:914–7.
Hunt CE, Hufford DR, Bourguignon C, Oess MA. Home documented monitoring of cardiorespiratory
pattern and oxygen saturation in healthy infants. Pediatr Res 1996;39:216–22.
101
Kahn A, Rebuffat E, Sottiaux M, Blum D. Management of an infant with an apparent life-threatening

event. Pediatrician 1988;15:204–11.
National Institutes of Health Consensus Development Conference on Infantile Apnea and Home
Monitoring, Sept 29 to Oct 1, 1986. Pediatrics 1987;79:292–9.
Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events recorded on home monitors:
Comparison of healthy infants with those at increased risk for SIDS. JAMA 2001;285:2199–207.
Rigatto H. Breathing and sleep in preterm infants. In: Loughlin G, Carroll J, Marcus C, eds. Sleep and
breathing in children. New York: Marcel Dekker, 2000:495–515.
Schmidt B, Roberts RS, Davis P, et al. Long-term effects of caffeine therapy for apnea of prematurity. N
Engl J Med 2007;357:1893–902.
Southall DP, Plunkett MC, Banks MW, Falkov AF, Samuels MP. Covert video recordings of life-
threatening child abuse: lessons for child protection [see comments]. Pediatrics 1997;100:735–60.
Treatment-Emergent Central Sleep Apnea

Alternate names
Complex sleep apnea.
Diagnostic Criteria
A. Diagnostic PSG shows five or more predominantly obstructive
respiratory events1 (obstructive or mixed apneas, hypopneas or RERAs)
per hour of sleep
B. PSG during use of positive airway pressure without a backup rate shows
significant resolution of obstructive events and emergence or persistence
of central apnea or central hypopnea with all of the following:
1. Central apnea—central hypopnea index [CAHI] ≥ 5/hour.
2. Number of central apneas and central hypopneas is ≥ 50% of total
number of apneas and hypopneas.
C. The central sleep apnea is not better explained by another CSA disorder
(e.g., CSA with CSB or CSA due to a medication or substance).
Notes
1. Respiratory events defined according the most recent version of the
2. A diagnosis of treatment-emergent central sleep apnea does not exclude
a diagnosis of OSA. That is, a diagnosis of OSA can be made based on
the diagnostic sleep study.
102
Essential Features
A diagnosis of treatment-emergent CSA is characterized by predominantly obstructive
events (obstructive or mixed apnea or hypopnea) during a diagnostic sleep study with
persistence or emergence of CSA during administration of positive airway pressure
without a backup rate, despite significant resolution of obstructive respiratory events.
If the central apnea is better explained by another CSA disorder, patients are given a
diagnosis of OSA and that CSA disorder rather than treatment-emergent CSA (e.g., a
patient with heart failure exhibits mainly obstructive events during diagnostic PSG
but then exhibits predominantly central apnea with CSB on positive airway pressure).
Associated Features
Patients with treatment-emergent CSA have several characteristics when placed on
positive airway pressure without a backup rate. A high number of arousals persist on
PAP treatment, and the AHI is often higher during NREM than REM sleep. This is
due to the fact that treatment-emergent central apneas almost invariably occur during
NREM sleep. Pressures that are effective in controlling obstructive events during
REM sleep prove ineffective during NREM sleep due to emergence of central apneas.
If patients can attain stage N3, central apneas often decrease until interrupted by an
arousal or transition to a lighter stage of sleep that precipitates another run of central
apneas or hypopneas. Patients with treatment-emergent CSA can have persistent sleep
fragmentation on CPAP treatment and may report little benefit from therapy.

None known.
Demographics
The percentage of patients with persistent or emergent central apnea on the initial poly-
somnographic positive airway pressure titration varies from 2% to 20% depending on
the characteristics of the group studied (community or referral sleep center) and the
methodology. If patients who are taking opioids or have underling central apnea with
CSB are included, the percentage is at the higher end of the range. The percentage of
patients with central sleep apnea that persists on chronic CPAP treatment (approxi-
mately 2%) is considerably lower than the percentage identified on the first or second
night of CPAP treatment.

A number of factors have been hypothesized to cause treatment-emergent CSA, but
definitive data are not available. The patients presumably have characteristics that
would predispose them to instability in ventilatory control or sleep maintenance.
103
These include a low arousal threshold and high ventilatory controller gain. Studies
have found that often a small increase in end-tidal PCO2 can stabilize breathing in
patients with treatment-emergent central apneas. Therefore, any events that predis-
pose a patient to hypocapnia can trigger treatment-emergent central apnea. In some,
but not all studies, the overall AHI on the diagnostic PSG (or diagnostic portion of a
split-night PSG) was higher in the treatment-emergent CSA group compared to the
patients without this diagnosis. In other studies, patients with treatment-emergent
CSA had more central apneas during the diagnostic PSG and were more likely to be
male. However, identified risk factors for treatment-emergent CSA vary considerably
from study to study.
Of note, the emergence of central apnea after treatment of obstructive apnea with tra-
cheostomy, maxillomandibular advancement, and oral appliance treatment for OSA
has been reported. A case report of the development of central apnea following nasal
surgery in a patient with known obstructive apnea has also recently been published.
Familial Patterns
None known.

The recognition of treatment-emergent CSA follows PAP titration. An accurate esti-
mate of the percentage of patients with treatment-emergent central apneas whose
central events persist on long-term PAP treatment does not exist, as most published
reports are retrospective and had a significant number of patients lost to follow-up. Of
interest, one study comparing the results of an initial CPAP titration study with one per-
formed after six months of therapy found patients who did not meet criteria for treat-
ment-emergent CSA on the initial study but met the criteria on the second study. Those
patients with treatment-emergent CSA that do not experience resolution of central
apneas on chronic PAP treatment are found to have a high number of residual events
on PAP machine interrogation in clinic follow-up. Nocturnal oximetry at home on PAP
treatment may show persistent arterial oxygen desaturation. Sleep fragmentation and
daytime sleepiness may persist if a significant number of central apneas remain. There
is the potential for poor adherence and acceptance of PAP treatment as a result of this.
Treatment-emergent sleep apnea has not been described in children but this may be due
to the relatively small number of children with OSA who are treated with PAP.
104

Due to variation in definitions of treatment-emergent CSA, the pathophysiology is not
clearly defined. A low arousal threshold and difficulty reaching stage N3 sleep may pre-
dispose to sleep instability. Arousals destabilize breathing. A high ventilatory response
to PaCO2 and a small difference between the sleeping PaCO2 and the apnea threshold
may also predispose patients to treatment-emergent central apneas. Treatment with
excessive positive airway pressure may trigger treatment-emergent central apneas in
susceptible individuals.
Objective Findings
PSG during a full night diagnostic study (or diagnostic portion of a split-night PSG)
shows predominantly obstructive or mixed apneas and hypopneas of five or more per
hour of sleep. PSG with PAP (either a full night titration study or PAP treatment portion
of a split night study) without a backup rate shows significant resolution of obstructive
events and emergence or persistence of central apneas or central hypopneas. The CAHI
is five or greater per hour, and more than 50% of the respiratory events are central in
nature. A diagnosis of treatment-emergent CSA excludes patients who manifest central
sleep apnea on PAP treatment when the CSA is better explained by another CSA dis-
order or by over-titration.
PSG with administration of PAP often reveals adequate treatment during REM sleep
and stage N3 sleep but repetitive episodes of central events during stages N1 and N2.
In some patients, progressive increases in pressure with a goal of preventing airflow
limitation reach a “break point” at which central apneas appear.
Many patients with OSA have a few central events while on PAP. However, in the
majority of cases, the central AHI is not ≥ 5/hour and central events are not ≥ 50% of
the total number of apneas and hypopneas. Other patients with OSA, while on PAP,
exhibit predominantly central events that are believed to be secondary to a CSA disor-
der classified elsewhere. In this case, a diagnosis of both OSA and the CSA disorder is
appropriate, rather than a diagnosis of treatment-emergent CSA. For example, a patient
taking methadone has predominantly obstructive events during the diagnostic portion
of a split-night PSG. Once obstructive events are eliminated on PAP, CSA with ataxic
breathing is noted. A diagnosis of both OSA and CSA due to a medication or substance
should be made if criteria for that disorder are met.
105

The true incidence of treatment-emergent sleep apnea as well as the percentage of
patients who have persistent central apnea on chronic PAP treatment remains to be
defined. Further prospective studies with clearly defined inclusion and exclusion crite-
ria are needed to better define the exact percentage of patients with treatment-emergent
CSA who have persistent CSA after chronic PAP treatment. There may be night-to-
night variability in the amount of CSA displayed by a given patient. It is unknown,
for example, whether treatment-emergent central apneas that resolve on chronic PAP
treatment will re-emerge if the patient discontinues PAP treatment for a period of time
and then restarts treatment. A number of factors have been hypothesized to increase
the likelihood of treatment-emergent central apneas including overtitration (excessive
pressure), undertitration (respiratory effort arousals followed by central apnea), the
use of bilevel PAP rather than CPAP, arousals from mask leak, and use of a split night
study. Further study is needed to verify that these factors do indeed predispose a patient
to develop treatment-emergent central apneas. The evolution of treatment-emergent
central apneas on chronic PAP treatment also remains to be determined; that is, to what
extent do central events resolve over time and what is the time course of this resolu-
tion? In light of the increasing utilization of auto-titrating PAP, further investigation of
the incidence of treatment-emergent CSA with this modality is indicated.
Bibliography
Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of
complex and central sleep apnea syndromes. Chest 2007;132:1839–46.
Dernaika T, Tawk M, Nazir S, Younis W, Kinasewitz GT. The significance and outcome of continuous
positive airway pressure-related central sleep apnea during split-night sleep studies. Chest
2007;132:81–7.
Gay PC. Complex sleep apnea: it really is a disease. J Clin Sleep Med 2008;4:403–5.
Gilmartin GS, Daly RW, Thomas RJ. Recognition and management of complex sleep-disordered breathing.
Curr Opin Pulm Med 2005;11:485–93.
Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep
Med 2009;5:205–11.
Lehman S, Antic NA, Thompson C, Catcheside PG, Mercer J, McEvoy RD. Central sleep apnea on
commencement of continuous positive airway pressure in patients with a primary diagnosis of
obstructive sleep apnea-hypopnea. J Clin Sleep Med 2007;3:462–6.
Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn’t really a disease. J Clin Sleep Med
2008;4:406–8.
Morgenthaler TI, Kagramanov V, Hanak V, et al. Complex sleep apnea syndrome: is it a unique clinical
syndrome? Sleep 2006;29:1203–9.
Thomas RJ, Daly RW, Weiss JW. Low-concentration carbon dioxide is an effective adjunct to positive
airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing.
Sleep 2005;28:69–77.
106
Thomas RJ, Mietus JE, Peng CK, et al. Differentiating obstructive from central and complex sleep apnea
using an automated electrocardiogram-based method. Sleep 2007;30:1756–69.
Thomas RJ, Terzano MG, Parrino L, Weiss JW. Obstructive sleep-disordered breathing with a dominant
cyclic alternating pattern--a recognizable polysomnographic variant with practical clinical implications.
Sleep 2004;27:229–34.
Westhoff M, Arzt M, Litterst P. Prevalence and treatment of central sleep apnoea emerging after initiation
of continuous positive airway pressure in patients with obstructive sleep apnoea without evidence of
heart failure. Sleep Breath 2012;16:71–8.
107
Sleep Related Hypoventilation Disorders

The primary feature of these disorders is insufficient sleep related ventilation, result-
ing in abnormally elevated arterial partial pressure of carbon dioxide (PaCO2) during
sleep. In addition, demonstration of daytime hypoventilation is required for a diagno-
sis of obesity hypoventilation syndrome (OHS). Awake hypoventilation is defined as
an arterial partial pressure of carbon dioxide (PaCO2) greater than 45 mm Hg. In the
sleep related hypoventilation disorders other than OHS, daytime hypoventilation may
or may not be present. If hypoventilation is present during wakefulness, it worsens
during sleep in all of these disorders.
General Criteria Sleep Related Hypoventilation

Criterion A must be met
A. Sleep related hypoventilation, as defined by the most recent version of
the AASM Manual for the Scoring of Sleep and Associated Events, is
present.1,2
Notes
1. Monitoring of arterial PCO2 during sleep is not practical. Acceptable
surrogates include end-tidal PCO2 or transcutaneous PCO2.
2. Arterial oxygen desaturation is often present but is not required for the
diagnosis.
Obesity Hypoventilation Syndrome

ICD-9-CM code: 278.03 ICD-10-CM code: E66.2
Alternate Names
Hypercapnic sleep apnea, sleep related hypoventilation associated with obesity.
Use of the term Pickwickian syndrome is discouraged because not only has it been
applied to those with OSA, but also indiscriminately used to describe persons who are
only obese and those with OHS.
Diagnostic Criteria
A. Presence of hypoventilation during wakefulness (PaCO2 > 45 mm Hg)
as measured by arterial PCO2, end-tidal PCO2, or transcutaneous PCO2.
B. Presence of obesity (BMI > 30 kg/m2; > 95th percentile for age and sex
for children).
108
C. Hypoventilation is not primarily due to lung parenchymal or airway

disease, pulmonary vascular pathology, chest wall disorder (other
than mass loading from obesity), medication use, neurologic disorder,
muscle weakness, or a known congenital or idiopathic central alveolar
hypoventilation syndrome.
Notes
1. PSG shows worsening of hypoventilation during sleep if PaCO2 or
noninvasive estimate of the PaCO2 is measured.
2. OSA is often present and, in such cases, a diagnosis of both OSA and
OHS should be made.
3. Arterial oxygen desaturation is usually present but is not required for
the diagnosis.
Essential Features
OHS is characterized by obesity and daytime hypercapnia (arterial PaCO2 > 45 mm Hg)
that cannot be fully attributed to an underlying cardiopulmonary or neurologic disease.
Hypercapnia worsens during sleep and is often associated with severe arterial oxygen
desaturation. Hypoventilation is often worse during REM than during NREM sleep.
The majority of OHS patients have comorbid OSA (80% to 90%). In these patients,
daytime hypercapnia may improve or even normalize with adequate PAP treatment and
sustained adherence to treatment. Those OHS patients without OSA exhibit sustained
or intermittent episodes of shallow breathing during sleep associated with worsening
hypoventilation and hypoxemia. Patients with OHS may have few, if any, sleep com-
plaints, or may present with considerable sleep disturbance including reduced sleep
efficiency and frequent awakenings. Hypercapnia and hypoxemia may remain unno-
ticed for quite some time until sudden deterioration with cardiopulmonary arrest or
severe decompensation (acute or chronic hypercapnic respiratory failure) develops.
Associated Features
Patients with OHS commonly complain of hypersomnolence. The severity of hyper-
somnolence may not correlate closely with degree of hypercapnia. Other symptoms
include morning headaches, fatigue, mood disturbance and impairments of memory
or concentration. Physical examination may reveal features suggestive of cor pul-
monale or circulatory congestion, such as plethora, scleral injection, and peripheral
edema. Laboratory testing commonly shows polycythemia and elevated serum CO2 on
electrolyte testing (≈ serum bicarbonate), reduced forced vital capacity during pulmo-
nary function testing, right heart strain, right ventricular hypertrophy and right atrial
enlargement on electrocardiography and ventricular dysfunction on echocardiography.
109
Consequences of chronic hypercapnia and hypoxemia include pulmonary artery hyper-

tension, cor pulmonale, and neurocognitive dysfunction.

Demographics
OHS may be underdiagnosed if CO2 analysis (≈ serum bicarbonate) is not performed in
obese patients presenting with complaints suggestive of OHS. The prevalence of OHS
in populations of patients with OSA varies across studies but is often in the range of
10% to 15% of obese patients with OSA. Although the prevalence of OHS is higher in
men than women the difference is not as prominent as in OSA.

Obesity is believed to be the primary pathophysiologic factor responsible for hypoven-
tilation and hypoxemia. Greater degrees of obesity are often associated with worse
sleep related hypoventilation, but individual variations in the severity of hypercap-
nia at similar weights may be seen. The use of central nervous system depressants,
such as alcohol, anxiolytics, and hypnotics, may further worsen respiratory impair-
ment. Patients who are hypercapnic and hypoxemic during wakefulness will invari-
ably become even more so during sleep, in particular REM sleep, but the relationship
between wake SaO2/PaCO2 and sleep related desaturation is not sufficiently strong to
have substantial predictive value in individual patients.
Familial Patterns

Persons who are eventually diagnosed with OHS either present initially for evalu-
ation of suspected OSA or are identified following one or more episodes of severe
hypercapnic respiratory failure. The course can be variable but is generally slowly pro-
gressive. Many affected individuals with severe hypercapnia and hypoxemia develop
pulmonary hypertension, heart failure, cardiac arrhythmias, and neurocognitive dys-
function. Polycythemia is common in those with chronic hypoxia. Although the risk
of increased morbidity and mortality appears to increase with worsening sleep related
hypoventilation/hypoxemia, the specific relationship between sleep related hypoventi-
lation/hypoxemia and morbidity and mortality is not well defined. Obesity, itself, can
lead to other respiratory complaints, including shortness of breath, dyspnea on exer-
tion and orthopnea, even in the absence of demonstrable elevation of daytime PaCO2.
110
However, in one study of inpatients with obesity, those with hypoventilation had an
18-month mortality of 23% compared with 9% in the group with equivalent obesity
but no hypoventilation. Many patients with OHS respond to CPAP or bilevel PAP with
improvement in daytime PaCO2. However, normalization of daytime PaCO2 occurs
in only a minority of patients. In one study, 34% of OHS patients using PAP more
than 4.5 hours per night had normalization of the PaCO2. In contrast hypercapnia may
worsen with oxygen therapy alone for the associated hypoxia.
Not known.

The etiology of hypoventilation is not completely understood. Although comorbid OSA
is common, hypercapnia and hypoxemia are not entirely a function of upper airway
obstruction. The importance of various factors leading to hypoventilation likely varies
among patients. It has been postulated that sustained nocturnal hypercapnia results from
the development of short (due to apnea-hypopnea) or longer (secondary to hypoven-
tilation) periods of hypercapnia accompanied by inadequate compensation (i.e., CO2
unloading) during periods of ventilation between obstructive events. Abnormal venti-
latory control (blunted hypercapnic ventilatory response) allows hypercapnia to persist
into wakefulness after the cause of acute hypercapnia is no longer present. A chronic
hypercapnic state would produce an elevation of bicarbonate. Although this blunts
the degree of acidosis due to an elevated PaCO2, it reduces the compensatory CO2
ventilatory response. Impaired renal bicarbonate excretion rate, as seen in hypoxia,
heart failure, or diuretic-related chloride deficiency, may contribute to the persistence
of hypercapnia. Obesity itself is also associated with several factors that predispose
to CO2 retention. Obesity itself increases CO2 production. There is an increased work
of breathing due to mass loading from the additional weight on the respiratory pump
as well as resistive loading due to intermittent upper airway obstruction during sleep.
Numerous factors impair CO2 elimination including altered lung volumes and mechan-
ics, ventilation-perfusion abnormalities secondary to atelectasis or pulmonary conges-
tion, reduced chemosensitivity and load responsiveness, and suppression of respiratory
drive due to obesity-related humoral factors, such as resistance to the elevated leptin
levels that occur in patients with the OHS (leptin is a respiratory stimulant). The impor-
tance of these factors likely varies from patient to patient.
Objective Findings
Arterial blood gas testing during wakefulness shows hypercapnia and often hypoxemia
in untreated patients. Even with effective treatment most OHS patients continue to
111
exhibit some degree of daytime hypoventilation. The characteristic polysomnographic

finding is sleep related hypoventilation and arterial oxygen desaturation during sleep
with or without obstructive apneas and hypopneas. Worsening hypoventilation during
sleep can be documented by an arterial blood gas measurement of PaCO2 during sleep
(rarely performed) or transcutaneous or end-tidal PCO2 measurements. Periods of
decreased tidal volume lasting up to several minutes with sustained arterial oxygen
desaturation are usually present. Intermittent arousals may be observed. OSA is present
in the majority of OHS patients, during at least a portion of the night. The transient ven-
tilation between obstructive events (even if associated with arousal from the preceding
obstructive event) is not sufficient to prevent worsening hypoventilation during sleep.
Severe arterial oxygen desaturation is usually associated with the obstructive events.
Chronic hypoxia can be associated with polycythemia. Electrocardiography, chest radi-
ography, and echocardiography may demonstrate evidence of pulmonary hypertension.
The serum bicarbonate level is usually elevated due to renal compensation for chronic
respiratory acidosis (hypercapnia). In one study, a serum bicarbonate level threshold
> 27 mEq/L had a sensitivity of 92% and a specificity of 50% of identifying OHS in
obese patients suspected of having OSA. This suggests that the serum bicarbonate
level may be useful to screen patients for possible OHS. However, an arterial blood
gas is required for diagnosis of OHS, as the serum bicarbonate level may be elevated
due to metabolic alkalosis.
The differential diagnosis includes any disorder that can give rise to hypoventilation
during wakefulness and sleep. This includes pulmonary airway and parenchymal dis-
orders, pulmonary vascular pathology, neuromuscular and chest wall disorders, severe
untreated hypothyroidism, use of respiratory suppressants, and congenital or idio-
pathic central alveolar hypoventilation syndromes. OSA and CSA syndromes can be
distinguished from sleep related hypoventilation by the periodic alterations in airflow
and accompanying periodic fluctuations in SaO2. In contrast, oxygen desaturation due
to sleep related hypoventilation is generally more sustained, usually several minutes or
longer in duration. When more than one disorder is believed to be responsible for the
ventilatory insufficiency during sleep, all pertinent diagnoses should be coded.

Future research into the pathogenesis of this disorder, including renal bicarbonate
homeostasis, is needed. Because it is clinically impractical to routinely obtain arterial
blood samples during sleep in most persons suspected of this disorder, other techniques
of measuring CO2 levels must be investigated. The degree and duration of hypercapnia/
112
hypoxemia necessary to produce adverse consequences, such as pulmonary hyperten-

sion, in individual patients is not well defined. Little information is available regarding
the effect of oxygen therapy or noninvasive ventilation on the course of the underlying
disease. Studies are needed to determine the optimal time to initiate these interventions
and the specific subpopulations of patients who will benefit most from these therapies.
Bibliography
Berger KI, Goldring RM, Rapoport DM. Obesity hypoventilation syndrome. Semin Respir Crit Care Med
2009;30:253.
Budweiser S, Riedl SG, Jörres RA, et al. Mortality and prognostic factors in patients with obesity-
hypoventilation syndrome undergoing noninvasive ventilation. J Intern Med 2007;261:375–83.
Littleton SW, Mokhlesi B. The pickwickian syndrome-obesity hypoventilation syndrome. Clin Chest Med
2009;30:467–78, vii-viii.
Mokhlesi B; Tulaimat A; Evans AT et al. Impact of adherence with positive airway pressure therapy on
hypercapnia in obstructive sleep apnea. J Clin Sleep Med 2006;2:57–62.
Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care 2010;55:1347–62.
Nowbar S, Burkart KM, Gonzales R, et al. Obesity-hypoventilation in hospitalized patients: prevalence,
effects, and outcome. Am J Med 2004;116:1–7.
Piper AJ, Grunstein RR. Obesity hypoventilation syndrome: mechanisms and management. Am J Respir
Crit Care Med 2011;183:292–8.
Piper AJ. Obesity hypoventilation syndrome--the big and the breathless. Sleep Med Rev 2011;15:79–89.
Congenital Central Alveolar Hypoventilation

Syndrome
Alternate Names
Congenital central hypoventilation syndrome.
The term Ondine’s curse is no longer recommended due to its negative connotations.
Diagnostic Criteria
A. Sleep related hypoventilation is present.
B. Mutation of the PHOX2B gene is present.
Notes
1. Sleep related hypoventilation may be associated with either daytime
hypoventilation (PaCO2 > 45 mm Hg) or normal daytime PaCO2 levels.
113
In either case, the PaCO2 is higher during sleep and meets criteria for
sleep related hypoventilation.
2. PSG monitoring demonstrates severe hypercapnia and arterial oxygen
desaturation. Some central apneas may occur but the predominant
pattern is reduced flow/tidal volume.
3. Although the condition is termed congenital, some patients with a
PHOX2B genotype may present phenotypically later in life (and even
in adulthood), especially in the presence of a stressor such as general
anesthesia or a severe respiratory illness.
Essential Features
Congenital central alveolar hypoventilation syndrome (CCHS) is a syndrome of auto-
nomic dysfunction, primarily the failure of automatic central control of breathing, due
to a mutation of the PHOX2B gene. CCHS is characterized by the onset of hypoven-
tilation, usually at birth. The hypoventilation is worse during sleep than wakefulness
and is unexplained by primary pulmonary, neurological, or metabolic disease. CCHS
typically presents in an otherwise normal-appearing infant who is noted to have cyano-
sis, feeding difficulties, hypotonia or, less commonly, central apnea. Some children are
diagnosed following cardiovascular collapse. The infant requires intubation and then
cannot be weaned from mechanically assisted ventilation, despite appearing vigorous
and having a normal chest radiograph. Some infants may appear to breathe adequately
on clinical examination but experience episodes of hypoventilation (not necessarily
apnea) characterized by hypoxemia and hypercapnia. Patients with CCHS may occa-
sionally present later in life with cyanosis, an apparent life-threatening event, cor pul-
monale, or hypoxic neurological damage. CCHS has been diagnosed in adults who
present with respiratory failure following anesthesia or in association with a minor
respiratory illness; these patients usually have a mild mutation, and may have evidence
of longstanding hypoxemia including cognitive deficits. Most patients with CCHS have
sufficiently severe hypoventilation during sleep that they require mechanically assisted
ventilation, although this state-dependent difference may not be apparent during early
infancy. Some patients (~15%) hypoventilate during wakefulness as well as during
sleep and require continuous ventilatory support. However, most patients with CCHS
do not require ventilatory support during wakefulness but may have subtle abnormali-
ties in gas exchange when physically inactive or during vigorous exercise.
Associated Features
Associated autonomic abnormalities include Hirschsprung disease in approximately
16% of patients with CCHS, autonomic dysfunction (e.g., decreased heart rate variabil-
ity or hypotension), neural tumors (e.g., ganglioneuromas or ganglioneuroblastomas),
114
swallowing dysfunction during the early years, and ocular abnormalities (e.g., stra-
bismus). Most patients are cognitively normal, although developmental delay may be
present, especially in patients in whom the hypoventilation has not been well controlled.

Research suggests that severity of illness is related to the type of mutation present. Most
patients have a polyalanine expansion mutation; those with more polyalanine repeats
are more likely to have severe disease including waking hypoventilation. Patients with
a point mutation or frame shift mutations are at greater risk for neural tumors.
Demographics
The prevalence of CCHS is not known, but the disease is rare. The condition occurs
equally among both sexes and all ethnic/racial groups.

This is a congenital genetic syndrome.
Familial Patterns
CCHS usually occurs as a de novo mutation, but siblings with the condition have been
reported. As the gene is dominant, patients are at risk of having children with CCHS.

The condition is genetic and is therefore present from birth, but some patients may
present later in life. The physiological abnormalities of CCHS persist for life and are not
ameliorated over time. However, the clinical consequences of hypoventilation can be
prevented by providing adequate ventilatory support. If untreated, death usually results
from cor pulmonale or complications of apnea or severe hypoventilation. Patients with
poorly controlled CCHS may develop mental retardation, growth failure, seizures, or
cor pulmonale. When treated, infants with CCHS may improve over the first six to 12
months. Some patients who initially require ventilatory support 24 hours a day may
progress to adequate ventilation during wakefulness. However, patients continue to
require ventilatory support during sleep. Conversely, some patients may develop the
need for continuous ventilatory support. It is unclear whether these patients had condi-
tions that worsened, were not adequately evaluated and treated initially, or were asso-
ciated with changing ventilatory demands. Even with treatment, patients with CCHS
require close monitoring, particularly during infancy. Minor medical illnesses, such
as upper respiratory tract illnesses or diarrhea, may precipitate bouts of respiratory
failure. Edema and lethargy are often early signs of impending respiratory failure. The
clinical signs of hypoxemia and hypoventilation in these patients may be subtle, as the
115
children do not show signs of distress or increased work of breathing, such as retrac-
tions and nasal flaring. As a result, gas exchange abnormalities may progress for some
time without notice until the child appears to deteriorate suddenly with cardiopulmo-
nary arrest or severe decompensation.
Not applicable.

The exact pathophysiology of CCHS is unknown. Radiologic and postmortem studies
have not shown gross central nervous system abnormalities. The PHOX2B gene plays
a role in the development of the autonomic system. Functional MRI and physiologic
studies have shown widespread cerebral abnormalities in response to stimuli such as
exogenous hypercapnia.
Objective Findings
Hypoxemia and hypercapnia are present on PSG during sleep. Central apneas may be
present, but hypoventilation associated with decreased tidal volume and respiratory rate
is more common. In contrast to most types of sleep disordered breathing in children,
abnormalities may be more severe during NREM than during REM sleep. Patients may
not arouse from sleep despite severe gas exchange abnormalities. Paradoxical breath-
ing and snoring do not typically occur.
Patients with CCHS have flat rebreathing hypoxic and hypercapnic responses, although
they may respond to transient ventilatory challenges of the peripheral chemorecep-
tors. Arterial blood gases may be normal during wakefulness but will be abnormal if
obtained from an arterial line during sleep. In patients with chronically untreated or
poorly controlled CCHS, a compensated respiratory acidosis may be present. In these
patients, polycythemia may be present and the serum bicarbonate level may be elevated.
Computed tomography and MRI scans of the head are normal. Electrocardiography,
echocardiography, or cardiac catheterization may reveal evidence of pulmonary hyper-
tension. Pulmonary function tests may be normal or show evidence of mild obstructive
or restrictive lung disease resulting from associated conditions such as tracheitis.
CCHS must be distinguished from other forms of central hypoventilation, such as
central hypoventilation due to Chiari malformation, other causes of central nervous
system disturbance such as trauma or tumors, metabolic conditions such as Leigh
disease, or obesity hypoventilation syndrome. CCHS must also be distinguished from
116
hypoventilation secondary to muscle weakness due to conditions such as diaphrag-

matic paralysis or muscular dystrophy. Infants presenting with apnea or an apparent
life-threatening event due to causes such as gastroesophageal reflux may be thought
to have CCHS. However, these infants typically have intermittent episodes of apnea
rather than sustained hypoventilation, and the episodes typically resolve once the
primary cause has been treated. CCHS patients presenting with cor pulmonale may be
misdiagnosed as having congenital heart disease.

There are many unresolved issues regarding CCHS, including prevalence data, precise
genotype-phenotype correlations, effect of aging on patients with CCHS, long-term
outcome of children with CCHS born to parents with CCHS, and the exact nature of
the gene-encoded deficit.
Bibliography
Amiel J, Laudier B, Attie-Bitach T, et al. Polyalanine expansion and frameshift mutations of the paired-like
homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 2003;33:459–61.
Gozal D, Marcus CL, Shoseyov D, Keens TG. Peripheral chemoreceptor function in children with the
congenital central hypoventilation syndrome. J Appl Physiol 1993;74:379–87.
Macey PM, Woo MA, Macey KE, et al. Hypoxia reveals posterior thalamic, cerebellar, midbrain, and
limbic deficits in congenital central hypoventilation syndrome. J Appl Physiol 2005;98:958–69.
Marcus CL, Jansen MT, Poulsen MK, Keens SE, Nield TA, Lipsker LE et al. Medical and psychosocial
outcome of children with congenital central hypoventilation syndrome. J Pediatr 1991;119:888–95.
Paton JY, Swaminathan S, Sargent CW, Hawksworth A, Keens TG. Ventilatory response to exercise in
children with congenital central hypoventilation syndrome. Am Rev Respir Dis 1993;147:1185–91.
Paton JY, Swaminathan S, Sargent CW, Keens TG. Hypoxic and hypercapnic ventilatory responses in awake
children with congenital central hypoventilation syndrome. Am Rev Respir Dis 1989;140:368–72.
Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Keens TG, Loghmanee DA, Trang H. An official ATS
clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and
management. Am J Respir Crit Care Med 2010;181:626–44.
Weese-Mayer DE, Berry-Kravis EM, Marazita ML. In pursuit (and discovery) of a genetic basis for
congenital central hypoventilation syndrome. Respir Physiol Neurobiol 2005;149:73–82.
117
Late-Onset Central Hypoventilation with

Hypothalamic Dysfunction
Alternate Names
Late-onset central hypoventilation syndrome; rapid-onset obesity with hypothalamic
dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD).
Diagnostic Criteria
B. Symptoms are absent during the first few years of life.
C. The patient has at least two of the following:
1. Obesity.
2. Endocrine abnormalities of hypothalamic origin.
3. Severe emotional or behavioral disturbances.
4. Tumor of neural origin.
D. Mutation of the PHOX2B gene is not present.
E. The disorder is not better explained by another sleep disorder, medical
or neurological disorder, medication use, or substance use disorder.
Notes
1. Central apneas may occur but the predominant pattern is reduced flow/tidal
volume associated with hypoventilation and arterial oxygen desaturation.
Essential Features
Late-onset central hypoventilation with hypothalamic dysfunction is a disorder of
central control of ventilation. Patients are usually healthy until early childhood (often
2-3 years of age) when they develop hyperphagia and severe obesity, followed by
central hypoventilation, which often presents as respiratory failure. The respiratory
failure may be precipitated by a mild respiratory illness or anesthesia. Patients require
ventilatory support during sleep; most patients breathe adequately during wakefulness
but some need ventilatory support during both wakefulness and sleep. The hypoventila-
tion persists even if the patients lose weight, differentiating the condition from obesity
hypoventilation syndrome. Patients often develop hypothalamic endocrine dysfunc-
tion characterized by increased or decreased hormone levels, which may include one or
more of the following: diabetes insipidus, inappropriate antidiuretic hormone hyperse-
cretion, precocious puberty, hypogonadism, hyperprolactinemia, hypothyroidism, and
decreased growth hormone secretion. Mood and behavior abnormalities, sometimes
118
severe, have frequently been reported. Developmental delay or autism may be present,
but many patients are cognitively normal. Other symptoms of hypothalamic dysfunc-
tion, such as temperature dysregulation, have been reported.
Associated Features
Tumors of neural origin such as ganglioneuroma may occur.

None known.
Demographics
There are no prevalence data. The disorder seems to occur equally among males and females.

Unknown. Patients do not have the PHOX2B genetic mutation of congenital central
Familial Patterns
Familial cases have not been reported.

Patients are typically normal at birth. Obesity often begins in early childhood, perhaps
because the child is old enough to walk around and obtain his/her own food. Respiratory
failure typically presents several years after the onset of obesity, and requires ventila-
tory support via face mask or tracheostomy. The respiratory failure does not improve
over time. Death has been reported from respiratory failure, cor pulmonale, or hyper-
natremia secondary to diabetes insipidus; case series have reported a high mortality.
Not applicable.

The cause of the disorder is not known. The brain typically appears normal on imaging
or at autopsy, or may show secondary signs of hypoxemia.
Objective Findings
Hypoxemia and hypercapnia are present on PSG during sleep. Central apneas may be
present, but hypoventilation associated with decreased tidal volume and respiratory rate
is more common. Obstructive apneas may occur but are not the primary abnormality.
119
Patients have flat hypoxic and hypercapnic responses. Oxygen and carbon dioxide
determinations may be normal during wakefulness but will demonstrate hypoxemia
and hypercapnia during sleep. In patients with chronically untreated or poorly con-
trolled hypoventilation, a compensated respiratory acidosis may be present, with ele-
vated serum bicarbonate levels. In these patients, polycythemia may be present. Serum
tests may show evidence of endocrine abnormalities; hypernatremia is common.
Computed tomography and MRI scans of the head are normal. Electrocardiography,
echocardiography, or cardiac catheterization may reveal evidence of pulmonary hyper-
tension. Pulmonary function tests may be normal or show evidence of mild obstructive
or restrictive lung disease resulting from associated conditions such as tracheitis.
The disorder can be distinguished from late presentation of congenital central hypoven-
tilation syndrome by testing for the PHOX2B gene. Genetic testing may also be useful
in distinguishing the disorder from Prader-Willi syndrome, which is characterized by a
known genetic abnormality. Most children with Prader-Willi syndrome have hypotonia
at birth and more severe developmental delay. The disorder can be distinguished from
obesity hypoventilation syndrome by the presence of endocrine abnormalities and other
associated hypothalamic abnormalities, and by the persistence of hypoventilation despite
weight loss. In addition, the patients typically have a totally flat hypercapnic ventilatory
response rather than the blunted response seen in children with obesity hypoventilation
syndrome. The disorder should be distinguished from isolated hypopituitarism or other
hypothalamic disease without hypoventilation, and from obesity-related OSA.

The etiology of the disorder is not known. Although the disorder shares some fea-
tures of congenital central hypoventilation syndrome, including the presence of neural
tumors, it does not share the same gene. Little information is available on prevalence
or long-term prognosis.
Bibliography
Ize-Ludlow D, Gray JA, Sperling MA, et al. Rapid-onset obesity with hypothalamic dysfunction,
hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics 2007;120:e179–88.
Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a
distinct clinical syndrome. Pediatr Pulmonol 2000;29:62–8.
120
Idiopathic Central Alveolar Hypoventilation

Alternate Names
Alveolar hypoventilation, central alveolar hypoventilation, idiopathic central alveolar
hypoventilation, nonapneic alveolar hypoventilation, primary alveolar hypoventilation.
Diagnostic Criteria
B. Hypoventilation is not primarily due to lung parenchymal or airway
disease, pulmonary vascular pathology, chest wall disorder, medication
use, neurologic disorder, muscle weakness, or obesity or congenital
hypoventilation syndromes.
Notes
1. The predominant respiratory pattern is one of reduced tidal volume
or ataxic breathing with associated arterial oxygen desaturation.
Although OSA may be present, it is not believed to be the major cause
of hypoventilation. When criteria are met, a diagnosis of both OSA and
idiopathic central alveolar hypoventilation may be made.
2. Arterial oxygen desaturation is often present but is not required for the
diagnosis.
Essential Features
Idiopathic central alveolar hypoventilation is defined as the presence of decreased alve-
olar ventilation resulting in sleep related hypercapnia and hypoxemia in individuals with
presumed normal mechanical properties of the lung and respiratory pump. Thus, chronic
hypoventilation during sleep exists without any readily identifiable impairments of res-
piration, such as pulmonary airway or parenchymal conditions, neurologic, neuromus-
cular or chest wall abnormalities, severe obesity, other sleep related breathing disorder,
or use of respiratory depressant medications or substances. Diurnal as well as nocturnal
hypoventilation is believed to be due primarily to blunted chemoresponsiveness to CO2
and O2. However, reported cases are few and not studied in enough detail to conclu-
sively establish a well-defined etiology. Alternatively, these cases may represent a mixed
group of patients with varied underlying conditions erroneously deemed idiopathic as a
result of incomplete diagnostic work-up. Patient may complain of morning headaches,
fatigue, neurocognitive decline and sleep disturbance, or may be entirely asymptomatic.
Frequent episodes of shallow breathing may be noted to occur during sleep.
121
Associated Features
tension, cor pulmonale, and neurocognitive dysfunction. Patients with other comorbid
sleep related breathing disorders are likely to experience greater severity and dura-
tion of sleep related hypoventilation than are patients with isolated idiopathic central
hypoventilation.

Demographics
Not known. It is likely that some patients with this diagnosis may have an underlying
anatomic or functional defect affecting respiratory mechanics and ventilatory drive
which remains undiagnosed.

The use of central nervous system depressants, such as alcohol, anxiolytics, and hyp-
notics, may further worsen hypercapnia/hypoxemia. Patients who are hypercapnic and
hypoxemic during wakefulness will generally become even more so during sleep, in
particular REM sleep, but the relationship between wake SaO2/PaCO2 and sleep related
desaturation is not sufficiently strong to have substantial predictive value in individual
patients.
Familial Patterns

The onset of the condition is variable, often presenting in adolescence or early adulthood.
The disorder is generally slowly progressive. Many affected individuals with severe
hypercapnia and hypoxemia develop respiratory impairment, pulmonary hypertension,
heart failure, cardiac arrhythmias, and neurocognitive dysfunction. Polycythemia is
common in those with chronic hypoxia. Although the risk of increased morbidity and
mortality appears to increase with worsening sleep related hypoventilation/hypoxemia,
the specific relationship between sleep related hypoventilation/hypoxemia and mor-
bidity and mortality is not well defined.
Not known.
122

The etiology of hypoventilation in these patients is not understood. Chronic hyper-
capnia and hypoxemia in idiopathic central alveolar hypoventilation is believed to
be due to defective CO2 and O2 homeostasis, with impaired CO2 unloading, reduced
chemoresponsiveness to CO2 and O2, and suppression of respiratory drive. Imaging
of the central nervous system does not document a structural defect. Hypoventilation
worsens during sleep compared to waking levels due to a further reduction in che-
mosensitivity and decreased activity of the ventilatory muscles. Additionally, daytime
hypoxemia, if sufficiently severe, may place the patient near or on the steep portion
of the oxyhemoglobin dissociation curve where even relatively small decrements in
arterial oxygen tension result in large decrements in oxyhemoglobin saturation. Thus,
sleep related hypoventilation in these patients may have a relatively great impact on
oxyhemoglobin saturation.
Objective Findings
The characteristic polysomnographic finding is demonstration of sleep related
hypoventilation (determination of PaCO2 by arterial blood gas or by a surrogate
measure [end-tidal CO2 or transcutaneous CO2]). Periods of decreased tidal volume
lasting up to several minutes, with sustained arterial oxygen desaturation, are usually
present. Intermittent arousals may be observed. Daytime arterial blood gases may be
normal or show hypoxia and hypercapnia. Chronic hypoxia can be associated with
polycythemia. Electrocardiography, chest radiography, and echocardiography may
demonstrate evidence of pulmonary hypertension. Central nervous system imaging is
generally unremarkable.
The differential diagnosis includes any disorder that can cause hypoventilation during
sleep. This includes obesity hypoventilation syndrome, pulmonary airway and paren-
chymal disorders, pulmonary vascular pathology, neuromuscular and chest wall dis-
orders, severe untreated hypothyroidism, and use of respiratory suppressants. CCHS
is associated with an abnormal PHOX2B gene. Unlike patients with late-onset central
hypoventilation with hypothalamic dysfunction, patients with idiopathic central
hypoventilation do not have evidence of hypothalamic dysfunction. It is essential to
excluded medical and neurological disorders that are associated with hypoventilation
before a diagnosis of idiopathic central hypoventilation can be made. OSA and CSA
syndromes can be distinguished from sleep related hypoventilation by the periodic
alterations in airflow and accompanying periodic fluctuations in SaO2. In contrast,
oxygen desaturation due to sleep related hypoventilation is generally more sustained,
usually several minutes or longer in duration. When more than one disorder is believed
123
to be responsible for the ventilatory insufficiency during sleep, all pertinent diagnoses
should be coded.

A better understanding of the etiology of idiopathic central alveolar hypoventilation is
essential to guide preventive and treatment measures. Because it is clinically imprac-
tical to routinely obtain arterial blood samples during sleep in most persons suspected
of this disorder, other techniques of measuring CO2 levels must be investigated. The
degree and duration of hypercapnia/hypoxemia necessary to produce adverse conse-
quences, such as pulmonary hypertension, in individual patients is not well defined.
Little information is available regarding the effect of oxygen therapy or noninvasive
ventilation on the course of the underlying disease. Studies are needed to determine the
optimal time to initiate these interventions and the specific subpopulations of patients
who will benefit most from these therapies.
Bibliography
Brown LK. Hypoventilation syndromes. Clin Chest Med 2010;31:249–70.
Casey KR, Cantillo KO, Brown LK. Sleep-related hypoventilation/hypoxemic syndromes. Chest
2007;131:1936–48.
Chebbo A, Tfaili A, Jones SF. Hypoventilation syndromes. Med Clin North Am 2011;95:1189–202.
Sleep Related Hypoventilation Due to a Medication or

Substance
Alternate Names
Alveolar hypoventilation, nocturnal hypoventilation, nonapneic alveolar hypoventila-
tion, secondary alveolar hypoventilation, sleep related hypoventilation.
Diagnostic Criteria
B. A medication or substance known to inhibit respiration and/or ventilatory
drive is believed to be the primary cause of sleep related hypoventilation.
C. Hypoventilation is not primarily due to lung parenchymal or airway
disease, pulmonary vascular pathology, chest wall disorder, neurologic
disorder, muscle weakness, obesity hypoventilation syndrome, or a
known congenital central alveolar hypoventilation syndrome.
124
Notes
1. Although OSA or CSA may be present, they are not believed to be the
major cause of hypoventilation. The predominant respiratory pattern
is one of reduced tidal volume or ataxic breathing and associated
arterial oxygen desaturation. When criteria are met, a diagnosis of both
OSA and CSA due to medication or substance as well as sleep related
hypoventilation due to a medication or substance may be made.
2. Arterial desaturation is often present but is not required for the
diagnosis.
3. Hypoventilation may be present during wakefulness but is not required
for the diagnosis.
Essential Features
This disorder is characterized primarily by chronic hypoventilation and hypercapnia
due to prolonged use of medications or substances known to depress ventilatory drive
and/or impair respiratory muscle mechanics. These agents include long-acting nar-
cotics, anesthetics, sedative compounds, and muscle relaxants. The risk of respiratory
insufficiency is increased with the concomitant use of alcohol or with polypharmacy.
Respiratory depressants can precipitate respiratory failure in patients with limited pul-
monary reserves or exacerbate hypoventilation in those with baseline hypercapnia.
Hypoxemia is commonly present and can show either a sustained reduction or episodic
fluctuations. Sleep related hypoventilation is present. Hypercapnia may also be present
during wakefulness in some patients. Patients can either be asymptomatic or present
with complaints of dyspnea, chest tightness, or fatigue. Neurocognitive dysfunction
may arise following use of narcotics.
Associated Features
Medications and substances that reduce respiratory drive may also alter the mechanics
of the upper airway. By decreasing upper airway muscle tone, these agents may pre-
cipitate or exacerbate OSA and CSA. It is not currently known whether chronic use of
respiratory depressants will eventually give rise to pulmonary artery hypertension or
cor pulmonale, but this seems unlikely.

Demographics
The demographics of sleep related hypoventilation due to use of respiratory suppressants
are not known. It is clear that baseline hypoventilation prior to initiation of respiratory
125
depressant medication will worsen following initiation of the medication. Thus, preva-
lence may be higher in patients with greater perturbations of pulmonary function or neuro-
muscular weakness. Individuals with chronic hypercapnia during wakefulness will expe-
rience even greater decrements of alveolar ventilation during sleep. Studies of patients on
methadone maintenance have generally found no or mild daytime hypoventilation. There
is scant literature about daytime or nocturnal PaCO2 in patients on potent opioids for pain.

The use of medications or substances that impair respiration mechanics or drive is
the primary pathophysiologic factor responsible for hypoventilation and hypoxemia.
There are significant inter-individual differences in sensitivity and tolerance to respira-
tory depressants. Obesity or the presence of medical and neurologic diseases that may
produce hypoventilation may further worsen hypercapnia/hypoxemia. Patients who
are hypercapnic and hypoxemic during wakefulness will generally become even more
so during sleep, in particular REM sleep, but the relationship between wake SaO2/
PaCO2 and sleep related desaturation is not sufficiently strong to have substantial pre-
dictive value in individual patients.
Familial Patterns

Onset and course of the hypoventilation parallel the use and dosing of medications
or substances that can impair respiration, as well as the development of tolerance to
these substances. There may be variability in susceptibility to hypoventilation in dif-
ferent individuals. Comorbid pulmonary or neurologic disorders may accentuate the
severity of hypoventilation. Patients may present for evaluation of suspected OSA
or may be identified following one or more episodes of respiratory failure. It is not
known if chronic use of respiratory depressants can lead to the development of pulmo-
nary hypertension, polycythemia, and cardiac arrhythmias. Neurocognitive dysfunc-
tion may develop either as a direct result of medication usage or as a consequence of
chronic hypoxia and hypercapnia.

Hypoventilation is a direct result of impaired respiratory drive and CO2 and O2 chemo-
sensitivity. Hypoventilation worsens during sleep, especially in REM sleep, compared
to waking levels, due to a further reduction in chemosensitivity and decreased activity
of the ventilatory muscles. In addition, use of respiratory suppressants may give rise to
OSA and CSA that may contribute to hypercapnia and hypoxemia.
126
Objective Findings
The characteristic PSG finding is demonstration of sleep related hypoventilation by
monitoring of PaCO2 or acceptable surrogate during sleep. Sustained oxygen desat-
uration during sleep that is unexplained by discrete apnea and hypopnea events is
common. However, this finding alone is not sufficient to make a diagnosis of sleep
related hypoventilation. Medication use can also produce obstructive or central apneas.
Intermittent arousals associated with hypoxemia may be observed. An ataxic breathing
pattern may be present.
The differential diagnosis encompasses essentially all disorders that can lead to
hypoventilation during sleep. This includes OHS, pulmonary airway and parenchy-
mal disorders, pulmonary vascular pathology, neuromuscular and chest wall disor-
ders, severe untreated hypothyroidism, and congenital or idiopathic central alveo-
lar hypoventilation syndromes. OSA and CSA syndromes can be distinguished from
sleep related hypoventilation by the periodic alterations in airflow and accompanying
periodic fluctuations in SaO2. In contrast, oxygen desaturation due to sleep related
hypoventilation is generally more sustained, usually several minutes or longer in dura-
tion. When more than one disorder is believed to be responsible for the ventilatory
insufficiency during sleep, all pertinent diagnoses should be coded.

Studies of the factors influencing individual susceptibility and tolerance to hypoven-
tilation/hypercapnia due to medications or substances are needed. The long-term con-
sequences of chronic use of respiratory depressants are poorly understood. The value
of routinely measuring PaCO2 during sleep in patients taking respiratory depressants
is not clear. Additionally, because it is clinically impractical to routinely obtain arterial
blood samples during sleep in most persons suspected of this disorder, other techniques
of measuring CO2 levels must be investigated. Little information is available regarding
the effect of oxygen therapy or noninvasive ventilation on the course of the underlying
disease. Studies are needed to determine the optimal time to initiate these interventions
and the specific subpopulations of patients who will benefit most from these therapies.
Bibliography
2007;131:1936–48.
Macintyre PE, Loadsman JA, Scott DA. Opioids, ventilation and acute pain management. Anaesth
Intensive Care 2011;39:545–58.
127
Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate-severe
cancer pain in comparison to long-acting morphine: a meta-analysis and systematic review of the
literature. J Palliat Med 2008;11:492–501.
Sleep Related Hypoventilation Due to a Medical

Disorder
Alternate Names
Alveolar hypoventilation, nonapneic alveolar hypoventilation, secondary alveolar
hypoventilation, sleep related hypoventilation.
Diagnostic Criteria
B. A lung parenchymal or airway disease, pulmonary vascular pathology,
chest wall disorder, neurologic disorder, or muscle weakness is believed
to be the primary cause of hypoventilation.
C. Hypoventilation is not primarily due to obesity hypoventilation
syndrome, medication use, or a known congenital central alveolar
Notes
1. Arterial desaturation is often present but is not required for the
diagnosis.
2. Although OSA or CSA may be present, they are not believed to be the
major cause of hypoventilation. The predominant respiratory pattern is
one of reduced tidal volume or ataxic breathing and associated arterial
oxygen desaturation. When criteria are met, a diagnosis of both OSA
and CSA due to medical or neurological condition as well as sleep
related hypoventilation due to a medical disorder may be made.
3. Hypoventilation may be present during wakefulness but is not required
for the diagnosis.
Essential Features
Lung airway or parenchymal disease, chest wall disorders, pulmonary hypertension,
neurologic and neuromuscular disorders, if sufficiently severe, can result in ventilatory
impairment and chronic hypercapnia and hypoxemia. Acute exacerbations of respiratory
disorders can accentuate the severity of hypoventilation. Sleep related hypoventilation
128
is present and is usually most severe during REM sleep. In some patients, hypercap-
nia may also be present during wakefulness. Patients can either be asymptomatic or
present with complaints of dyspnea, chest tightness, or fatigue. Polycythemia is often
noted with severe chronic hypoxemia. Specific respiratory disorders are associated
with abnormal findings on pulmonary function testing, radiographic imaging, echo-
cardiography, and pulmonary artery catheter measurements. Suspected neurologic or
neuromuscular causes of hypoventilation may be investigated using central nervous
system imaging or measures of peripheral nerve or muscular function.
Associated Features
Consequences of chronic hypercapnia and hypoxemia arising as a result of medical and
neurologic disorders include pulmonary artery hypertension, cor pulmonale, and neu-
rocognitive dysfunction. Some of these disorders are prevalent diseases and commonly
overlap. Patients with multiple disorders are likely to experience greater severity and
duration of sleep related hypoventilation than are patients with either disorder alone.

The clinical presentation varies with the underlying disorder responsible for the sleep
related hypoventilation. Chronic obstructive pulmonary disease is characterized by
generally fixed and not fully reversible lower airways obstruction, and includes
chronic bronchitis, emphysema, cystic fibrosis, and bronchiectasis. Chronic bron-
chitis is a clinical entity defined by the presence of chronic productive cough for
at least three months of the year, for at least two consecutive years, in the absence
of other identifiable etiologies. Emphysema is characterized by destruction of lung
tissue and the dilation of peripheral airspaces without evident fibrosis. Emphysema
and chronic bronchitis often coexist. Alpha-1 antitrypsin deficiency is a genetic cause
of chronic obstructive pulmonary disease. Both bronchiectasis and cystic fibrosis
are characterized by lower airway inflammation and destruction of airways and lung
parenchyma. Patients with chronic lower airways obstruction are increasingly predis-
posed to developing hypoventilation as the severity of the underlying lower airways
obstruction increases.
Parenchymal lung disease associated with restrictive ventilatory dysfunction (e.g.,

interstitial lung disease) can also be associated with sleep related hypoventilation.
Neurologic, neuromuscular, and chest wall disorders can produce hypoventilation due
to an abnormal ventilatory pump (secondary to reduced muscle strength or anatomic
distortion of the chest wall structures) that is unable to meet the ventilatory require-
ments for maintaining PaCO2 at or below 45 mm Hg. In addition, some of these patients
have reduced central neural chemoresponsiveness. Last, hypoxemia may be worsened
129
by the development of atelectasis or aspiration due to defective swallowing associated

with some neurologic and neuromuscular conditions.
Demographics
The demographics of sleep related hypoventilation due to a medical disorder are a
function of the prevalence, clinical characteristics, and degree of severity of the under-
lying conditions. Thus, prevalence may be higher in patients with greater perturbations
of pulmonary function or neuromuscular weakness. Individuals with chronic hyper-
capnia during wakefulness will experience even greater decrements of alveolar venti-
lation during sleep.

Greater impairments of respiratory function are associated with greater risk for sleep
related hypoventilation and hypoxemia. However, there is no recognized threshold
of pulmonary parenchymal or vascular disease severity that adequately predicts the
risk of sleep related hypoventilation in individual patients. Reduced chemosensitivity
may be present in some neuromuscular disorders. The use of central nervous system
depressants, such as alcohol, anxiolytics, and hypnotics, may further worsen respira-
tory impairment. Patients who are hypercapnic and hypoxemic during wakefulness
will generally become even more so during sleep, in particular REM sleep, but the rela-
tionship between wake SaO2/PaCO2 and sleep related desaturation is not sufficiently
strong to have substantial predictive value in individual patients.
Familial Patterns
Genetic patterns for many of the disorders are not known. Alpha-1 antitrypsin defi-
ciency is a genetic disorder characterized by defective production of the enzyme inhib-
itor; severe forms of deficiency can lead to emphysema. Genetic causes of bronchi-
ectasis include primary ciliary dyskinesia and cystic fibrosis. Muscular dystrophies
are genetically inherited. The familial patterns of sleep related hypoventilation due to
these disorders reflect those of the underlying inherited conditions.

Onset and course of the hypoventilation parallels the presence and severity of the
underlying medical or neurological disorders that impair respiration although substan-
tial variability in course is observed even within the same underlying condition. Many
affected individuals with severe hypercapnia and hypoxemia develop respiratory
impairment, pulmonary hypertension, heart failure, cardiac arrhythmias, and neurocog-
nitive dysfunction. Polycythemia is common in those with chronic hypoxia. Although
the risk of increased morbidity and mortality appears to increase with worsening sleep
130
related hypoventilation, the specific relationship between sleep related hypoventilation

and morbidity and mortality is not well defined. Many patients respond to assisted ven-
tilation, whereas hypercapnia may worsen with oxygen therapy alone.

Pulmonary parenchymal diseases are characterized by altered lung volumes (e.g.,
reduced functional residual capacity) and abnormal ventilation/perfusion relationships,
which can result in hypercapnia and hypoxemia during wakefulness. Decreased lung
volume is associated with reduced oxygen reserves that increase the risk of hypoxemia.
In addition, sleep may be associated with an altered pattern of ventilatory-muscle acti-
vation, particularly during REM sleep when, due to reduced activation of the intercos-
tal and accessory muscles, there is a disproportionate ventilatory burden placed on the
diaphragm. This may lead to hypoventilation in patients with chest wall abnormalities
or in those with chronic obstructive pulmonary disease. In the latter, lung hyperinfla-
tion creates a mechanical disadvantage to the diaphragm. Many neurologic and neu-
romuscular disorders are associated with impaired respiratory mechanics and reduced
CO2 chemosensitivity. Finally, daytime hypoxemia, if sufficiently severe, may place
the patient near or on the steep portion of the oxyhemoglobin dissociation curve, where
even relatively small decrements in arterial oxygen tension result in large decrements
in oxyhemoglobin saturation. Thus, sleep related hypoventilation in these patients may
have a relatively great impact on oxyhemoglobin saturation.
Objective Findings
The characteristic polysomnographic finding is demonstration of sleep related hypoven-
tilation (by arterial PaCO2, transcutaneous PCO2, or end-tidal PCO2). Sustained oxygen
desaturation during sleep that is unexplained by discrete apnea and hypopnea events is
common but is not sufficient to establish a diagnosis of sleep related hypoventilation.
Intermittent arousals associated with hypoxemia may be observed. Many medical and
neurologic disorders are associated with significant sleep disturbances and changes in
sleep architecture, including prolonged sleep onset latency, reduced sleep efficiency,
and decreased sleep stages N3 and REM, may be present. Obstructive and central
apneas, when present, will further disturb sleep and accentuate sleep related oxyhe-
moglobin desaturation. Daytime arterial blood gases may be normal or show hypoxia
and hypercapnia. Chronic hypoxia (especially when present during the day as well as
at night) can be associated with polycythemia. Electrocardiography, chest radiography,
and echocardiography may demonstrate evidence of pulmonary hypertension.
In patients with neuromuscular weakness or restrictive chest wall disorders spirometry

shows a restrictive ventilatory dysfunction with the forced vital capacity (FVC) often
131
less than 50% of predicted. However, significant nocturnal desaturation can occur with
FVC values greater than 50% of predicted.
The differential diagnosis includes all disorders which can give rise to hypoventila-
tion during sleep. This includes OHS, use of medications or substances that can sup-
press respiratory drive, and congenital or idiopathic central alveolar hypoventilation
syndromes. OSA and CSA can be distinguished from sleep related hypoventilation by
the periodic alterations in airflow and accompanying periodic fluctuations in SaO2. In
contrast, oxygen desaturation due to sleep related hypoventilation is generally more
sustained, usually several minutes or longer in duration. When more than one disorder
is believed to be responsible for the ventilatory insufficiency during sleep, all pertinent
diagnoses should be coded.

Thresholds of impairments of ventilation and respiratory drive producing hypercapnia/
hypoxemia need to be identified. The degree and duration of hypercapnia/hypoxemia
necessary to produce adverse consequences, such as pulmonary hypertension, in indi-
vidual patients is not well defined. The value of routinely measuring PaCO2 during
sleep in these patients is not clear. Additionally, because it is clinically impractical to
routinely obtain arterial blood samples during sleep in most persons suspected of this
disorder, other techniques of measuring CO2 levels must be investigated. Little infor-
mation is available regarding the effect of oxygen therapy or noninvasive ventilation
on the course of the underlying disease. Studies are needed to determine the optimal
time to initiate these interventions and the specific subpopulations of patients who will
benefit most from these therapies.
Bibliography
Ambrosino N, Carpenè N, Gherardi M. Chronic respiratory care for neuromuscular diseases in adults. Eur
Respir J 2009;34:444–51.
Beuther DA. Hypoventilation in asthma and chronic obstructive pulmonary disease. Semin Respir Crit
Care Med 2009;30:321–9.
Biering-Sørensen F, Jennum P, Laub M. Sleep disordered breathing following spinal cord injury. Respir
Physiol Neurobiol 2009;169:165–70.
Castriotta RJ, Murthy JN. Hypoventilation after spinal cord injury. Semin Respir Crit Care Med
2009;30:330–8.
Dhand UK, Dhand R. Sleep disorders in neuromuscular diseases. Curr Opin Pulm Med 2006;12:402–8.
Donath J, Miller A. Restrictive chest wall disorders. Semin Respir Crit Care Med 2009;30:275–92.
Fathi M, Lundberg IE, Tornling G. Pulmonary complications of polymyositis and dermatomyositis. Semin
Respir Crit Care Med 2007;28:451–8.
132
Glass GA, Josephs KA, Ahlskog JE. Respiratory insufficiency as the primary presenting symptom of
multiple-system atrophy. Arch Neurol 2006;63:978–81.
Kennedy JD, Martin AJ. Chronic respiratory failure and neuromuscular disease. Pediatr Clin North Am
2009;56:261–73, xii.
Taylor-Cousar JL. Hypoventilation in cystic fibrosis. Semin Respir Crit Care Med 2009;30:293–302.
Toussaint M, Chatwin M, Soudon P. Mechanical ventilation in Duchenne patients with chronic respiratory
insufficiency: clinical implications of 20 years published experience. Chron Respir Dis 2007;4:167–77.
Vazquez-Sandoval A, Huang EJ, Jones SF. Hypoventilation in neuromuscular disease. Semin Respir Crit
Care Med 2009;30:348–58.
Wider C, Wszolek ZK. Rapidly progressive familial parkinsonism with central hypoventilation, depression
and weight loss (Perry syndrome)--a literature review. Parkinsonism Relat Disord 2008;14:1–7.
133
Sleep Related Hypoxemia Disorder
Sleep Related Hypoxemia

Alternate Names
Nocturnal oxygen (or oxyhemoglobin) desaturation, low nocturnal oxygen saturation,
nocturnal hypoxemia, sleep related hypoxemia, sleep related oxygen desaturation.
Diagnostic Criteria
A. PSG, OCST or nocturnal oximetry shows the arterial oxygen saturation
(SpO2) during sleep of ≤ 88% in adults or ≤ 90% in children for ≥ 5
minutes.
B. Sleep related hypoventilation is not documented.1
Notes
1. If sleep related hypoventilation is documented (as measured by arterial
blood gas, transcutaneous PCO2, or end-tidal CO2 sensors), the disorder
is classified as sleep related hypoventilation.
2. OSA or CSA may be present, but these are not believed to be the major
cause of hypoxemia.
3. Physiological causes, if known, should be indicated (e.g., shunt,
ventilation-perfusion [V/Q] mismatch, low mixed venous oxygen, and/
or high altitude).
Essential Features
Significant hypoxemia during sleep is present and is believed to be secondary to a
medical or neurological disorder. The presence of hypoxemia is not better explained
by another sleep related breathing disorder (e.g., OSA). Although some amount of
obstructive or central apnea may be present, these disorders are not thought to be pri-
marily responsible for the hypoxemia during sleep. Some patients with sleep related
hypoxemia also exhibit hypoxemia during wakefulness. Sleep related hypoventilation
has not been documented (if so, a diagnosis of sleep related hypoventilation is made).
The presentation of patients with sleep related hypoxemia varies with the underly-
ing medical or neurological disorders. Chronic hypoxemia can arise from airway or
parenchymal pulmonary disease, chest wall disorders, pulmonary hypertension, or
neurologic and neuromuscular disorders. Acute exacerbations of respiratory disorders
134
can accentuate the severity of hypoxemia. Hypoxemia due to underlying lower airway
obstructive disease, pulmonary parenchymal disease, vascular pathology, and other
causes of hypoventilation is generally sustained (several minutes or longer), whereas
sawtooth fluctuations of oxygen saturation (typically less than one minute) characterize
hypoxemia due to OSA or CSA. Patients can either be asymptomatic or present with
complaints of nocturnal dyspnea, impaired sleep quality, chest tightness, or fatigue.
Polycythemia is often noted with severe chronic hypoxemia.
Associated Features
tension, cor pulmonale, and neurocognitive dysfunction. Some of the disorders causing
hypoxemia are prevalent diseases and not uncommonly overlap. Patients with multi-
ple breathing disorders are likely to experience greater severity and duration of sleep
related hypoxemia than are patients with a single disorder.
Clinical and Pathologic Subtypes

Specific variations in the sleep related findings have not been described for the various
etiologies.
Demographics
The demographics of sleep related hypoxemia are a function of the prevalence, clinical
characteristics and degree of severity of the underlying conditions. Thus, prevalence
may be higher in patients with greater perturbations of pulmonary function or neu-
romuscular weakness. Individuals with chronic hypoxemia during wakefulness will
experience even greater decrements of oxygenation during sleep.

Greater impairments of respiratory function are associated with greater risk for sleep
related hypoxemia. However, there is no recognized threshold of pulmonary paren-
chymal or vascular disease severity or extent of neuromuscular weakness that ade-
quately predicts the risk of sleep related hypoxemia in individual patients. Patients
who are hypoxemic during wakefulness will generally become even more so during
sleep, especially REM sleep. Among the best predictors of sleep related hypoxemia are
reduced baseline wake SaO2 and hypercapnia. Patients with wake hypercapnia should
be suspected of sleep related hypoxemia. However, the relationship between wake
SaO2/PaCO2 and sleep related desaturation is not sufficiently strong to have substantial
predictive value in individual patients.
135
Familial Patterns
Genetic patterns for many of the disorders are not known. Alpha-1 antitrypsin defi-
ciency is a genetic disorder characterized by defective production of the enzyme inhib-
itor; severe forms of deficiency can lead to emphysema. Genetic causes of bronchiec-
tasis include primary ciliary dyskinesia and cystic fibrosis. Muscular dystrophies are
genetically inherited. The familial patterns of sleep related hypoxemia due to these
disorders reflect those of the underlying inherited conditions.

Onset and course of sleep related hypoxemia parallel the presence and severity of the
underlying medical or neurological disorders that impair respiration, although sub-
stantial variability in course is observed even within the same underlying condition.
Many affected individuals with severe hypercapnia and hypoxemia develop respiratory
impairment, pulmonary hypertension, heart failure, cardiac arrhythmias, and neuro-
cognitive dysfunction. Polycythemia is common in those with chronic hypoxia. Higher
rates of painful crises accompany hypoxemia in children with sickle cell disease.
Although the risk of increased morbidity and mortality appears to increase with wors-
ening sleep related hypoxemia, the specific relationship between sleep related hypox-
emia and morbidity and mortality is not well defined. Many patients respond to oxygen
therapy; in some, hypercapnia may worsen with oxygen therapy alone for hypoxia.

Hypoxemia may arise from a shunt physiology, ventilation-perfusion [V/Q] mismatch-
ing, low mixed venous oxygen, and/or high altitude. Hypoventilation also gives rise
to hypoxemia; however, when hypoventilation has been documented, a diagnosis of
sleep related hypoventilation should be assigned, rather than sleep related hypoxemia.
Pulmonary parenchymal diseases are characterized by altered lung volumes (e.g.,
reduced functional residual capacity) and abnormal ventilation/perfusion relationships,
which can result in hypercapnia and hypoxemia during wakefulness. Decreased lung
volume is associated with reduced oxygen reserves that increase the risk of hypoxemia.
In addition, sleep may be associated with an altered pattern of ventilatory muscle acti-
vation, particularly during REM sleep when, due to reduced activation of the intercos-
tal and accessory muscles, there is a disproportionate ventilatory burden placed on the
diaphragm. This may lead to hypoventilation in patients with chest wall abnormalities
or chronic obstructive pulmonary disease. In the latter, lung hyperinflation creates a
mechanical disadvantage to the diaphragm. In sickle cell anemia, decreased oxyhemo-
globin affinity may partly contribute to hypoxemia. Many neurologic and neuromuscu-
lar disorders are associated with impaired respiratory mechanics and reduced CO2 che-
mosensitivity. Finally, daytime hypoxemia, if sufficiently severe, may place the patient
136
near or on the steep portion of the oxyhemoglobin dissociation curve where even rela-
tively small decrements in arterial oxygen tension result in large decrements in oxyhe-
moglobin saturation. Thus, sleep related hypoventilation in these patients might have a
relatively great impact on oxyhemoglobin saturation.
Objective Findings
Various patterns of oxygen desaturation (sustained, intermittent, or episodic) may be
observed during sleep. The diagnosis is generally made on the basis of overnight oxim-
etry (alone or as a component of PSG or OCST); less commonly, arterial blood gas mea-
surements are indicated, especially if concomitant hypoventilation is suspected. PSG
may demonstrate normal sleep architecture or frequent arousals, increased wakeful-
ness after sleep onset and reduced sleep efficiency; however, the contribution of sleep
related hypoxemia to the altered sleep architecture, if present, is uncertain. Daytime
arterial blood gases may be normal or show hypoxia and hypercapnia. Nocturnal oxim-
etry usually shows sustained periods of reduced arterial oxygen but clusters of more
severe drops in the arterial oxygen saturation can occur every one to two hours due to
worsening of breathing during REM sleep. A sawtooth pattern of briefer desaturations
(typically less than one minute) suggests the presence of discrete events (apneas or
hypopneas). Some sawtooth changes may be superimposed on low baseline oxygen
saturation but are not the predominant pattern. Chronic hypoxia can be associated with
polycythemia. Electrocardiography, chest radiography, and echocardiography may
demonstrate evidence of pulmonary hypertension.
The differential diagnosis encompasses all disorders which can give to hypoxemia
during sleep. This includes pulmonary airway and parenchymal disorders, pulmonary
vascular pathology, neuromuscular and chest wall disorders, OHS, use of medications
or substances that can suppress respiratory drive, and congenital or idiopathic central
alveolar hypoventilation syndromes. OSA and CSA syndromes can be distinguished
from sleep related hypoxemia by the periodic alterations in airflow and accompanying
periodic fluctuations in SaO2. In contrast, oxygen desaturation associated with sleep
related hypoxemia is generally more sustained, usually several minutes or longer in
duration. In cases when more than one disorder is believed to be responsible for the
ventilatory insufficiency during sleep, all pertinent diagnoses should be coded.

The degree and duration of hypercapnia/hypoxemia necessary to produce adverse
consequences, such as pulmonary hypertension, in individual patients is not well
defined. The value of routinely measuring arterial blood gases or SaO2 during sleep
137
is not clear. With the exception of COPD, little information is available regarding the
effect of oxygen therapy on the course of the underlying disease. Even less is under-
stood regarding the consequences of isolated sleep related hypoxemia and the need for
oxygen supplementation in patients with normal daytime wake oxygen levels. Studies
are needed to determine the optimal time to initiate oxygen therapy and the specific
subpopulations of patients who will benefit most from this intervention.
Bibliography
Berry RB, Sriram P. Evaluation of hypoventilation. Semin Respir Crit Care Med 2009;30:303–14.
2007;131:1936–48.
Mogri M, Desai H, Webster L, Grant BJ, Mador MJ. Hypoxemia in patients on chronic opiate therapy with
and without sleep apnea. Sleep Breath 2009;13:49–57.
138
Snoring
ICD-9-CM code: 786.09 ICD-10-CM code: R06.83
Snoring is a respiratory sound generated in the upper airway during sleep that typically
occurs during inspiration but may also occur in expiration; the snoring described here
occurs without episodes of apnea, hypopnea, RERAs or hypoventilation. The intensity
of snoring may vary and often will disturb the bed partner’s sleep and even awaken
the patient. Snoring in this context does not cause symptoms of daytime sleepiness or
insomnia in the patient. This type of snoring has variously been referred to as habitual,
primary or simple snoring.
Snoring is a cardinal symptom of obstructive sleep apnea. A designation of habitual

snoring cannot be made in those who exhibit symptoms (daytime sleepiness/fatigue or
other related symptoms) or report possible breathing pauses, without objective mea-
surement of breathing during sleep. In addition, those individuals with snoring and
comorbid cardiovascular disease (especially pulmonary or systemic hypertension, cor-
onary artery disease, or atrial fibrillation) are at increased risk for the presence of OSA
even in the absence of complaints of daytime sleepiness. Therefore, PSG or OCST
is required in order to effectively rule out OSA in such populations. It should also be
noted that patients who initially have isolated snoring may be at risk for developing
OSA with aging or weight gain.
Occasional snoring is almost universal. Estimates on snoring vary widely depending

on its definition. The incidence of snoring in children is reported to be 10% to 12%.
The Wisconsin cohort study reports habitual snoring in about 24% of adult women
and 40% of adult men. Prevalence of snoring increases with age in both sexes, except
that the prevalence of reported snoring starts to decrease again in men after 70 years of
age. Some have hypothesized that his may be due to decreased hearing acuity in older
individuals.
Snoring is most common in adult men and is also linked to obesity. Nasal obstruc-
tion increases the risk of snoring. Ingestion of alcohol, muscle relaxants, narcotics,
or other substances that decrease upper airway muscle tone predisposes an individual
to snoring. Smoking, particularly in males, has also been shown to be a risk factor.
Snoring has also been shown to increase during pregnancy. In children, an association
has been reported between snoring and adenotonsillar hypertrophy. During snoring
139
there is vibration of the uvula and soft palate, although it may also involve the faucial
pillars, pharyngeal walls, and lower structures. Snorers have been shown to have mor-
phologic derangements of the palate consistent with neurogenic lesions. These are
thought to be due to trauma from vibration. If PSG is performed, snoring tends to be
loudest during stage N3 sleep or REM sleep.
Epidemiologic studies are difficult to interpret if sleep apnea was not excluded by
PSG. Based on the current literature, habitual snoring in children may be associated
with worse school performance, but conclusive evidence for this is lacking. Some
studies have suggested that adult snorers may have a higher prevalence of cardiovas-
cular disease, including hypertension, stroke, and ischemic heart disease. However, a
large observational study in which all subjects underwent PSG found no increased risk
of cardiovascular morbidity or mortality with habitual snoring. Of interest, one study
found that snoring was associated with atherosclerosis of the carotid artery, but this has
not been confirmed by other studies. As snoring tends to increase during pregnancy,
the impact of snoring on maternal health is of great interest. A study found that preg-
nancy-onset habitual snoring (but not chronic [pre-conceptual] snoring) was associated
with increased risk of gestational hypertension and preeclampsia. Further studies are
needed in this area.
Bibliography
Cho JG, Witting PK, Verma M, et al. Tissue vibration induces carotid artery endothelial dysfunction: a
mechanism linking snoring and carotid atherosclerosis? Sleep 2011;34:751–7.
Kezirian EJ, Chang JL. Snoring without OSA and health consequences: the jury is still out. Sleep
2013;36:613.
Lee SA, Amis TC, Byth K, et al. Heavy snoring as a cause of carotid artery atherosclerosis. Sleep
2008;31:1207–13.
Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive
sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an
observational study. Lancet 2005;365:1046–53.
Mason RH, Mehta Z, Fonseca AC, Stradling JR, Rothwell PM. Snoring and severity of symptomatic and
asymptomatic carotid stenosis: a population-based study. Sleep 2012;35:1147–51.
O’Brien LM, Bullough AS, Owusu JT, et al. Pregnancy-onset habitual snoring, gestational hypertension,
and preeclampsia: prospective cohort study. Am J Obstet Gynecol 2012;207:487.e1–9.
Rich J, Raviv A, Raviv N, Brietzke SE. An epidemiologic study of snoring and all-cause mortality.
Otolaryngol Head Neck Surg 2011;145:341–46.
140
Catathrenia
Catathrenia, also known as sleep related groaning, is included in the SRBD section
because it appears to be associated with prolonged expiration, usually during REM
sleep. However, some studies have documented catathrenia during NREM sleep.
Typically, a deep inspiration is followed by prolonged expiration and a monotonous
vocalization resembling groaning. The pattern is sometimes called bradypnea (low
respiratory rate). The affected individual is usually unaware of the problem, but clini-
cal evaluation is sought due to complaints of the bed partner or family members. The
recurrent bradypneic episodes may resemble central apnea except that central apneas
are not typically associated with vocalization. Catathrenia is thought to be rare and
more common in men. Several episodes may occur nightly and often in clusters. The
long-term consequences of catathrenia are unknown, but the disorder is primarily a
social problem for the affected individual. The episodes of catathrenia are not associ-
ated with sleep talking or body movement. No association with psychiatric disorders
has been demonstrated. The onset of catathrenia has recently been reported in patients
taking sodium oxybate for narcolepsy with cataplexy. The clinical significance of this
finding is unclear.
Bibliography
Abbasi AA, Morgenthaler TI, Slocumb NL, et al. Nocturnal moaning and groaning-catathrenia or
nocturnal vocalizations. Sleep Breath 2012;16:367–73.
Pevernagie DA, Boon PA, Mariman ANN, Verhaeghen DB, Pauwels RA. Vocalization during episodes of
prolonged expiration: a parasomnia related to REM sleep. Sleep Med 2001;2:19–30.
Poli F, Ricotta L, Vandi S, et al. Catathrenia under sodium oxybate in narcolepsy with cataplexy. Sleep
Breath 2012;16:427–34.
Vetrugno R, Lugaresi E, Plazzi G, Provini F, D’Angelo R, Montagna P. Catathrenia (nocturnal groaning):
an abnormal respiratory pattern during sleep. Eur J Neurol 2007;14:1236–43.
Vetrugno R, Provini F, Plazzi G, Vignatelli L, Lugaresi E, Montagna P. Catathrenia (nocturnal groaning):
a new type of parasomnia. Neurology 2001;56:681–3.
141
Central Disorders of
Hypersomnolence
Narcolepsy Type 1.......................................................................................146
Narcolepsy Type 2.......................................................................................155
Idiopathic Hypersomnia...............................................................................161
Kleine-Levin Syndrome...............................................................................166
Hypersomnia Due to a Medical Disorder.....................................................171
Hypersomnia Due to a Medication or Substance........................................175
Hypersomnia Associated with a Psychiatric Disorder.................................179
Insufficient Sleep Syndrome........................................................................182

Long Sleeper...............................................................................................187
Adequate alertness is necessary for well-being and performance in modern society.

Sleepiness predisposes an individual to developing serious performance decrements
in multiple areas of function, as well as to potentially life-threatening domestic, occu-
pational, and vehicular accidents. This section includes a group of disorders in which
the primary complaint is daytime sleepiness not caused by disturbed nocturnal sleep
or misaligned circadian rhythms. Other sleep disorders may be present, but they
must be adequately treated before a diagnosis in this category can be established. In
this nosology, the term hypersomnolence is used to describe the symptom of exces-
sive sleepiness, whereas hypersomnia refers to specific disorders, such as idiopathic
hypersomnia.
Daytime sleepiness is defined as the inability to stay awake and alert during the major
waking episodes of the day, resulting in periods of irrepressible need for sleep or unin-
tended lapses into drowsiness or sleep. Sleepiness may vary in severity and is more
likely to occur in sedentary, boring, and monotonous situations that require little active
participation. Some patients are aware of increasing sleepiness before falling asleep,
whereas others can fall asleep with little or no prodromal symptoms (“sleep attacks”).
This group of patients sometimes can present following motor vehicle accidents attrib-
utable to sleepiness. In some forms of hypersomnolence, sleepiness is associated with
large increases in total daily amount of sleep without any genuine feeling of resto-
ration. In others, sleepiness can be alleviated temporarily by naps but reoccurs shortly
thereafter. In young children, sleepiness may express itself as excessively long night
sleep or with the recurrence of previously discontinued daytime napping. Children may
143
Central Disorders of Hypersomnolence
paradoxically present with inattentiveness, emotional lability, hyperactive behavior,

or decreased performance in school. In most cases, excessive sleepiness is a chronic
symptom. It must occur for at least three months prior to diagnosis.
The severity of daytime sleepiness can be quantified subjectively using severity

scales such as the Epworth Sleepiness Scale and objectively using the Multiple Sleep
Latency Test (MSLT). These measures do not always correlate with each other and
must be used with appropriate clinical judgment. When applied in clinical settings, the
MSLT is sensitive to sleep deprivation and circadian effects. It has not been validated
as a diagnostic test in people who are habitually awake throughout the night and sleep
during the day. Normal and abnormal ranges of sleep latencies have not been estab-
lished when this test is administered at times other than the hours between 8:00 a.m.
and 6:00 p.m.
Normative data are not available for children younger than six years.
The MSLT measures the physiological tendency to fall asleep in quiet situations. In the
context of diagnosing central disorders of hypersomnolence, the MSLT should be con-
ducted according to standardized procedures, as defined in the American Academy of
Sleep Medicine (AASM) practice parameters. In particular, patients should be encour-
aged to sleep as much as possible during the week and, especially, during the night
prior to the MSLT. Delaying wake-up time and subsequent MSLT start time may be
appropriate in some patients with delayed sleep phase syndrome. It is strongly rec-
ommended that adequate sleep be documented by sleep log and, whenever possible,
actigraphy for a period of one to two weeks prior to the MSLT. MSLT mean sleep
latencies should be considered a continuum with values below five minutes generally
considered as indicative of sleepiness and those over 10 minutes generally consid-
ered indicative of normal alertness. In this section, a mean MSLT sleep latency of
less than eight minutes is used to define sleepiness for diagnostic purposes. This value
has been shown to be the best cutoff in the context of diagnosing narcolepsy, with
approximately 90% of patients with narcolepsy having a latency below this level. The
presence of multiple sleep onset rapid eye movement periods (SOREMPs) during the
MSLT is a more specific finding in narcolepsy than is a mean sleep latency less than or
equal to eight minutes, although SOREMPs can also be seen in the presence of insuffi-
cient sleep, circadian rhythm disorders (including delayed sleep phase disorder or shift
work), sleep related breathing disorders or, occasionally, normal subjects. The results
of an MSLT should be carefully interpreted in the context of the patient’s history and
the complaint of daytime sleepiness.
144
The maintenance of wakefulness test is a measure of the ability to remain awake during
the daytime in a darkened, quiet environment and is usually administered to assess
response to treatment. It should not be used for diagnostic purposes.
A 24-hour continuous sleep recording or an actigraphic recording of at least one week

is useful in the diagnosis of some patients with idiopathic hypersomnia. In all cases
in which a diagnosis of hypersomnolence is to be made, a review of other sleep,
medical, and psychiatric disorders, as well as substance and medication use, should
be performed.
In this edition of International Classification of Sleep Disorders the preferred names

of certain central disorders of hypersomnolence have been changed. In particular, nar-
colepsy has been divided into narcolepsy type 1 and narcolepsy type 2 rather than
narcolepsy with and without cataplexy. This change is predicated on the concept that
absence of hypocretin (orexin) is a fundamental marker of the most precisely defined
category of the disorder. Because some patients without cataplexy will also have low
cerebrospinal fluid (CSF) hypocretin-1 levels, the use of the term “narcolepsy with
cataplexy” or “narcolepsy-cataplexy” is inappropriate. The change is not intended to
imply that the presence or absence of cataplexy is unimportant clinically nor that mea-
suring CSF hypocretin-1 levels is obligatory. The motivation behind the decision to
eliminate the subcategories of idiopathic hypersomnia is discussed in the appropriate
section. The decision to use Kleine-Levin syndrome as the preferred name in place of
recurrent hypersomnia is based on data suggesting that the condition is fairly homo-
geneous, as well as the lack of definite evidence for other major subcategories of the
disorder.
Bibliography
Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. A Review by the MSLT and MWT Task
Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. The
clinical use of the MSLT and MWT. Sleep 2005;28:123–44.
Aurora RN, Lamm CI, Zak RS, et al. Practice parameters for the non-respiratory indications for
polysomnography and multiple sleep latency testing for children. Sleep 2012;35:1467–73.
Littner MR, Kushida C, Wise M, et al.; Standards of Practice Committee of the American Academy
of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the
maintenance of wakefulness test. Sleep 2005;28:113–21.
Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency
Test in community adults. Brain 2006;129:1609–23.
145
Narcolepsy Type 1
Alternate Names
Hypocretin deficiency syndrome, narcolepsy-cataplexy, narcolepsy with cataplexy.
Diagnostic Criteria
A. The patient has daily periods of irrepressible need to sleep or daytime
lapses into sleep occurring for at least three months.1
B. The presence of one or both of the following:
1. Cataplexy (as defined under Essential Features) and a mean
sleep latency of ≤ 8 minutes and two or more sleep onset REM
periods (SOREMPs) on an MSLT performed according to standard
techniques. A SOREMP (within 15 minutes of sleep onset) on
the preceding nocturnal polysomnogram may replace one of the
SOREMPs on the MSLT.2
2. CSF hypocretin-1 concentration, measured by immunoreactivity,
is either ≤ 110 pg/mL or <1/3 of mean values obtained in normal
subjects with the same standardized assay.
Notes
1. In young children, narcolepsy may sometimes present as excessively
long night sleep or as resumption of previously discontinued daytime
napping.
2. If narcolepsy type I is strongly suspected clinically but the MSLT
criteria of B1 are not met, a possible strategy is to repeat the MSLT.
Essential Features
Narcolepsy type 1 is a disorder primarily characterized by excessive daytime sleepi-
ness and signs of REM-sleep dissociation, the most specific of which is cataplexy. It
has now been firmly established that narcolepsy type 1 is caused by a deficiency of
hypothalamic hypocretin (orexin) signaling. Patients with low or undetectable concen-
trations of hypocretin-1 in the CSF compose a specific disease population with a single
etiology and relatively homogenous clinical and polysomnographic features. Patients
with sleepiness and low or absent CSF hypocretin-1 levels are classified as having nar-
colepsy type 1, even if they do not manifest cataplexy.
146
Excessive daytime sleepiness is the cardinal symptom, and often the most disabling.
Patients with narcolepsy type 1 experience repeated daily episodes of an irrepressible
need to sleep or lapses into sleep. Most patients awaken refreshed after a sleep episode
but begin to feel sleepy again after variable times. Sleepiness is most likely to occur
in monotonous situations that require no active participation; for example, watching
television or riding in a car. Physical activity may temporarily suppress the urge to
sleep. In some cases sleepiness manifests as sudden irresistible sleep “attacks” that
may occur in unusual situations such as eating or walking. Often, such sleep attacks
occur on a background of overall sleepiness. Even when seemingly awake, many nar-
colepsy patients have lapses in vigilance, sometimes in combination with automatic
behavior, such as writing gibberish or interrupting a conversation with a completely
different topic. Sleepiness generally has a serious impact on the ability of the patient to
function in educational, social, and occupational situations.
Because patients are rarely examined during an attack of cataplexy, its presence needs
to be established based on the clinical interview alone. Cataplexy is defined as more
than one episode of generally brief (< 2 minutes), usually bilaterally symmetrical
sudden loss of muscle tone with retained consciousness. The episodes are precipitated
by strong emotions, usually positive, with almost all patients reporting some episodes
precipitated by emotions associated with laughter. The finding of transient reversible
loss of deep tendon reflexes during an attack, if observed, is a strong diagnostic finding.
In children (and rarely adults), cataplexy may present close to disease onset as facial
(or generalized) hypotonia with droopy eyelids, mouth opening, and protruded tongue,
or gait unsteadiness, which clearly are not related to emotion. Facial and masticatory
movements may occur. In children, anticipation of a reward is a common precipitant.
It is important to use child-appropriate contexts and language when trying to elicit a
history of cataplexy in children.
The cataplexy phenotype differs widely between patients, ranging from sporadic
partial attacks triggered by laughter, to frequent complete attacks of collapse brought
about by a variety of emotions. In the vast majority of attacks, cataplexy is bilateral,
although patients sometimes report one side of the body to be more affected than the
other. Partial attacks can be very subtle and sometimes only recognized by experi-
enced observers such as the patient’s partner. Neck weakness, producing head drop,
is a common complaint, whereas facial weakness may lead to sagging of the jaw and
dysarthria. Respiratory muscles are not involved although patients sometimes describe
shortness of breath when symptomatic. Attacks start abruptly and usually build up
over several seconds, especially in attacks producing complete peripheral weakness
and collapse. Positive motor phenomena are not uncommon, with muscle twitching
147
or small jerks, particularly of the face. Although many emotions can potentially lead
to cataplexy, those associated with mirth are usually the most potent. Laughing out
loud, telling a joke, and making a witty remark are typical examples. The frequency
of cataplexy is variable, ranging from less than one attack per month to more than 20
attacks per day. Cataplexy is generally short-lived, lasting a matter of seconds, with
the vast majority of attacks lasting less than two minutes. However, if a particular
trigger continues, consecutive attacks may merge together to form what seems to be
one long episode. Sudden withdrawal of anticataplectic medication, especially anti-
depressants, can result in “status cataplecticus” in which long-lasting attacks happen
virtually continuously.
Associated Features
In addition to sleepiness and cataplexy, patients with narcolepsy type 1 often report
several other symptoms, none of which are specific for the disorder. Many patients
report disruption of nocturnal sleep, which can sometimes be of major concern.
Although sleep onset is rarely a problem, an inability to maintain continuous sleep
is very common. 33% to 80% of narcolepsy patients have hypnagogic hallucinations
and/or sleep paralysis. Hypnagogic hallucinations are defined as vivid dreamlike expe-
riences occurring at the transition from wake to sleep. Typically, hypnagogic halluci-
nations have a multimodal or “holistic” character, often combining visual, auditory,
and tactile phenomena. Hypnopompic hallucinations are similar but occur at sleep to
wake transitions. Sleep paralysis describes the disturbing temporary inability to move
voluntary muscles at sleep-wake transitions. Despite being awake and conscious of the
sleeping environment, it is impossible for subjects to move their limbs or even open
their eyes. The experience may last for several minutes and can be very distressing.
Other symptoms may include ptosis, blurred vision, and diplopia, presumably as a
result of sleepiness.
Epidemiological studies have shown that obesity is a common symptom of narco-

lepsy. Around disease onset, an unexplained increase in body weight is often observed.
Obesity (defined as a body mass index ≥ 30 kg/m2) occurs more than twice as often in
narcoleptic populations as in control groups. An increased frequency of several other
sleep abnormalities has been described in narcolepsy, including sleep talking, periodic
limb movements of sleep, sleep disordered breathing, and REM sleep behavior disor-
der. There is an increased prevalence of depressive symptoms, although there are con-
flicting reports on how often these symptoms qualify as a clinical depression. Recent
studies point to a high level of anxiety disorders in patients with narcolepsy, with panic
attacks or social phobias in about 20%. More than half of patients report severe fatigue,
which can be distinct from sleepiness.
148

Narcolepsy type 1 due to a medical condition: This condition is primarily associated
with central nervous system (CNS) disorders, including autoimmune or paraneoplastic
disorders associated with anti-Ma2 or antiaquaporin4 antibodies, and tumors or other
lesions of the hypothalamus. In addition, undetectable hypocretin-1 levels have been
reported in association with sleepiness after severe head trauma. The condition must
fulfill criteria for narcolepsy type 1 and be attributable to another medical disorder.
Narcolepsy without cataplexy with low CSF Hcrt-1 levels: Narcolepsy type 1 should
be diagnosed, even in the absence of cataplexy, if diagnostic criteria A and B2 are
fulfilled.
Demographics
Narcolepsy with cataplexy occurs in 0.02% to 0.18% of the United States and western
European populations. A lower prevalence has been reported in Israel, whereas narco-
lepsy with cataplexy may be slightly more common in Japan (0.16% to 0.18%). Both
sexes are affected, with a slight preponderance of males.

Several unproven precipitating factors have been suggested in case reports, including
head trauma, sustained sleep deprivation, unspecified viral illness, and sudden changes
in sleep-wake patterns. Several studies have pointed to seasonal patterns in the onset
of narcolepsy, which may point to a specific environmental trigger. Recent studies have
shown an increase in antibodies against beta-hemolytic streptococcus, which were
strongest around onset of narcolepsy and decreased with disease duration, suggesting
that streptococcal infections may constitute an environmental trigger. There have been
reports of narcolepsy type 1 occurring after vaccination against H1N1 associated influ-
enza, but a definite causal association has not yet been established. Tribbles homolog
2 antibodies, found in some patients with autoimmune uveitis, have been described in
14% to 26% of narcolepsy patients, but the significance is uncertain.
Familial Patterns
At the genetic level, narcolepsy with cataplexy is closely associated with the human
leukocyte antigen (HLA) subtypes DR2/DRB1*1501 and DQB1*0602. These two
subtypes are always found together in whites and Asians, but in blacks, DQB1*0602
is more specifically associated with narcolepsy. Almost all patients with cataplexy
are positive for DQB1*0602, compared with 12% to 38% of the general population
who have this HLA subtype. Other subtypes also have less striking associations.
For example, DQB1*0301 is associated with increased susceptibility to narcolepsy,
149
whereas subtypes such as DQB1*0501 and DQB1*0601, are protective in the presence
of DQB1*0602. Genomewide studies have found associations between narcolepsy and
polymorphisms in T cell receptor alpha, tumor necrosis factor (TNF)-alpha 2, and TNF
receptor 2 as well as the purinergic receptor P2Y11 genes.
There is a low prevalence of familial cases; the risk of narcolepsy type 1 in first-de-
gree relatives of affected individuals is approximately 1% to 2%. When compared to
the population prevalence, this indicates a tenfold to fortyfold increase in risk. This
increased risk cannot be explained solely by HLA gene effects, suggesting the exis-
tence of other genetic factors. Multiplex families with more than two affected members
are uncommon. In most cases, normal CSF hypocretin levels have been found in these
families, and the association with HLA DQB1*0602 is much weaker compared to spo-
radic narcolepsy. So far, only a single case of narcolepsy type 1 has been described in
association with a preprohypocretin mutation.

Onset usually occurs after five years of age and most typically between ages 10 and 25
years. However, a bimodal distribution in the age at onset has been described in some
populations with a first peak occurring at adolescence (age 15 years) and a second at
the age of 35 years. Recent studies highlight the fact that narcolepsy, and especially
cataplexy, in young children may present somewhat differently, resulting in delayed
diagnosis and erroneously high estimates of age of onset.
Sleepiness is usually the first symptom to manifest. Cataplexy most often occurs within
one year of onset but in rare cases, may precede the onset of sleepiness or commence
up to 40 years later. Hypnagogic hallucinations, sleep paralysis, and disturbed noctur-
nal sleep often manifest later in the course of the disease.
When left untreated, narcolepsy type 1 is often socially disabling and isolating. Patients
have a tendency to fail in school and are often dismissed from their jobs. Driving
may be avoided for fear of a motor vehicle accident. The inability to sleep at night
may further contribute to a loss of control these patients have over their schedule.
Depression and weight gain also are common.
In most cases, symptoms gradually develop over several years. When the clinical
picture has fully developed, there are usually only minor fluctuations in severity.
Cataplexy may lessen with age, or occasionally increase in frequency and severity.
150
In recent years, increasing attention has been given to the clinical presentation of nar-
colepsy in childhood. Narcolepsy with cataplexy is infrequent prior to the age of four
years. In addition, the clinical presentation in children may be different from that of
adults. In young children, sleepiness may be difficult to assess, and may express itself
as excessively long night sleep, or the recurrence of previously discontinued daytime
napping. Moreover, children may paradoxically present with hyperactive behavior,
behavioral problems or decreased performance in school. Inattentiveness, lack of
energy, insomnia, bizarre hallucinations, or a combination thereof can lead to a psy-
chiatric misdiagnosis of schizophrenia or depression. In this population, the presence
of ancillary symptoms such as sleep paralysis or hypnagogic hallucinations may also
be difficult to confirm, depending on the child’s verbal ability. Precocious puberty and
obesity may also develop around the time of symptom onset. REM sleep behavior dis-
order or REM sleep without atonia may also be manifest at the time of symptom onset.
Cataplexy may be very severe around disease onset and appear phenotypically differ-
ent from typical episodes seen in adulthood. In addition to typical attacks triggered by
positive emotions, children can also present with weakness involving the face, eyelids,
and mouth not clearly associated with emotion. Together with tongue protrusion, this
characteristic pattern has been termed a cataplectic facies. Children with cataplexy
may also display positive motor phenomena, ranging from perioral dyskinetic or dys-
tonic movements to frank stereotypies. In children, anticipation of reward may also be
a precipitant.
The diagnosis of narcolepsy type 1 in children may be complicated because of diffi-

culties performing the MSLT, and lack of normative values in children younger than
six years. If the MSLT shows equivocal results, repeating it after a time interval may
be helpful. Given these difficulties, CSF hypocretin-1 measurements are of particular
value, as hypocretin-1 levels are low or undetectable very shortly after disease onset
in children as well.

It is now firmly established that narcolepsy type 1 is caused by deficiencies in hypo-
cretin signaling, most likely due to a selective loss of hypothalamic hypocretin pro-
ducing neurons. Several animal models lacking hypocretin neurotransmission demon-
strate narcolepsy, indicating a causal relationship. The vast majority of patients (90%
to 95%) with narcolepsy and cataplexy have undetectable or low (< 110 pg/mL) levels
of hypocretin-1 in the CSF. Patients without cataplexy can be hypocretin deficient as
well, although at a much lower frequency, and are thus also classified as narcolepsy
151
type 1. The strong HLA association in narcolepsy has led to the hypothesis that auto-
immunity is a likely etiological mechanism, potentially explaining the selectivity of
neuronal destruction in the hypothalamus. However, definitive proof for autoimmunity
has not been obtained.
Objective Findings
Narcolepsy type 1 is essentially defined as a hypocretin deficiency syndrome, which is
reflected in the need for objective measurements in the clinical criteria. This require-
ment is further driven by the fact that many patients require lifelong treatment with
potentially addictive medications, underscoring the importance of objective confirma-
tion of the diagnosis.
It is strongly recommended that the MSLT be preceded by at least one week of acti-
graphic recording with a sleep log to establish whether the results could be biased
by insufficient sleep, shift work, or another circadian sleep disorder. In patients with
narcolepsy type 1, the MSLT demonstrates a mean sleep latency of less than eight
minutes and typically less than five minutes. Meta-analysis shows mean sleep latencies
in narcoleptic patients with cataplexy of 3.1 ± 2.9 minutes. In addition, two or more
SOREMPs must be present. Recent data suggest that a SOREMP within 15 minutes
of onset of nocturnal sleep is a highly specific finding in the absence of another sleep
disorder, but with low sensitivity. Therefore, the criteria for narcolepsy type 1 allow the
“replacement” of one SOREMP in the MSLT with a SOREMP on the preceding poly-
somnogram. For the correct interpretation of MSLT findings, the recordings should
be performed with the following conditions: (1) the patient must be free of drugs that
influence sleep for at least 14 days (or at least five times the half-life of the drug and
longer-acting metabolite), confirmed by a urine drug screen; (2) the sleep-wake sched-
ule must have been standardized and, if necessary, extended to a minimum of seven
hours in bed each night (longer for children) for at least seven days before polysom-
nography (preferably documented by sleep log and, whenever possible, actigraphy);
and (3) nocturnal polysomnography should be performed on the night immediately
preceding the MSLT to rule out other sleep disorders that could mimic the diagnostic
features of narcolepsy type 1. Sleep time during polysomnography should be curtailed
as little as possible with the goal of at least seven hours asleep. The overnight poly-
somnogram may demonstrate an increase in the amount of stage N1 sleep, and there
may be a disruption of the normal sleep pattern, with frequent awakenings. REM sleep
without atonia may be present.
Measuring CSF levels of hypocretin-1 is a highly specific and sensitive test for the
diagnosis of narcolepsy type 1. Hypocretin-1 can be measured in crude CSF, using a
152
commercially available radioimmunoassay. When using the Stanford reference sample,

values less than 110 pg/mL are highly specific. Alternatively, a laboratory may elect to
obtain control data themselves, in which case a level of less than 33% of mean control
values is considered abnormal. Issues concerning the standardization of CSF hypocre-
tin measurements remain, but extensive protocols are available. Low CSF hypocre-
tin values are occasionally observed in seriously ill patients with other disorders and
should be interpreted within the clinical context.
HLA typing of narcoleptic patients with cataplexy almost always shows the presence
of HLA DQB1*0602 (and DR2 or DRB1*1501 in whites and Asians), but this is not
diagnostic for narcolepsy. Approximately 25% of the normal Caucasian population,
12% of the Japanese population, and 38% of the black population are positive for
DQB1*0602. HLA typing could be considered when a spinal tap is contemplated to
assess hypocretin-1 values: if the patient is HLA-negative, hypocretin-1 levels are
most likely normal.
In the absence of cataplexy, narcolepsy type 1 can be diagnosed based on the pres-
ence of hypersomnolence and low CSF hypocretin-1 levels. When cataplexy is absent
and CSF hypocretin-1 levels are normal or unknown, narcolepsy type 2 should be
diagnosed.
Cataplexy must be differentiated from cataplexy-like episodes that are occasionally

observed in normal individuals. For example, feelings of muscle weakness are some-
times reported when healthy subjects laugh out loud. In genuine cataplexy, episodes
most often occur with a significant frequency, and are associated with loss of muscle
tone. Cataplexy should be differentiated from hypotension, transient ischemic attacks,
drop attacks, akinetic seizures, neuromuscular disorders, vestibular disorders, psycho-
logical or psychiatric disorders, and sleep paralysis. Clear improvement with antide-
pressant medications may favor a diagnosis of cataplexy in difficult cases.
Sleepiness may be secondary to obstructive sleep apnea, insufficient sleep syndrome,

shift work, the effects of substances or medications, or other sleep disorders. Many
of these conditions can result in early onset REM sleep as well. When cataplexy is
present, these disorders do not preclude a diagnosis of narcolepsy type 1. When there
is a questionable history of cataplexy in such cases, either comorbid conditions should
be adequately treated before performing an MSLT or CSF hypocretin-1 should be
measured.
153
Idiopathic hypersomnia is differentiated from narcolepsy type 1 by the absence of cat-

aplexy and the lack of two or more SOREMPs on the MSLT. In contrast with patients
who have narcolepsy, patients with idiopathic hypersomnia generally have high sleep
efficiency, sleep drunkenness, and long, unrefreshing naps.
In insufficient sleep syndrome, there is no cataplexy, and normalizing sleep time elim-
inates the daytime sleepiness. Chronic fatigue syndrome and depression may mimic
narcolepsy but do not show the typical MSLT findings. Malingering and substance
abuse disorder should be considered in patients who try to mislead the clinician in
order to obtain stimulant medications.

Ten percent of patients with narcolepsy with cataplexy have normal hypocretin-1
levels in the CSF, which suggests that CSF levels either do not perfectly reflect brain
hypocretin neurotransmission or that narcolepsy with cataplexy can be caused by
factors other than hypocretin deficiency. The cause of the hypocretin cell destruction
remains unknown, although an autoimmune-mediated mechanism is suspected. Levels
of hypocretin-1 have been reported in the blood of some subjects. The development of
serum tests to determine hypocretin deficiency would provide a less invasive diagnos-
tic approach.
Bibliography
Andlauer O, Moore H, Jouhier L, et al. Nocturnal REM sleep latency for identifying patients with
narcolepsy/hypocretin deficiency. JAMA Neurol 2013;6:1–12.
Aran A, Einen M, Lin L, Palazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of childhood
narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010;33:1457–64.
Arii J, Kanbayashi T, Tanabe Y, et al. CSF hypocretin-1 (orexin-A) levels in childhood narcolepsy and
neurologic disorders. Neurology 2004;63:2440–2.
Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders.
Lancet Neurol 2008;7:649–62.
Dauvilliers Y, Gosselin A, Paquet J, Touchon J, Billiard M, Montplaisir J. Effect of age on MSLT results
in patients with narcolepsy-cataplexy. Neurology 2004;62:46–50.
Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007;369:499–511.
Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med
2004;5:147–50.
Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the
diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59:1553–62.
154
Nevsimalova S, Prihodova I, Kemlink D, Lin L, Mignot E. REM sleep behavior disorder (RBD) can be
one of the first symptoms of childhood narcolepsy. Sleep Med 2007;8:784–6.
Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ. The clinical
features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1
deficiency. Sleep Med 2011;12:12–8.
Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy
with cataplexy. Brain 2013 Oct 18. [Epub ahead of print]
Plazzi G, Parmeggiani A, Mignot E, et al. Narcolepsy-cataplexy associated with precocious puberty.
Neurology 2006;66:1577–9.
Serra L, Montagna P, Mignot E, Lugaresi E, Plazzi G. Cataplexy features in childhood narcolepsy. Mov
Disord 2008;23:858–65.
Narcolepsy Type 2
Alternate Names
Narcolepsy without cataplexy.
Diagnostic Criteria
lapses into sleep occurring for at least three months.
B. A mean sleep latency of ≤ 8 minutes and two or more sleep onset REM
periods (SOREMPs) are found on a MSLT performed according to
standard techniques. A SOREMP (within 15 minutes of sleep onset)
on the preceding nocturnal polysomnogram may replace one of the
SOREMPs on the MSLT.
C. Cataplexy is absent.1
D. Either CSF hypocretin-1 concentration has not been measured or CSF
hypocretin-1 concentration measured by immunoreactivity is either >
110 pg/mL or > 1/3 of mean values obtained in normal subjects with the
same standardized assay.2
E. The hypersomnolence and/or MSLT findings are not better explained by
other causes such as insufficient sleep, obstructive sleep apnea, delayed
sleep phase disorder, or the effect of medication or substances or their
withdrawal.
Notes
1. If cataplexy develops later, then the disorder should be reclassified as
narcolepsy type 1.
155
2. If the CSF Hcrt-1 concentration is tested at a later stage and found

to be either ≤ 110 pg/mL or < 1/3 of mean values obtained in normal
subjects with the same assay, then the disorder should be reclassified as
narcolepsy type 1.
Essential Features
Narcolepsy type 2 is characterized by excessive daytime sleepiness and abnormal man-
ifestations of REM sleep on polysomnography/MSLT. Cataplexy is absent, although
some atypical sensations of weakness triggered by unusual emotions such as stress and
anger may be reported. Refreshing daytime naps are characteristic.
An essential feature of the diagnosis is the presence of a mean sleep latency less than
or equal to eight minutes and two or more SOREMPs on an MSLT (or one SOREMP
on an MSLT and one on the preceding nocturnal polysomnogram). The presence of
CSF hypocretin-1 concentrations ≤ 110 pg/mL or less than one third of mean values
obtained in normal subjects with the same assay excludes the diagnosis, but most
patients with narcolepsy type 2 will not have undergone CSF examination.
Associated Features
Sleep paralysis, hypnagogic hallucinations, or automatic behavior may be present.
Memory lapses, automatic behavior, ptosis, blurred vision, and diplopia may occur in
association with sleepiness. REM sleep behavior disorder and nonrapid eye movement
(NREM) parasomnias may occur. Nocturnal sleep disruption with frequent awaken-
ings may be present.

Narcolepsy type 2 due to a medical condition: This condition fulfills criteria for nar-
colepsy type 2 and is attributable to another medical disorder. Neurologic disorders
associated with narcolepsy type 2 include tumors or sarcoidosis of the hypothalamus,
autoimmune or paraneoplastic disorders associated with anti-Ma-2 or anti-aquaporin-4
antibodies, multiple sclerosis, myotonic dystrophy, Prader-Willi syndrome, Parkinson
disease, and head trauma. In disorders associated with both sleep apnea and narco-
lepsy type 2, such as myotonic dystrophy or Prader-Willi syndrome, a diagnosis of
narcolepsy type 2 should only be made if abnormal MSLT findings persist after the
sleep apnea is adequately treated. In all cases, especially with complex problems such
as head trauma, clinical judgment should be used to determine if the development of
narcolepsy was a mere coincidence or was triggered by the event or disorder.
156
Demographics
The exact prevalence of narcolepsy type 2 is uncertain. Cases of narcolepsy without cat-
aplexy represent 15% to 25% of the clinic narcoleptic population. A population-based
study suggested a higher percentage (36%), corresponding to a point prevalence of
20.5/100,000. Population-based studies have shown that approximately 4% to 9.5%
of adults may have multiple SOREMPs during random MSLTs, but shift workers and
subjects with sleep deprivation or sleep apnea were included in the studies. Although
both sexes can be affected, the prevalence may be slightly higher in men. The age of
onset mirrors that of narcolepsy type 1.

As discussed below, about 24% of patients with narcolepsy but no cataplexy will have
low CSF Hcrt-1 levels and almost all of these will be positive for the HLA DQB1*0602
antigen. These patients probably share a common pathogenesis with narcolepsy with
cataplexy and should be classified as narcolepsy type 1. Underlying genetic and envi-
ronmental factors associated with other patients with narcolepsy type 2 are unknown.
Environmental precipitating factors are suspected from case reports but have never
been proven to trigger narcolepsy without cataplexy. Among the most commonly
reported triggers are head trauma and unspecified viral illnesses.
Familial Patterns
The detailed genetic pattern of narcolepsy type 2 is unknown. Relatives of patients
with narcolepsy type 1 may be more likely to experience partial narcolepsy symptoms
compatible with the diagnosis of narcolepsy type 2.

Onset typically occurs during adolescence. In about 10% of patients, cataplexy will
develop later in the course of the disease, necessitating a change in diagnosis to narco-
lepsy type 1. Most of these patients will, if tested, have absent or intermediate levels
of CSF Hcrt-1. In a cohort of patients with narcolepsy without cataplexy in whom
CSF Hcrt-1 status was known, 33% of those with low levels later developed cataplexy,
compared with 18% with intermediate levels and only 1% with normal levels. When
left untreated, narcolepsy type 2 is socially disabling and isolating. Patients have a ten-
dency to fail in school and are often dismissed from their jobs. Driving may be avoided
for fear of a motor vehicle accident. The inability to sleep at night may further contrib-
ute to a loss of control these patients have over their schedule. Depression and weight
gain also are common.
157
Children with narcolepsy type 2 will typically present with a reappearance of regular
daytime napping after naps had been discontinued. In all pediatric cases, one should
consider the possibility of an evolving disorder with the development of cataplexy
over time. Once the patient develops clear cataplexy, the diagnosis should be changed
to narcolepsy type 1. Limited information is available on narcolepsy type 2 prior to
adolescence. Descriptions of the experience of sleep paralysis or hypnagogic halluci-
nations are very difficult to evoke in young patients, and normative data are not avail-
able for the MSLT in children younger than six years of age. In peripubertal children
and adolescents, the diagnosis is often challenging. The most common causes of short
sleep latencies, often with multiple SOREMPs on the MSLT, are chronic sleep depri-
vation and delayed sleep phase disorder. Behavioral problems may be associated with
the onset of the disorder, and symptoms may be hidden by the patient. Inattentiveness,
lack of energy, insomnia, bizarre hallucinations, or a combination thereof can lead to a
psychiatric misdiagnosis of schizophrenia or depression. If the MSLT shows equivocal
results, repeating it after a time interval may be helpful, as SOREMPs often emerge
later in children.

Narcolepsy type 2 is most likely a heterogeneous disorder. Approximately 24% of nar-
coleptic patients without cataplexy have a low CSF Hcrt-1 concentration, and another
8% have intermediate levels (> 110 pg/mL but ≤ 200 pg/mL). The CSF Hcrt-1 status
of most patients with narcolepsy type 2 is unknown (those patients who are known to
have absent CSF Hcrt-1 levels are classified as narcolepsy type 1). Therefore, there
will be a subgroup of about one fourth to one third of narcolepsy type 2 patients who
will have hypocretin deficiency, presumably from loss of the hypocretin-producing
neurons. This group of patients cannot be accurately separated clinically or by labora-
tory tests (other than CSF Hcrt-1 level) from the majority of patients without cataplexy
who have normal CSF Hcrt-1 levels. Although those with low CSF Hcrt-1 levels have
a younger age of onset and their MSLT shows shorter mean sleep latency with more
SOREMPs in comparison with those with normal levels, there is too much overlap
between the groups for these differences to be helpful diagnostically in individual
patients. One hundred percent of patients with low CSF Hcrt-1 levels are positive
for HLA DQB1*0602. About 26% of patients with normal levels are also HLA posi-
tive, a percentage not higher than that seen in the normal population. The underlying
pathophysiology of the remainder of patients who have normal CSF Hcrt-1 levels is
unknown. It is possible some may have partial hypocretin deficiency severe enough
to cause sleepiness but not severe enough to result in cataplexy or low CSF Hcrt-1
levels. However, support for this hypothesis is lacking in that there are no major
158
differences in clinical or polysomnographic findings in those positive or negative for

HLA DQB1*0602. In the only postmortem study of a case of narcolepsy without cata-
plexy (CSF Hcrt-1 status unknown), the number of hypocretin cells was decreased but
not as much as in cases of narcolepsy with cataplexy.
Objective Findings
It is strongly rcommended that the MSLT be preceded by at least one week of acti-
graphic recording with a sleep log to establish whether the results could be biased by
insufficient sleep, shift work, or another circadian sleep disorder. The MSLT demon-
strates a mean latency of less than eight minutes, typically less than five minutes, with
two or more SOREMPs or one SOREMP together with a SOREMP on the preceding
polysomnogram. Meta-analysis shows mean sleep latencies in narcoleptic patients with
cataplexy of 3.1 ± 2.9 minutes. Recent data suggest that a SOREMP within 15 minutes
of onset of nocturnal sleep is a highly specific finding in the absence of another sleep
disorder, but with low sensitivity. Therefore, the criteria for narcolepsy type 2 allow the
“replacement” of one SOREMP in the MSLT with a SOREMP on the preceding poly-
somnogram. For the correct interpretation of MSLT findings, the recordings should
be performed with the following conditions: (1) the patient must be free of drugs that
influence sleep for at least 14 days (or at least five times the half-life of the drug and
longer-acting metabolite), confirmed by a urine drug screen; (2) the sleep-wake sched-
ule must have been standardized and, if necessary, extended to a minimum of seven
hours in bed each night (longer for children) for at least seven days before polysom-
nography (preferably documented by sleep log and, whenever possible, actigraphy);
and (3) nocturnal polysomnography should be performed on the night immediately
preceding the MSLT to rule out other sleep disorders that could mimic the diagnostic
features of narcolepsy type 2. Sleep time during polysomnography should be curtailed
as little as possible, with the goal of at least seven hours asleep. The overnight poly-
somnogram may demonstrate an increase in the amount of stage N1 sleep, and there
may be a disruption of the normal sleep pattern, with frequent awakenings. REM sleep
without atonia may be present.
About 45% of narcolepsy type 2 cases have been reported to be HLA DQB1*0602
positive, compared with 12% to 38% of controls. Whereas essentially all patients who
have low CSF Hcrt-1 levels will be positive, about 25% of those with normal levels
will also be positive. Assuming that 24% of patients with narcolepsy but no cataplexy
will have low CSF Hcrt-1 levels, the probability that an HLA- positive patient will
have low Hcrt-1 levels is only 0.56. Therefore the HLA status of a patient cannot be
used to diagnose narcolepsy type 2 nor to predict with high probability the patient’s
CSF Hcrt-1 levels. However, if lumbar puncture is contemplated to measure CSF
159
Hcrt-1 levels, HLA typing should be performed first; if the patient is HLA negative,
CSF Hcrt-1 levels will almost certainly be normal and the lumbar puncture will be
unnecessary.
Approximately 24% of narcoleptic patients without cataplexy have a low CSF Hcrt-1
concentration and another 8% have intermediate levels (> 110 pg/mL but ≤ 200 pg/
mL). If the CSF Hcrt-1 levels of such patients are known to be low, they are classified
as narcolepsy type 1, but the CSF Hcrt-1 status will not be known for most of these
patients. Possible indications for considering measuring CSF Hcrt-1 levels as a diag-
nostic procedure would be the presence of disorders such as obstructive sleep apnea or
the use of psychotropic medications that may complicate interpretation of an MSLT.
Narcolepsy type 1 is diagnosed if cataplexy is present or the CSF hypocretin levels
are known to be low even in the absence of cataplexy. Patients with idiopathic hyper-
somnia may have mean sleep latencies on MSLT similar to those of narcolepsy type
2, but have fewer than two SOREMPs on MSLT and the preceding polysomnogram
combined. In contrast to narcolepsy, patients with idiopathic hypersomnia generally
have high sleep efficiency, sleep drunkenness, and long, unrefreshing naps. Sleepiness
may be secondary to obstructive sleep apnea (OSA), insufficient sleep syndrome, shift
work, the effects of substances or medications, or other sleep disorders. Many of these
conditions can result in early-onset REM sleep, so their clinical and polysomnographic
exclusion is essential before a diagnosis of narcolepsy type 2 is made. However, the
presence of other sleep disorders does not preclude a diagnosis of narcolepsy type 2
if daytime sleepiness and REM abnormalities persist after adequate treatment of the
initial disorder. Chronic fatigue syndrome and depression may mimic narcolepsy but
do not show the typical MSLT findings. Malingering and substance abuse disorder
should be considered in patients who try to mislead the clinician in order to obtain
stimulant medications.

Excluding the minority of patients with definite hypocretin deficiency, the underlying
biology of narcolepsy without the presence of cataplexy is unknown. It is not estab-
lished whether narcolepsy type 2 is a homogeneous or heterogeneous condition. It is
uncertain whether or not some patients have partial hypocretin deficiency not iden-
tifiable from CSF measurements. Further advances in classification will depend on
answers to these unknowns. Further studies on the natural history of narcolepsy type 2
are needed to determine the cause of the hypersomnolence and the risk of development
of cataplexy over time.
160
Bibliography
Andlauer O, Moore IV H, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy
without cataplexy. Sleep 2012;35:1247–55.
Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders.
Lancet Neurol 2008;7:649–62.
Oka Y, Inoue Y, Kanbayashi T, et al. Narcolepsy without cataplexy: 2 subtypes based on CSF hypocretin-1/
orexin-A findings. Sleep 2006;29:1439–43.
Sasai T, Inoue Y, Komada Y, Sugiura T, Matsushima E. Comparison of clinical characteristics among
narcolepsy with and without cataplexy and idiopathic hypersomnia without long sleep time, focusing
on HLA-DRB1(*)1501/DQB1(*)0602 finding. Sleep Med 2009;10:961–6.
Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County,
Minnesota: a population-based study. Sleep 2002;25:197–202.
Takei Y, Komada Y, Namba K, et al. Differences in findings of nocturnal polysomnography and
multiple sleep latency test between narcolepsy and idiopathic hypersomnia. Clin Neurophysiol
2012;123:137–41.
Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without
cataplexy. Sleep 2009;32:993–8.
Idiopathic Hypersomnia
Alternate Names
Idiopathic CNS hypersomnolence.
Diagnostic Criteria
lapses into sleep occurring for at least three months.1
B. Cataplexy is absent.
C. An MSLT performed according to standard techniques shows fewer
than two sleep onset REM periods or no sleep onset REM periods if the
REM latency on the preceding polysomnogram was less than or equal to
15 minutes.2
D. The presence of at least one of the following:
1. The MSLT shows a mean sleep latency of ≤ 8 minutes.
2. Total 24-hour sleep time is ≥ 660 minutes (typically 12–14 hours)3
on 24-hour polysomnographic monitoring (performed after
correction of chronic sleep deprivation), or by wrist actigraphy in
161
association with a sleep log (averaged over at least seven days with
unrestricted sleep).4
E. Insufficient sleep syndrome is ruled out (if deemed necessary, by
lack of improvement of sleepiness after an adequate trial of increased
nocturnal time in bed, preferably confirmed by at least a week of wrist
actigraphy).
F. The hypersomnolence and/or MSLT findings are not better explained by
another sleep disorder, other medical or psychiatric disorder, or use of
drugs or medications.
Notes
1. Severe and prolonged sleep inertia, known as sleep drunkenness
(defined as prolonged difficulty waking up with repeated returns to
sleep, irritability, automatic behavior, and confusion) and/or long (> 1
hour), unrefreshing naps are additional supportive clinical features.
2. A high sleep efficiency (≥ 90%) on the preceding polysomnogram is a
supportive finding (as long as sleep insufficiency is ruled out).
3. The total 24-hour sleep time required for diagnosis may need to be
adapted to account for normal changes in sleep time associated with
stages of development in children and adolescents as well as for
variability across cultures in all age groups.
4. Occasionally, patients fulfilling other criteria may have an MSLT mean
sleep latency longer than 8 minutes and total 24-hour sleep time shorter
than 660 minutes. Clinical judgment should be used in deciding if these
patients should be considered to have idiopathic hypersomnia (IH).
Great caution should be exercised to exclude other conditions that might
mimic the disorder. A repeat MSLT at a later date is advisable if the
clinical suspicion for IH remains high.
Essential Features
IH is characterized by excessive daytime sleepiness that occurs in the absence of cat-
aplexy, is accompanied by no more than one SOREMP on MSLT and preceding poly-
somnogram combined, and is not adequately explained by another disorder. Other dis-
orders causing sleepiness must be carefully considered and excluded, especially insuf-
ficient sleep syndrome. Objective evidence of hypersomnolence must be demonstrated
by an MSLT showing a mean sleep latency of ≤ 8 minutes or by polysomnography or
wrist actigraphy showing a total 24-hour sleep time of ≥ 660 minutes. A prolonged
and severe form of sleep inertia, historically known as sleep drunkenness, consists of
prolonged difficulty waking up with repeated returns to sleep, irritability, automatic
162
behavior, and confusion. It is reported in 36% to 66% of patients with IH in differ-

ent series. Subjects typically do not easily awaken to alarm clocks and frequently use
special devices or procedures to wake up. Naps are generally long, often more than 60
minutes, and described as unrefreshing by 46% to 78% of patients. Sleep efficiency on
polysomnogram is usually high (mean 90% to 94%). Self-reported total sleep time is
longer than in controls and is ≥ 10 hours in at least 30% of patients.
Associated Features
Associated symptoms which suggest a dysfunction of the autonomic nervous system
may be present. These symptoms include headache, orthostatic disturbance, perception
of temperature dysregulation, and peripheral vascular complaints (Raynaud-type phe-
nomena with cold hands and feet). Sleep paralysis and hypnagogic hallucinations may
also be reported, but the frequency is uncertain (4% to 40% in different series).

The 2005 2nd edition of the International Classification of Sleep Disorders divided
IH into two disorders: IH with long sleep time, and IH without long sleep time. IH is
likely a heterogeneous condition, the pathophysiology of which is currently unknown.
However, recent studies suggest that a division of the disorder based on the length of
nocturnal sleep lacks validity. Comparison of patients with ≥ 10 hours of sleep to those
with < 10 hours show no differences in Epworth Sleepiness Scale scores, MSLT mean
sleep latencies, or percentage with sleep drunkenness, unrefreshing naps, hypnago-
gic hallucinations, or sleep paralysis. The only reported differences are that the group
with long sleep is somewhat younger and thinner, with lower Horne-Ostberg scores
and marginally higher sleep efficiency. If MSLT mean sleep latencies are not used as
a diagnostic criterion, the distribution of latencies is unimodal, suggesting no sepa-
rate subtypes. In addition, an actigraphy study has shown that patients with IH tend to
overestimate their sleep time by a mean of 0.99 hours, thus making the fundamental
criterion for distinguishing between patients with long and shorter sleep inaccurate.
Clinicians may wish to continue to note sleep duration as an important clinical feature,
but the caveats discussed above should be clearly considered. Any future separation
of IH into distinct conditions must await advances in understanding the underlying
biology.
Demographics
Prevalence and incidence of IH are not known. Some studies have suggested a higher
prevalence in women.
163

In contrast to narcolepsy, the disorder is not known to be HLA associated, and no con-
sistent precipitating factor has been identified.
Familial Patterns
A familial predisposition to hypersomnia has been reported but rigorous studies have
not been performed.

The mean age of onset of IH in different series is 16.6–21.2 years. Once established,
the disorder is generally stable in severity and long lasting, although a spontaneous
remission rate of 14% has been reported in one series. Complications are mostly social
and professional, and include poor work or school performance, reduced earnings, and
loss of employment.
IH frequently develops in adolescence. Exclusion of other causes of hypersomno-
lence in that age group, including delayed sleep-wake phase disorder, obstructive sleep
apnea, insufficient sleep syndrome, and use of recreational drugs, is essential. Early in
the development of narcolepsy, SOREMPs may not be present on MSLT; therefore,
some patients may need to be reclassified later as narcolepsy type 2. If the 24-hour
total sleep time is used to confirm the diagnosis of IH in a child or adolescent, normal
values may need to be adapted to account for changes in sleep time associated with
stages of development.

The pathophysiology of IH is unknown. Neurochemical studies measuring monoamine
metabolites in the CSF have been inconclusive. CSF hypocretin-1 concentrations in
patients with IH are normal. CSF histamine levels have been reported to be low in
patients with narcolepsy and IH, but a recent study did not confirm these findings.
Objective Findings
Polysomnographic monitoring generally demonstrates NREM and REM sleep in
expected proportions with normal REM latency. Total sleep time is often prolonged.
Sleep apnea should be either absent or adequately treated before diagnosing this disor-
der, with special attention paid to excluding significant respiratory effort related arous-
als. The MSLT should not show more than one SOREMP (or none if a SOREMP was
observed on the preceding night’s polysomnogram (PSG)). The mean sleep latency on
164
the MSLT is usually shorter than in controls but longer than in most patients with nar-
colepsy, averaging 8.3 and 7.8 minutes in two large studies.
In patients with MSLT mean latencies > 8 minutes, prolonged sleep monitoring should
be performed by polysomnography (24 hours) or wrist actigraphy (7 days with unre-
stricted sleep) after correction of sleep deprivation, exclusion of other sleep disorders,
and discontinuation of sedating medication as required for an MSLT (see Narcolepsy–
Objective Findings). Total 24-hour sleep time in adults (major sleep episode plus naps)
must be ≥ 660 minutes (note that the use of 24-hour PSG monitoring for the diagnosis
of IH has been validated against controls, but the use of seven days of actigraphic mon-
itoring still awaits validation).
IH may be confused with OSA, especially when respiratory-related arousals (rather
than apneas or hypopneas) are present. Narcolepsy type 2 is distinguished from IH
by the presence of two or more sleep onset REM periods on the MSLT or preceding
PSG. Insufficient sleep syndrome must be carefully excluded by extending the patient’s
sleep before testing. Historical information, physical examination, and, if indicated,
laboratory testing including brain imaging should help rule out hypersomnolence due
to a medical disorder. In particular, posttraumatic hypersomnolence, residual hyper-
somnolence following adequate treatment of sleep apnea, and sleep fragmentation due
to pain may mimic IH. Hypersomnolence due to a medication or substance must be
considered and ruled out by discontinuation of possible causative agents, if clinically
appropriate. Hypersomnia associated with a psychiatric disorder should be consid-
ered in patients with a psychiatric condition, most typically depression. The complaint
of excessive sleepiness and prolonged sleep may be rather similar to that of patients
with IH, except that it may vary from day to day and is often associated with poor
sleep at night. The MSLT in hypersomnia associated with a psychiatric disorder does
not demonstrate a short mean sleep latency. Chronic fatigue syndrome is character-
ized by persistent or relapsing fatigue that does not resolve with sleep or rest. Patients
clearly complain of fatigue rather than excessive daytime sleepiness, and the mean
MSLT sleep latency is normal. Long sleepers feel fully refreshed and do not experience
daytime sleepiness if they are allowed to sleep as long as they need, in contrast with
patients with IH who continue to feel sleepy regardless of prior sleep duration.
Unresolved Issues and Future Directions

There is a paucity of knowledge regarding the neurobiology of IH. Further research in
this area, as well as more precise characterization of clinical characteristics and treat-
ment response, is required.
165
Bibliography
Ali M, Auger RR, Slocumb NL, Morgenthaler TI. Idiopathic hypersomnia: clinical features and response
to treatment. J Clin Sleep Med 2009;5:562–8.
Anderson KN, Pilsworth S, Sharples RD, Smith IE, Shneerson JM. Idiopathic hypersomnia: a study of 77
cases. Sleep 2007;30:1274–81.
Bassetti C, Aldrich MS. Idiopathic hypersomnia: a series of 42 patients. Brain 1997;120:1423–35.
Dauvilliers Y, Delallee N, Jaussent I, et al. Normal cerebrospinal fluid histamine and tele-methylhistamine
levels in hypersomnia conditions. Sleep 2012;35:1359–66.
Kanbayashi T, Kodama T, Kondo H, et al. CSH histamine contents in narcolepsy, idiopathic hypersomnia
and obstructive sleep apnea syndrome. Sleep 2009;32:181–7.
Vernet C, Arnulf I. Idiopathic hypersomnia with and without long sleep time: a controlled series of 75
patients. Sleep 2009;32:753–9.
Vernet C, Leu-Semenescu S, Buzare MA, Arnulf I. Subjective sleepiness in idiopathic hypersomnia:
beyond excessive sleepiness. J Sleep Res 2010;19:525–34.
Kleine-Levin Syndrome
Alternate Names
Recurrent hypersomnia, periodic hypersomnolence.
Diagnostic Criteria
A. The patient experiences at least two recurrent episodes of excessive
sleepiness and sleep duration, each persisting for two days to five
weeks.
B. Episodes recur usually more than once a year and at least once every 18
months.
C. The patient has normal alertness, cognitive function, behavior, and
mood between episodes.
D. The patient must demonstrate at least one of the following during
episodes:
1. Cognitive dysfunction.
2. Altered perception.
3. Eating disorder (anorexia or hyperphagia).
4. Disinhibited behavior (such as hypersexuality).
E. The hypersomnolence and related symptoms are not better explained by
another sleep disorder, other medical, neurologic, or psychiatric disorder
(especially bipolar disorder), or use of drugs or medications.
166
Essential Features
Kleine-Levin syndrome is characterized by relapsing-remitting episodes of severe
hypersomnolence in association with cognitive, psychiatric, and behavioral distur-
bances. A typical episode lasts a median 10 days (range, 2.5–80 days), with rare epi-
sodes lasting several weeks to months. The first episode is often triggered by an infec-
tion or alcohol intake, with further episodes recurring every 1–12 months (median
three months) for years. During episodes, patients may sleep as long as 16 to 20 hours
per day, waking or getting up only to eat and void (incontinence is not observed). They
remain rousable, but are irritable if prevented from sleeping. When they are awake
during episodes, most patients are exhausted, apathetic, confused, and slow in speaking
and answering. Anterograde amnesia is typical. Almost all report a dreamlike, altered
perception of the environment (derealization). Less commonly, patients eat ravenously
(66%, although one third eat less), are hypersexual (53%, principally men), childish,
depressed (53%, predominantly women), and anxious at being left alone and seeing
strangers, and experience hallucinations and delusions (30%). Patients are remark-
ably normal between episodes with regard to sleep, cognition, mood, and eating. The
disease typically resolves after a median of 14 years, except in adult-onset cases, when
the course may be more prolonged. The simultaneous occurrence of all these symp-
toms is the exception rather than the rule, with hypersomnolence being more char-
acteristic at the disease onset and during the first part of the episodes, and disinhib-
ited behaviors being evident during only a few episodes. In occasional cases, isolated
recurrent hypersomnolence may be the only symptom. Amnesia, transient dysphoria,
or elation with insomnia may signal the termination of an episode.
Associated Features
Physical examination is unremarkable, except for general psychomotor slowing. Social
and occupational impairment during attacks is often severe, with teenagers bedridden
for days, but can be variable depending on the frequency, severity, and duration of
episodes.

Menstrual-related Kleine-Levin syndrome (alternate name: menstrual-related hyper-
somnia): This descriptor is used when episodes are exclusively associated with men-
struation (occurring just before or during menses), a condition reported in only 18
women worldwide. Hypersomnolence episodes in these cases have been associated
with compulsive eating in 65%, sexual disinhibition in 29%, and depressive mood
in 35%. Episodes last 3 to 15 days and recur less than three times a year. One boy
with Kleine-Levin syndrome is reported to have a sister affected by menstrual-related
hypersomnolence. Menstrual-related hypersomnia may be a variant of Kleine-Levin
167
syndrome, although response to contraceptive doses of estrogen and progesterone,

reported in some cases, suggests a reproductive endocrine disturbance.
Demographics
Kleine-Levin syndrome is rare, with a prevalence estimated around 1 to 2 cases per million.
Roughly 500 cases have been reported to date in the literature, from all countries in which
the disease has been investigated. The disease starts during the second decade in 81% of
patients, with a male/female ratio of 2:1. Adults and younger children may also be affected.

Birth and developmental problems, as well as Jewish heritage, are risk factors for devel-
oping the syndrome. The frequency of the HLA DQB1*02 was increased compared
with controls in a retrospective, multicenter series of 30 patients with Kleine-Levin
syndrome, but not in another larger prospective series (n = 108). A flu-like illness or an
infection of the upper airway (and more rarely gastroenteritis) is often reported imme-
diately prior to the onset of the first episode, and more rarely before relapses. Other
less frequently reported triggering events include alcohol consumption, head trauma,
travel, or exposure to anesthesia.
Familial Patterns
Familial cases of Kleine-Levin syndrome are found in 5% of patients, including twins,
parent-child, siblings, and uncle-nephew associations. There is no increased history of
mood disorders in family members of patients.

Early adolescence (second decade) is the usual age of onset. The course of Kleine-
Levin syndrome is characterized by recurrent episodes of severe sleepiness, lasting up
to several weeks, with normal functioning between episodes. Several long-term studies
suggest an often-benign course, with episodes lessening in duration, severity, and fre-
quency over a median course of 14 years. Male sex, age at onset younger than 12 years
or older than 20 years, as well as the presence of hypersexuality during episodes, predict
longer disease duration. Complications are mainly social and occupational. In rare
cases, subjects have been reported to choke while eating voraciously, to have suicidal
thoughts, or to be involved in a car accident. A reduced long-term working memory
capacity following episodes was reported in eight patients with Kleine-Levin syndrome.
Adolescents are affected in most cases. However, the onset of the condition has been
reported in children as young as four years.
168

Postmortem examination of the central nervous system has been performed in only
four cases, with inconsistent findings. One subject showed significant perivascular
lymphocytic infiltrations in the hypothalamus, amygdala, and the grey matter of the
temporal lobes; a second demonstrated similar infiltrations in the thalamus; and a third
in the diencephalon and the midbrain with a suggestion of mild localized encephali-
tis. In the fourth case, a smaller locus coeruleus and decreased pigmentation in the
substantia nigra were reported. Magnetic resonance imaging was unremarkable. In
contrast, functional brain imaging studies during episodes are frequently abnormal,
showing hypometabolism in the thalamus, hypothalamus, mesial temporal lobe, and
frontal lobe. Some of these abnormalities persist during asymptomatic periods in half
of the patients. An autoimmune basis for the disorder is suggested clinically (onset
occurs during adolescence, often in conjunction with an infection) and by the occa-
sional association with HLA DQB1*02.
Objective Findings
Routine electroencephalograms obtained during episodes have shown general slowing
of background electroencephalographic activity and often paroxysmal—0.5-2.0-sec-
ond—bursts of bisynchronous, generalized, moderate- to high-voltage 5- to 7-Hz
waves. Polysomnography studies are often difficult to interpret, and results are depen-
dent on the duration of recording (overnight vs. 24-hour monitoring) as well as the
timing (at the beginning versus the end of episodes or at onset of the disease or later
in its course). Twenty-four-hour polysomnography demonstrates prolonged total sleep
time (a mean 11–12 hours), and 18 hours or more in some reports. During nocturnal
polysomnography in 17 children, nighttime slow wave sleep percentage was decreased
during the first half of the episodes, and REM sleep decreased during the second half.
Results of the MSLT are highly dependent on the subjects’ willingness to comply with
the procedure, and may either be normal or abnormal, showing short latencies or mul-
tiple SOREMPs. CSF cytology and protein are normal. CSF levels of hypocretin-1
were within normal range in 16 patients, although intraepisodic levels are lower than
interepisodic levels. Computed tomography scans and magnetic resonance imaging
are normal. Brain functional imaging is abnormal in most cases, with hypoperfusion of
the left or right temporal and frontal lobes as well as the diencephalon. These abnor-
malities are present during the episode of hypersomnolence and sometimes between
episodes. Hormone levels are normal, as are 24-hour secretory patterns.
Recurrent waxing and waning episodes of sleepiness may be secondary to struc-
tural insults of the central nervous system. Tumors within the third ventricle (such as
169
colloid cysts, pedunculated astrocytomas, or, in some cases, craniopharyngiomas) may

produce intermittent obstructions of ventricular flow, leading to headaches, vomiting,
vague sensorial disturbances, and a paroxysmal impairment of alertness. Encephalitis,
hyperammonemic encephalopathy, multiple sclerosis, head trauma, porphyria, Lyme
disease, basilar migraine, and complex partial status epilepticus less frequently
mimic symptoms of Kleine-Levin syndrome. Recurrent episodes of sleepiness also are
reported in the context of psychiatric disorders, such as depression, bipolar disorder,
seasonal affective disorder, and somatoform disorder. However, the onset and offset
of symptoms are less abrupt than in Kleine-Levin syndrome and persist to some extent
between episodes. Other differential diagnoses include excessive sleepiness due to a
medication or substance, OSA, narcolepsy, IH, and insufficient sleep. In these disor-
ders, however, the complaint of excessive sleepiness occurs daily and is usually not
recurrent or periodic. There is no evidence that Kleine-Levin syndrome occurs as a
result of a seizure disorder.

The pathophysiology of this disorder is not known. Evidence to date suggests that a
localized but multifocal encephalopathy occurs during episodes of Kleine-Levin syn-
drome, as functional imaging and electroencephalography (EEG) slowing indicate tha-
lamic, temporal, and frontal lobe involvement. The cause of these episodic abnormali-
ties may be genetic, autoimmune, inflammatory, or metabolic.
Bibliography
Arnulf I, Lin L, Gadoth N, et al. Kleine-Levin syndrome: a systematic study of 108 patients. Ann Neurol
2008;63:482–93.
Arnulf I, Zeitzer JM, File J, Farber N, Mignot E. Kleine-Levin syndrome: a systematic review of 186 cases
in the literature. Brain 2005;128:2763–76.
Billiard M, Jaussent I, Dauvilliers Y, Besset A. Recurrent hypersomnia: a review of 339 cases. Sleep Med
Rev 2011;15:247–57.
Dauvilliers Y, Mayer G, Lecendreux M, et al. Kleine-Levin syndrome. An autoimmune hypothesis based
on clinical and genetic analyses. Neurology 2002;59:1739–45.
Engström M, Vigren P, Karlsson T, Landtblom A. Working memory in 8 Kleine-Levin syndrome patients:
An fMRI study. Sleep 2009;32:681–8.
Gadoth N, Kesler A, Vainstein G, Peled R, Lavie P. Clinical and polysomnographic characteristics of 34
patients with Kleine-Levin syndrome. J Sleep Res 2001;10:337–41.
Huang Y, Lin Y, Guilleminault C. Polysomnography in Kleine-Levin syndrome. Neurology
2008;70:795–801.
Huang Y, Guilleminault C, Lin K, Hwang F, Liu F, Kung Y. Relationship between Kleine-Levin Syndrome
and upper respiratory infection in Taiwan. Sleep 2012;35:123–9.
170
Hypersomnia Due to a Medical Disorder

Alternate Names
Not applicable.
Diagnostic Criteria
B. The daytime sleepiness occurs as a consequence of a significant
underlying medical or neurological condition.
C. If an MSLT is performed, the mean sleep latency is ≤ 8 minutes, and
fewer than two sleep onset REM periods (SOREMPs) are observed.1
D. The symptoms are not better explained by another untreated sleep
disorder,2 a mental disorder, or the effects of medications or drugs.
Notes
1. In the subtype of residual hypersomnolence after treatment of
obstructive sleep apnea, the MSLT mean latency may be > 8 minutes.
2. Should criteria for narcolepsy be fulfilled, a diagnosis of narcolepsy
type 1 or type 2 due to a medical condition should be used rather than
hypersomnia due to a medical condition.
3. In patients with severe neurological or medical disorders in whom it is
not possible or desirable to perform sleep studies, the diagnosis can be
made by clinical criteria.
Essential Features
Patients with this disorder have excessive nocturnal sleep, daytime sleepiness, or
excessive napping that is attributable to a coexisting medical or neurological disor-
der. Daytime sleepiness may be of variable severity and may resemble that of narco-
lepsy (i.e., refreshing naps) or idiopathic hypersomnia (i.e., long periods of unrefresh-
ing sleep). Sleep paralysis, hypnagogic hallucinations, or automatic behavior may be
present, but if the patient has cataplexy, the MSLT shows two or more SOREMPs, or
CSF Hcrt-1 levels are low, then narcolepsy (type 1 or type 2) due to a medical condi-
tion should be diagnosed. In patients with both sleep related breathing disorders and
hypersomnia due to a medical disorder, the latter diagnosis should be made only if the
hypersomnolence persists after adequate treatment of the sleep disordered breathing.
Hypersomnia due to a medical disorder is only diagnosed if the medical condition is
171
judged to be directly causing the excessive sleepiness. Hypersomnolence has been

described in association with a large range of conditions, including metabolic enceph-
alopathy, head trauma, stroke, brain tumors, encephalitis, systemic inflammation (e.g.,
chronic infections, rheumatologic disorders, cancer), genetic disorders, and neurode-
generative diseases.
Associated Features

Many medical conditions can cause hypersomnolence.
Hypersomnia secondary to Parkinson disease: Significant hypersomnolence docu-

mented by MSLT has been reported in some cases of Parkinson disease. Hypersomnia
in Parkinson disease may be due to insufficient control of nocturnal symptoms, result-
ing in insufficient sleep and daytime sleepiness. If so, the diagnosis should be insomnia
disorder. Cases of hypersomnolence that are due to the side effects of dopaminergic
agents should be coded as hypersomnia due to a medication or substance. In other
cases, however, hypersomnolence is likely of central origin and should be classified in
this section. Parkinson disease patients with an MSLT profile consistent with narco-
lepsy should be coded as narcolepsy due to a medical condition.
Posttraumatic hypersomnia: Hypersomnolence appears to be common after trau-

matic brain injury (TBI), with one meta-analysis suggesting a frequency of 28% of
TBI patients. In some cases this may be caused by injury to the hypocretin/orexin
neurons or other wake-promoting neural systems. However, the prevalence of sleep
related breathing disorder (SRBD) in patients with head trauma is high (frequency
23% to 25%). The nature of the relationship between TBI and OSA remains undefined.
Therefore, control of other potential sleep disorders is necessary prior to making a
diagnosis of hypersomnia due to a medical disorder (posttraumatic hypersomnia).
Genetic disorders associated with primary central nervous system somnolence:

Genetic disorders such as Niemann Pick type C disease and Norrie disease have been
associated with daytime somnolence. Prader-Willi syndrome, myotonic dystrophy,
Moebius syndrome, and fragile X syndrome are other examples of centrally mediated
sleepiness. A number of genetic disorders have been reported to be associated with
both sleep disordered breathing and hypersomnolence (e.g., myotonic dystrophy and
Prader-Willi syndrome). In these cases, hypersomnia due to a medical disorder should
be diagnosed only if the excessive sleepiness is still present after adequate treatment of
172
the SRBD. Smith-Magenis syndrome is a neurodevelopmental disorder characterized

by dysmorphic facial features, behavioral disturbance with onset in early childhood,
daytime somnolence, and night awakenings in association with reversal in the timing
of the melatonin secretion pattern (i.e., the serum levels of melatonin are high during
the daytime and low at night).
Hypersomnia secondary to brain tumors, infections, or other central nervous system

lesions: Strokes, infections, tumors, sarcoidosis, or neurodegenerative lesions of the
brain, especially in the hypothalamus or rostral midbrain, may produce daytime sleepi-
ness. In patients with brain tumors, the sleepiness may be due to the tumor itself or the
effects of treatment.
Hypersomnia secondary to endocrine disorder: Hypothyroidism is the most recog-

nized example of this condition.
Hypersomnia secondary to metabolic encephalopathy: Hepatic encephalopathy,

chronic renal insufficiency, adrenal or pancreatic insufficiency, exposure to toxins, and
certain inherited metabolic disorders in childhood may result in hypersomnolence.
Residual hypersomnia in patients with adequately treated OSA: Some patients with
SRBDs report persistent sleepiness despite apparently adequate amounts of sleep and
optimal treatment of their sleep apnea and other known sleep disorders. They may have
moderately elevated Epworth Sleepiness Scale scores, but most have mean sleep laten-
cies > 8 minutes on MSLT. They also report more fatigue, apathy, and depression. It is
essential that sleep disordered breathing be fully treated for at least three months, and
that control of the SRBD be confirmed by: (1) a download of positive airway pressure
(PAP) machine compliance data demonstrating optimal usage (preferably at least 7
hours a night); and (2) a polysomnogram demonstrating elimination of essentially all
sleep disordered breathing. Other causes of sleepiness, such as insufficient sleep syn-
drome, psychiatric disorders, or hypersomnolence related to medications or drugs must
be eliminated. Animal studies have suggested this residual sleepiness could be caused
by hypoxic injury to monoamine systems. Obesity itself may also contribute, and more
research is needed to understand the underlying mechanism.
Demographics
Demographics reflect those of the underlying condition.

Predisposing and precipitating factors reflect those of the underlying condition.
173
Familial Patterns
Familial patterns reflect those of the underlying condition.

Onset, course, and complications reflect those of the underlying condition.
Daytime naps are normal in children younger than 3-4 years; thus, it is difficult to dif-
ferentiate physiologic napping from hypersomnolence in children younger than this
age. Inattentiveness, mood swings, and learning difficulties often accompany child-
hood daytime sleepiness. Reference values for the MSLT in children differ from those
of adults, and this issue should be considered during the evaluation process. Special
attention should be paid to genetic disorders in children.

Pathology and pathophysiology reflect those of the underlying condition.
Objective Findings
Nocturnal polysomnography may show normal or moderately disturbed sleep. In
patients with a metabolic encephalopathy, EEG abnormalities may be present, such
as an increase in the amount of slow wave sleep. MSLT must show fewer than 2
SOREMPs and usually will show a mean sleep latency less than eight minutes. If clin-
ically significant sleep disordered breathing or periodic limb movements are present,
they should be treated prior to diagnosing hypersomnia due to a medical disorder.
See the differential diagnosis in previous hypersomnolence sections. The major chal-
lenge in establishing a diagnosis of hypersomnia due to a medical disorder is deter-
mining whether the associated medical or neurological disorder is truly causing the
hypersomnolence.

This area is understudied. Multiple complex neurological, metabolic, endocrine, and
medication-related interactions may be present. Further studies are needed to define
the reciprocal relationships between sleep disorders and other diseases.
Bibliography
Bruin VM, Bittencourt LR, Tufik S. Sleep-wake disturbances in Parkinson’s disease: current evidence
regarding diagnostic and therapeutic decisions. Eur Neurol 2012;67:257–67.
174
Castriotti RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and consequences of sleep
disorders in traumatic brain injury. J Clin Sleep Med 2007;3:349–56.
Guilleminault C, Yuen KM, Gulevich MG, Karadeniz D, Leger D, Philip D. Hypersomnia after head-neck
trauma: a medico-legal dilemma. Neurology 2000;54:653–9.
Kempf J, Werth E, Kaiser PR, et al. Sleep-wake disturbances 3 years after traumatic brain injury. J Neurol
Neurosurg Psychiatry 2010;81:1402–5.
Martinez-Rodriguez JE, Lin L, Iranzo A, et al. Decreased hypocretin-1 (orexin-A) levels in the cerebrospinal
fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 2003;26:287–90.
Mathias JL, Alvaro PK. Prevalence of sleep disturbances, disorders, and problems following traumatic
brain injury: a meta-analysis. Sleep Med 2012;13:898–905.
Panossian L, Veasey S. Daytime sleepiness in obesity: mechanisms beyond obstructive sleep apnea--a
review. Sleep 2012;35:605–15.
Vernet C, Redolfi S, Attali, V, et al. Residual sleepiness in obstructive sleep apnoea: phenotype and related
symptoms. Eur Respir J 2011;38:98–105.
Wienecke M, Werth E, Poryazova R, et al. Progressive dopamine and hypocretin deficiencies in Parkinson’s
disease: is there an impact on sleep and wakefulness? J Sleep Res 2012;21:710–7.
Zhu Y, Fenik P, Zhan G, et al. Selective loss of catecholaminergic wake active neurons in a murine sleep
apnea model. J Neurosci 2007;27:10060–71.
Hypersomnia Due to a Medication or Substance

ICD-9-CM code: 292.85 (drug-induced); 291.82 (alcohol-induced)
ICD-10-CM code: F11-F19 (see table in Appendix B for detailed coding
instructions)
Alternate Names
Hypersomnia due to substance abuse, hypersomnia due to stimulant withdrawal, hyper-
somnia due to sedative abuse, toxic hypersomnia, toxic encephalopathy.
Diagnostic Criteria
lapses into sleep.
B. The daytime sleepiness occurs as a consequence of current medication
or substance use or withdrawal from a wake-promoting medication or
substance.
C. The symptoms are not better explained by another untreated sleep
disorder, medical or neurological disorder, or mental disorder.
175
Essential Features
Patients with this disorder have excessive nocturnal sleep, daytime sleepiness, or
excessive napping that is attributable to sedating medications, alcohol, or drugs of
abuse. This diagnosis also includes hypersomnolence associated with withdrawal from
amphetamines and other drugs. If narcolepsy or hypersomnolence existed prior to
stimulant abuse, the diagnosis of hypersomnia due to a medication or substance should
not be used.
Associated Features
Associated features reflect those of the medications or substances responsible.
Clinical and Pathological Subtypes

Hypersomnia due to sedating medications: Sedation is a common side effect of many
prescription medications including benzodiazepines, nonbenzodiazepine hypnot-
ics, opioids, barbiturates, anticonvulsants, antipsychotics, anticholinergics, and some
antidepressants and antihistamines. Sleepiness also can occur with some dopamine
agonists such as pramipexole or ropinirole, and with many antiseizure medications.
Though less common, sleepiness can also occur with nonsteroidal anti-inflammatory
drugs, some antibiotics, antispasmodics, antiarryhthmics, and beta-blockers. Over-the-
counter medications, such as valerian and melatonin, can produce sedation. Excessive
sleepiness is especially common when these drugs are used in elderly patients or those
with multiple medical conditions, or in combination. Some tolerance to the sedative
effects can occur with time.
Hypersomnia due to substance abuse: Daytime sleepiness can occur with abuse
of alcohol, benzodiazepines, barbiturates, gamma hydroxybutyrate, opiates, and
marijuana.
Hypersomnia due to stimulant withdrawal: Daytime sleepiness is common with abrupt

discontinuation of stimulants. In chronically heavy amphetamine users, sleepiness is
most severe in the first week of withdrawal and can persist for up to three weeks; indi-
viduals may have an increase in total sleep and daytime napping, but sleep may seem
fragmented and nonrestorative. Significant depression often accompanies the hyper-
somnolence. Infrequently, sleepiness may be a residual complaint in those who have
used stimulants in the past but have been abstinent for many years. In people who
regularly consume coffee or other sources of caffeine, discontinuation can produce
sleepiness, fatigue, and inattentiveness for two to nine days.
176
Demographics
Patients of any age can experience sleepiness from sedating medications. Stimulant
abuse and the consequent sleepiness during withdrawal are most common in adoles-
cents and young adults.

Sleepiness from sedating medications may be more common in older patients and in
those with multiple medical problems.
Familial Patterns

Onset, course, and complications reflect those of the medications or substances
responsible.

Objective Findings
Polysomnography is generally unnecessary unless a concomitant sleep disorder is sus-
pected. Polysomnography and MSLT results vary depending on the specific substance
in question and the timing of the most recent intake. With stimulant withdrawal, noc-
turnal polysomnography may show normal sleep, whereas the MSLT typically demon-
strates a short mean sleep latency with or without multiple SOREMPs. A urine tox-
icology screen may be positive for the suspected substance. The diagnosis is often
confirmed if symptoms resolve after the causal agent is removed.
Major sleep disorders that are associated with excessive sleepiness, especially SRBDs,
periodic limb movement disorder, narcolepsy, IH, and insufficient sleep syndrome
should be ruled out. A urine drug screen should routinely accompany an MSLT as
the use of or withdrawal from some medications or substances may affect MSLT test
results.
Although many psychotropic medications may result in daytime sleepiness, it is import-

ant for clinicians to recognize that many psychiatric disorders also are associated with
increased prevalence of other sleep disorders (e.g., insomnia, SRBD, circadian disor-
ders, and movement disorders). Although sedative effects of the psychotropic agents
177
may contribute to sleepiness, clinicians must maintain a high index of suspicion for
other sleep related etiologies. When other sleep disorders are identified, multiple diag-
noses may be appropriate.

Sedatives can worsen sleep related breathing disorders, and more research is needed to
understand and manage this interaction.
Bibliography
Ancoli-Israel S. Sleep and its disorders in aging populations. Sleep Med 2009;10 Suppl 1:S7–11.
España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep 2011;34:845–58.
Gillin JC, Smith TL, Irwin M, Butters N, Demodena A, Schuckit M. Increased pressure for rapid eye
movement sleep at time of hospital admission predicts relapse in nondepressed patients with primary
alcoholism at 3-month follow-up. Arch Gen Psychiatry 1994;51:189–97.
Guilleminault C, Brooks SN. Excessive daytime sleepiness: a challenge for the practicing neurologist.
Brain 2001;124:1482–91.
Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and
signs, incidence, severity, and associated features. Psychopharmacology (Berl) 2004; 176:1–29.
McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM. The nature, time
course and severity of methamphetamine withdrawal. Addiction 2005;100:1320–9.
Mogri M, Desai H, Webster L, Grant BJ, Mador MJ. Hypoxemia in patients on chronic opiate therapy with
and without sleep apnea. Sleep Breath 2009;13:49–57.
Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:136–43.
Qureshi A, Lee-Chiong T. Medications and their effects on sleep. Med Clin North Am 2004;88:751–66.
Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health 2001;25:101–9.
Roehrs T, Bonahoom A, Pedrosi B, Zorick F, Roth T. Nighttime versus daytime hypnotic self-
administration. Psychopharmacology 2002;161:137–42.
Schweitzer P. Drugs that disturb sleep and wakefulness. In: Kryger MH, Roth T, Dement WC, eds.
Principles and practice of sleep medicine, 5th ed. St Louis: Elsevier Saunders, 2011:542–60.
William Ishak W, Ugochukwu C, Bagot K, Khalili D, Zaky C. Energy drinks: psychological effects and
impact on well-being and quality of life-a literature review. Innov Clin Neurosci 2012;9:25–34.
178
Hypersomnia Associated with a Psychiatric Disorder

Alternate Names
Hypersomnia not due to substance or known physiological condition, nonorganic
hypersomnia, pseudohypersomnia, or pseudonarcolepsy.
Diagnostic Criteria
B. The daytime sleepiness occurs in association with a concurrent
psychiatric disorder.
C. The symptoms are not better explained by another untreated sleep
disorder, a medical or neurological disorder, or the effects of
medications or drugs.
Essential Features
Patients with hypersomnia associated with a psychiatric disorder may report excessive
nocturnal sleep, daytime sleepiness, or excessive napping. In addition, they often feel
their sleep is of poor quality and nonrestorative. Patients are often intensely focused
on their hypersomnolence, and psychiatric symptoms may become apparent only
after prolonged interviews or psychometric testing. Associated psychiatric conditions
include mood disorders, conversion or undifferentiated somatoform disorder, and less
frequently other mental disorders such as schizoaffective disorder, adjustment disor-
der, or personality disorders.
Associated Features
Poor work attendance, spending full days in bed several times a week, or abruptly
leaving work because of a perceived need to sleep are common symptoms. Patients
may also have social withdrawal, apathy, and feelings of low energy.

Hypersomnia associated with mood disorder: Hypersomnolence in the context of
depression is a frequent feature of atypical depression and bipolar II disorder (recur-
rent major depressive episodes with hypomanic episodes). In seasonal affective disor-
der, daytime fatigue, loss of concentration, increased appetite for carbohydrates, and
weight gain are reported. MSLT results are usually normal, but long hours spent in bed
are reported.
179
Hypersomnia associated with a conversion disorder or somatic symptom disorder:

Pseudohypersomnia or pseudonarcolepsy, sometimes with pseudocataplexy, has been
described.
Demographics
Hypersomnia associated with a psychiatric disorder accounts for 5% to 7% of hyper-
somnolence cases. Women are more susceptible than men, and the typical age range is
between 20 and 50 years. In patients with major depression, the prevalence of hypersom-
nolence ranges from 5% to over 50% depending on how hypersomnolence is defined.
Hypersomnolence affects over 50% of patients with seasonal affective disorder.

Familial Patterns
Not known, except for the familial patterns of certain psychiatric disorders (e.g.,
bipolar II disorder).

The mean age of onset is usually in the third decade in both sexes. With major depres-
sion, hypersomnolence may persist even after the depressive episode improves, and
persistent hypersomnolence is associated with increased risk of recurrent depression.
Complications are mostly social and occupational.
Hypersomnolence occurs in 10% to 20% of children with major depression, some-
times in combination with insomnia, but sleep quality appears normal. Although sleep
problems may develop at any stage of depression, they are most pronounced during the
acute phase. Children and adolescents with depression who manifest either insomnia
or hypersomnolence generally manifest more pronounced symptoms, such as anhedo-
nia and weight loss.

The underlying cause is unknown. Although patients with this disorder report sleep-
iness, sleep studies reveal little or no evidence of increased propensity to sleep. In
some patients, fragmented nighttime sleep may contribute to their daytime sleepiness.
Because of uncertainty about the nature of the relationship, the term “hypersomnia
associated with a psychiatric disorder” is preferred to “hypersomnia due to a psychi-
atric disorder.”
180
Objective Findings
Nocturnal polysomnography typically shows a prolonged total time in bed with frag-
mented sleep. Sleep latency is prolonged, wake time after sleep onset is increased,
awakenings may be frequent and prolonged, and sleep efficiency is low. REM sleep
latency may be shortened in the case of untreated depression. Sleep latencies on the
MSLT are often within normal limits, a result contrasting with the subjective complaint
of daytime sleepiness and an elevated score on the Epworth Sleepiness Scale. 24-hour
continuous sleep-recording studies typically show considerable time spent in bed
during day and night, a behavior sometime referred to as clinophilia. Psychiatric inter-
views and evaluations are essential to diagnose the underlying psychiatric condition.
As there are no definitive tests for diagnosing hypersomnolence associated with a psy-
chiatric disorder, it is essential to rule out other common causes of sleepiness such
as insufficient sleep, sedation from medications or substances, SRBD, periodic limb
movement disorder, and IH. Chronic fatigue syndrome is characterized by persistent
or relapsing fatigue that does not resolve with sleep or rest, but the main complaint is
usually fatigue rather than sleepiness. Insufficient sleep syndrome is associated with
excessive daytime sleepiness, impaired concentration, and lowered energy level, but a
detailed history of the subject’s current sleep schedule reveals chronic sleep deprivation.

The lack of concordance between subjective and objective findings raises multiple
issues. It is unclear to what extent these patients are objectively sleepy or, instead, suffer
from decreased energy and lack of interest that confines them to bed. More research
is needed to create an effective definition of hypersomnolence in this population and
to develop tools for measuring it. Finally, future efforts should define the mechanism
through which some patients express their psychiatric symptoms as excessive sleepiness.
Bibliography
Guilleminault C, Brooks SN. Excessive daytime sleepiness: a challenge for the practicing neurologist.
Brain 2001;124:1282–91.
Kaplan KA, Harvey AG. Hypersomnia across mood disorders: a review and synthesis. Sleep Med Rev
2009;13:275–85.
Kotagal S. Hypersomnia in children: interface with psychiatric disorders. Child Adolesc Psychiatr Clin N
Am 2009;18:967–77.
Liu X, Buysse DJ, Gentzler AL, et al. Insomnia and hypersomnia associated with depressive phenomenology
and comorbidity in childhood depression. Sleep 2007;30:83–90.
Nofzinger EA, Thase ME, Reynolds CF 3rd, et al. Hypersomnia in bipolar depression: a comparison with
narcolepsy using the Multiple Sleep Latency Test. Am J Psychiatry 1991;148:1177–81.
181
Partonen T, Lönnqvist J. Seasonal affective disorder. Lancet 1998;352:1369–74.

van den Berg JF, Luijendijk HJ, Tulen JH, Hofman A, Neven AK, Tiemeier H. Sleep in depression and
anxiety disorders: a population-based study of elderly persons. J Clin Psychiatry 2009;70:1105–13.
Vgontzas AN, Bixler EO, Kales A, Criley C, Vela-Bueno A. Differences in nocturnal and daytime sleep
between primary and psychiatric hypersomnia: diagnosis and treatment implications. Psychosom Med
2000;62:220–6.
Insufficient Sleep Syndrome

Alternate Names
Behaviorally induced insufficient sleep syndrome, insufficient nocturnal sleep, chronic
sleep deprivation, sleep restriction.
Diagnostic Criteria
lapses into sleep or, in the case of prepubertal children, there is a
complaint of behavioral abnormalities attributable to sleepiness.
B. The patient’s sleep time, established by personal or collateral history,
sleep logs, or actigraphy1 is usually shorter than expected for age.2
C. The curtailed sleep pattern is present most days for at least three
months.
D. The patient curtails sleep time by such measures as an alarm clock or
being awakened by another person and generally sleeps longer when
such measures are not used, such as on weekends or vacations.
E. Extension of total sleep time results in resolution of the symptoms of
sleepiness.
F. The symptoms are not better explained by another untreated sleep
disorder, the effects of medications or drugs, or other medical,
neurologic, or mental disorder.
Notes
1. If there is doubt about the accuracy of personal history or sleep logs,
then actigraphy should be performed, preferably for at least two weeks.
2. In the case of long sleepers, reported habitual sleep periods may be
normal based on age. However, these sleep periods may be insufficient
for these patients.
182
Essential Features
Insufficient sleep syndrome occurs when an individual persistently fails to obtain
the amount of sleep required to maintain normal levels of alertness and wakefulness.
The individual is chronically sleep deprived as a result of failure to achieve necessary
sleep time due to reduced time in bed. There is a U-shaped relationship between age
and average sleep time, with the minimum in middle-aged individuals. Examination
reveals unimpaired or above-average ability to initiate and maintain sleep, with little
or no psychopathology. Physical examination reveals no medical explanation for the
patient’s sleepiness. A detailed history of the sleep pattern reveals a substantial dis-
parity between the need for sleep and the amount actually obtained. The significance
of this disparity often goes unappreciated by the patient. Sleep time that is markedly
extended on weekend nights or during holidays compared to weekday nights is also
suggestive of this disorder. A therapeutic trial of a longer major sleep episode can
reverse the symptoms. In individuals with physiologic sleep requirements significantly
in excess of seven to eight hours, reported “average” amounts of sleep (e.g., seven
hours/night) may, in fact, be insufficient. Additional symptoms such as sleep paralysis
and hypnagogic hallucinations may occur.
Associated Features
Depending upon chronicity and extent of sleep loss, individuals with this condition
may show irritability, concentration and attention deficits, reduced vigilance, distract-
ibility, reduced motivation, anergia, dysphoria, fatigue, restlessness, uncoordination,
and malaise. Secondary symptoms may become the main focus of the patient, serving
to obscure the primary cause of the difficulties. Psychologically and somatically normal
individuals who chronically obtain less sleep than they physiologically require typi-
cally experience daytime sleepiness. Situational factors such as demands of the family
and work schedule may, on occasion, make it very difficult to obtain adequate sleep.
Clinical and Pathophysiologic Subtypes

Demographics
Insufficient sleep syndrome affects all ages and both sexes. It may be more frequent in
adolescence, when sleep need is high, but social pressure and tendency to delay sleep
often lead to chronic restricted sleep. Cultural factors may also influence sleep dura-
tion, with students from different countries reporting sleep time varying between six
and eight hours per night.
183

Social and psychological factors may impact nocturnal sleep length and daytime sleep-
iness. Cultural habits such as the siesta may enhance evening alertness at the expense
of reducing nocturnal sleep efficiency. Also, the evening preference chronotype predis-
poses to complaints of insomnia and insufficient sleep. The association of eveningness
with insufficient sleep persists after controlling for variables such as sex, age, and sleep
duration.
Familial Patterns

This condition results in increased daytime sleepiness, concentration problems, lowered
energy level, and malaise. If unchecked, insufficient sleep syndrome may predispose
to depression and other psychological difficulties, as well as poor work performance
and withdrawal from family and social activities. Abuse of stimulants may also occur.
Traffic accidents or injury at work may result.
Insufficient sleep syndrome is a common problem in adolescents. It should be differ-
entiated from delayed sleep phase disorder, the effects of recreational drug use, and
school avoidance behavior. Increased predisposition to substance use and accidents in
teens may be consequent to insufficient sleep.

Symptoms are due to normal physiological and psychological responses to sleep depri-
vation. Sleep restriction studies in normal volunteers have shown that even mild sleep
restriction (for example, six hours of nocturnal sleep per night) results in a correspond-
ing decrease in performance and increased sleepiness. Sleep restriction to four hours
per night (i.e., extension of wakefulness to 20 hours per day) will likely lead to greater
buildup of homeostatic sleep drive during the waking hours and greater likelihood of
impaired performance on a psychomotor vigilance task. The effects of sleep depriva-
tion on neurobehavioral performance measures may vary with the nature of the task
being considered.
In some long sleepers, it is important to be aware that extending sleep to nine or more
hours often results in improved performance. The diagnosis of insufficient sleep syn-
drome may be especially difficult to make in subjects who have a physiologic need for
unusually large amounts of sleep.
184
Objective Findings
Actigraphy combined with sleep diaries maintained for a 2- to 3-week period may
be helpful by documenting total time in bed, sleep latency, total sleep time, and sleep
efficiency. Polysomnography and MSLT are not required to establish a diagnosis of
insufficient sleep syndrome. Rather, sleep time is extended first, and the patient is
reevaluated. If a therapeutic trial with a longer sleep episode eliminates the symptoms,
insufficient sleep syndrome is diagnosed.
Polysomnography, when performed, reveals reduced sleep onset latency, and high
(greater than 90%) sleep efficiency. When extended sleep is permitted, prolonged
sleep time with slow wave rebound may be seen. Noting a disparity between reported
sleep at home and observed total sleep time in the sleep laboratory can be helpful.
The MSLT reveals excessive sleepiness, with stage N1 sleep occurring in most naps,
with short sleep latency. Stage N2 sleep occurs in more than 80% of MSLT naps.
SOREMPs can occur.
Insufficient sleep syndrome may be confused with narcolepsy or other hypersom-
nolence disorders because an abnormal MSLT (even with two SOREMPs) can be
observed as the result of acute or chronic sleep deprivation. The confusion may be
most frequently encountered in adolescents or young adults. The differential diagno-
sis of insufficient sleep syndrome includes numerous other conditions that may result
in daytime sleepiness or shortening of nocturnal sleep duration. These include other
central disorders of hypersomnolence, long sleeper or short sleeper, SRBD, circadian
rhythm sleep disorders, insomnia disorder, affective disorder, and periodic limb move-
ment disorder.

The correlation between subjectively reported sleepiness, performance-test decre-
ments, and MSLT-measured sleepiness after sleep deprivation is poor. Short sleepers
often have a higher NREM sleep pressure, as measured by EEG delta power, than long
sleepers, even if they do not complain of daytime sleepiness. There is interindividual
susceptibility to sleep deprivation, with some people being consistently more tired
and experiencing greater performance decrement after even a mild degree of sleep
deprivation.
Bibliography
Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skills
1979;48:495–506.
185
Habeck C, Rakitin BC, Moeller J, et al. An event related fMRI study of the neurobehavioral impact of
sleep deprivation on performance of a delayed match to sample task. Cogn Brain Res 2004;18:306–21.
Merikanto I,Kronholm E, Peltonen M, Laatikainen T, Lahti T, Partonen T. Relation of chronotype to sleep
complaints in the general Finnish population. Chronobiol Int 2012;29:311–7.
Mont TH, Buysse DJ, Carrier J, Bart BD, Rose LR. Effects of afternoon “siesta” naps on sleep, alertness,
performance, and circadian rhythms in the elderly. Sleep 2001;24:680–7.
Mu Q, Mishory A, Johnson KA, et al. Decreased brain activation during a working memory task at rested
wakefulness is associated with vulnerability to sleep deprivation. Sleep 2005;28:433–46.
Roehrs T, Zorick F, Sicklesteel J, Wittig R, Roth T. Excessive daytime sleepiness associated with
insufficient sleep. Sleep 1983;6:319–25.
Taylor DJ, Bramoweth AD. Patterns and consequences of inadequate sleep among college students:
substance use and motor vehicle accidents. J Adolesc Health 2010;46:610–2.
Tucker AM, Whitney P, Belenky G, Hinson JM, Van Dongen HPA. Effects of sleep deprivation on
dissociated components of executive functioning. Sleep 2010;33:47–57.
Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness:
dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction
and total sleep deprivation. Sleep 2003;26:117–26.
186
Long Sleeper
A long sleeper is an individual who consistently sleeps substantially more in 24 hours
than does the typical person of his or her age group. For adults, the usually accepted
figure is 10 hours or more, but many epidemiologic studies have used sleep times of
8–10 hours. For children and adolescents, the entity should be considered if sleep time
is more than two hours longer than age-specific norms. Sleep, although long, is basi-
cally normal in architecture and physiology. Sleep efficiency and timing are normal.
A consistent daily pattern, documented by a carefully kept sleep log (preferably con-
firmed by actigraphy), showing 10 or more hours of sleep per night over a minimum
of seven days is desirable for the identification of the long sleeper. In general, long
sleepers seek medical help when they develop sleepiness as a result of being forced
to curtail their sleep time to less than their required amounts. Usually, the long sleep
pattern began in childhood, is well established by early adolescence, and persists
throughout life. Many long sleepers, because of occupational or educational demands,
function with reasonable success on nine hours of sleep per night during the work or
school week, with increases to 12 or more hours on weekends and holidays.
About 2% of men and 1.5% of women report sleeping at least 10 hours per night.
Epidemiologic studies have consistently found an increased mortality (and sometimes
increased body mass index, lower glucose tolerance, higher prevalence of type 2 dia-
betes and coronary heart disease) associated with long sleep, compared to average-du-
ration sleep, but it is not clear whether most of the subjects were naturally long sleep-
ers or had disorders resulting in excessive duration of sleep. In subjects older than 60
years, sleep duration longer than 9.5 hours is associated with male sex, low education,
no physical exercise, and more physical diseases. Long (> nine hours) sleep duration
has a high heritability (44%) and concordance between monozygotic twins, which is
higher if they live together. Genomewide studies favor a polygenic origin of sleep
duration, with influence of clock and other genes (DEC2, K+ channel regulatory pro-
teins genes). Long sleepers presumably represent the extreme high end of the normal
sleep duration continuum.
Long sleepers, like short sleepers, have normal absolute amounts of stage N3 sleep,
unless there is chronic sleep restriction preceding polysomnography, in which case the
absolute amount of N3 stage is increased. Amounts of stages N2 and REM sleep are
somewhat higher than normal. The individual has no problem with time distortion or
ability to be accurate about the quantity or quality of sleep. Assuming that individuals
187
have obtained their usual sleep amounts for several nights before the procedure, no
sleepiness is evident on the MSLT. It is important to differentiate the long sleeper
from patients with narcolepsy, idiopathic hypersomnia, sleep disordered breathing, or
medical causes of hypersomnolence. Many pathologic causes of increased sleep have
an acute or subacute onset, may not be present since childhood, and rarely show the
stable course of the long sleeper. Nevertheless, differentiation from pathologic con-
ditions of hypersomnolence may be difficult in the child or adolescent because the
normal continuum of sleep duration is somewhat higher in these age groups than in
adults. The correct determination is often made by exclusion of specific diagnostic
features associated with other conditions and by the absence of complaints concerning
the quality of the individual’s awake-state functioning when adequate sleep is obtained
(e.g., during prolonged holidays). In particular, the differentiation of a genuine long
sleeper from a patient with idiopathic hypersomnia may be difficult. In the genuine
long sleeper, sleeping long hours is refreshing, and sleepiness disappears when long
hours of nocturnal sleep are enforced.
Bibliography
Aeschbach D, Cajochen C, Landolt H, Borbély AA. Homeostatic sleep regulation in habitual short sleepers
and long sleepers. Am J Physiol 1996;270:R41–53.
Hartmann E, Baekeland F, Zwilling GR. Psychological differences between long and short sleepers. Arch
Gen Psychiatry 1972;26:463–8.
Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration
and insomnia. Arch Gen Psychiatry 2002;59:131–6.
Kripke DF, Simons RN, Garfinkel L, Hammond EC. Short and long sleep and sleeping pills. Is increased
mortality associated? Arch Gen Psychiatry 1979;36:103–16.
Webb WB. Are short and long sleepers different? Psychol Rep 1979;44:259–64.
188
Circadian Rhythm Sleep-Wake
Disorders
Delayed Sleep-Wake Phase Disorder.........................................................191
Advanced Sleep-Wake Phase Disorder......................................................198
Irregular Sleep-Wake Rhythm Disorder.......................................................204
Non-24-Hour Sleep-Wake Rhythm Disorder...............................................209
Shift Work Disorder.....................................................................................215
Jet Lag Disorder..........................................................................................220
Circadian Sleep-Wake Disorder Not Otherwise Specified (NOS)...............224
Circadian rhythms are endogenous, near-24-hour biological rhythms that exist in all
living organisms. The internal near-24-hour circadian clock is entrained or synchro-
nized to the 24-hour light-dark cycle. In humans, the endogenous period of the circa-
dian oscillation is genetically determined and typically is slightly longer than 24 hours.
In order to maintain entrainment, the endogenous rhythm must be reset each day to the
24-hour clock time. For optimal sleep, the actual sleep time should match the timing
of the circadian rhythm of sleep and wake propensity. Therefore, a recurrent or chronic
pattern of sleep and wake disturbance may result from disruption of the internal circa-
dian timing system or a misalignment between the timing of the individual’s circadian
sleep-wake propensity and the 24-hour social and physical environments (e.g., sleep
episodes scheduled entirely or in part during a phase of circadian alertness promotion).
As used herein, a circadian rhythm sleep-wake disorder (CRSWD) is defined by the
following criterion: The disorder is caused by alterations of the circadian time-keeping
system, its entrainment mechanisms, or a misalignment of the endogenous circadian
rhythm and the external environment.
Most CRSWDs arise when a substantial misalignment exists between the internal
rhythm and the required timing of the patient’s school, work, or social activities.
Therefore, measurement of endogenous circadian timing is important for the accu-
rate diagnosis of CRSWDs. In addition to the history, multiple tools are available to
assess sleep-wake patterns. Sleep log and actigraphy are essential instruments in the
evaluation of CRSWDs and should be conducted for at least seven days, preferably
for 14 days, to capture work and non-work days. Circadian chronotype (Morningness-
Eveningness Questionnaires) and physiological measures of endogenous circadian
timing (salivary or plasma dim light melatonin onset and urinary 6-sulfatoxymelatonin)
also can provide important diagnostic information. Circadian chronotype is a reflec-
tion of an individual’s optimal timing of sleep and wake propensity, as well as other
189
Circadian Rhythm Sleep-Wake Disorders
physiological and mental functions. Several questionnaires can be used to assess chro-
notype of “eveningness” or “morningness” (e.g., Munich Chronotype Questionnaire,
or Morningness-Eveningness Questionnaire).
The most common presenting symptoms of CRSWDs are difficulty initiating and
maintaining sleep, and excessive sleepiness, but their impact extends to adverse
health outcomes, impairments in social, occupational and educational performance,
and safety concerns. Important advances have been made in the identification of clin-
ical CRSWD subtypes, particularly in the area of pediatrics. However, the challenge
remains to develop more precise and clinically practical tools to improve diagnostic
accuracy for CRSWDs.
General Criteria for Circadian Rhythm Sleep-Wake Disorder

A. A chronic or recurrent pattern of sleep-wake rhythm disruption
primarily due to alteration of the endogenous circadian timing system
or misalignment between the endogenous circadian rhythm and the
sleep-wake schedule desired or required by an individual’s physical
environment or social/work schedules.
B. The circadian rhythm disruption leads to insomnia symptoms, excessive
sleepiness, or both.
C. The sleep and wake disturbances cause clinically significant distress or
impairment in mental, physical, social, occupational, educational, or
other important areas of functioning.
All disorders described in the ensuing section imply a sleep difficulty that meets each
of the above criteria. The specific features that characterize each type of CRSWD are
included within the individual diagnostic criteria.
190
Delayed Sleep-Wake Phase Disorder

Alternate Names
Delayed sleep phase syndrome, delayed sleep phase pattern, motivated delayed sleep
phase disorder.
Diagnostic Criteria
A. There is a significant delay in the phase of the major sleep episode
in relation to the desired or required sleep time and wake-up time,
as evidenced by a chronic or recurrent complaint by the patient or a
caregiver of inability to fall asleep and difficulty awakening at a desired
or required clock time.
B. The symptoms are present for at least three months.
C. When patients are allowed to choose their ad libitum schedule, they
will exhibit improved sleep quality and duration for age and maintain a
delayed phase of the 24-hour sleep-wake pattern.
D. Sleep log and, whenever possible, actigraphy monitoring for at least
seven days (preferably 14 days) demonstrate a delay in the timing of
the habitual sleep period. Both work/school days and free days must be
included within this monitoring.
E. The sleep disturbance is not better explained by another current sleep
disorder, medical or neurological disorder, mental disorder, medication
use, or substance use disorder.
Notes
1. Standardized chronotype questionnaires are useful tools to assess the
chronotype of eveningness and morningness. Individuals with this
disorder typically score as evening types. This tool can also be useful in
determining whether an eveningness circadian preference contributes to
sleep initiation difficulties among those who do not meet full criteria for
the disorder.
2. Demonstration of a delay in the timing of other circadian rhythms,
such as melatonin (measured by dim light melatonin onset or urinary
6-sulfatoxymelatonin sampled across a 24-hour period), is desirable to
confirm the delayed circadian phase.
191
Essential Features
Delayed sleep-wake phase disorder (DSWPD) is characterized by habitual sleep-
wake timing that is delayed, usually more than two hours, relative to conventional or
socially acceptable timing. Affected individuals complain of difficulty falling asleep at
a socially acceptable time, as required to obtain sufficient sleep duration on a school or
work night. Once sleep onset occurs, it is reportedly of normal duration. These individ-
uals also experience difficulty arising at a socially acceptable wake time, as required to
prepare for school or work. When allowed to follow his or her preferred schedule, the
patient’s timing of sleep is delayed.
Associated Features
Individuals with DSWPD may demonstrate excessive sleep inertia (extreme difficulty
awakening and confusion) in the morning as a result of curtailed sleep time and awak-
ening during a circadian phase of high sleep propensity. Individuals with this disor-
der as well as normal sleepers with evening chronotypes may have increased rates of
mental disturbances, such as Diagnostic and Statistical Manual of Mental Disorders
(DSM) Axis I disorders or symptoms (e.g., mood disorders or depressive symptoms).
In some individuals with DSWPD, there may be an overlap with non-24-hour sleep-
wake disorder, or an alternation between symptoms of the two disorders. Attempts to
cope with the inability to fall asleep earlier may result in the development of insomnia
disorder. Individuals may use alcohol, sedatives, hypnotics, or stimulant substances to
alleviate symptoms of insomnia and excessive sleepiness, thereby perpetuating their
underlying sleep disorder.

Motivated delayed sleep-wake phase disorder is a subtype typically composed of ado-
lescents who have little intrinsic motivation to successfully complete treatment and
thereby resume a normal lifestyle (regular school attendance, developmentally appro-
priate peer interactions, etc). A history of mood or anxiety disorder (especially school
phobia and separation and social anxiety) or other factors (e.g., learning disabilities,
attention deficit hyperactivity disorder) are often present and may motivate the patient
(sometimes unconsciously) to avoid a return to normal adolescent activities, espe-
cially regular school attendance. It is not uncommon that ill-defined medical issues
(e.g., chronic fatigue, recurrent mononucleosis episodes, pain syndromes) trigger the
onset or complicate the course of the disorder. Important clues, in addition to the exis-
tence of premorbid mental disorders, include exaggerated presenting symptoms (e.g.,
“can’t wake up even if I throw cold water on him”) and failure to comply with basic
straightforward treatment recommendations (e.g., refusal or inability to stop napping
during the day).
192
Although social, psychological, and environmental factors may play a significant role
in the development of delayed sleep-wake phase, International Classification of Sleep
Disorders, 3rd Edition has chosen to list only a single delayed sleep-wake phase diag-
nosis, with the recognition that most cases reflect variable chronobiologic and behav-
ioral contributions.
Demographics
The exact prevalence of DSWPD in the general population is unknown. The condition
is more common among adolescents and young adults, with a reported prevalence of
7% to 16%. It is estimated that DSWPD is seen in approximately 10% of patients pre-
senting in sleep clinics with recurrent insomnia complaints. There have been no studies
assessing racial/ethnic differences in DSWPD.

Most individuals with DSWPD are evening chronotypes. Many adolescents experi-
ence a biological endogenous shift towards later bedtimes beginning around puberty.
Genetic factors such as polymorphism in the circadian clock gene hPer3 are associated
with DSWPD. Environmental factors, including decreased exposure to light during
the phase advance region of the phase response curve (PRC) (i.e., in the morning on
days with early wake times) or increased exposure to bright light during the phase
delay portion of the PRC (i.e., late in the evening) may exacerbate the delayed circa-
dian phase. Individuals may have increased sensitivity in the phase delay region or
decreased sensitivity in the phase advance region of the phase response curve to light.
Maladjustment to changes in work and social schedules, travel across time zones, and
shift work can precipitate this disorder. Individuals may consume excessive caffeine
and other stimulants, which may further delay sleep onset and thus exacerbate the
delayed sleep time.
Social and behavioral factors play an important role in the development and mainte-
nance of the delayed sleep patterns for many affected individuals. Personal, social,
and occupational activities that continue into the late evening may perpetuate and
exacerbate the sleep phase delay. In adolescents, the role of school avoidance, social
maladjustment, and family dysfunction should be considered as contributing factors.
Individuals with a psychiatric disorder, such as a mood disorder (major depression or
bipolar disorder), severe obsessive-compulsive disorder, attention deficit hyperactivity
disorder, or other neurodevelopmental disorders may have a delayed sleep phase.
193
Familial Patterns
A positive family history has been reported in approximately 40% of individuals with
DSWPD. In one pedigree, DSWPD was suggested to segregate as an autosomal domi-
nant trait. Polymorphisms in hPer3, arylalkylamine N-acetyltransferase, human leuko-
cyte antigen, and Clock have been suggested to be associated with DSWPD.

A delayed sleep pattern typically begins during adolescence. Onset in early childhood
is also described, especially in familial cases; the onset may follow psychological,
medical, or environmental stressors. Without treatment, DSWPD is a chronic condition
that may last into late life. However, with increasing age across adulthood, the timing
of the sleep-wake cycle may advance, thereby decreasing the propensity to delayed
sleep phase. Phototherapy, as well as behavioral and pharmacologic treatments, can
advance the timing of sleep hours, but there is usually a continual tendency and prefer-
ence for delayed sleep hours, and recurrence is high. Use of alcohol, sedatives, hypnot-
ics, or stimulants to treat symptoms of insomnia and sleepiness during normal waking
hours may lead to substance abuse.
DSWPD may be encountered in any age group but is especially prevalent among ado-
lescents and young adults. In addition to the clinical features described elsewhere,
DSWPD may present in older children and adolescents with chief complaints of
truancy, repeated school absences, chronic tardiness and/or school failure, rather than
sleep complaints per se. In severe cases, school attendance is completely curtailed and
the patient may have failed to attend school regularly for many months. Extreme diffi-
culty in morning awakening, requiring intensive parental involvement, may also be the
presenting concern. An increased risk of motor vehicle accidents has been associated
with delayed sleep onset and resultant insufficient sleep in adolescents; thus, the occur-
rence of a car crash or “near-miss” incident should alert the clinician to probe for addi-
tional evidence of circadian pathology. Adolescents may also present primarily with
mood complaints (depression, suicidal ideation). Chronic insomnia is commonly asso-
ciated with and may be the chief presenting complaint in adolescents with DSWPD as
a result of repeated attempts and failures to achieve sleep onset at their desired bedtime.
In younger children, the condition may be associated with delays in other markers of
circadian phase, including the typical presleep surge in alertness referred to as the “for-
bidden zone” or “second wind phenomenon.” Thus, especially in younger children,
DSWPD may present primarily as bedtime resistance, as caregivers attempt to establish
bedtimes that directly conflict with the child’s circadian-mediated readiness for sleep.
194
Several pediatric populations appear to have an increased vulnerability to DSWPD

and sleep disturbances, likely of multifactorial etiology. These include children with
attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).
Several studies have examined melatonin onset in children with ADHD and reported
significant delays in comparison with typically developing children, as well as suc-
cessful treatment with melatonin. Children with ASD have a high prevalence (up to
80%) of sleep disturbances, including delayed sleep onset, night and early morning
awakenings, and irregular sleep patterns, at least some of which appear associated with
circadian abnormalities. These children reportedly have a number of alterations in mel-
atonin synthesis, levels, amplitude, and patterns of secretion.
Little is known about the natural history of the clinical entity of DSWPD in the pediat-
ric population, including the impact of various treatment modalities, the likelihood of
spontaneous resolution of symptoms, or long-term consequences.
There is increasing evidence to suggest that the evening chronotype is associated in both
children and adolescents with a number of adverse consequences, including decreased
health-related quality of life, higher rates of behavioral/emotional problems including
depression and suicidality, decreased sleep duration and increased daytime sleepiness,
more sleep complaints, impairments in academic functioning, and increased likelihood
of substance use. Thus, eveningness may confer an increased risk for physical and
mental health problems.

The exact mechanisms responsible for DSWPD are unknown. An abnormal interac-
tion between the endogenous circadian rhythm and the sleep homeostatic process that
regulates sleep and wakefulness may play an essential role in the pathophysiology of
DSWPD. Early studies reported an altered phase relationship between the sleep-wake
cycle and circadian phase, whereas more recent studies have failed to support this
finding. In these patients, sleep onset, sleep offset, and phase of circadian markers such
as core body temperature and melatonin are delayed relative to clock time when com-
pared with controls. Although this condition may be predominantly due to a misalign-
ment between circadian timing and the external environment, alterations in the length
of the circadian period or an altered homeostatic process (indicated by decreased sleep
propensity in response to sleep deprivation) also may be contributing factors. In chil-
dren and adults, voluntary behaviors such as staying awake late at night and waking
up late in the morning or afternoon may result in an abnormal relationship between the
endogenous circadian rhythm and the sleep homeostatic process that regulates sleep
and wakefulness. Delayed bedtimes and wake times may increase exposure to bright
195
light in the late evening (a delay signal for the circadian clock) and decrease expo-
sure to light in the early morning (an advance signal for the circadian clock), thereby
promoting and perpetuating the delay in the circadian sleep phase. Given a sufficient
discrepancy between early and late wake times, early wake times may be associated
with bright light exposure during the maximal phase delay region, perpetuating the cir-
cadian phase delay and the disorder. Individuals may have alterations in sensitivity to
the phase shifting effects of light. For example, partial sleep deprivation encountered
with this disorder can also attenuate the ability to phase-advance the circadian system,
further perpetuating the delayed circadian phase.
Objective Findings
Recordings of sleep logs and actigraphy over an interval of at least seven (and pref-
erably fourteen) consecutive days demonstrate delayed sleep onset and sleep offset
(typically greater than two hours) relative to socially acceptable times. Though clock
times may be culture dependent, for many affected individuals sleep onset is typi-
cally delayed until 1:00 a.m. to 6:00 a.m., (though may be earlier based on age and
developmental status), and wake time occurs in the late morning or afternoon. Daily
demands and schedules may result in an earlier than desired wake-up time during work
or school days, but a delay in bedtime and wake-up time is almost always seen during
free days and vacation. Polysomnography (though not routinely indicated nor required
for the diagnosis), when performed at preferred (delayed) sleep times, is essentially
normal for age. If a conventional bedtime and wake-up time are enforced, however,
polysomnographic recording may show prolonged sleep latency and decreased total
sleep time. Laboratory measures of circadian timing generally show the expected
phase delay in the timing of the nadir of the core body temperature rhythm and dim-
light melatonin onset (DLMO). Several questionnaires are useful in assessing the chro-
notype, the degree of eveningness or morningness (e.g., “Morningness-Eveningness
Questionnaire,” “Munich Chronotype Questionnaire”). Individuals with DSWPD, typ-
ically score high as evening types, though normal sleepers can also score high on eve-
ningness. Elevations are expected in self-report of daytime sleepiness, such as on the
Epworth Sleepiness Scale.
The results of polysomnography and other diagnostic tools in younger age groups
are similar to those seen in adults. Actigraphy and/or sleep logs are useful in the
diagnosis of DSWPD in the pediatric population. Several validated instruments
are available for assessing phase preference in the pediatric and adolescent pop-
ulations. These include the Children’s Chronotype Questionnaire (CCTQ) (par-
ent-report), the Morningness-Eveningness Scale for Children (self-report), and
the Morningness-Eveningness Questionnaire for Children and Adolescents. These
196
surveys have been used to assess chronotype in the pediatric population and may be
useful in clinical settings.
Delayed sleep-wake phase disorder must be distinguished from “normal” sleep pat-
terns, particularly in adolescents and young adults who maintain delayed schedules
regularly or intermittently, without distress or impaired functioning. DSWPD must be
distinguished from other causes of difficulty initiating sleep, including chronic insom-
nia disorder. In DSWPD, sleep initiation and maintenance are improved when the
patient is allowed to sleep on the preferred schedule. When individuals with DSWPD
must arise before the desired wake time, excessive sleep inertia and excessive daytime
sleepiness may be evident. Other forms of excessive daytime sleepiness, from which this
must be distinguished, do not generally exhibit the pronounced circadian pattern and
do not abate with alterations in the sleep-wake schedule. The development of DSWPD
may be influenced by alterations in circadian physiology as well as behavioral factors.
Inadequate sleep hygiene and insufficient sleep syndrome must also be considered in
the differential.

There is limited knowledge of the underlying pathophysiology of DSWPD. Recent
evidence suggests that alteration in the homeostatic regulation of sleep and alertness
may play an important role. The intrinsic circadian period may be abnormally long.
Recent advances in the understanding of the molecular basis for the generation and
entrainment of circadian rhythms, together with the identification of a familial form of
DSWPD, will lead to improved understanding of the mechanisms responsible for this
condition, as well as targeted, evidence-based therapies.
Bibliography
Ancoli-Israel S, Schnierow B, Kelsoe J, Fink R. A pedigree of one family with delayed sleep phase
syndrome. Chronobiol Int 2001;18:831–41.
Archer SN, Carpen JD, Gibson M, et al. Polymorphism in the PER3 promoter associates with diurnal
preference and delayed sleep phase disorder. Sleep 2010;33:695–701.
Bijlenga D, Van Someren EJW, Gruber R, et al. Body temperature, activity, and melatonin profiles in
adults with attention-deficit/hyperactivity disorder and delayed sleep: a case-control study. J Sleep
Res 2013; 22:607–16.
Dagan Y, Stein D, Steinbock M, Yovel I, Hallis D. Frequency of delayed sleep phase syndrome among
hospitalized adolescent psychiatric patients. Psychosom Res 1998;45:15–20.
Gruber R, Sheshko D. Circadian sleep disorders in children and adolescents. In Ivanenko A. (ed), Sleep
and psychiatric disorders in children and adolescents. USA: Informa Healthcare, 2008; 61-78.
197
Gruber R, Fontil L, Bergmame L, et al. Contributions of circadian tendencies and behavioural problems
to sleep onset problems of children with ADHD. BMC Psychiat 2012;12:212.
Kripke DF, Rex KM, Ancoli-Israel S, Nievergelt CM, Klimecki W, Kelsoe JR. Delayed sleep phase cases
and controls. J Circadian Rhythms 2008;6:6.
Marchetti LM, Biello SM, Broomfield NM, Macmahon KM, Espie CA. Who is pre-occupied with
sleep? A comparison of attention bias in people with psychophysiological insomnia, delayed sleep
phase syndrome and good sleepers using the induced change blindness paradigm. J Sleep Res
2006;15:212–21.
Rahman SA, Kayumov L, Tchmoutina EA, Shapiro CM. Clinical efficacy of dim light melatonin onset
testing in diagnosing delayed sleep phase syndrome. Sleep Med 2009;10:549–55.
Reid KJ, Jaksa AA, Eisengart JB, et al. Systematic evaluation of Axis-I DSM diagnoses in delayed sleep
phase disorder and evening-type circadian preference. Sleep Med 2012;13:1171–7.
Shibui K, Uchiyama M, Okawa M. Melatonin rhythms in delayed sleep phase syndrome. J Biol Rhythms
1999;14:72–6.
Uchiyama M, Okawa M, Shibui K, et al. Poor compensatory function for sleep loss as a pathogenic factor
in patients with delayed sleep phase syndrome. Sleep 2000;23:553–8.
Weitzman E, Czeisler C, Coleman R, Spielman, et al. Delayed sleep phase syndrome: a chronobiological
disorder with sleep onset insomnia. Arch Gen Psychiatry 1981;38:737–46.
Wyatt JK, Stepanski EJ, Kirkby J. Circadian phase in delayed sleep phase syndrome: predictors and
temporal stability across multiple assessments. Sleep 2006;29:1075–80.
Advanced Sleep-Wake Phase Disorder

Alternate Names
Advanced sleep phase type, advanced sleep phase disorder, advanced sleep phase
syndrome.
Diagnostic Criteria
A. There is an advance (early timing) in the phase of the major sleep
episode in relation to the desired or required sleep time and wake-up
time, as evidenced by a chronic or recurrent complaint of difficulty
staying awake until the required or desired conventional bedtime,
together with an inability to remain asleep until the required or desired
time for awakening.
B. Symptoms are present for at least three months.
C. When patients are allowed to sleep in accordance with their internal
biological clock, sleep quality and duration are improved with a
consistent but advanced timing of the major sleep episode.
198
D. Sleep log and, whenever possible, actigraphy monitoring for at least

seven days (preferably 14 days) demonstrate a stable advance in the
timing of the habitual sleep period. Both work/school days and free days
must be included within this monitoring.
E. The sleep disturbance is not better explained by another current sleep
Notes
1. Standardized chronotype questionnaires are useful tools to assess the
chronotype of eveningness and morningness. Individuals with advanced
sleep phase score as morning types.
2. Demonstration of an advance (typically greater than two
hours) in the timing of other circadian rhythms such as DLMO
or urinary 6-sulfatoxymelatonin is desirable to confirm the
advanced circadian phase.
Essential Features
Advanced sleep-wake phase disorder (ASWPD) is characterized by a stable advance
(earlier timing) of the major sleep episode, such that habitual sleep onset and offset
occur typically two or more hours prior to required or desired times. Affected individ-
uals complain of early morning or maintenance insomnia and excessive evening sleep-
iness. When affected individuals are allowed to maintain an advanced schedule, sleep
quality and quantity are improved.
Associated Features
Individuals with ASWPD may experience chronic partial sleep loss due to early morning
and maintenance insomnia, particularly if sleep is resisted during early evening.

Familial patterns are discussed below.
Demographics
The prevalence of ASWPD in the general population is unknown. In one large survey
study involving middle-aged adults (40-64 years), the population prevalence was esti-
mated at 1%, although it is unclear what proportion of these subjects would deem their
schedule to be significantly troublesome so as to warrant clinical attention. Until the
identification of familial cohorts (see below), only four cases were described in the lit-
erature. There is no known sex difference.
199

Advanced age appears to be a risk factor. Among a cohort aged 20 to 59 years, older
age was associated with increased morningness, which was determined to be a sig-
nificant mediator of numerous age-sleep relationships. A patient’s ability to sleep
at an abnormal circadian phase (phase tolerance) also impacts the degree to which
adverse symptoms are experienced, and this adaptability varies among individuals.
Conflicting results have been obtained with respect to the relationship between age
and phase tolerance, with some suggesting that age decreases phase tolerance, and
others suggesting that age may actually be protective. Methodological differences
preclude direct comparisons of the investigations, as do wide variations in the age
groups studied. Genetic factors also can influence the development of the condition,
as has been definitively demonstrated among select familial cohorts (see Pathology
and Pathophysiology section). Environmental influences may precipitate, maintain, or
exacerbate the advanced circadian phase, but this has not been proven. ASWPD has
been reported in children with neurodevelopmental disorders. In particular, studies in
children with autism spectrum disorders and Smith-Magenis syndrome have shown
profound alterations in melatonin secretion profiles, which may manifest as a phase
advance with very early morning waking.
Familial Patterns
Various groups have described kindreds with familial ASWPD. These cases may be
characterized by an earlier age of onset. It is not clear whether the familial or non
familial variety of the condition is more common.

Repetitive attempts to resume sleep with awakenings may result in the development of
a comorbid chronic insomnia disorder. Individuals may use alcohol, other sedatives,
and/or stimulants to alleviate symptoms, potentially exacerbating the underlying sleep/
wake disorder. The impact on caregivers of children with neurodevelopmental disor-
ders and ASWPD may be particularly profound.
ASWPD is most frequently encountered among older age groups. An early age of
onset of ASWPD should prompt further probing for a familial pattern. Caregivers may
report that a child wakes “too early” in the morning, which is disruptive to the house-
hold routine and may curtail parental sleep. This is particularly true for younger chil-
dren, who may require adult supervision once they are awake. However, this complaint
regarding the waking pattern is often more related to unrealistic caregiver expecta-
tions regarding an “appropriate” wake time for a young child and/or a developmentally
200
inappropriate early bedtime resulting in prolonged time in bed, rather than to a true
advance in sleep onset and offset. In some cases, children are motivated to wake up
earlier than desired because they are reinforced for this behavior by parental attention
or the opportunity to watch television or utilize other media upon waking. The com-
plaint that a child “falls asleep too early” in the evening, especially in adolescence,
is rare and should raise concerns regarding the possibility of chronically insufficient
sleep and/or a sleep disorder resulting in increased sleep needs. The rarity of observa-
tions of advanced sleep onset and offset times among young children may also be due
in part to societal expectations of earlier bed and wake times for this age group; thus, a
misalignment with circadian preference is less likely.

Possible etiologies include: (1) an alteration in the ability of the circadian clock to
phase delay; (2) a dominant phase advance region of the light phase response curve to
entraining agents; (3) altered strength of entraining agents, such as light exposure at
the appropriate circadian time (voluntarily or involuntarily induced); or (4) a shortened
endogenous circadian period of the pacemaker. Among these proposed mechanisms,
only the latter has been definitively demonstrated among select familial ASWPD sub-
jects. Genetic analyses revealed a missense mutation in a casein kinase (CK1ε) binding
region of a Period gene (hPer2), culminating in hypophosphorylation by CK1ε in vitro.
Hypophosphorylation of the Period protein results in promotion of its transcription
and, ultimately, a decrease in the period length of the clock. However, genetic het-
erogeneity is apparent within familial ASWPD, as demonstrated by the fact that other
cohorts from this same study and another study did not reveal mutations in hPer2. A
separate report of a Japanese familial ASWPD cohort described a missense mutation
in a different casein kinase gene (CKIδ ), which also resulted in decreased enzymatic
activity in vitro. Yet another group described associations between hPer1 and hPer2
polymorphisms and extreme morningness circadian preferences (questionnaire-based),
in the absence of discrete ASWPD.
Objective Findings
Among patients with familial ASWPD, laboratory measures to determine the phase of
circadian rhythms reliably show the expected phase advance in the timing of the nadir
of the temperature rhythm and the dim light melatonin onset, in comparison with unaf-
fected controls. Among those with nonfamilial ASWPD, a wider range of timing of
circadian markers is found, with some values approaching those of unaffected controls.
Polysomnography (though not routinely indicated nor required for the diagnosis),
when performed at preferred (advanced) sleep times, is essentially normal for age. If
201
a conventional bedtime and wake-up time is enforced, however, polysomnographic

recording may show short sleep latency and early awakening with curtailment of
total sleep time.
ASWPD must be distinguished from “normal” sleep patterns, particularly among the
elderly or very young, who often maintain advanced schedules without distress or
impaired functioning. ASWPD must also be distinguished from other causes of early
awakening, including chronic insomnia disorder. Poor sleep hygiene practices, partic-
ularly evening napping among the elderly, and irregularity of the sleep-wake schedule
should also be considered. The possibility of a “free-running” (nonentrained) circadian
rhythm also merits consideration, but patients with this condition are most commonly
blind and report only periodic complaints of insomnia depending on the relative rela-
tionship between the internal rhythm and that of the light/dark cycle. Major depressive
disorder is a common cause of early awakening that must be considered. These patients
do not typically manifest the early evening sleepiness that is characteristic of ASWPD.
As with any sleep disturbances that persists over time, insomnia can develop second-
arily. The Horne-Östberg questionnaire (or other chronotype questionnaire) may assist
in determining the contribution of a morningness circadian preference to the presenting
sleep/wake complaint. The presence of more than one contributing variable seems to
be the norm, and each entity needs to be treated accordingly.

The existing literature suggests that clinicians are unlikely to encounter patients with
stringently defined ASWPD. Until the identification of familial cohorts, only four
cases were described. Various treatment trials also support this contention with demon-
stration of objectively conventional sleep and wake times despite study entry based
on subjective reports of advanced sleep phase. Select studies of patients with sole
complaints of maintenance insomnia/early-morning awakenings have demonstrated
marked advances (earlier timing) of physiologically measured circadian rhythms. The
absence of the early evening sleepiness complaint may be due to the fact that the
timing of sleep onset can be more readily modified than wake time, and is likely to be
more actively resisted due to its propensity to conflict with social or family obligations.
Alternatively, evening sleep that occurs prior to entering the bed/bedroom may not be
reported as such. If it is definitively demonstrated that the evening sleepiness complaint
is not present or is not prominent, the term advance-related sleep complaints may be
used in lieu of ASWPD. If this broader term is used, the condition is observed more
commonly (~7% of respondents in a study of individuals aged 40-64 years). There
is limited knowledge of the pathophysiology of ASWPD (or advance-related sleep
202
complaints) beyond those associated with select cases of familial ASWPD. Increased
use of physiologic circadian assessments will require the development of normative
values to guide practitioners. Knowledge gaps are even more prominent within pediat-
ric and adolescent populations.
Bibliography
Ando K, Kripke DF, Ancoli-Israel S. Delayed and advanced sleep phase symptoms. Isr J Psychiatry Relat
Sci 2002;39:11–8.
Auger R. Advance-related sleep complaints and advanced sleep phase disorder. Sleep Med Clin
2009;4:219–27.
Campbell SS, Dawson D, Anderson MW. Alleviation of sleep maintenance insomnia with timed exposure
to bright light. J Am Geriatr Soc 1993;41:829–36.
Carpen JD, Archer SN, Skene DJ, Smits M, von Schantz M. A single-nucleotide polymorphism in
the 5’-untranslated region of the hPER2 gene is associated with diurnal preference. J Sleep Res
2005;14:293–7.
Carpen JD, von Schantz M, Smits M, Skene DJ, Archer SN. A silent polymorphism in the PER1 gene
associates with extreme diurnal preference in humans. J Hum Genet 2006;51:1122–5.
Carrier J, Monk TH, Buysse DJ, Kupfer DJ. Sleep and morningness-eveningness in the ‘middle’ years of
life (20-59 y). J Sleep Res 1997;6:230–7.
Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human
circadian rhythms. Int J Chronobiol 1976;4:97–110.
Jones C, Campbell SS, Zone SE, et al. Familial advanced sleep phase syndrome: A short-period circadian
rhythm variant in humans. Nature Med 1999;5:1062–5.
Kamei R, Hughes L, Miles L, et al. Advanced-sleep phase syndrome studied in a time isolation facility.
Chronobiologia 1979;6:115.
Moldofsky H, Musisi S, Phillipson EA. Treatment of a case of advanced sleep phase syndrome by phase
advance chronotherapy. Sleep 1986;9:61–5.
Palmer CR, Kripke DF, Savage HC Jr, Cindrich LA, Loving RT, Elliott JA. Efficacy of enhanced evening
light for advanced sleep phase syndrome. Behav Sleep Med 2003;1:213–26.
Sack RL, Auckley D, Auger RR, et al., Circadian rhythm sleep disorders: part II, advanced sleep phase
disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An
American Academy of Sleep Medicine review. Sleep 2007;30:1484–501.
Satoh K, Mishima K, Inoue Y, Ebisawa T, Shimizu T. Two pedigrees of familial advanced sleep phase
syndrome in Japan. Sleep 2003;26:416–7.
Singer CM, Lewy AJ. Case report: use of the dim light melatonin onset in the treatment of ASPS with
bright light [abstract]. Sleep Res 1989;18:445.
Toh K, Jones CR, He Y, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase
syndrome. Science 2001;291:1040–3.
Xu Y, Padiath QS, Shapiro RE, et al. Functional consequences of a CKIdelta mutation causing familial
advanced sleep phase syndrome. Nature 2005;434:640–4.
Yoon IY, Kripke DF, Elliott JA, Youngstedt SD, Rex KM, Hauger RL. Age-related changes of circadian
rhythms and sleep-wake cycles. J Am Geriatr Soc 2003;51:1085–91.
203
Irregular Sleep-Wake Rhythm Disorder

Alternate Names
Irregular sleep-wake cycle disorder, irregular sleep-wake rhythm type.
Diagnostic Criteria
A. The patient or caregiver reports a chronic or recurrent pattern of irregular
sleep and wake episodes throughout the 24-hour period, characterized
by symptoms of insomnia during the scheduled sleep period (usually at
night), excessive sleepiness (napping) during the day, or both.
B. Symptoms are present for at least three months.
C. Sleep log and, whenever possible, actigraphy monitoring for at least
seven days, preferably 14 days, demonstrate no major sleep period and
multiple irregular sleep bouts (at least three) during a 24-hour period.
D. The sleep disturbance is not better explained by another current sleep
Essential Features
Irregular sleep-wake rhythm disorder (ISWRD) is characterized by lack of a clearly
defined circadian rhythm of sleep and wake. The chronic or recurring sleep-wake pattern
is temporally disorganized so that sleep and wake episodes are variable throughout
the 24-hour cycle. Individuals have symptoms of insomnia and excessive sleepiness,
depending on the time of day and their particular sleep-wake pattern.
Associated Features
ISWRD is more commonly observed in neurodegenerative disorders, such as demen-
tia, and in children with developmental disorders. Individuals typically present with
insomnia or excessive sleepiness, depending on the time of day. Sleep and wake epi-
sodes across the 24-hour cycle are fragmented, with the longest sleep bout being typi-
cally less than four hours. Individuals or caregivers report frequent naps throughout the
daytime. Total sleep time across the 24 hours may be normal for age.

Older adults with Alzheimer disease who experience sundowning may represent a clin-
ical subtype with more severe sleep fragmentation and lower circadian rhythm ampli-
tude than those who do not experience sundowning.
204
Demographics
Demographic patterns generally parallel those of associated risk factors such as neuro-
developmental and neurodegenerative disorders.

Neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and
Huntington disease increase the risk for ISWRD. Children with developmental disor-
ders also are at increased risk for ISWRD.
Poor sleep hygiene and lack of exposure to external synchronizing agents such as
light, activity, and social schedules may be predisposing as well as precipitating factors
involved in the development of ISWRD, particularly in the institutionalized elderly.
Familial Patterns

Onset of the condition may occur at any age. Little is known regarding the course and
complications of ISWRD in adults. Due to the multiple awakenings and, in the elderly,
nocturnal wandering, falls can be an indirect complication. In addition to the patient’s
sleep-wake dysfunction, the caregiver’s sleep is often disrupted. The sleep and wake
disruption associated with ISWRD is a common cause of institutionalization.
Caregivers may report that a child with ISWRD has difficulty falling asleep at the
desired bedtime or “falls asleep too early” in the evening, wakes “too early” or has dif-
ficulty waking in the morning, and/or exhibits developmentally inappropriate napping
behavior during the day. Parents may complain that their child sleeps too much or
too little or at inappropriate times. Attempts to keep the child awake during the day,
especially during sedentary activities, are often unsuccessful. The key characteristics
that distinguish ISWRD from other sleep complaints or circadian sleep wake disor-
ders are the lack of prolonged consolidated sleep periods, the often seemingly random
distribution in sleep periods across the 24-hour day, and the marked day-to-day and
week-to-week variability with little in the way of a clearly predictable major sleep-
wake pattern. The impact on caregivers’ sleep and daytime functioning is likely to be
particularly profound.
There may be phenotypes of ISWRD in children, with differences regarding symptom

presentation and severity and chronicity that are related to the underlying condition.
205
For example, it is possible that children with chronic neurologic conditions such as
autism or chromosomal syndromes characterized by developmental delays may have
a more intractable and treatment resistant pattern compared with children with more
self-limited conditions (e.g., postconcussion).
Although ISWRD appears to be rare in typically developing children, it may be envi-

ronmentally or behaviorally induced. This may be seen in children with irregular or
fragmented sleep and wake schedules because of a chaotic household. Children with
developmental disorders are at increased risk for ISWRD. For example, children with
autism, Asperger syndrome, or pervasive developmental disorder not otherwise spec-
ified often have highly irregular sleep patterns. In addition, these children often have
circadian rhythm abnormalities which are both more severe and chronic and they are
at increased risk for relapse.
Both ISWRD and non-24-hour sleep-wake rhythm disorder are also common in
Angelman syndrome, a neurodevelopmental disorder associated with an abnormality of
chromosome 15q11-q13, and have been reported in children with Williams syndrome, a
neurodevelopmental genetic disorder characterized by physical abnormalities and a dis-
tinctive cognitive profile with intellectual disabilities and learning difficulties. Studies in
children and adults with autism spectrum disorders and in children with Smith-Magenis
syndrome have shown profound alterations in melatonin secretion profiles. Smith-
Magenis syndrome is a developmental disorder caused by an abnormality in the short
(p) arm of chromosome 17. It is characterized by mild to moderate intellectual disabil-
ity, distinctive facial features, sleep disturbances, and behavioral problems. Decreased
concentrations of melatonin and its metabolites and daytime elevation and abnormal
rhythm/decreased amplitude of melatonin secretion have been reported in these popu-
lations. These findings may be due to polymorphisms in melatonin enzymes synthesis
or variants in genes coding for melatonin receptors. Other postulated mechanisms for
circadian rhythm disturbances, particularly ISWRD, in these populations include clock
gene polymorphisms and decreased levels of entrainment by social/environmental cues.
There may also be medical conditions that predispose typically developing children
and adolescents to ISWRD. These include traumatic brain injury and chronic fatigue
syndrome. Brain tumor survivors, especially patients who have experienced disrup-
tion in the hypothalamic-pituitary axis, may have an increased prevalence of circadian
rhythm disorders, including ISWRD.
There is very little literature on ISWRD in the pediatric population; prevalence, sex,
and racial/ethnic differences are unknown. Little is known about the natural history
206
of the clinical entity of ISWRD in the pediatric population, including the impact of
various treatment modalities, the likelihood of spontaneous resolution of symptoms, or
long-term consequences. The impact on caregivers of children with neurodevelopmen-
tal disorders and ISWRD may be particularly profound.
The prevalence of ISWRD increases with advancing age, but it is likely that age-re-
lated increase in neurodegenerative disorders, rather than aging per se, explains this
relationship.

The etiology of ISWRD is likely multifactorial. Anatomic or functional abnormal-
ities of the circadian clock can result in an arrhythmic pattern of rest and activity.
Decreased exposure to environmental-entraining agents, such as light and structured
physical and social activities (common in institutionalized elderly, and children with
developmental disorders), also can contribute to the development of an irregular
sleep-wake cycle.
Objective Findings
In addition to a careful sleep history, sleep log and actigraphy monitoring show the
expected lack of a clearly defined circadian rhythm of the sleep-wake cycle, which,
instead, is characterized by multiple irregular sleep and wake bouts throughout the
24-hour period. The use of sleep log and actigraphy is indicated for the identification
of irregular sleep wake rhythm. The irregular sleep-wake pattern is defined as having
multiple sleep bouts (typically 2–4 hours) during a 24-hour period. The pattern may
vary from day to day, thus monitoring for at least seven days and preferably 14 days
may be needed to differentiate the irregular pattern from other circadian rhythm sleep-
wake disorders.
Polysomnography is not required to establish the diagnosis. Polysomnography may be

useful for the diagnosis of other comorbid sleep disorders. Monitoring of other circa-
dian rhythms, such as core body temperature and melatonin for at least 24 hours, may
also show a loss of clear circadian rhythmicity or a low amplitude rhythm.
Poor sleep hygiene and voluntary maintenance of irregular sleep schedules should be
distinguished from irregular sleep-wake pattern. Individuals with irregular sleep-wake
rhythms may present with complaints of insomnia. Careful analysis of sleep logs or
actigraphy will demonstrate multiple irregular periods of sleep throughout the 24-hour
cycle. In both adults and children, other causes of sleep fragmentation and daytime
207
napping, including comorbid medical and psychiatric disorders, other sleep disorders,
or medication should be identified and treated.

There is limited knowledge of the pathophysiology and natural history, response to
treatment, and complications of the disorder in adults and children. Further research
into the relative contribution of alterations in environmental synchronizing agents,
such as light and activity, versus a dysfunction of the endogenous circadian clock in the
development of irregular sleep and wake patterns will lead to improved understanding
of this condition.
Bibliography
Hopkins R, Rindlisbacher P. Fragmentation of activity periods in Alzheimer’s disease. Int J Geriatr
Psychiatry 1992;7:805–12.
McCurry SM, Ancoli-Israel S. Sleep dysfunction in Alzheimer’s disease and other dementias. Curr Treat
Options Neurol 2003;5:261–72.
Okawa M, Mishima K, Hishikawa Y, Hozumi S, Hori H, Takahashi K. Circadian rhythm disorders in
sleep-waking and body temperature in elderly patients with dementia and their treatment. Sleep
1991;14:478–85.
Pillar G, Shahar E, Peled N, Ravid S, Lavie P, Etzioni A. Melatonin improves sleep-wake patterns in
psychomotor retarded children. Pediatr Neurol 2000;23:225–8.
Pollack C, Stokes P. Circadian rest-activity rhythms in demented and non-demented older community
residents and their caregivers. J Am Geriatr Soc 1997;45:446-52.
Shochat T, Martin J, Marler M, Ancoli-Israel S. Illumination levels in nursing home patients: Effects on
sleep and activity rhythms. J Sleep Res 2000;9:373–9.
Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A. Sundowning and circadian rhythms in
Alzheimer’s disease. Am J Psychiatry 2001;158:704–11.
Witting W, Kwa I, Eikelenboom P, Mirmiran M, Swaab D. Alterations in the circadian rest-activity rhythm
in aging and Alzheimer’s disease. Biol Psychiatry 1990;27:563–72.
Zee PC, Vitiello MV. Circadian rhythm sleep disorder: irregular sleep wake rhythm type. Sleep Med Clin
2009;4:213–8.
208
Non-24-Hour Sleep-Wake Rhythm Disorder

Alternate Names
Free-running disorder, nonentrained disorder, hypernychthemeral syndrome.
Diagnostic Criteria
A. There is a history of insomnia, excessive daytime sleepiness, or both,
which alternate with asymptomatic episodes, due to misalignment
between the 24-hour light-dark cycle and the non-entrained endogenous
circadian rhythm of sleep-wake propensity.
B. Symptoms persist over the course of at least three months.
C. Daily sleep logs and actigraphy for at least 14 days, preferably longer for
blind persons, demonstrate a pattern of sleep and wake times that typically
delay each day, with a circadian period that is usually longer than 24 hours.
D. The sleep disturbance is not better explained by another current sleep
Notes
1. Patients may present with a progressively delaying sleep-wake
pattern and intermittent insomnia and excessive sleepiness. Individual
symptoms will depend on when an individual tries to sleep in relation
to the circadian rhythm of sleep-wake propensity. The magnitude of the
daily delay will depend on the endogenous circadian period, and may
range from less than 30 minutes (when the period is close to 24 hours)
to more than an hour (when the period is longer than 25 hours).
2. The symptomatic episode will typically begin with a gradual increase in
sleep latency and delayed sleep onset. As the sleep propensity rhythm
shifts into the daytime, patients will have difficulty falling asleep at
night and staying awake during the day. As the sleep-wake propensity
rhythm drifts further, patients will eventually complain of late afternoon
and evening sleepiness and naps as well as an early sleep onset time and
short sleep latency.
3. Other circadian rhythms, such as the DLMO or urinary 6-sulfatoxy
melatonin rhythm obtained at two time points 2-4 weeks apart (i.e., to
allow sufficient time for the drift to be apparent) is desirable to confirm
the nonentrained rhythm.
209
Essential Features
Non-24-hour sleep-wake disorder (N24SWD) is characterized by symptoms of
insomnia or excessive sleepiness that occur because the intrinsic circadian pace-
maker is not entrained to a 24-hour light/dark cycle. The non-24-hour period can be
shorter or, more typically, longer than 24 hours. Because the endogenous circadian
rhythm is not aligned to the external 24-hour environment, symptoms will depend
on when an individual tries to sleep in relation to the circadian rhythm of sleep
and wake propensity. Individuals typically present with episodes of difficulty falling
asleep or staying asleep, excessive sleepiness or both, alternating with short asymp-
tomatic periods. The severity of individual sleep-wake symptoms can be variable.
Starting with the asymptomatic period when the individual’s endogenous rhythm
is aligned to the external environment and required sleep-wake times, sleep latency
will gradually increase and the individual will complain of sleep-onset insomnia.
As the sleep phase continues to drift so that maximal endogenous sleep propensity
is now in the daytime, individuals will have trouble staying awake during the day
(exhibiting multiple daytime naps) and complain of sleepiness.
Associated Features
Most individuals with nonentrained circadian rhythms are totally blind, and the
failure to entrain circadian rhythms is related to the lack of photic input to the cir-
cadian pacemaker. A small proportion of totally blind people may retain functional
circadian photoreception and entrained rhythms if their blindness is due exclusively
to an outer retina disorder (rod and cone layer) with retention of functional, intrin-
sically photosensitive retinal ganglion cells and the retinohypothalamic pathway.
Some blind people may also be able to entrain to nonphotic cues (e.g., the timing
of physical activity), producing entrainment at an adverse phase in some cases.
In sighted people, social and behavioral factors also play an important role in the
development and maintenance of the disorder, as there is an increased incidence of
psychiatric disorders. Occasionally, the disorder is associated with developmental
intellectual disability or dementia. In sighted individuals, there is often a history of
delayed sleep phase, and decreased exposure to light and structured social and phys-
ical activity. Some sighted individuals with N24SWD also demonstrate increased
sleep duration.
Demographics
It is thought that over half of totally blind individuals have non-24-hour circa-
dian rhythms; 50% to 80% of blind individuals complain of sleep disturbances.
The prevalence, sex, and racial/ethnic differences of N24SWD in adults and
children are unknown.
210

Total blindness is the most common predisposing condition. In sighted people, the dis-
order can be induced by certain environmental conditions, such as decreased or inap-
propriately timed exposure to circadian entraining agents, particularly light. Delayed
sleep-wake phase disorder may predispose to N24SWD in sighted persons. The con-
dition has developed after chronotherapy for DSWPD. This disorder has also been
reported in adults following traumatic brain injury.
Familial Patterns
Caregivers may report that a child has difficulty falling asleep at the desired bedtime
or “falls asleep too early” in the evening, wakes “too early” or has difficulty waking
in the morning and staying awake during the day. Parents may complain that their
child sleeps too much or too little or at inappropriate times. The key characteristics
that distinguish N24SWD from other sleep complaints or circadian sleep wake dis-
orders are twofold: (1) the predictable pattern of misalignment between the child’s
sleep patterns and the light-dark 24-hour cycle (progressive delay in sleep onset-offset
across days to weeks); and (2) periods of apparent “symptom remission” during those
transient intervals when the child’s circadian sleep-wake propensity coincides with the
desired bed and wake times. The impact on caregivers’ sleep and daytime functioning
is often profound.
Although N24SWD is extremely rare in typically developing or sighted children, it

has been reported with some frequency in children with intellectual disabilities and
blindness. For example, children with optic nerve hypoplasia due to a variety of under-
lying causes, especially those children with hypoplastic corpus callosum and comor-
bid severe intellectual and visual impairments, have been reported to have features of
N24SWD. N24SWD has also been described in pediatric patients with Rett syndrome
(a genetic disorder occurring almost exclusively in girls, characterized by severe
developmental regression, language delays, and limited social interactions), autism
spectrum disorders, and Angelman syndrome, a neurodevelopmental disorder asso-
ciated with an abnormality of chromosome 15q11-q13. The common mechanism in
all of these disorders is postulated to be lack of entrainment to the 24-hour day that
results from the failure to perceive and/or attend to social/environmental zeitgebers
(time cues). There have also been several case reports which describe the emergence
of N24SWD in intellectually normal sighted children or adolescents who have limited
or inappropriate exposure to environmental and other entraining cues (e.g., decreased
211
light during the day and/or excessive light exposure in the evening). These individuals
are likely to have significant psychiatric impairments that predispose them to avoid-
ance of social interactions (e.g., anxiety) or medical conditions that involve enforced
prolonged periods of inactivity (traumatic brain injury, chronic fatigue).
Little is known about the natural history of the clinical entity of N24SWD in the pedi-
atric population, including the impact of various treatment modalities, the likelihood of
spontaneous resolution of symptoms, or long-term consequences.
There may be varying phenotypes of N24SWD in children, with differences in regard

to symptom presentation, severity, and chronicity that are related to the underlying
condition. For example, it is likely that children with chronic neurologic conditions
such as blindness or neurodevelopmental disabilities have a more intractable and treat-
ment resistant pattern compared to children with more self-limited conditions (e.g.,
traumatic brain injury).

Onset may occur at any age in blind individuals, coincident with loss of light percep-
tion, and, in congenitally blind children, onset can occur from birth or during infancy.
If untreated, the course is chronic. Attempts to regulate sleep and wake times may
involve the use of alcohol, sedatives-hypnotics, and stimulants, which in turn can exac-
erbate the underlying sleep disorder. Depressive symptoms and mood disorders can be
comorbid conditions, particularly in sighted patients. The adverse effects on school or
work performance, as well as other psychosocial complications, due to a lack of pre-
dictable sleep and wake times and excessive daytime sleepiness, are key motivations
for seeking treatment.

The intrinsic period of the human circadian pacemaker is usually longer than 24 hours
and requires daily input from the environment to maintain synchrony to the 24-hour
day. The light-dark cycle is the most important environmental time cue (zeitgeber) in
humans (as in other species), although nonphotic time cues also play a role in normal
entrainment. A lack of photic input to the circadian pacemaker is clearly the cause of
nonentrained rhythms in totally blind people. It has been suggested that, in sighted
individuals, a systematic delay due to inadequate exposure to light may contribute to
the development of N24SWD. In addition, the disorder may be caused by an extremely
prolonged endogenous circadian period that is outside of the range for entrainment
to the 24-hour cycle or by an alteration in the response of the circadian clock to the
entraining effects of light.
212
Objective Findings
Sleep studies yield different results depending on the degree of synchrony between
sleep times and the circadian pacemaker at the time when the sleep study is performed.
Recording of sleep log and actigraphy over prolonged periods (at least 14 days, but
ideally longer in blind individuals) demonstrate the lack of a stable relationship
between the timing of the sleep-wake cycle and the 24-hour day. When sleep sched-
ules follow the endogenous circadian propensity for sleep and wake, sleep onset and
wake times are typically delayed each day. Serial measurements of circadian rhythms,
such as melatonin, usually show a progressive daily delay of the phase of the rhythm
consistent with a period that is longer than 24 hours.

Totally blind patients with N24SWD are clinically different than sighted patients.
In sighted patients with N24SWD, the circadian period is often 25 hours or longer,
whereas in totally blind patients with the disorder, the circadian period follows
an average period length which is often closer to 24 hours and rarely may be
shorter than 24 hours.
Some individuals with severe DSWPD may demonstrate progressive delay of their
sleep period by 30 minutes or more for several days, and their symptoms may be con-
fused with N24SWD.
Behavioral factors and psychiatric disorders, as well as medical and neurological dis-
orders (especially blindness, but also dementia or mental retardation), may play a role
in the development of N24SWD. In many of these cases, however, multiple physio-
logic, behavioral, and environmental factors contribute to the condition. In the major-
ity of these cases, the disorder should be coded as N24SWD. This includes non-24-
hour sleep-wake patterns that are associated with blindness.

There is only limited knowledge of the underlying pathophysiology of sighted persons
with N24SWD. The primary risk factor in sighted persons appears to be a long circa-
dian period that is beyond the range of entrainment to a 24-hour cycle or a progressive
delay due to inappropriate exposure to light. This risk may explain the overlap between
DSWPD and N24SWD. Future studies are needed to understand the role of genetic
predisposition, environmental or social cues and traumatic brain injury in the develop-
ment of N24SWD, and to delineate other health consequences of the condition. There
are substantial knowledge gaps regarding the prevalence, pathophysiology, clinical
213
presentation, natural history, effective treatment strategies, and prognosis of N24SWD

in children and adolescents compared with adults.
Bibliography
Ayalon L, Borodkin K, Dishon L, Kanety H, Dagan Y. Circadian rhythm sleep disorders following mild
traumatic brain injury. Neurology 2007;68:1136–40.
Boivin DB, James FO, Santo JB, Caliyurt O, Chalk C. Non-24-hour sleep-wake syndrome following a car
accident. Neurology 2003;60:1841–3.
Czeisler CA, Shanahan TL, Klerman EB, et al. Suppression of melatonin secretion in some blind patients
by exposure to bright light. N Engl J Med 1995;332:6–11.
Hayakawa T, Uchiyama M, Kamei Y, et al. Clinical analyses of sighted patients with non-24-hour sleep-
wake syndrome: A study of 57 consecutively diagnosed cases. Sleep 2005;28:945–52.
Lewy AJ, Newsome DA. Different types of melatonin circadian secretory rhythms in some blind subjects.
J Clin Endocrinol Metab 1983;56:1103–7.
Lockley SW, Arendt J, Skene DJ. Visual impairment and circadian rhythm disorders. Dialogues Clin
Neurosci 2007;9:301–14.
Lockley SW, Dijk DJ, Kosti O, Skene DJ, Arendt J. Alertness, mood and performance rhythm disturbances
associated with circadian sleep disorders in the blind. J Sleep Res 2008;17:207–16.
Lockley SW, Skene DJ, Butler LJ, Arendt J. Sleep and activity rhythms are related to circadian phase in
the blind. Sleep 1999;22:616–23.
McArthur A, Lewy A, Sack R. Non-24 hour sleep-wake syndrome in a sighted man: circadian rhythm
studies and efficacy of melatonin treatment. Sleep 1996;19:544–53.
Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and
treatment of circadian rhythm sleep disorders: An American Academy of Sleep Medicine report. Sleep
2007;30:1445–59.
Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind
people: incidence and clinical significance. J Clin Endocrinol Metab 1992;75:127–34.
Uchiyama M, Lockley SW. Non-24-hour sleep-wake syndrome in sighted and blind patients. Sleep Med
Clin 2009;4:195–211.
Uchiyama M, Okawa M, Shibui K, et al. Altered phase relation between sleep timing and core body
temperature rhythm in delayed sleep phase syndrome and non-24-hour sleep-wake syndrome in
humans. Neurosci Lett 2000;294:101–4.
Uchiyama M, Shibui K, Hayakawa T, et al. Larger phase angle between sleep propensity and melatonin
rhythms in sighted humans with non-24-hour sleep-wake syndrome. Sleep 2002;25:83–8.
Zaidi FH, Hull JT, Peirson SN, et al. Short-wavelength light sensitivity of circadian, pupillary, and visual
awareness in humans lacking an outer retina. Curr Biol 2007;17:2122–8.
214
Shift Work Disorder

Alternate Names
Shift work sleep disorder.
Diagnostic Criteria
A. There is a report of insomnia and/or excessive sleepiness, accompanied
by a reduction of total sleep time, which is associated with a recurring
work schedule that overlaps the usual time for sleep.
B. The symptoms have been present and associated with the shift work
schedule for at least three months.
C. Sleep log and actigraphy monitoring (whenever possible and preferably
with concurrent light exposure measurement) for at least 14 days (work
and free days) demonstrate a disturbed sleep and wake pattern.
D. The sleep and/or wake disturbance are not better explained by another
current sleep disorder, medical or neurological disorder, mental disorder,
medication use, poor sleep hygiene, or substance use disorder.
Essential Features
Shift work disorder is characterized by complaints of insomnia or excessive sleepi-
ness that occur in association with work hours that occur, at least in part, during the
usual sleep episode. There are several types of shift-work schedules, including evening
shifts, night shifts, early morning shifts, rotating shifts, split shifts, on-call overnight
duty, and long duration work shifts that include work hours at night. The sleep distur-
bance is most commonly reported in association with night shifts, early morning shifts,
and rotating shifts. Total sleep time is typically curtailed by one to four hours, and
sleep quality is perceived as unsatisfactory in night, early morning, and rotating shift
workers as well as in those who work long-duration shifts. In addition to impairment
of performance at work, reduced alertness may also be associated with consequences
for safety during the work schedule and on the commute to and from work. The sleep
disorder occurs despite attempts to optimize environmental conditions for sleep. The
condition usually persists only for the duration of the shift work schedule. However, in
some individuals, the sleep disturbance may persist beyond the duration of shift work.
Associated Features
Early morning work shifts starting between 4:00 a.m. and 7:00 a.m. can also be asso-
ciated with complaints of difficulty in sleep initiation as well as difficulty awakening.
215
Permanent evening shifts may be primarily associated with sleep maintenance dif-
ficulty. Excessive sleepiness usually occurs during work shifts (mainly night, early
morning, and rotating shifts), often accompanied by the need to nap and by impaired
mental ability due to the reduced alertness. Reduced alertness and increased fatigue
throughout the waking period may be associated with reduced performance capacity,
and with consequences for safety. Also, major portions of free time may have to be
used for recovery of sleep, resulting in adverse social consequences. When compared
with shift workers without shift work disorder, patients with shift work disorder report
greater mood problems, such as impatience, avoidance of interaction with coworkers, a
higher risk of depression, impaired social functioning, and lower coping skills. Patients
with shift work disorder also have a higher risk of subjective health complaints, ulcers,
and substance abuse. Risk for sleepiness-related errors and accidents are highest at
night, especially in the early morning hours. Drowsy driving accident risk is highest
in the morning hours when night shift workers commute home and early morning
workers commute to work.

There are substantial individual differences in the ability to adjust to shift work.
However, mechanisms underlying these individual differences are not known.
Requirement of extended work hours, such as on-call overnight duty and long-duration
work shifts that include work hours at night, represents a specific clinical subtype. In
addition to the circadian misalignment (having to work during the night), sleep loss
and fatigue associated with prolonged continuous work may increase the severity of
excessive sleepiness and performance impairments.
Demographics
The prevalence of shift work disorder depends on the prevalence of shift work in the
population. It has been estimated that approximately 20% of the workforce in indus-
trialized countries is employed in a job that requires shift work. Although the actual
prevalence of clinically significant sleep disturbance and excessive daytime sleepiness
due to work schedules is unknown, the total number of night-shift workers suggests
that an estimated prevalence of 2% to 5% of the general population is reasonable.
The prevalence of shift work disorder among rotating- and night-shift workers has
been estimated to be between ~10% and 38%. These figures do not, however, include
individuals with early morning or split shift work, which may be other at-risk groups.
There is no known sex or racial difference in vulnerability.
216

Depending on the type of shift, circadian preference may influence the ability to adjust
to or tolerate shift work. For example, individuals described as morning types obtain
shorter daytime sleep after a night shift. Persons with comorbid medical, psychiat-
ric, and other sleep disorders such as sleep apnea and individuals with a strong need
for stable hours of sleep may be at particular risk. Social pressures before and after a
work shift also contribute to short sleep durations in shift workers (e.g., social inter-
actions with family and friends, domestic obligations, a second job, and leisure activ-
ities). Social pressures also diminish the desire or willingness to maintain a consis-
tent daytime sleep schedule on days off, thereby reducing the likelihood of circadian
adjustment.
Familial Patterns

The condition is closely linked to work schedules and typically remits when the major
sleep episode is scheduled at a conventional time. Because there are so many different
work schedules, ranging from an occasional overnight shift to regular night work, the
course is quite variable. Because shift work is often combined with extended hours of
duty, fatigue can be a complicating factor. Circadian adaptation is often counteracted
by exposure to light at the wrong time of the day and the tendency of most workers
to resume full daytime activities and nighttime sleep during weekends and vacations.
It has been hypothesized that in some individuals, the condition may lead to chronic
sleep disturbances. Complications may include exacerbation of gastrointestinal, met-
abolic, reproductive, neoplastic, and cardiovascular disorders. Disruptions of social
and family life are frequent. Drug and alcohol dependency may result from attempts to
improve the sleep and wakefulness disturbances produced by shift work. Fatigue and
excessive sleepiness due to the combination of sleep loss and circadian misalignment
pose important safety concerns. The level of alertness required of the worker, in addi-
tion to the intensity of symptoms, needs to be taken into account when evaluating the
disorder. For example, the threshold for intervention may be lower for workers whose
performance is critical for personal or public safety (for example, health care workers
or nuclear power plant or public transport operators).
217

The condition is thought to be directly related to circadian misalignment and sleep
loss. The sleep disturbance is generated by a circadian alerting process that corre-
sponds with the time that the worker needs to sleep. The excessive sleepiness during
the night and early morning appears to be partly related to cumulative sleep loss and
partly due to a decreased circadian alerting signal that corresponds with the work time
and the commute to and from work. Tolerance to night work varies considerably and
may involve differences in the degree of circadian adaptation (“clock resetting”) to a
night-work, day-sleep schedule. Alternatively, tolerance may be related to individual
differences in response to circadian and homeostatic influences on sleep and wakeful-
ness regulation. Environmental and social factors may exacerbate sleep loss associated
with shift work schedules.
Objective Findings
The condition can usually be diagnosed by history. Sleep logs and actigraphy are rec-
ommended to demonstrate a disrupted sleep-wake pattern consistent with shift work
disorder. Polysomnographic recordings, while not required for the diagnosis, are
useful if the etiology of the sleep disturbance is in question (for example to rule out
sleep apnea or narcolepsy). Polysomnography during a typical daytime sleep episode
after a work shift also can be useful to determine the severity of the sleep disruption,
although this is undertaken almost exclusively for research studies of shift work disor-
der. Polysomnography may demonstrate impaired sleep quality, with prolonged sleep
latency, sleep maintenance difficulty, or shortened total sleep time, depending on the
timing of the sleep episode in relation to the underlying phase of the circadian timing
system. The sleep episode may be fragmented, with frequent arousals and awaken-
ings. The Multiple Sleep Latency Test (MSLT) may demonstrate excessive sleepiness
during the time of the work shift. If available, measures of the unmasked melatonin
rhythm are useful to indicate the degree of circadian misalignment.
The excessive sleepiness should be differentiated from that caused by other primary
sleep disorders such as obstructive sleep apnea or narcolepsy. Insufficient sleep related
to conflicting daytime activities (for example, child care) or from environmental
interference with sleep (for example, daytime noise) often contributes to sleepiness.
Sometimes patients with DSWPD may adopt a night-work schedule that is more con-
gruent with their sleep preferences. Insomnia and excessive sleepiness may also suggest
other persistent circadian rhythm sleep-wake disorders. However, historical informa-
tion on the relation between the occurrence of disturbed sleep and work-hour distribu-
tion should provide sufficient information to indicate the correct diagnosis. Increasing
218
frustration, negative expectations, and poor sleep hygiene may predispose the person
to the development of coexisting chronic insomnia disorder that could persist beyond
the shift work schedule (i.e., shift work may represent a precipitating event that leads
to chronic problems with insomnia). Drug and alcohol abuse or dependency may result
from efforts to treat the sleep disturbance.

Although there is sufficient information regarding the prevalence of shift work in indus-
trialized populations, less information is available regarding the actual prevalence of shift
work disorder and its impact on health and safety. Further research is needed to improve
the definition of what constitutes shift work disorder, to develop diagnostic tools for
shift work disorder, to determine the prevalence of shift work disorder using diagnostic
criteria, to elucidate the burden of shift work disorder over and above that which may be
due to shift work in general, to investigate mechanisms underlying the health and safety
consequences of shift work disorder, and to determine which shift workers are at greatest
risk of shift work disorder. Furthermore, there is limited information on the role of age,
sex, and circadian chronotype on the vulnerability to shift work disorder.
Bibliography
Akerstedt T. Shift work and disturbed sleep/wakefulness. Occup Med 2003;53:89–94.
Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak C. The role of actigraphy in the
study of sleep and circadian rhythms. Sleep 2003;26:342–92.
Boggild H, Knutsson A. Shift work, risk factors and cardiovascular disease. Scand J Work Environ Health
1999;25:85–99.
Costa G. Shift work and occupational medicine: an overview. Occup Med 2003;53:83–8.
Drake CL, Roehrs T, Richardson G, Walsh JK, Roth T. Shift work sleep disorder: prevalence and
consequences beyond that of symptomatic day workers. Sleep 2004;27:1453–62.
Drake CL, Wright KP Jr. Shift work, shift work disorder, and jet lag. In: Kryger MH, Roth T, Dement WC,
eds. Principles and practice of sleep medicine, 5th ed. Philadelphia: Elsevier Saunders, 2011:784–98.
Flo E, Pallesen S, Magerøy N, et al. Shift work disorder in nurses--assessment, prevalence and related
health problems. PLoS One 2012;7:e33981.
Folkard S, Tucker P. Shift work, safety and productivity. Occup Med 2003;53:95–101.
Horne J, Reyner L. Vehicle accidents related to sleep: a review. Occup Environ Med 1999;56:289–94.
Knutsson A. Health disorders of shift workers. Occup Environ Med 2003;53:103–8.
Swanson LM, Arnedt JT, Rosekind MR, Belenky G, Balkin TJ, Drake C. Sleep disorders and work
performance: findings from the 2008 National Sleep Foundation Sleep in America poll. J Sleep Res
2011;20:487–94.
Waage S, Moen BE, Pallesen S, et al. Shift work disorder among oil rig workers in the North Sea. Sleep
2009;32:558–65.
Wright KP Jr, Bogan RK, Wyatt JK. Shift work and the assessment and management of shift work disorder
(SWD). Sleep Med Rev 2013;17:41–54.
219
Jet Lag Disorder

Alternate Names
Jet lag, time zone change syndrome, jet lag syndrome, jet lag type.
Diagnostic Criteria
A. There is a complaint of insomnia or excessive daytime sleepiness,
accompanied by a reduction of total sleep time, associated with
transmeridian jet travel across at least two time zones.
B. There is associated impairment of daytime function, general malaise, or
somatic symptoms (e.g., gastrointestinal disturbance) within one to two
days after travel.
C. The sleep disturbance is not better explained by another current sleep
Essential Features
Jet lag disorder is characterized by a temporary mismatch between the timing of the
sleep and wake cycle generated by the endogenous circadian clock and that of the
sleep and wake pattern required by a change in time zone. Individuals complain of
disturbed sleep, sleepiness and fatigue, and impaired daytime function. The severity
and duration of symptoms is dependent on the number of time zones traveled, the
ability to sleep while traveling, exposure to appropriate circadian times cues in the
new environment, tolerance to circadian misalignment when awake during the bio-
logical night, and the direction of the travel. Eastward travel (requiring advancing
circadian rhythms and sleep-wake hours) is usually more difficult to adjust to than
westward travel.
Associated Features
In addition to sleep disturbance and decreased daytime alertness, associated features
may include general malaise and gastrointestinal symptoms. Numerous other variables
related to travel, such as sleep loss, decreased mobility, and alcohol and/or caffeine
intake, contribute to the overall fatigue. Daytime sleepiness can lead to memory diffi-
culties, problems concentrating, driving and flying, and to impaired decision-making.
Sleepiness, sleep disturbance and circadian misalignment associated with jet lag may
also impair athletic performance. Effects of jet lag not only affect travelers, but also
can have significant consequences for airline pilots and flight attendants.
220

There are individual differences in the ability to adjust to rapid shifts in time zones;
however, specific clinical subtypes have not been identified.
Demographics
Jet lag affects all age, sex, and racial groups. Limited available data suggest that older
individuals may experience fewer jet lag symptoms compared with younger individu-
als. However, the data have limitations and further research is needed to better define
the relationship between age and the development of jet lag disorder.
There are no studies on the prevalence of jet lag disorder.

Disturbed sleep and/or shortened sleep duration before and during travel contribute to
jet lag symptoms. Prolonged uncomfortable sitting positions, air quality and pressure,
stress, and excessive caffeine and alcohol consumption may increase the severity of
insomnia and impaired alertness and function associated with transmeridian travel.
Eastward travel often leads to difficulties with sleep onset as attempts to sleep are
made at an earlier internal circadian time when the travelers’ biological clock is pro-
moting alertness (i.e., biological day). Difficulty awakening and daytime sleepiness
and fatigue occur because wake time also occurs at an earlier biological time when
the circadian clock is still promoting sleep (i.e., during the travelers’ biological night).
Westward jet travel often leads to sleepiness and fatigue in the evening hours of the
new time zone as the internal circadian clock of the traveler is promoting sleep (i.e.,
biological night). Sleep disturbance in the new time zone is typically manifest as a
sleep maintenance issue with early morning awakenings and difficulty returning to
sleep because the internal circadian clock of the traveler is promoting wakefulness
during the sleep episode (i.e., biological day).
Basic circadian science principles suggest that inappropriately timed exposure to light
and darkness during and immediately after jet travel can shift the circadian clock in the
wrong direction, thereby increasing the duration of jet lag symptoms. Time at destina-
tion upon arrival may also influence jet lag symptoms with fewer symptoms reported
following midday arrivals after eastward travel.
An individual’s innate circadian preference may also confer a greater or lesser ability
to adjust to a particular time shift, but this finding has not been systematically assessed.
221
Jet lag is often reported to be worse after eastward than westward travel. Westward
travel may generally be easier because the genetically determined period of the cir-
cadian clock in humans is on average longer than 24 hours. A circadian period longer
than 24 hours is associated with a circadian drive or physiological tendency for bed and
wake times to be later, thus making it easier to shift the circadian clock during west-
ward travel to more delayed sleep and wake times. However, 20% to 25% of humans
have circadian periods that are near to, or shorter than, 24 hours, and these individuals
may find it easier to adapt to eastward travel.
Familial Patterns

Jet lag is usually a temporary condition. Symptoms begin approximately one to two
days after air travel across at least two time zones and are self-limited. The severity
and duration of symptoms are usually in proportion to the number of time zones trav-
eled and the direction of travel. It is estimated that it takes one day per time zone for
circadian rhythms to adjust to the local time. However, if traveling more than six time
zones, circadian rhythms may shift in the opposite direction, resulting in a prolonged
period of adjustment that may last up to several weeks and increased severity of jet-lag
symptoms. Exposure to light at inappropriate times may prolong the time of adjust-
ment by shifting the circadian rhythms in the opposite direction. Menstrual and repro-
ductive problems have been associated with frequent transmeridian travel in female
airline personnel. Poor sleep hygiene practices may perpetuate sleep/wake complaints,
and repetitive failed attempts to initiate or maintain sleep at desired times may predis-
pose to the development of insomnia disorder.
The effect of age on the development or severity of jet lag disorder symptoms is unknown.

The symptoms of jet lag disorder are due to both desynchronization of endogenous
circadian rhythms with local time and sleep disturbance. The severity of symptoms
can be influenced by the environment and behaviors of the traveler. Factors inherent
to jet travel, including prolonged time spent sitting in a confined space, ability to sleep
on long-haul flights, decreased physical activity, and a low oxygen environment, may
influence severity.
222
Objective Findings
Objective laboratory testing usually is not indicated. When performed, polysomnogra-
phy or actigraphy shows disturbed sleep and a loss of a normal sleep-wake pattern or
a mismatch between the timing of sleep and wakefulness with the desired sleep-wake
pattern of the local time.
A thorough history and physical examination should be performed to exclude other
mental, physical, or sleep disorders. Somatic complaints of gastrointestinal symptoms
may indicate an underlying medical condition. When jet lag symptoms persist, increas-
ing frustration, negative expectations, and poor sleep hygiene may predispose the indi-
vidual to the development of chronic insomnia disorder.

Understanding mechanisms of individual differences in vulnerability and tolerance to
disturbed sleep and wakefulness during jet lag is necessary. Development of effective
and practical strategies to combat jet-lag symptoms and improve sleep, performance
and safety are needed.
It is unknown how expression of the disorder varies across the life span.
Bibliography
Auger RR, Morgenthaler TI. Jet lag and other sleep disorders relevant to the traveler. Travel Med Infect
Dis 2009;7:60–8.
Burgess HJ, Crowley SJ, Gazda CJ, Fogg LF. Eastman CI. Preflight adjustment to eastward travel: 3 days
of advancing sleep with and without morning bright light. J Biol Rhythms 2003;18:318–28.
Daan S, Lewy AJ. Scheduled exposure to daylight: a potential strategy to reduce “jet lag” following
transmeridian flight. Psychopharmacol Bull 1984;20:566–8.
Dawson D, Campbell SS. Timed exposure to bright light improves sleep and alertness during simulated
night shifts. Sleep 1991;14:511–6.
Drake CL, Wright KP Jr. Shift work, shift work disorder, and jet lag. In: Kryger MH, Roth T, Dement WC,
eds. Principles and practice of sleep medicine, 5th ed. Philadelphia: Elsevier Saunders, 2011; 784–98.
Eastman CI, Gazda CJ, Burgess HJ, Crowley SJ, Fogg LF. Advancing circadian rhythms before eastward
flight: a strategy to prevent or reduce jet lag. Sleep 2005;28:33–44.
Moline ML, Pollak CP, Monk TH, et al. Age-related differences in recovery from simulated jet lag. Sleep
1992;15:28–40.
Muhm, JM, Rock PB, McMullin DL, et al. Effect of aircraft-cabin altitude on passenger discomfort. N
Engl J Med 2007;357:18–27.
Sack R, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: part i, basic principles, shift work
and jet lag: An American Academy of Sleep Medicine Review. Sleep 2007;30:1456–79.
Suhner A, Schlagenhauf P, Höfer I, Johnson R, Tschopp A, Steffen R. Effectiveness and tolerability of
melatonin and zolpidem for the alleviation of jet lag. Aviat Space Environ Med 2001;72:638–46.
223
Tresguerres JA, Ariznavarreta C, Granados B, et al. Circadian urinary 6-sulphatoxymelatonin,

cortisol excretion and locomotor activity in airline pilots during transmeridian flights. J Pineal Res
2001;31:16–22.
Waterhouse J, Edwards B, Nevill A, et al. Identifying some determinants of “jet lag” and its symptoms: a
study of athletes and other travellers. Br J Sports Med 2002;36:54–60.
Circadian Sleep-Wake Disorder Not Otherwise

Specified (NOS)
Patients who meet all of the general diagnostic criteria for a CRSWD but do not meet
criteria for one of the specific types of circadian rhythm sleep-wake disorders are clas-
sified here. This diagnosis is intended primarily for patients with alterations in circa-
dian sleep-wake patterns due to underlying medical, neurologic, and psychiatric dis-
orders. The underlying neurological, psychiatric, or medical condition is typically the
precipitating factor. Patients may present with a variety of symptoms, including dis-
turbed nocturnal sleep and excessive sleepiness. The sleep-wake pattern may range
from alterations in the phase of the sleep-wake cycle to irregular sleep-wake pattern.
Recordings of sleep logs and actigraphy over a period of at least seven days, preferably
for 14 days or longer, demonstrate sleep onsets and sleep offsets that may be delayed
or advanced relative to conventional times, irregular or non-24-hour.
Sleep-wake disturbances are common in patients with neurodegenerative disorders

(Alzheimer disease, Parkinson disease, Huntington disease), as well as neurodevelop-
mental disorders. Sleep-wake disturbances associated with these disorders may exhibit
some features of irregular sleep-wake patterns, but do not have a consistent pattern of
at least three sleep periods per day. The particular features of this disorder vary with
the type of underlying medical, psychiatric, or neurological condition. The disruption
of the sleep-wake cycle has been implicated in the etiology of sundowning and noc-
turnal wandering in older adults with dementia. Patients with Parkinson disease may
exhibit various types of circadian-rhythm alterations. In addition, motor fluctuations
can exhibit marked diurnal fluctuation in patients with Parkinson disease.
224
Parasomnias
NREM-Related Parasomnias
Disorders of Arousal (From NREM Sleep)..................................................228
Confusional Arousals...................................................................................229
Sleepwalking...............................................................................................229
Sleep Terrors...............................................................................................230
Sleep Related Eating Disorder....................................................................240
REM-Related Parasomnias
REM Sleep Behavior Disorder....................................................................246
Recurrent Isolated Sleep Paralysis.............................................................254
Nightmare Disorder.....................................................................................257
Other Parasomnias
Exploding Head Syndrome..........................................................................264
Sleep Related Hallucinations......................................................................267
Sleep Enuresis............................................................................................270
Parasomnia Due to a Medical Disorder.......................................................276
Parasomnia Due to a Medication or Substance..........................................276
Parasomnia, Unspecified ...........................................................................278

Sleep Talking...............................................................................................279
Parasomnias are undesirable physical events or experiences that occur during entry
into sleep, within sleep, or during arousal from sleep. Parasomnias may occur during
non-rapid eye movement sleep (NREM), rapid eye movement sleep (REM), or during
transitions to and from sleep.
Parasomnias encompass abnormal sleep related complex movements, behaviors, emo-

tions, perceptions, dreams, and autonomic nervous system activity. Parasomnias are
clinical disorders because of the resulting injuries, sleep disruption, adverse health
effects, and untoward psychosocial effects. The clinical consequences of the parasom-
nias can affect the patient, the bed partner, or both.
Human consciousness consists of three essential states: Wake, NREM sleep, and REM
sleep. The three states are modulated by a host of influences including the degree of ami-
nergic and cholinergic neurochemical bias, central nervous system (CNS) activation,
225
Parasomnias
and the degree of endogenous versus exogenous input. Under normal physiologic
conditions, which include homeostatic drive and circadian rhythmicity, the process of
state declaration is maintained in a stable and predictable fashion throughout a 24-hour
period. However, as the sleep-wake cycle oscillates, the normally distinct states of con-
sciousness may be rendered into a state that is not fully declared, resulting in a tempo-
rary unstable state of dissociation. Thus, sleep and wake can be viewed as occurring on
a spectrum rather than being entirely dichotomous states.
Parasomnias are the result of such state dissociation. Recent research has shown that com-
binations of one or more of these states do occur and may result in unstable states of altered
consciousness manifesting as parasomnias. Disorders of arousal, such as sleepwalking,
sleep terrors, and confusional arousals are an admixture of wakefulness and NREM sleep.
Higher cognitive function is severely impaired, if not absent, while the potential for motor
capacity has, for the most part, been retained. REM sleep behavior disorder (RBD) is
an admixture of REM sleep coupled with waking or NREM sleep levels of tonic EMG
activity. All three states may be present in the same individual as an overlap of disorders.
The comingling of basic states of consciousness is the result of different forms of

pathophysiology. In disorders of arousal, no identifiable neuropathology is present,
but functional changes in cerebral activity during NREM sleep are present, essentially
resulting in a brain in which certain areas are deactivated (asleep) and others remain
activated (awake). This CNS activation, with concomitant skeletal muscle and auto-
nomic nervous system activation, is believed to reflect a functional disabling of, or
damage to, brain areas usually responsible for the inhibition of these activities during
sleep. Additionally, sleep inertia, sleep state instability, and locomotor/central pattern
generators are thought to contribute to the occurrence of NREM parasomnias.
NREM disorders of arousal frequently appear to involve the disinhibition of “basic

drive states” such as feeding, sex, and aggression. Here, it has been postulated that
central pattern generators elicit primal fixed action patterns that would otherwise have
been inhibited by the prefrontal cortex during wake. In this regard, aggression is typ-
ically abrupt in onset and characterized by apparent instinctual defensive posturing as
opposed to behaviors that are complex and procedural. These can emerge in pathologic
forms with the parasomnias, as seen with sleep related aggression and locomotion,
sleep related eating disorder (SRED), and abnormal sleep related sexual behaviors.
In contrast, RBD often results from serious neuropathology. Initially, this neuropathology
affects the area of the brain responsible for inhibiting muscle tone during REM sleep. As
a result, dreams may be enacted. In the case of REM-related behaviors, the experience
226
Parasomnias
and activity reflect the actual, often aggressive content of a dream. It is frequently pos-
sible to correlate observed movements with later descriptions of the dream. The initial
appearance of RBD symptoms is often followed years later by the development of neu-
rodegenerative disorders, particularly Parkinson disease and related synucleinopathies.
Abnormal sleep related movements comprise a separate category of disorders, which is

detailed in the sleep related movement disorders section. Unlike the parasomnias, which typ-
ically entail more complex movements and behavior, the movement disorders encompass
a broad range of predominantly simple motoric activities: myoclonic, repetitive, rocking,
rhythmic, grinding, cramping, fragmentary, dystonic, or dyskinetic movements or tremors,
which are not usually associated with dream mentation or experiential concomitants.
Parasomnias involve sleep related behaviors and experiences over which there is no
conscious deliberate control. There are ten core categories of parasomnias listed in the
International Classification of Sleep Disorders, 3rd Edition. Only one of the core cat-
egories, RBD, requires video-polysomnographic documentation as one of the essen-
tial diagnostic criteria. However, for most of the other parasomnias, polysomnographic
monitoring can provide corroborative documentation in support of the clinical diagnosis.
Considerable advances have taken place in understanding the neurophysiologic

aspects of abnormal arousals from slow wave sleep associated with the disorders of
arousal. Advances in the clinical understanding of these NREM sleep parasomnias
have occurred as well, particularly in regard to their prevalence and severity in adults.
In regard to RBD, long-term delayed emergence of neurodegeneration has frequently
been found in middle-aged and older adults following onset of RBD. When combined
with thorough clinical interviews, video-polysomnography a powerful discriminating
tool for identifying the cause of sleep related injury in adults.
Bibliography
Cramer Bornemann MA, Mahowald MW. Sleep forensics. In: Kryger MH, Roth T, Dement WC, eds.
Principles and practice of sleep medicine, 5th ed. Philadelphia: Elsevier Saunders, 2010.
Hobson JA. REM sleep and dreaming: towards a theory of protoconsciousness. Nat Rev Neurosci
2009;10:803–13.
Ohayon M, Caulet M, Priest R. Violent behavior during sleep. J Clin Psychiatry 1997;58:369–76.
Ohayon M, Mahowald M, Dauvilliers Y, Krystal A, Leger D. Prevalence and comorbidity of nocturnal
wandering in the US adult general population. Neurology 2012;78:1583–9.
Schenck C, Milner D, Hurwitz T, Bundlie S, Mahowald M. A polysomnographic and clinical report on
sleep related injury in 100 adult patients. Am J Psychiatry 1989;146:1166–73.
Siclari F, Khatami R, Urbaniok F, et al. Violence in sleep. Brain 2010;133:3494–509.
Tassinari C, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-
limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26:s225–32.
227
Parasomnias
NREM-Related Parasomnias
Disorders of Arousal (From NREM Sleep)

This group of NREM-related disorders, which includes confusional arousals, sleep-
walking, and sleep terrors, arise as a result of incomplete arousals from deep sleep. The
conditions share: (1) similar genetic and familial patterns; (2) similar pathophysiology
of partial arousals from deep sleep; and (3) similar priming by sleep deprivation and
biopsychosocial stressors. Disorders of arousal are: (1) not secondary to psychiatric
disorders; (2) not generally secondary to neuropathology or head injury; (3) associated
with absent or minimal cognitive functioning; (4) associated with amnesia for the prior
episode; and (5) may be triggered by sound, touch, or other stimuli.
General Diagnostic Criteria for Disorders of Arousal

A. Recurrent episodes of incomplete awakening from sleep.1
B. Inappropriate or absent responsiveness to efforts of others to intervene
or redirect the person during the episode.
C. Limited (e.g., a single visual scene) or no associated cognition or dream
imagery.
D. Partial or complete amnesia for the episode.
E. The disturbance is not better explained by another sleep disorder, mental
disorder, medical condition, medication, or substance use.
Notes
1. The events usually occur during the first third of the major sleep
episode.
2. The individual may continue to appear confused and disoriented for
several minutes or longer following the episode.
228
Parasomnias
Confusional Arousals
Alternate Names
Elpenor syndrome.
Diagnostic Criteria
A. The disorder meets general criteria for NREM disorders of arousal.
B. The episodes are characterized by mental confusion or confused
behavior that occurs while the patient is in bed.
C. There is an absence of terror or ambulation outside of the bed.
Notes
1. There is typically a lack of autonomic arousal such as mydriasis,
tachycardia, tachypnea, and diaphoresis during an episode.
Sleepwalking
Alternate Names
Somnambulism.
Diagnostic Criteria
B. The arousals are associated with ambulation and other complex
behaviors out of bed.
229
Parasomnias
Sleep Terrors
Alternate Names
Night terrors, pavor nocturnus.
Diagnostic Criteria
B. The arousals are characterized by episodes of abrupt terror, typically
beginning with an alarming vocalization such as a frightening scream.
C. There is intense fear and signs of autonomic arousal, including
mydriasis, tachycardia, tachypnea, and diaphoresis during an episode.
Essential Features
Disorders of arousal consist of complex behaviors that are usually initiated during
partial arousals from slow wave (N3) sleep. Most episodes are brief, but they may
last as long as 30 to 40 minutes in some children. Sleep talking and shouting may
accompany these events. The eyes are usually open during an episode and, not uncom-
monly, are wide open with a confused “glassy” stare. The patient with a disorder of
arousal may be very difficult to awaken and, when awakened, is often confused. There
is usually amnesia for these episodes, although adults may remember fragments of
episodes. Dream-like mentation is sometimes reported in adults. Other high-level cog-
nitive functions such as attention, planning, social interaction, and intent are absent.
Because disorders of arousal usually originate from slow wave sleep, they most often
emerge in the first third or first half of the typical sleep period. They may occur during
other times of increased slow wave sleep, such as during recovery sleep following
sleep deprivation. They rarely arise from a daytime nap.
Disorders of arousal are encountered most commonly in children and typically resolve
by puberty but may persist (or, infrequently, arise de novo) in adolescence or adulthood.
Confusional Arousals: Confusional arousals, unlike sleepwalking, occur with the

patient in bed. When the patient leaves the bed, sleepwalking has been initiated.
Confusional arousals often start with the individual sitting up in bed and looking about
in a confused manner.
Sleepwalking: Sleepwalking episodes typically begin as confusional arousals.

Sleepwalking episodes can also begin with the individual immediately leaving the
230
Parasomnias
bed and walking or even “bolting” from the bed and running. Highly inappropriate,
agitated, resistive, belligerent, or violent behavior can also occur. Behaviors can be
simple and non–goal-directed, or complex and protracted, and may involve inappro-
priate sexual activity with oneself or an individual in close proximity such as a bed
partner. The ambulation may terminate spontaneously, at times in inappropriate places,
or the sleepwalker may return to bed, lie down, and continue to sleep without reach-
ing conscious awareness at any point. The sleepwalking individual is disoriented in
time and place, with slow speech, with severely diminished mentation, and blunted
response to questions or requests. There is often prominent anterograde and retrograde
memory impairment. Despite diminished external perception as a result of blockade of
sensory input, the individual may appear to be awake during some or most of a disorder
of arousal with reduced vigilance and impaired cognitive response.
Sleep Terrors: Sleep terrors differ from other disorders of arousal in that the events are
often accompanied by a cry or piercing scream, accompanied by autonomic nervous
system and behavioral manifestations of intense fear. There is often intense autonomic
discharge, with tachycardia, tachypnea, flushing of the skin, diaphoresis, mydriasis,
and increased muscle tone. The person usually sits up in bed; is unresponsive to exter-
nal stimuli; and, if awakened, is confused and disoriented. However, bolting out of bed
and running is not uncommon in adults and also can be associated with violent behav-
iors, particularly if attempts are made to block or restrain the individual. The sleep
terror episode may be accompanied by incoherent vocalizations. Sometimes there is
prolonged inconsolability associated with a sleep terror in children or adults.
Associated Features
Disorders of arousal are devoid of higher cognitive functions such as planning, memory
from before an incident, formation of a memory during an incident, true social inter-
action, or recognition of others. Patients exhibiting disorders of arousal are not con-
sciously aware and behaviors are often thought to be “automatic” in nature. Self-injury
may occur as well as injury to others in close proximity.
Disorders of arousal, in particular sleepwalking, can involve normal, routine behav-

iors that are inappropriate only in regard to their timing. More often, however, sleep-
walking involves inappropriate behaviors, such as urinating in a wastebasket, moving
furniture around haphazardly, or climbing out a window. Sleepwalkers are sometimes
able to navigate in familiar surroundings, but are prone to bumping into objects or
falling down. A sudden arousal consistent with sleep terrors may segue rapidly into
agitated sleepwalking and panicky running and other potentially dangerous behav-
iors. Self-injury is not unusual and when resulting in death has been given the term of
231
Parasomnias
“parasomnia pseudosuicide.” Cuts, bruises, and other injuries may occur—often to the
surprise of the sleepwalker once awake. Sleepwalkers are reported to have a high tol-
erance for pain. Knife cuts, burns, and other self-injury sustained during sleepwalking
may not awaken them.
Violence to others also can occur with adult sleepwalking, especially in men. The
sleepwalker does not generally seek out the eventual victim of violence. More typi-
cally, a person attempting to block, grab, restrain, redirect or awaken a sleepwalker
during an episode may be violently attacked, even if they are family members or
friends. This may result in a form of primitive defensive aggression including pushing,
hitting, kicking, or throwing objects. This pattern also has been reported in the sleep
laboratory when technical personnel have attempted to return sleepwalking patients to
bed. In extreme cases, victims have been stabbed with knives or blunt objects. Such
inappropriate and antisocial behaviors have legal and forensic implications, as sleep-
walkers have been arrested and charged with assault and battery, attempted homicide,
homicide, and sexual assault with indecency.
The child with calm sleepwalking may quietly walk toward a light or to the parents’
bedroom. Occasionally, children will walk toward a window or door or even go outside,
with obvious attendant risk.
Clinical or Pathophysiological Subtypes

Sleep related abnormal sexual behaviors are primarily classified as confusional arous-
als in that they typically occur without any behaviors outside of the bed (or chosen sleep-
ing accommodation), but have also been less commonly associated with sleepwalking.
Other terms for this condition include “atypical sexual behavior during sleep,” “sexsom-
nia,” and “sleep sex.” Sleep related abnormal sexual behaviors often have major inter-
personal, clinical, and occasional criminal consequences. The set of abnormal sexual
behaviors during disordered arousals includes prolonged or violent masturbation, sexual
molestation and assaults (of minors and adults), initiation of sexual intercourse irre-
spective of the menstrual status of the bed partner (in contrast to waking intercourse for
those individuals), and loud (sexual) vocalizations during sleep—followed by morning
amnesia. The preponderance of patients have also been diagnosed with a NREM sleep
parasomnia, most often confusional arousals alone but on occasion with sleepwalking,
sleep related driving, or sleep related eating disorder. Obstructive sleep apnea (OSA) is
another recognized precipitant of sleep related abnormal sexual behaviors.
The presence of an overlap disorder, in which RBD and a partial arousal disorder
(sleepwalking or sleep terrors) are comorbid in a patient, may complicate diagnosis of
232
Parasomnias
each condition. Careful review of history and use of polysomnography may facilitate
identification of this presentation.
Demographics
There is no sex difference with disorders of arousals. They are especially prevalent
among children and adults younger than 35 years. The prevalence rate of confusional
arousals and sleepwalking are similar.
The prevalence of confusional arousals in children three to 13 years of age in a large

population-based study was 17.3%. Lifetime prevalence of confusional arousals has
recently been reported as 18.5% (16.1-20.9 confidence interval). The prevalence
among adults older than 15 years is 2.9% to 4.2%.
The lifetime prevalence of sleepwalking is as high as 18.3%. A recent study of “noctur-

nal wandering” that likely included a large percentage of sleepwalkers reported a life-
time prevalence of 29.2%. A Swedish study of children aged 6-16 years found the inci-
dence of sleepwalking to be 40%. Up to 4.3% of adults sleepwalk. In one series, one
third of 54 adult patients with injurious sleepwalking (with or without night terrors)
began sleepwalking after 16 years of age.
The prevalence of sleep terrors has not been studied as thoroughly. Prevalence rates
of 1% to 6.5% in children and 2.2% in adults have been reported, with a virtually
constant prevalence rate of 2.3% to 2.6% in the 15-year-old to 64-year-old age
group, before falling to 1% in the older than 65 years age group. Other studies have
reported the intermittent appearance of sleep terrors in 25% of children younger
than five years.

Disorders of arousal are most often evaluated in terms of predisposing, priming, and
precipitating (triggering) factors. Most often a simultaneous co-occurrence of these
factors is thought necessary in order for a disorder of arousal occur. However, the
reason a disorder of arousal occurs on one night and not others is not fully understood.
A genetic predisposition has been hypothesized and several studies have identified dif-
ferent genetic loci and modes of inheritance (see Familial Pattern, below). In childhood,
disorder of arousal can usually be considered an expected and normal developmental
sleep phenomenon, apart from those cases with clinical consequences. However, dis-
orders of arousal that persist beyond adolescence or begin in adulthood can often be
problematic and may require clinical attention.
233
Parasomnias
Many priming factors for disorders of arousal, in particular sleepwalking, have

been identified. Sleep deprivation and situational stress are the most potent factors.
Hyperthyroidism, migraines, head injury, encephalitis, stroke, and other conditions
have also been reported much more rarely as potential priming factors.
OSA and other sleep related respiratory events are increasingly recognized precipitants
of disorders of arousal in both children and adults. Treatment of these comorbid con-
ditions may reduce or eliminate the occurrence of disorders of arousal. Disorders of
arousal may also be triggered by environmental stimuli such as telephone calls, pagers,
messaging from electronic devices, and a host of other stimuli. It is clinically important
to note that first responders, physicians, and others on call may be vulnerable to such
stimuli, increasing the potential for inappropriate responses and behavior.
Travel, sleeping in unfamiliar surroundings, febrile states in children, physical or emo-

tional stress in adults, the premenstrual period in women, as well as the use of psycho-
tropic medications such as lithium carbonate, phenothiazines, anticholinergic agents,
and sedative/hypnotic agents have been associated with the onset of sleepwalking, but
a causal relationship has yet to be established. Alcohol has been identified in previous
reports as a potential sleepwalking trigger. However, the amnesia associated with dis-
orders of arousal makes these reports unreliable. More recent evidence-based reviews
have found no compelling relationship between alcohol and disorders of arousal.
Internal stimuli, such as a distended bladder, or external stimuli, such as noise or light,
can also precipitate episodes.
There is no significant association between childhood disorders of arousal and psycho-

pathology. In adult sleepwalking, although a considerable number of patients may have
a past or current history of nonpsychotic depressive and anxiety disorders, it does not
appear that the psychiatric disorder and sleepwalking, in particular, are tightly linked.
In addition, when the two conditions emerge in close temporal proximity, control of
the psychiatric disorder often does not control the parasomnia, for which separate
treatment is required.
Familial Pattern
Genetic factors appear to play an important role in all of the disorders of arousal.
However, published research data exist primarily for patients who sleepwalk.
Sleepwalking has a familial pattern. The rate of childhood sleepwalking increases in
relation to the number of affected parents: 22% when neither parent has the disor-
der, 45% if one parent is affected, and 60% when both are affected. Population-based
studies of monozygotic and dizygotic twins suggest that genetic factors play a role
234
Parasomnias
in 65% of cases of sleepwalking. Different models of modes of inheritance includ-

ing multifactorial, recessive with incomplete penetrance, and autosomal dominant trait
with reduced penetrance have been proposed, based primarily on analysis of family
histories. However, these finding are not sufficiently specific to be used for diagnostic
testing. Further, the mechanisms by which a genetic predisposition for confusional
arousal or other related disorders contributes to their occurrence are not known.

Confusional arousals most often appear in early childhood around the age of two
years. This childhood form of confusional arousals is typically benign, but may cause
concern in parents. Confusional arousals of early childhood diminish in occurrence
after the age of five years.
Sleepwalking can begin as soon as a child is able to walk but may begin at almost any
time in the life cycle, including as late as the seventh decade. Sleepwalking is often
preceded by confusional arousals. Childhood sleepwalking usually disappears sponta-
neously around puberty but may persist into adolescence. Episodes can occur sporad-
ically or with high frequency, such as multiple times nightly for several consecutive
nights. Sleepwalking may occur for the first time in adulthood or may recur in adult-
hood during periods of sleep deprivation or stress.
Sleep terrors usually emerge in children aged four to 12 years (but can also emerge
in adulthood) and tend to resolve spontaneously by early adolescence, as does sleep-
walking. Social embarrassment over the sleep terrors can impair social relationships in
children and adults. Serious or even lethal injuries can occur.
As noted above, disorders of arousal most often occur initially in childhood and
decrease in occurrence steadily until young adulthood. However, they may occur for
the first time in adulthood or reappear after many asymptomatic years, often related to
stress, sleep deprivation, or development of another sleep disorder.

The overwhelming majority of individuals with disorders of arousal do not have neuro-
logical or psychological pathology. There are rare reported cases of confusional arous-
als associated with brain lesions in areas subserving arousal, such as the posterior
hypothalamus, midbrain reticular area, and periventricular gray matter. However, data
from a single patient with confusional arousals suggest that they may be due to a func-
tional abnormality in the brain that leaves some regions, such as hippocampus and
235
Parasomnias
frontal associative cortices, asleep, while other parts of the brain such as motor, cingu-
late, insular, amygdala, and temporopolar cortices, are active or awake.
It is generally considered that disorders of arousal represent a dissociation of different

regions of the brain in addition to activation of locomotor centers/central pattern gen-
erators, accompanied by sleep inertia and sleep state instability.
Objective Findings
Although not routinely indicated for the evaluation of typical, uncomplicated, and non-
injurious parasomnias, polysomnographic studies demonstrate that disorders of arousal
typically begin after an arousal from slow wave sleep, most commonly toward the end
of the first or second episode of slow wave sleep. Occasionally, disorders of arousal
can emerge from stage N2 sleep. Heart rate acceleration, increased muscle tone, and
muscle twitching may rarely be observed before a slow wave sleep arousal.
Diagnostic polysomnography may note high-amplitude hypersynchronous delta waves

and frequent arousals from slow wave sleep. However, these findings have a low spec-
ificity and have been reported to occur in other disorders such as OSA and in asymp-
tomatic individuals. On rare occasions, polysomnography can provide support for the
clinical diagnosis by documenting arousals from slow wave sleep accompanied by
behaviors typical of confusional arousals. Out-of-bed behaviors are very rare in the
sleep laboratory. Changes between the home and sleep laboratory environment, timing,
habits, and other factors may serve to decrease the likelihood of sleepwalking in the
laboratory. Time-synchronized video-polysomnographic (vPSG) recording is essen-
tial if polysomnography (PSG) is to be used as support for the diagnosis. However, a
normal PSG does not rule out the diagnosis of a disorder of arousal. In adults in whom
there are only one or two episodes per year, there is a very low likelihood of occurrence
in the sleep laboratory. However, the sleep study may assist in ruling out disorders
with similar presentations, such as RBD or nocturnal epilepsy. PSG may further be
useful by identifying potential triggers, such as sleep related breathing disorder or peri-
odic leg movements that are currently present. Provocative sleep studies using sleep
deprivation and acoustic stimuli have been used for research purposes, with success.
However, the sensitivity and specificity of these techniques for clinical purposes are
unknown.
Postarousal EEG recordings in children and adults with sleepwalking often demon-
strate a partial or virtually complete persistence of sleep, with diffuse, rhythmic delta
activity; diffuse delta and theta activity; mixed delta, theta, alpha, and beta activity; or
at times alpha and beta activity.
236
Parasomnias
PSG also may be helpful in excluding the diagnosis of RBD by demonstration of

normal muscle atonia in REM sleep (assuming adequate amounts of REM sleep are
observed). Although the “macrostructure” of sleep (i.e., the cycling of various NREM
and REM sleep stages and the relative distributions of these sleep stages) is generally
preserved with sleepwalking, the “microstructure” of sleep can be perturbed. Power
spectral analyses of slow wave activity in adult sleepwalkers have revealed several
forms of slow wave sleep dysregulation, including high amounts of slow wave sleep
fragmentation (particularly during the first NREM-REM sleep cycle), a significant
increase in delta power just prior to an arousal, and increased slow wave activity across
all NREM sleep cycles.
Disorders of arousal should be carefully distinguished from other disorders with
similar presentations, but different pathophysiologies, courses, and treatments. Other
disorders to be considered include RBD, sleep related epilepsy, sleep related dissocia-
tive disorders, alcohol and drug related behaviors, and OSA.
RBD typically presents as dream-enacting behaviors during the second half of the night
and usually affects middle-aged men, but also can affect women and virtually any age
group. Because sleepwalking in adults can also present as dream-enacting behaviors
that emerge during any time of the night, vPSG may be necessary to distinguish sleep-
walking from RBD. In contrast to disorders of arousal, signs of RBD, particularly
tonic/phasic EMG activity during REM sleep, are almost always present during sleep
studies. If sleepwalking (or sleep terrors) occurs with RBD in the same patient, both
should be diagnosed. This has been referred to as a parasomnia overlap disorder.
Other sleep disorders, such as OSA, can precipitate disorders of arousal. Therefore, a
careful history must be obtained to identify other sleep disorders. Sleep related epilepsy
can manifest with wandering behavior or with frenzied walking or running. In adults,
a diagnosis of malingering also should be considered. If a neurologic or medical disor-
der is identified as the precipitant of a disorder of arousal, then the sleepwalking should
be diagnosed as parasomnia due to a medical disorder.
Disorders of arousal should not be diagnosed in the presence of alcohol intoxication.

The behavior of the alcohol-intoxicated individual may superficially resemble that of
the sleepwalker. However, the sleepwalker is typically severely cognitively impaired,
but with only limited motor impairment. The alcohol-intoxicated individual’s level of
cognitive functioning may be reduced, but not absent, whereas motor behavior is often
severely impaired. In alcoholic blackouts, where anterograde amnesia is, by definition,
237
Parasomnias
the cardinal manifestation, it is important to note that outward motor behavior and cog-
nitive function may not be impaired and may be perceived as normal. Thus, the impor-
tance of appreciating the neuroscience of alcoholic blackouts and its potential role
in the explanation of unusual and bizarre nocturnal behaviors cannot be understated
because these can mimic parasomnias. The former are exponentially more prevalent
and thus should be given appropriate weight when attributing likely causation in cases
with criminal allegations.

With the development of sophisticated genetic testing and neuroimaging, direct
research into the causes and mechanisms of disorders or arousals is anticipated. Further
investigations that aid in the characterization of the pathophysiology are necessary.
Further development of sleep laboratory-based techniques for provoking episodes of
sleepwalking would improve diagnostic accuracy.
Bibliography
Achermann P, Werth E, Dijk DJ, Borbély AA. Time course of sleep inertia after nighttime and daytime
sleep episodes. Arch Ital Biol 1995;134:109–19.
Broughton RJ. Sleep disorders: disorders of arousal? Science 1968;159:1070–8.
Fisher C, Kahn E, Edwards A, Davis D, Fine J. A psychophysiological study of nightmares and night
terrors. III. Mental content and recall of stage 4 night terrors. J Nerv Ment Dis 1974;158:174–88.
Fisher C, Kahn E, Edwards D, Davis D. A psychophysiological study of nightmares and night terrors:
physiological aspects of the stage 4 night terror. J Nerv Ment Dis 1973;157:75–98.
Gastaut H, Broughton R. A clinical and polygraphic study of episodic phenomena during sleep. In: Wortis
J, ed. Recent advances in biological psychiatry, Volume 7. New York: Plenum Press, 1965:197–223.
Guilleminault C, Moscovitch A, Yuen K, Poyares D. Atypical sexual behavior during sleep. Psychosom
Med 2002;64:328–36.
Guilleminault C, Silvestri JM. Disorders of arousal and epilepsy during sleep. In: Sterman M, Shouse M,
Passouant P, eds. Sleep and epilepsy. New York: Academic Press, 1983:513–31.
Hublin C, Kaprio J, Partinen M, Heikkila K, Koskenvuo M. Parasomnias: co-occurrence and genetics.
Psychiatr Genet 2001;11:65–70.
Hublin C, Kaprio J, Partinen M, Heikkila K, Koskenvuo M. Prevalence and genetics of sleepwalking: a
population-based twin study. Neurology 1997;48:177–81.
Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior
disorder. Sleep 2005;28:203–6.
Kales A, Soldatos C, Bixler E, et al. Hereditary factors in sleepwalking and night terrors. Br J Psychiatry
1980;137:111–8.
Klackenberg G. Somnambulism in childhood—prevalence, course and behavioral correlations: a
prospective longitudinal study (3-16 years). Acta Paediatr Scand 1982;71:495–9.
Mahowald M, Schenck C, Goldner M, Bachelder V, Cramer Bornemann M. Parasomnia pseudo-suicide.
J Forensic Sci 2003;48:1158–62.
238
Parasomnias
Nino-Murcia G, Dement W. Psychophysiological and pharmacological aspects of somnambulism and

night terrors in children. In: Meltzer H, ed. Psychopharmacology: the third generation of progress.
New York: Raven Press, 1987:873–9.
Ohayon M, Guilleminault C, Priest R. Night terrors, sleepwalking, and confusional arousals in the general
population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry
1999;60:268–76.
Ohayon M, Priest R, Zulley J, Smirne S. The place of confusional arousals in sleep and mental disorders:
findings in a general population sample of 13,057 subjects. J Nerv Ment Dis 2000;188:340–8.
Pilon M, Zadra A, Joncas S, Montplaisir J. Hypersynchronous delta waves and somnambulism: brain
topography and effect of sleep deprivation. Sleep 2006;29:77–84.
Pressman M, Mahowald M, Schenck C, Cramer Bornemann M. Alcohol-induced sleepwalking or
confusional arousal as a defense to criminal behavior: a review of scientific evidence, methods and
forensic considerations. J Sleep Rev 2007;16:198–212.
Pressman M. Factors that predispose, prime and precipitate NREM parasomnias in adults: clinical and
forensic implications. Sleep Med Rev 2007;11:5–30.
Pressman MR. Hypersynchronous delta sleep EEG activity and sudden arousals from slow wave sleep in
adults without a history of parasomnias: clinical and forensic implications. Sleep 2004; 27:706–10.
Schenck C, Arnulf I, Mahowald M. Sleep and sex: what can go wrong? A review of the literature on sleep
related disorders and abnormal sexual behaviors and experiences. Sleep 2007;30:683–702.
Schenck C, Boyd J, Mahowald M. A parasomnia overlap disorder involving sleepwalking, sleep terrors,
and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997;20:972–81.
Schenck C, Mahowald M. On the reported association of psychopathology with sleep terrors in adults.
Sleep 2000;23:448–9.
Simonds J, Parraga H. Prevalence of sleep disorders and sleep behaviors in children and adolescents. J Am
Acad Child Adolesc Psychiatry 1982;21:383–8.
Zadra A, Desautels A, Petit D, Montplaisir J. Somnambulism: clinical aspects and pathophysiological
hypotheses. Lancet Neurol 2013;12:285–94.
239
Parasomnias
Sleep Related Eating Disorder

Alternate Names
Sleep eating
Diagnostic Criteria
A. Recurrent episodes of dysfunctional eating that occur after an arousal
during the main sleep period.
B. The presence of at least one of the following in association with the
recurrent episodes of involuntary eating:
1. Consumption of peculiar forms or combinations of food or inedible
or toxic substances.
2. Sleep related injurious or potentially injurious behaviors performed
while in pursuit of food or while cooking food.
3. Adverse health consequences from recurrent nocturnal eating.
C. There is partial or complete loss of conscious awareness during the
eating episode, with subsequent impaired recall.
D. The disturbance is not better explained by another sleep disorder, mental
disorder, medical disorder, medication, or substance use.
Essential Features
SRED consists of recurrent episodes of involuntary eating and drinking during arous-
als from sleep, associated with diminished levels of consciousness and subsequent
recall, with problematic consequences.
The episodes of eating always occur in an involuntary or “out of control” manner

after an interval of sleep. Typically, they occur during partial arousals from sleep with
subsequent partial recall. On the one hand, some patients cannot be easily brought to
full consciousness during an episode of eating, as is the case with sleepwalking, and
may have no recall of having eaten during the night. On the other hand, some patients
seemingly have considerable alertness during an episode and have substantial recall
in the morning. There may be variability of awareness and subsequent recall within
one night, and across the evolution of the disorder in individual patients. The recurrent
episodes of involuntary eating and drinking during the main sleep period are typically
associated with a feeling of lack of control over eating.
240
Parasomnias
Problematic features of the recurrent sleep related eating include the following: con-
sumption of peculiar forms or combinations of food, or of inedible or toxic substances
(e.g., frozen pizzas, raw bacon, buttered cigarettes, cat food and salt sandwiches, coffee
grounds, ammonia cleaning solutions); sleep related injury (e.g., lacerations from care-
less manipulation of kitchen utensils; internal or external burns from consuming or
spilling hot foods or beverages; or poisoning and internal injuries from ingesting toxic
substances); adverse health consequences (e.g., dental caries and tooth chipping from
biting frozen foods); weight gain; obesity (including morbid obesity resulting in bar-
iatric surgery); various metabolic problems, such as destabilization or precipitation
of diabetes mellitus, hypertriglyceridemia, and hypercholesterolemia; nonrestorative
sleep from sleep disruption; morning anorexia and abdominal distention. SRED carries
the risk of consuming foods to which one is allergic. Also, overnight fasting prior to
next-day surgery or testing can be compromised. Secondary depressive disorders may
emerge from longstanding personal dejection and a sense of failure over the inability to
control the nocturnal eating. Secondary food restriction, prompted by despair over not
being able to stop the nocturnal eating, often occurs at some point during the course of
the disorder. Patients may engage in potentially hazardous (and expensive) weight-loss
regimens. Insomnia can also be a complication.
Associated Features
Nightly eating, including multiple episodes nightly, is reported by a majority of
affected individuals. The episodes of eating occur during any time in the sleep cycle.
High-caloric foods are typically preferred. The foods preferentially consumed during
sleep related eating are not typically consumed with preference during the daytime.
Paradoxically, to the extent that there is recall, hunger and thirst are notably absent
during episodes of compulsive eating with SRED. The episodes of eating are some-
times experienced as food-related enactment of a dream. Simple foods or entire hot
or cold meals may be prepared and consumed. Careless food handling often occurs.
Alcoholic beverages are almost never consumed. The usual response to interference
during an eating episode is irritability and agitation.

None known.
Demographics
The following rates of SRED, as determined by self-administered questionnaire, have
been reported: 16.7% in an inpatient eating disorders group; 8.7% in an outpatient
eating disorders group; and 4.6% in an unselected university student group. This study
would indicate a high prevalence of SRED, although confirmatory studies across
241
Parasomnias
different clinical and nonclinical population groups are needed. Females comprise
60% to 83% of patients in reported series. Mean age of onset of SRED is reported to be
22-39 years. In the reported series, the mean duration of SRED prior to clinical presen-
tation ranged from four to 15 years, suggesting that SRED often is a chronic disorder.

SRED can be idiopathic, but it appears to be most commonly associated with a primary
sleep disorder, another clinical condition, or use of a sedative-hypnotic medication.
Sleepwalking is the most common sleep disorder associated with sleep related eating,
although once eating becomes part of the behavioral repertoire, it quickly becomes the
predominant, if not the exclusive, nocturnal “sleepwalking” behavior. This would indi-
cate that SRED is most often a “sleepwalking variant disorder.” A history of sleepwalk-
ing during childhood appears to be a predisposing factor in many cases. A recent retro-
spective controlled study of SRED patients, sleepwalking patients, and controls found
that SRED patients were mainly women with onset of the disturbance in adulthood.
They typically experienced nightly episodes and had more frequent eating problems in
childhood and higher current anorexia scores than sleepwalking patients or controls.
They also shared commonalities with sleepwalking patients, including a high (66%)
frequency of past or current sleepwalking, a similar timing of parasomnia episodes (in
the first half of the night), and numerous arousals from stage N3. On video-polysom-
nography, eating episodes occurred mostly within one minute after awakening from
stage N2 or N3. The frequencies of RLS, PLMs, and sleep apnea were similar across
the three groups.
Other sleep disorders that can be closely associated with SRED include: RLS,
PLMD, OSA, and circadian rhythm sleep-wake disorders, particularly irregular sleep/
wake pattern. Multiple sleep disorders in the same patient have been reported with
SRED, including sexsomnia and a variant of confusional arousals and sleepwalking.
Medication-induced SRED has been reported with zolpidem, in particular, but also
with a broad range of sedative hypnotics, including benzodiazepines, benzodiazepine
receptor agonists, mirtazapine, risperidone, quetiapine, lithium carbonate, anticholin-
ergics, and various other psychotropic agents. Onset of SRED also has been reported
with cessation of cigarette smoking, cessation of alcohol and substance abuse, acute
stress (usually involving major separation reactions), after daytime dieting, and with
onset of narcolepsy, autoimmune hepatitis, encephalitis, and other conditions. SRED
can also be associated with daytime eating disorders, and with nocturnal dissocia-
tive disorder. In a controlled study of 65 patients with narcolepsy-cataplexy, 32% of
patients had SRED vs. 2% of controls. Nocturnal smoking was present in 33% of
SRED-narcolepsy-cataplexy patients and in 16% of narcolepsy-cataplexy patients
242
Parasomnias
without SRED. (A link between SRED and nocturnal smoking had previously been
identified when nocturnal smoking was first reported in 2008). A study of 88 patients
with RLS and 42 patients with insomnia who were systematically questioned for the
presence of SRED or other nocturnal eating demonstrated that 36% of patients with
RLS versus zero patients with insomnia had SRED, and the very significant difference
was not related to arousal frequency. In that study, patients with RLS who were taking
hypnotic medications were at additional risk for SRED.
Familial Pattern
A familial basis for SRED is not uncommon, including co-occurrence in fraternal
twins, although detailed genetic studies have not been carried out.

The onset of SRED can be insidious and sporadic, or it can be precipitous and fulmi-
nant with rapid development of nightly episodes of eating, related or unrelated to the
start of hypnotic medication therapy of insomnia. The course is usually unremitting.
Fires can occur when the individual with SRED begins to cook foods on the stove
or in the oven, and then abandons them. A variety of other complications have been
described previously.
SRED can emerge in childhood, either associated or unassociated with a family history
of SRED.

The underlying pathophysiology of SRED is unclear. Despite the broad range of pre-
disposing and precipitating factors in SRED, the relatively homogeneous set of clinical
features suggests the presence of a “final common pathway” that can be accessed by a
variety of factors. Although SRED has prominent features of both a sleep disorder and
an eating disorder, its relatively homogeneous presentation supports its classification
as a separate diagnostic entity. More than half of patients with SRED have a history
of another parasomnia that preceded the onset of nocturnal eating, suggesting that the
presence of another parasomnia is a major risk factor for SRED. However, the female
predominance in SRED is more consistent with eating disorders, which are female pre-
dominant, than with sleepwalking or movement disorders (RLS/PLMD) which have
slight to no female bias. Thus it appears that two basic drive states—sleeping and
eating—are pathologically intertwined in SRED.
243
Parasomnias
Objective Findings
Although not routinely indicated in the assessment of SRED, vPSG evaluations have
often reported positive findings. The most common finding consists of multiple confu-
sional arousals, with or without eating, arising from slow wave sleep. However, abnor-
mal arousals have been documented from all stages of NREM sleep and also occasion-
ally from REM sleep. The level of consciousness has typically spanned the range from
virtual unconsciousness to various levels of partial consciousness despite a concurrent
EEG pattern that is often predominantly awake, suggesting dissociation between the
EEG and the level of consciousness. This dissociation also can be found in adult sleep-
walking without associated eating. In contrast, classic sleepwalking in childhood is
usually associated with the persistence of high-voltage delta waves or the admixture of
delta, theta, and alpha activity. A predominant wake pattern is rare in childhood sleep-
walking. PLMs and OSA may be observed in polysomnographic monitoring of SRED
patients. In one recent study that addressed the boundaries between SRED and fully
conscious abnormal nocturnal eating, 22 of 35 patients had PLMs, 5 of 35 had RLS,
and 29 of 35 had recurring chewing and swallowing movements during sleep that were
associated with nearly half of the total number of EEG arousals.
SRED must be distinguished primarily from night eating syndrome (NES), which is
characterized by excessive eating between dinner and bedtime and during full awaken-
ings during the sleep period. In contrast to daytime eating disorders (bulimia nervosa,
anorexia nervosa), inappropriate compensatory behavior, such as self-induced vom-
iting, enemas, misuse of laxatives, diuretics, or other medications, or other purging
activity, are not present in SRED, although the two conditions may be comorbid. A
person with a daytime eating disorder may also have a coexisting SRED that is asso-
ciated with confusional arousals but not associated with purging behaviors during the
night or upon arising in the morning. Patients with longstanding SRED and excessive
weight gain may eventually fast during the daytime and/or engage in excessive exer-
cise to prevent obesity from the SRED. Likewise, patients who otherwise fulfill crite-
ria for SRED may consciously eat during the prebedtime period in a futile attempt to
suppress the compulsion to eat after subsequently falling asleep.
SRED appears to be considerably more female predominant that NES (which has <
60% female prevalence), and mood disorders are more common with NES than with
SRED. Nevertheless, SRED and NES share a considerable number of overlapping
features and may exist along a common spectrum of pathophysiology. SRED should
also be distinguished from nocturnal (sleep related) extensions of bulimia nervosa,
binge-eating disorder, and anorexia nervosa, binge/purge type.
244
Parasomnias
The nocturnal eating (drinking) syndrome described in the original International

Classification of Sleep Disorders is primarily a disorder of infancy that is characterized
by recurrent awakenings with the inability to resume sleep without eating or drinking.
Kleine-Levin syndrome (periodic hypersomnia) can present with inappropriate noctur-
nal eating, but its predominance in adolescent males and its hallmark symptom complex
of periodic hypersomnia, hypersexuality, and hyperphagia lasting days to weeks should
easily distinguish it from SRED. Medical and neurologic disorders that could be asso-
ciated with abnormal recurrent eating during the main sleep period (usually with full
or almost full alertness) should also be excluded. These include: hypoglycemic states,
peptic ulcer disease, reflux esophagitis, and Kluver-Bucy syndrome.

The extent of overlap and divergence between SRED and NES needs to be further
elucidated.
Bibliography
Brion A, Flamand M, Oudiette D, Voillery D, Golmard JL, Arnulf I. Sleep related eating disorder versus
sleepwalking: a controlled study. Sleep Med 2012; 3:1094–101.
Howell MJ, Schenck CH, Crow SJ. A review of nighttime eating disorders. Sleep Med Rev 2009;13:23–-34.
Howell MJ, Schenck CH. Restless nocturnal eating: a common feature of Willis-Ekbom syndrome (RLS).
J Clin Sleep Med 2012;8:413–9.
Palaia V, Poli F, Pizz F, et al. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors:
a case-control study. Sleep 2011;34:1365–71.
Schenck CH, Hurwitz TD, Bundlie SR, Mahowald MW. Sleep-related eating disorders: polysomnographic
correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep 1991;14:419–31.
Schenck CH, Hurwitz TD, O’Connor KA, Mahowald MW. Additional categories of sleep-related eating
disorders and the current status of treatment. Sleep 1993;16:457–66.
Vetrugno R, Manconi M, Ferini-Strambi L, Provini F, Plazzi G, Montagna P. Nocturnal eating: sleep-related
eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006;29:949–54.
Vinai P, Ferri R, Ferini-Strambi L, et al. Defining the borders between sleep-related eating disorder and
night eating syndrome. Sleep Med 2012;13:686–90.
Winkelman JW. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry
1998;59:14–9.
Winkelman JW, Herzog DB, Fava M. The prevalence of sleep-related eating disorder in psychiatric and
non-psychiatric populations. Psychol Med 1999;29:1461–6.
Winkelman JW. Sleep-related eating disorder and night eating syndrome: sleep disorders, eating disorders,
or both? Sleep 2006;29:876–7.
245
Parasomnias
REM-Related Parasomnias
REM Sleep Behavior Disorder

Alternate Names
None.
Diagnostic Criteria
A. Repeated episodes of sleep related vocalization and/or complex motor
behaviors.1,2
B. These behaviors are documented by polysomnography to occur during
REM sleep or, based on clinical history of dream enactment, are
presumed to occur during REM sleep.
C. Polysomnographic recording demonstrates REM sleep without atonia
(RWA)3
D. The disturbance is not better explained by another sleep disorder, mental
disorder, medication, or substance use.
Notes
1. This criterion can be fulfilled by observation of repetitive episodes
during a single night of video polysomnography.
2. The observed vocalizations or behaviors often correlate with
simultaneously occurring dream mentation, leading to the frequent
report of “acting out one’s dreams.”
3. As defined by the guidelines for scoring PSG features of RBD in the
most recent version of the American Academy of Sleep Medicine
(AASM) Manual for the Scoring of Sleep and Associated Events.
4. Upon awakening, the individual is typically awake, alert, coherent, and
oriented.
5. On occasion, there may be patients with a typical clinical history of
RBD with dream-enacting behaviors, who also exhibit typical RBD
behaviors during vPSG, but do not demonstrate sufficient RWA,
based on the current evidence-based data, to satisfy the PSG criteria
for diagnosing RBD. In such patients, RBD may be provisionally
diagnosed, based on clinical judgment. The same rule applies when
vPSG is not readily available.
246
Parasomnias
6. Medications may unmask latent RBD with preexisting RWA, according

to current expert opinion. Therefore, medication-induced RBD
can be diagnosed as RBD, using clinical judgment, pending future
longitudinal studies.
Essential Features
RBD is characterized by abnormal behaviors emerging during REM sleep that may
cause injury or sleep disruption. RBD is also associated with EMG abnormalities
during REM sleep. The EMG demonstrates an excess of muscle tone during REM
sleep, and/or an excess of phasic EMG twitch activity during REM sleep.
A complaint of sleep related injury is common with RBD, which usually manifests as
an attempted enactment of unpleasant, action-filled, and violent dreams in which the
individual is being confronted, attacked, or chased by unfamiliar people or animals.
Typically, at the end of an episode, the individual awakens quickly, becomes rapidly
alert, and reports a dream with a coherent story. The dream action corresponds closely
to the observed sleep behaviors.
Sleep and dream-related behaviors reported by history and documented during vPSG
include both violent and (less commonly) nonviolent behaviors: talking (including
giving speeches), smiling, laughing, singing, whistling, shouting, swearing profan-
ities, crying, chewing, gesturing, reaching, grabbing, arm flailing, clapping, slap-
ping, punching, kicking, sitting up, leaping from bed, crawling, running, or dancing.
Walking, however, is quite uncommon with RBD, and leaving the room is especially
rare, because the eyes are usually closed, precluding attention to the environment.
There can be rare occurrences of smoking a fictive cigarette, masturbation-like behav-
ior, pelvic thrusting, and mimics of eating, drinking, urinating, and defecating. The
eyes usually remain closed during an RBD episode, with the person attending to the
dream action and not to the actual environment.
Medical attention is usually sought after sleep related injury has occurred to either the
person or the bed partner, and rarely because of sleep disruption. Because RBD occurs
during REM sleep, it usually appears at least 90 minutes after sleep onset, unless there
is coexisting narcolepsy, in which case RBD can emerge shortly after sleep onset during
a sleep onset rapid eye movement period (SOREMP). There is an acute form of RBD
that emerges during intense REM sleep rebound states, such as during withdrawal from
alcohol and sedative-hypnotic agents, or in association with certain medication use,
drug intoxication, or relapsing multiple sclerosis.
247
Parasomnias
Associated Features
PLMs during NREM sleep are very common with RBD and may disturb the sleep of
the bed partner. Daytime tiredness or sleepiness is uncommon, unless narcolepsy is
also present. There is typically no history of irritable, aggressive, or violent behav-
ior during the day. There may be a longstanding prodromal history of sleep talking,
yelling, limb twitching, and jerking during sleep that may or may not be dream related.

Parasomnia overlap disorder is a condition in which patients have both RBD and either
a disorder of arousal, sleep related eating disorder, sexsomnia, or rhythmic movement
disorder. This condition is male predominant, but less so than isolated RBD. Most cases
begin during childhood or adolescence. Virtually all age groups can be affected. It can
be idiopathic or symptomatic of a broad set of disorders, including narcolepsy, mul-
tiple sclerosis, brain tumor (and therapy), rhombencephalitis (right pontine tegmen-
tum/medulla lesion), brain trauma, congenital Moebius syndrome, agrypnia excitata,
Machado-Joseph disease, various psychiatric disorders and their pharmacotherapies,
and substance abuse disorders and withdrawal states.
Status dissociatus can be classified as a subtype of RBD that manifests as an extreme

form of state dissociation without identifiable sleep stages, but with sleep and
dream-related behaviors that closely resemble RBD. Status dissociatus represents a
major breakdown of the polysomnographic markers for REM sleep, NREM sleep, and
wakefulness, with admixtures of these states being present, but with conventional sleep
stages not being identifiable during polysomnographic monitoring. There is abnormal
behavioral release that can be associated with disturbed dreaming, strongly suggestive
of dream-enacting behaviors that closely resemble RBD. Not uncommonly, the indi-
vidual thinks he is awake when observers presume he is asleep and attempting to act
out a dream, or vice versa. An underlying neurologic or medical condition, spanning a
broad range of pathology, is virtually always present.
Dream enactment (“oneirism”) that is REM sleep related or related to a dissociated

REM sleep-wakefulness state can be a core feature of a pathologic condition called
agrypnia excitata that is characterized by generalized motor overactivity, impaired
ability to initiate and maintain sleep (with “wakeful dreaming”), loss of slow wave
sleep, and marked motor and autonomic sympathetic activation. Agrypnia excitata is
found with such diverse conditions as delirium tremens, Morvan syndrome, and fatal
familial insomnia. Thus, agrypnia excitata manifests as both a severe parasomnia and
a severe insomnia.
248
Parasomnias
Demographics
RBD is a male predominant disorder that usually emerges after age 50 years. Cases
of RBD from early childhood up to age 88 years have been reported. RBD emerging
in adults before age 50 years tends to have different demographics and associated
features, including greater sex parity and increased rates of idiopathic RBD and para-
somnia overlap disorder (POD), comorbid narcolepsy, antidepressant medication use,
and possibly autoimmune diseases. In addition, the clinical presentation of RBD in
younger adults differs from that in older adults in being less aggressive and violent,
presumably due to greater female representation and higher rates of comorbid narco-
lepsy (which manifests with milder RBD behaviors).
RBD associated with neurologic disorders and other symptomatic forms of RBD are as
male predominant as idiopathic RBD, with the exception of narcolepsy (as described
below) and multiple system atrophy. Of note, RBD may not be the presenting com-
plaint to a sleep disorders center. Therefore, systematic questioning for RBD should be
included for all newly evaluated patients at a sleep center. RBD in children is virtually
never idiopathic and is usually associated with narcolepsy (at times emerging months
before the emergence of narcoleptic symptoms), brainstem tumors, antidepressant
medications, neurodevelopmental disorders, and various rare conditions.
The prevalence is not known with much certainty, although a prevalence of 0.38%
to 0.5% is reported in the elderly and the general population. A 2.1% prevalence of
current sleep related violence has been reported; 38% of these events have associated
dream enactment, suggesting a prevalence of RBD as high as 0.8%.

The major predisposing factors are male sex, age 50 years or older, and an under-
lying neurological disorder, particularly Parkinson disease, multiple system atrophy,
dementia with Lewy bodies, narcolepsy, or stroke. A recent multicenter case-control
study of environmental risk factors of RBD found that smoking, head injury, pesticide
exposure, and farming were significant risk factors. Medications, particularly the anti-
depressants venlafaxine, serotonin-specific reuptake inhibitors (SSRIs), mirtazapine,
and other antidepressant agents (but not bupropion) are an increasingly recognized
precipitating factor. Beta-blockers (bisoprolol, atenolol), anticholinesterase inhibitors,
and selegiline can also trigger RBD. Psychiatric disorders involving depression (that
require antidepressant pharmacotherapy) may comprise a predisposing factor, particu-
larly in adults younger than 50 years. RBD may also be associated with posttraumatic
stress disorder.
249
Parasomnias
Familial Pattern
A recent multicenter controlled study revealed a significantly increased positive family
history of dream enactment, raising the possibility of a genetic contribution to RBD.

Onset of chronic RBD can be gradual or rapid, and the course is often progressive.
Complications include sleep related injuries to self and/or bed partner that at times are
life threatening, and disruption of the bed partner’s sleep that can be severe. Marital
discord due to the RBD is uncommon but can be severe when present, due to repeated
injury and/or disruption of the bed partner’s sleep.
Delayed emergence of a neurodegenerative disorder, often more than a decade after the
onset of idiopathic RBD, is very common in men 50 years of age and older. These dis-
orders include Parkinson disease (PD), multiple system atrophy (MSA), and dementia
with Lewy bodies (DLB). Two recently reported series found 81% and 82% eventual
conversion rates from idiopathic RBD to parkinsonism/dementia (and also mild cog-
nitive impairment in the latter study). Conversely, RBD is present in >90% of reported
cases of MSA, in approximately 50% of reported cases of DLB, and in up to 46% of
reported patients with PD.
As stated previously, RBD can emerge in children, usually in association with narco-
lepsy-cataplexy, brainstem tumors, or antidepressant medications.

Current evidence suggests a selective association between RBD and neurodegenera-
tive disorders. The synucleinopathies comprise a set of neurodegenerative disorders
that share a common pathologic lesion composed of aggregates of insoluble α-synu-
clein protein in selectively vulnerable populations of neurons and glial cells. These
pathologic aggregates appear to be closely linked to the onset and progression of clin-
ical symptoms and the degeneration of affected brain regions in neurodegenerative
disorders. The major synucleinopathies include PD, DLB, and MSA.
RBD can be strongly linked with narcolepsy (almost always narcolepsy type 1), rep-
resenting another form of REM sleep motor-behavioral dyscontrol. The RBD may be
precipitated or worsened by the pharmacologic treatment of cataplexy. RBD associ-
ated with narcolepsy is now considered to be a distinct phenotype of RBD, character-
ized by lack of sex predominance, less complex and more elementary movements in
REM sleep, less violent behavior in REM sleep, earlier age of onset, and hypocretin
250
Parasomnias
deficiency (that is characteristic of narcolepsy type 1). The presence of RBD in pediat-
ric patients may be an initial manifestation of narcolepsy type 1.
Other reported etiologic associations of RBD with neurologic disorders include isch-
emic or hemorrhagic cerebrovascular disease, multiple sclerosis, progressive supranu-
clear palsy, Guillain-Barré syndrome, brainstem neoplasms (including cerebellopon-
tine angle tumors), Machado-Joseph disease (spinocerebellar ataxia type 3), mitochon-
drial encephalomyopathy, normal pressure hydrocephalus, Tourette syndrome, group
A xeroderma, and autism.
The pathophysiology of human RBD is presumed to correspond to the findings from

an animal model of RBD with respect to interruption of the REM atonia pathway and/
or disinhibition of brainstem motor pattern generators.
Objective Findings
Polysomnography demonstrates an excessive amount of sustained or intermittent loss
of REM atonia and/or excessive phasic muscle twitch activity of the submental and/or
limb EMGs during REM sleep. Some patients have almost exclusively arm and hand
behaviors during REM sleep, indicating the need for both upper and lower extremity
EMG monitoring in fully evaluating for RBD. Some patients preserve most of their
REM atonia but have excessive EMG twitching during REM sleep. The most current
evidence-based data for detecting RWA in the evaluation of RBD indicate that any
(tonic/phasic) chin EMG activity combined with bilateral phasic activity of the flexor
digitorum superficialis muscles in >27% of REM sleep (scored in 30-second epochs)
reliably distinguishes RBD patients from controls. Autonomic nervous system activa-
tion (such as tachycardia) is uncommon during REM sleep motor activation in RBD, in
contrast to the disorders of arousal. Approximately 75% of patients have PLMs during
NREM sleep; a low percentage of these movements is associated with EEG signs of
arousal. Increased percentages of slow wave sleep and increased delta power in RBD
have been found in controlled and uncontrolled studies, but this can be a highly vari-
able finding in RBD, depending on the clinical population. Sleep architecture and the
customary cycling among REM and NREM sleep stages are usually preserved in RBD,
although some patients show a shift toward N1 sleep.
Validated RBD screening questionnaires that can assist in the process of diagnosing
RBD are currently available.
251
Parasomnias
RBD is one of several disorders that can manifest as complex, injurious, and violent
sleep related and dream-related behaviors in adults. Other disorders that can mimic
RBD in adults and/or children include sleepwalking, sleep terrors, OSA, nocturnal
seizures (nocturnal frontal lobe epilepsy; nocturnal complex partial seizures); rhyth-
mic movement disorders; sleep related dissociative disorders, frightening hypnopom-
pic hallucinations, and posttraumatic stress disorder; a diagnosis of malingering also
should be considered.
In general, RBD involves attempted enactment of unpleasant, aggressive dreams that

usually occurs two or more hours after sleep onset, with rapid awakening from an
episode. In contrast, sleepwalking and sleep terror episodes often emerge within two
hours after sleep onset, are not usually associated with rapid alertness, and are rarely
associated with dreaming in children. Adults can have dreams associated with disor-
ders of arousal, but they are usually more fragmentary and limited than RBD dreams.
Sleep related seizures usually present with repetitive, stereotypical behaviors.
Parasomnia overlap disorder can be distinguished from status dissociatus in several

ways: if there is an awakening after an episode of RBD, sleepwalking, or sleep terror,
there is the realization of having just been asleep; status dissociatus, however, is more
likely to manifest with confusion over whether one is asleep, awake, or dreaming.
vPSG in overlap conditions shows the typical findings for both RBD and disorders of
arousal, whereas with status dissociatus, there is an inability to discern sleep stages.
Also, patients with status dissociatus do not walk far during an episode, and their
behavioral repertoire more closely resembles that of RBD than that of the disorders
of arousal.

Numerous questions related to the vPSG evaluation of RBD remain unresolved. These
include issues of defining and quantifying RWA and RBD activity such as: (1) What
is the minimum REM sleep percentage of total sleep time (and minimum absolute
REM sleep time) needed to diagnose RWA or rule out RWA? (2) What is the minimum
number of REM sleep epochs and minimum duration of REM sleep epochs necessary
to diagnose RWA or rule out RWA? (3) What guidelines can be developed for diag-
nosing or ruling out RWA in the setting of disrupted REM sleep continuity associated
with conditions such as obstructive sleep apnea and with medications? (4) What are
the minimal amounts of true RBD behaviors documented by vPSG needed to identify
RBD in patients without sufficient RWA?
252
Parasomnias
It is unclear why there is a male predominance of this disorder in middle-aged and older
adults. It is unknown if RBD subgroups other than men age 50 years or older demon-
strate increased risk for development of parkinsonism or dementia. One such subgroup
comprises patients with antidepressant-triggered RBD for whom the potential risk for
future parkinsonism and dementia is unclear. New antidepressant or other psychotro-
pic agents being developed for clinical use should be assessed for their immediate and
long-term effects on REM atonia, REM phasic activity, REM sleep behavioral release,
and proclivity to precipitate dream-enacting behaviors.
Bibliography
Boeve BF. REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior
disorder-neurodegenerative disease association, evolving concepts, controversies, and future
directions. Ann N Y Acad Sci 2010;1184:15–54.
Dauvilliers Y, Jennum P, Plazzi G. REM sleep behaviour disorder and REM sleep without atonia in
narcolepsy. Sleep Med 2013;14:775–81.
Frauscher B, Gschliesser V, Brandauer E, et al. REM sleep behavior disorder in 703 sleep-disorder
patients: the importance of eliciting a comprehensive sleep history. Sleep Med 2010;11:167–71.
Frauscher B, Iranzo A, Gaig C, et al. Normative EMG values during REM sleep for the diagnosis of REM
sleep behavior disorder. Sleep 2012;35:835–47.
Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior
disorder. Sleep 2005;28:203–6.
Iranzo A, Santamaria J, Tolosa E. The clinical and pathophysiological relevance of REM sleep behavior
disorder in neurodegenerative diseases. Sleep Med Rev 2009;13:385–401.
Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post-mortem pathology in
isolated rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol
2013;12:443–53.
Ju YE. Rapid eye movement sleep behavior disorder in adults younger than 50 years of age. Sleep Med
2013;14:768–74.
Lloyd R, Tippman-Peikert M, Slocumb N, Kotagal S. Characteristics of REM sleep behavior disorder in
childhood. J Clin Sleep Med 2012:15:127–31.
Olson E, Boeve B, Silber M. Rapid eye movement sleep behavior disorder: demographic, clinical, and
laboratory findings in 93 cases. Brain 2000;123:331–9.
Oudiette D, De Cock VC, Lavault S, Leu S, Vidailhet M, Arnulf I. Non-violent elaborate behaviors may
also occur in REM sleep behavior disorder. Neurology 2009;72:551–7.
Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying
the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology
2009;72:1296–300.
Schenck CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience
perspectives 16 years after its formal identification in SLEEP. Sleep 2002;25:120–38.
Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in
81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16 year
update on a previously reported series. Sleep Med 2013;14:744–8.
Schenck CH, Howell MJ. Spectrum of RBD (overlap between RBD and other parasomnias). Sleep and
Biological Rhythms 2013;11(Supplement 1):27–34.
253
Parasomnias
Recurrent Isolated Sleep Paralysis

Alternate Names
Hypnagogic and hypnopompic paralysis, predormital and postdormital paralysis,
kanashibari (Japan).
Diagnostic Criteria
A. A recurrent inability to move the trunk and all of the limbs at sleep onset
or upon awakening from sleep.
B. Each episode lasts seconds to a few minutes.
C. The episodes cause clinically significant distress including bedtime
anxiety or fear of sleep.
D. The disturbance is not better explained by another sleep disorder
(especially narcolepsy), mental disorder, medical condition, medication,
or substance use.
Essential Features
Recurrent isolated sleep paralysis is characterized by an inability to perform voluntary
movements at sleep onset (hypnagogic or predormital form) or on waking from sleep
(hypnopompic or postdormital form) in the absence of a diagnosis of narcolepsy. The
event consists of an inability to speak or to move the limbs, trunk, and head. Respiration
is usually unaffected. Consciousness is preserved, and full recall is present. An episode
of sleep paralysis lasts seconds to minutes. It usually resolves spontaneously but can be
aborted by sensory stimulation, such as being touched or spoken to, or by the patient
making intense efforts to move.
Associated Features
At least during the initial episodes, intense anxiety is usually present. Hallucinatory
experiences accompany the paralysis in about 25% to 75% of patients. These may
include auditory, visual, or tactile hallucinations, or the sense of a presence in the
room. Some patients experience predormital or postdormital hallucinations at separate
times from episodes of sleep paralysis.

A familial form of sleep paralysis has been described (see below).
254
Parasomnias
Demographics
Estimates of the prevalence of sleep paralysis vary widely due to differences in the
definition used, the age of the population sampled, and possibly cultural and ethnic
factors. Most prevalence studies of sleep paralysis (usually of students younger than
30 years) have investigated the occurrence of one or more episodes without require-
ment of recurrence or distress. These suggest a 15% to 40% prevalence of at least one
episode of sleep paralysis. Two notable exceptions are a 1962 study of mostly college
students that reported a prevalence of 5%, and a 1999 study of all adult ages that
found a prevalence of 6%. No consistent sex differences have emerged from multiple
studies. The mean age of onset is 14 to 17 years, although onset earlier and later in life
has been reported.

Sleep deprivation and irregular sleep-wake schedules have been identified as predis-
posing factors to episodes of sleep paralysis. Mental stress has been reported as a
precipitating factor in some but not other studies. Sleep paralysis appears to be more
common with sleep in the supine position. Personality factors have not been shown
to play a major role, although one study found a higher score on the paranoia scale of
the Minnesota Multiphasic Personality Inventory in patients with sleep paralysis com-
pared to controls. Other factors that have been noted on regression analysis include an
association with bipolar disorder, the use of anxiolytic medication, and sleep related
leg cramps.
Familial Pattern
Two families with apparent familial sleep paralysis occurring over three and four gen-
erations have been reported. A maternal form of transmission has been postulated.

Onset is usually in adolescence. Most events appear to occur in the second and third
decades, but may continue later in life. There are no known complications, apart from
anxiety over the episodes.
Though sleep paralysis may be present as part of the narcolepsy tetrad in children,
there is no information currently available about childhood presentation of recurrent
isolated sleep paralysis.
255
Parasomnias

Episodes of sleep paralysis elicited by awakening patients from nocturnal sleep appear
to arise from REM sleep. Sleep paralysis is an example of state dissociation with ele-
ments of REM sleep persisting into wakefulness. Early-onset REM sleep after forced
awakenings has been shown to predispose an individual to having sleep paralysis. It
may be that subjects with less tolerance to sleep disruption are more likely to experi-
ence the phenomenon.
Objective Findings
Analysis of sleep paralysis after forced awakenings during PSG studies reveals the
event to be a dissociated state with the persistence of REM-related electromyographic
atonia into conscious wakefulness. Hallucinatory experiences may be present but are
not essential for the diagnosis.
Cataplexy produces similar generalized paralysis of skeletal muscles but occurs during
wakefulness and is precipitated by emotion. Atonic seizures occur during wakefulness.
Nocturnal panic attacks are not usually associated with paralysis. Familial periodic
paralysis syndromes, especially hypokalemic periodic paralysis, may occur at rest and
on awakening. However, the episodes usually last hours, may be associated with car-
bohydrate intake, and are usually accompanied by hypokalemia. There are also hyper-
kalemic and normokalemic periodic paralysis syndromes.

Bibliography
Fukuda K. Sleep paralysis and sleep-onset REM period in normal individuals. In: Olgilvie R, Harsh J,
eds. Sleep onset: normal and abnormal processes. Washington: American Psychological Association,
1994:161–81.
Goode G. Sleep paralysis. Arch Neurol 1962;6:228–34.
Hishikawa Y. Sleep paralysis. In: Guilleminault C, Dement W, Passouant P, eds. Narcolepsy. New York:
Spectrum, 1976:97–124.
Ohayon M, Zulley J, Guilleminault C, Smirne S. Prevalence and pathologic associations of sleep paralysis
in the general population. Neurology 1999;52:1194–200.
Takeuchi T, Fukuda K, Sasaki Y, Inugami M, Murphy T. Factors related to the occurrence of isolated sleep
paralysis elicited during a multi-phasic sleep-wake schedule. Sleep 2002;25:89–96.
Takeuchi T, Miyasita A, Sasaki Y, Inugami M, Fukuda K. Isolated sleep paralysis elicited by sleep
interruption. Sleep 1992;15:217–25.
256
Parasomnias
Nightmare Disorder
Alternate Names
Nightmares, REM nightmares, recurrent nightmares, dream anxiety disorder, anxiety
dreams.
Diagnostic Criteria
A. Repeated occurrences of extended, extremely dysphoric, and well-
remembered dreams that usually involve threats to survival, security, or
physical integrity.
B. On awakening from the dysphoric dreams, the person rapidly becomes
oriented and alert.
C. The dream experience, or the sleep disturbance produced by awakening
from it, causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning as indicated by the
report of at least one of the following:
1. Mood disturbance (e.g., persistence of nightmare affect, anxiety,
dysphoria).
2. Sleep resistance (e.g., bedtime anxiety, fear of sleep/subsequent
nightmares).
3. Cognitive impairments (e.g., intrusive nightmare imagery, impaired
concentration, or memory).
4. Negative impact on caregiver or family functioning (e.g., nighttime
disruption).
5. Behavioral problems (e.g., bedtime avoidance, fear of the dark).
7. Fatigue or low energy.
8. Impaired occupational or educational function.
9. Impaired interpersonal/social function
Notes
1. Nightmare disorder in children is most likely to occur in those exposed
to severe psychosocial stressors. Because childhood nightmares often
resolve spontaneously, the diagnosis should be given only if there is
persistent distress or impairment.
257
Parasomnias
Essential Features
Nightmare disorder is characterized by recurrent, highly dysphoric dreams, which are
disturbing mental experiences that generally occur during REM sleep and that often
result in awakening. Given that these experiences are most often associated with REM
sleep, the episodes have a greater tendency to occur during the second half of the
major sleep episode when the REM pressure is most pronounced. Nightmares involve
an internally generated conscious experience or dream sequence that seems vivid and
real. They have a tendency to become increasingly more disturbing as they unfold.
Emotions are characteristically negative and most frequently involve anxiety, fear, or
terror but may also involve anger, rage, embarrassment, and disgust. Nightmare content
most often focuses on imminent physical danger to the individual but may also involve
other distressing themes. Ability to detail the nightmare’s contents upon awakening is
common in nightmare disorder. Multiple nightmares within a single sleep episode may
occur and may bear similar themes. Because nightmares typically arise during REM
sleep, they may occur at any moment that REM pressure is high.
Nightmares are very common in children. They typically occur in the last third of the
night and result in a complete awakening, after which the child can often provide a
detailed description of the frightening scenario. However, clear distinction from con-
fusional arousals and sleep terrors in young children is often not possible.
Associated Features
Postawakening anxiety and difficulty returning to sleep may be present. Nightmares
are more common in those with higher levels of anxiety. Additionally, nightmares are
commonly seen in those who have been physically or sexually abused and in those suf-
fering from posttraumatic stress disorder.
Nightmares arising either immediately following a trauma (acute stress disorder

[ASD]) or one month or more after a trauma (posttraumatic stress disorder [PTSD])
have been described during NREM sleep, especially N2, as well as during REM sleep
and at sleep onset. Posttraumatic nightmares may take the form of a realistic reliving of
a traumatic event or may depict only some of its elements or emotional content.

None known.
Demographics
Occasional nightmares are very common in children, occurring in 60% to 75% of chil-
dren, beginning as young as 2.5 years of age. The occurrence of occasional nightmares
258
Parasomnias
in children does not constitute a nightmare disorder. However, frequent nightmares are
uncommon, occurring in 1% to 5% of preadolescent children. It is estimated that 10%
to 50% of children aged three to five years have at least occasional nightmares severe
enough to disturb their parents. Nightmares appear to be a trait-like characteristic that
persists over time during childhood. The best predictor of recurrent nightmares at an
older age is recurrent nightmares in childhood. Approximately 2% to 8% of the general
population has a current problem with nightmares, and this frequency is higher in clini-
cal populations. Trauma-related nightmares are the most consistent problem reported by
patients with PTSD. Nightmares beginning within three months of a trauma are present
in up to 80% of patients with PTSD. Although approximately 50% of PTSD cases
resolve within three months, posttraumatic nightmares may persist throughout life.

Frequent nightmares are associated with enduring personality characteristics and psy-
chopathologies; they are inversely correlated with measures of well-being. Associations
with psychopathology have been identified for adults and adolescents, but research on
children is largely absent other than for assessments of PTSD. Measures of nightmare
distress are much more robustly associated with psychopathology than are measures
of nightmare frequency.
The clinical use of pharmacologic agents affecting the neurotransmitters

norepinephrine, serotonin, and dopamine is associated with the complaint of night-
mares. A majority of these agents are antidepressants, antihypertensives, and dopa-
mine-receptor agonists. Agents affecting the neurotransmitters gamma-aminobutyric
acid (GABA), acetylcholine, and histamine, and the withdrawal of REM sleep sup-
pressive agents also can be associated with the complaint of nightmares. Of note,
nightmares are a common reaction in varenicline, which is an agent that blocks
α-4-β-2 nicotinic acetylcholine receptors.
Familial Pattern
Twin-based studies have identified persistent genetic predisposition to nightmares in
childhood (reported retrospectively by adults) and adulthood as well as genetic influ-
ences on the co-occurrence of nightmares and some other parasomnias, such as sleep
talking (somniloquy).

Nightmares usually start between ages three years and six years. The proportion
of children reporting nightmares reaches a peak between six and ten years of age
and decreases thereafter. A subgroup of children continue to have nightmares into
259
Parasomnias
adolescence or adulthood and may become lifelong nightmare sufferers. Nightmares

generally diminish in frequency and intensity over the course of decades, but some
patients still describe frequent episodes at the age of 60 or 70 years. Nightmare dis-
order can lead to sleep avoidance and deprivation, and thereby to more intense night-
mares, which can produce insomnia.
ASD and PTSD associated nightmares can develop at any age after physical or emo-
tional trauma. Individuals with PTSD are at risk for developing mood disorders and
depression, social and employment consequences, self-destructive and impulsive
behavior, and substance abuse; it is not known to what extent the nightmares symp-
tomatic of PTSD contribute to these complications.
As stated above, nightmares are very common in children but the occurrence of occa-
sional nightmares does not constitute nightmare disorder. Population studies have
revealed that the prevalence and frequency of nightmares increases through childhood
into adolescence. For example, preschoolers seldom report “bad dreams.” Furthermore,
in regard to the prevalence of nightmares, children appear to exhibit a sex divergence
over time, with girls demonstrating higher prevalence by late adolescence.

Objective Findings
PSG recordings during actual nightmares are few in number and, in some instances,
have shown abrupt awakenings from REM sleep preceded by accelerated heart and
respiratory rates. Highly disturbing dream content frequently contrasts strikingly with
relatively minor autonomic changes. Distinctive anomalies in nightly sleep architec-
ture have not been demonstrated; brainstem and auditory-evoked potentials appear
normal. Recordings during posttraumatic nightmares are few but have been recorded
from both REM and NREM sleep. PSG recordings of sleep in patients with PTSD have
provided widely variable results.
PSG evaluation is not routinely performed but may be indicated in some circumstances
to exclude other parasomnias such as disorders of arousal and sleep-associated sei-
zures. A PSG is particularly appropriate if patients report nightmares in conjunction
with sleep behaviors that are repetitive or stereotyped or are injurious to self or others.
260
Parasomnias
Nightmare disorder must be distinguished from dream disturbances associated with
certain other neurological and sleep disorders. Rare cases of seizures presenting only as
“nightmares” have been reported and should be considered in the differential diagno-
sis, particularly in those patients who present with a history of central nervous system
disease. PSG or continuous video EEG may be necessary to identify nightmares asso-
ciated with nocturnal seizures. Nightmares differ from sleep terrors in having detailed
recollection of dreaming in contrast to fragments of dreams or no dream recall, pre-
senting no or minimal overt movement or autonomic activity, occurring late in the
night, being followed by rapid awakening and difficulty returning to sleep, and most
often arising from REM sleep. RBD occurs more often in late middle-aged men and
is more often associated with violent explosive movements and a history of nocturnal
injuries. The dream disturbance of RBD usually involves being threatened or attacked
by unfamiliar people or animals and is controlled in tandem with the sleep behavioral
disturbance by appropriate medication. Nightmares occur at any age and are not typ-
ically associated with movements, overt behaviors, or injuries. Anxiety may accom-
pany episodes of sleep paralysis occurring either at sleep onset (hypnagogic) or offset
(hypnopompic), when the individual feels conscious but unable to move, speak, and,
at times, breathe properly. Anxiety may be further worsened if disturbing hypnago-
gic hallucinations or dream sequences accompany the paralysis. Nightmares, although
they may involve some degree of movement inhibition or some degree of apparent
wakefulness, are usually not accompanied by feelings of either total paralysis or com-
plete waking consciousness.
Patients with narcolepsy often report nightmares; these may occur at sleep onset.
However, narcolepsy and nightmare disorder are clearly distinguishable by other
clinical symptoms. Nocturnal panic attacks occur either during or immediately after
nocturnal awakenings from NREM sleep, usually in the first four hours of the sleep
episode. Although frequency of panic attacks is correlated with frequency of night-
mares and many patients report that dysphoric dreams precede their attacks, there may
be no dream recall reported on awakening with a panic attack.
Sleep related dissociative disorders comprise a sleep related variant of the dissociative
disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-V). These include dissociative identity disorder (formerly called multi-
ple personality disorder) and dissociative fugue, in which individuals meeting waking
criteria for these diagnoses may at times experience the recall of actual physical or
emotional trauma as a “dream” during periods of EEG-documented nocturnal waking.
261
Parasomnias
Nightmares that occur intermittently during the course of ASD or PTSD are an expected
symptom of those mental disorders and do not always require independent coding as
nightmare disorder. However, as is often the case, when the frequency and/or severity
of posttraumatic nightmares is such that they require independent clinical attention,
then a diagnosis of nightmare disorder should be applied. In some cases, other symp-
toms of PTSD may have largely resolved while the nightmares persist. Nightmare
disorder should be coded in these cases as well. It is clinically important to establish
whether nightmares are associated with PTSD or ASD because the evaluation, course,
complications, and treatment differ significantly for these groups.

Basic pathophysiologic studies are still needed, especially studies contrasting “idio-
pathic” nightmare disorder and nightmares associated with PTSD. In particular, deter-
mining whether posttraumatic nightmares arise from sleep or primarily from wakeful-
ness would be an important distinguishing feature particularly when determining effec-
tive clinical interventions. The PSG correlates of nightmare disorder and posttraumatic
nightmares as well as the variables affecting dream mentation and recall require further
definition and delineation.
The distinction between nightmares and sleep terrors is difficult when assessed only
by questionnaires. It still remains unclear to what degree and level of complexity sleep
mentation is associated with sleep terrors. The topic of NREM sleep dream distur-
bances (other than disturbed mentation that may occur with sleep terrors) also needs
formal investigation, including whether or not the term NREM sleep nightmare should
be utilized.
The optimal methods for assessing nightmare frequency and nightmare distress are
still unclear. Standardized scales assessing nightmare distress should be developed and
utilized. Retrospective questionnaire-based evaluations of nightmares are problematic
inasmuch as they underestimate nightmare frequencies relative to home logs, whereas
home logs may selectively increase recall of nightmares.
Bibliography
Germain A, Nielsen T. Sleep pathophysiology in posttraumatic stress disorder and idiopathic nightmare
sufferers. Biol Psychiatry 2003;54:1092–8.
Hobson J. REM sleep and dreaming: towards a theory of protoconsciousness. Nat Rev Neurosci
2009;10:803–13.
Hublin C, Kaprio J, Partinen M, Koskenvuo M. Nightmares: familial aggregation and association with
psychiatric disorders in a nationwide twin cohort. Am J Med Genet 1999;88:329–36.
262
Parasomnias
Lavie P. Sleep disturbances in the wake of traumatic events. N Engl J Med 2001;345:1825–32.
Levin R, Fireman G. Nightmare prevalence, nightmare distress, and self-reported psychological
disturbance. Sleep 2002;25:205–12.
Muzur A, Pace-Schott EF, Hobson J. The prefrontal cortex in sleep. Trends Cogn Sci 2002;6:475–81.
Nielsen T, Zadra A. Idiopathic nightmares and dream disturbances associated with sleep-wake transitions.
In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of sleep medicine, 5th ed.
Philadelphia: Elsevier Saunders, 2010:1106–15.
Pagel J, Helfter P. Drug induced nightmares—an etiology based review. Hum Psychopharmacol
2003;18:59–67.
Zadra A, Donderi D. Nightmares and bad dreams: their prevalence and relationship to well-being. J
Abnorm Psychol 2000;109:273–81.
263
Parasomnias
Other Parasomnias
Exploding Head Syndrome

Alternate Names
Sensory sleep starts, sensory sleep shocks.
Diagnostic Criteria
A. There is a complaint of a sudden loud noise or sense of explosion in the
head either at the wake-sleep transition or upon waking during the night.
B. The individual experiences abrupt arousal following the event, often
with a sense of fright.
C. The experience is not associated with significant complaints of pain.
Essential Features
Exploding head syndrome is characterized by a sudden, loud imagined noise or sense
of a violent explosion in the head occurring as the patient is falling asleep or waking
during the night.
The event is variously described as a painless loud bang, an explosion, a clash of

cymbals, or a bomb exploding, but occasionally may be a less alarming sound. It is
usually associated with a sense of fright, and many patients believe they are having
a stroke. In a minority of cases a flash of light or myoclonic jerk may accompany
the event. The abnormal sensation lasts a few seconds and may recur during further
attempts at sleeping. The number of attacks varies—from many on a single night to
infrequent—with some patients reporting clustering of attacks over several nights fol-
lowed by a gap of weeks to months. A high level of clinical distress can be associated
with recurrent attacks, with concern about their underlying cause.
Associated Features
A flash of light may accompany the sound, and a myoclonic jerk may sometimes occur.
Although the event is typically painless, a simultaneous stab of pain in the head has
occasionally been reported. An insomnia complaint may develop as a result of the
recurring arousals and anxiety regarding the events.
264
Parasomnias

None known.
Demographics
The prevalence is unknown. Exploding head syndrome is reported to be more common
in women than in men. The median age of onset is 58 years, but onset at all ages has
been reported, including the first and eighth decades.

Most patients do not detect precipitating factors, but some report increased numbers of
attacks when under personal stress or overtired.
Familial Pattern
Occasional cases of exploding head syndrome occurring in the same family have been
reported, although it is not clear whether this represents a true familial pattern.
Onset, Course, and Complication

The course is benign with no reported neurologic sequelae. Frequent events on a single
night can result in insomnia. Clinical levels of anxiety may result from patient concern
about a serious medical basis for the exploding head syndrome. The condition may
also exacerbate a comorbid migraine disorder. In many patients, the symptoms appear
to remit spontaneously over some years.
Not known or applicable.

The events occur most frequently during a period of drowsiness preceding sleep. Some
events are reported to occur upon waking during the night, but may actually be occur-
ring during reinitiating sleep. The condition appears to be a sensory variant of the
better-known transient motor phenomenon of sleep starts or hypnic jerks occurring at
wake-sleep transition. The neurophysiologic mechanisms underlying these hypnago-
gic phenomena are unknown.
Objective Findings
VPSG in a small sample of patients found that events arose from early drowsiness with
predominant alpha rhythm interspersed with some theta activity. In one patient, events
arose during transition from N1 sleep, in another patient from N1 sleep to wakeful-
ness, and in a third patient from N2 sleep to wakefulness. Events occurring in the N1/
265
Parasomnias
N2 to wake transition have been recorded during both nocturnal vPSG and MSLTs.
Slow eye movements were present in the only tracing reproduced in the report of a
patient with exploding head syndrome emerging during wake to N1 sleep transition.
Arousals occurred immediately following the episodes. No epileptiform discharges
accompany the event.
Exploding head syndrome should be distinguished from sudden onset-headache syn-
dromes. “Idiopathic stabbing headache” (ice-pick headache) is a benign syndrome of
brief stabs of pain on the side of the head. Although they can occur at sleep onset,
they are more common during wakefulness. “Thunderclap headache” is a very severe
sudden onset headache characteristic of subarachnoid hemorrhage but also resulting
from other causes and occasionally occurring as a benign symptom. It does not usually
occur at sleep onset. “Hypnic headache syndrome” affects older people who regularly
awaken 4-6 hours after sleep onset, with a diffuse headache that lasts 30-60 minutes and
is often associated with nausea but no autonomic symptoms. Other conditions to be con-
sidered include sleep related migraines, cluster headaches, and nocturnal paroxysmal
hemicrania. In contrast to headache syndromes, exploding head syndrome is usually
painless. Simple partial seizures can present with sensory phenomena but do not usually
occur predominantly at sleep onset. Nocturnal panic attacks can waken a person from
sleep, but are not usually associated with a sense of noise or explosion. Recurrent night-
mares are characterized by recall of more complex and longer-lasting visual imagery.
Sleep starts occur at wake-sleep transition but are predominantly a motor phenomenon
with sudden myoclonic jerks rather than an emphasis on sensory symptoms.

The neurophysiologic basis of these events requires further study.
Bibliography
Chakravarty A. Exploding head syndrome: report of two new cases. Cephalalgia 2008;28:399–400.
Evans RW. Exploding head syndrome followed by sleep paralysis: a rare migraine aura. Headache
2006;46:682–3.
Kallweit U, Khatami R, Bassetti CL. Exploding head syndrome - more than “snapping of the brain”?
Sleep Med 2008;9:589.
Palikh GM, Vaughn BV. Topiramate responsive exploding head syndrome. J Clin Sleep Med 2010;6:382–3.
Pearce JM. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry
1989;52:907–10.
Sachs C, Svanborg E. The exploding head syndrome: polysomnographic recordings and therapeutic
suggestions. Sleep 1991;14:263–6.
266
Parasomnias
Sleep Related Hallucinations

ICD-9-CM code: 368.16 ICD-10-CM code: H53.16
Alternate Names
Hypnagogic hallucinations, hypnopompic hallucinations, complex nocturnal visual
hallucinations.
Diagnostic Criteria
A. There is a complaint of recurrent hallucinations that are experienced just
prior to sleep onset or upon awakening during the night or in the morning.
B. The hallucinations are predominantly visual.
C. The disturbance is not better explained by another sleep disorder
(especially narcolepsy), mental disorder, medical disorder, medication,
or substance use.
Essential Features
Sleep related hallucinations are hallucinatory experiences that occur at sleep onset
or on awakening from sleep. Sleep related hallucinations are predominantly visual
but may include auditory, tactile, or kinetic phenomena. Hallucinations at sleep onset
(hypnagogic hallucinations) may be difficult to differentiate from sleep onset dream-
ing. Hallucinations on waking in the morning (hypnopompic hallucinations) may arise
out of a period of REM sleep, and patients also may be uncertain whether they rep-
resent waking or dream-related experiences. Complex nocturnal visual hallucinations
may represent a distinct form of sleep related hallucinations. They typically occur fol-
lowing a sudden awakening, without recall of a preceding dream. They usually take the
form of complex, vivid, relatively immobile images of people or animals, sometimes
distorted in shape or size. These hallucinations may remain present for many minutes
but usually disappear if ambient illumination is increased. Patients are clearly awake
but often initially perceive the hallucinations as real and frightening.
Associated Features
Sleep related hallucinations may be associated with episodes of sleep paralysis, either
at the same time or on different nights. Patients with complex nocturnal visual hal-
lucinations may jump out of the bed in terror, sometimes injuring themselves. Some
patients may experience other parasomnias, such as sleep talking or sleepwalking, sep-
arate from the hallucinations; some patients may also experience similar complex hal-
lucinations during the day, unassociated with sleep.
267
Parasomnias

Dream-like hypnagogic and hypnopompic hallucinations appear to differ in clini-
cal features and pathogenesis from complex nocturnal visual hallucinations arising
in wakefulness after sudden arousals during the night. Sleep related hallucinations
are common in narcolepsy and also occur as occasional phenomena in a high per-
centage of the general population. In contrast, complex nocturnal visual hallucina-
tions appear to be rare and occur in the setting of a range of neurologic and visual
disorders (see Differential Diagnosis) as well as in an idiopathic form. However,
further work is needed to establish whether or not these forms of hallucinations
represent different entities.
Demographics
In large European population studies, sleep related hallucinations have been reported
to occur with a prevalence of 25% to 37% for hypnagogic hallucinations, whereas the
equivalent reported prevalence for hypnopompic hallucinations is 7% to 13%. Both
hypnagogic and hypnopompic hallucinations are more common in younger persons
and occur slightly more frequently in women than in men.

Multivariate analyses in large population studies have suggested that sleep related hal-
lucinations are associated with younger age, current drug use, past alcohol use, anxiety,
mood disorder, sleep onset insomnia, and perceived insufficient sleep.
Familial Pattern

Sleep related hallucinations appear to be more common in adolescence and early adult-
hood. In many patients, the frequency appears to decrease with age. The natural history
of complex nocturnal visual hallucinations depends on the underlying cause.

It is presumed that most sleep related hallucinations are due to dream ideation of REM
sleep intruding into wakefulness, but this has not been firmly established. Infrequent
hallucinations of this type may be within the limits of normal sleep-wake transition.
Complex nocturnal visual hallucinations may in some cases be release phenomena in
268
Parasomnias
which loss of visual input or decreased reticular activating system activity results in the
visual cortex generating aberrant images.
Objective Findings
Hypnagogic hallucinations appear to arise predominantly from sleep onset REM
periods. However, the very few reports of polysomnography in complex nocturnal
visual hallucinations suggest an onset from NREM sleep. MRI scans of the brain,
PSG, EEG, and neuropsychological testing may help in the differential diagnosis and
in identifying underlying disorders.
Nightmares are frightening dreams awakening the patient from sleep. They are clearly
recognized as dreams and do not persist into wakefulness. Exploding head syndrome
consists of a sudden sensation of an explosion in the head, usually at sleep onset and
sometimes accompanied by a noise or flash of light. It does not involve complex visual
imagery and lasts only seconds. In RBD, the patient acts out dreams during REM sleep.
If not awakened by an observer, the person usually has little recollection of dream
content. Sleepwalking may occasionally be associated with dream ideation, but the
patient recognizes that the dream occurred during sleep. Visual hallucinations can be
due to epileptic seizures but are usually brief, stereotyped, and fragmentary in such
cases. Occasionally, complex visual hallucinations may be associated with migraine
but are usually followed by a headache.
Complex nocturnal visual hallucinations may be seen in patients with narcolepsy, PD,
DLB, visual loss (Charles Bonnet hallucinations), and midbrain and diencephalic
pathology (peduncular hallucinosis), as well as with the use of β-adrenergic receptor-
blocking medications. Anxiety disorders have been noted in some patients.

In contrast to the extensive study of sleep paralysis, little work has been reported on
sleep related hallucinations. It is uncertain whether they represent normal variants or
pathologic entities. It is unclear whether they are always associated with REM sleep
intruding into wakefulness. It is uncertain how frequently complex nocturnal visual
hallucinations are an independent entity, as opposed to representing a final common
pathway of a range of other disorders. Further work is needed to determine from which
stages of sleep they arise.
269
Parasomnias
Bibliography
Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a review and phenomenological survey.
J Neurol Neurosurg Psychiatry 2001;70:727–33.
Kavey N, Whyte J. Somnambulism associated with hallucinations. Psychosomatics 1993;34:86–90.
Mahowald M, Woods S, Schenck C. Sleeping dreams, waking hallucinations, and the central nervous
system. Dreaming 1998;8:89–102.
Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain
1998;121:1819–40.
Ohayon M. Prevalence of hallucinations and their pathological associations in the general population.
Psychiatry Res 2000;97:153–64.
Ohayon M, Priest R, Caulet M, Guilleminault C. Hypnagogic and hypnopompic hallucinations:
pathological phenomena? Br J Psychiatry 1996;169:459–67.
Silber MH, Hansen M, Girish M. Complex nocturnal visual hallucinations. Sleep Med 2005;6:363–6.
Sleep Enuresis
ICD-9-CM code: 788.36 ICD-10-CM code: N39.44
Alternate Names
Enuresis nocturna; nocturnal bedwetting; primary, familial, functional, idiopathic,
monosymptomatic, or essential enuresis; night wetting; sleep related enuresis.
Diagnostic Criteria
Primary Sleep Enuresis – Criteria A-D must be met
A. The patient is older than five years.
B. The patient exhibits recurrent involuntary voiding during sleep,
occurring at least twice a week.
C. The condition has been present for at least three months.
D. The patient has never been consistently dry during sleep.
Secondary Sleep Enuresis – Criteria A-D must be met

A. The patient is older than five years.
B. The patient exhibits recurrent involuntary voiding during sleep,
occurring at least twice a week.
C. The condition has been present for at least three months.
D. The patient has previously been consistently dry during sleep for at least
six months.
270
Parasomnias
Essential Features
Sleep enuresis (SE) is characterized by recurrent involuntary voiding that occurs
during sleep. In primary SE, recurrent involuntary voiding occurs at least twice a week
during sleep after five years of age in a patient who has never been consistently dry
during sleep for six consecutive months. SE is considered secondary in a child or adult
who had previously been dry for six consecutive months and then began wetting at
least twice a week. Both primary and secondary enuresis must be present for a period
of at least three months. Though primary and secondary enuresis share the common
symptom of voiding during sleep, they are understood as distinct phenomena with
different etiologies.
SE is associated with difficulty arousing from sleep in response to an urge to urinate

and may occur during any sleep stage. Sleep disorders that fragment sleep such as
sleep apnea are associated with SE, and treatment of these disorders may cure or
reduce their incidence.
Associated Features
Involuntary voiding during wakefulness may be associated with SE and, if present,
generally points toward a physiological etiology. Psychosocial problems are consid-
ered a relatively rare cause in primary SE, though it does occur more commonly in
children with attention deficit hyperactivity disorder and in children living in disorga-
nized families. Secondary SE is seen more commonly in children who have recently
experienced a significant psychosocial stress, such as parental divorce, physical or
sexual abuse, or neglect. Chronic constipation and encopresis (fecal soiling) often
occur in children with secondary SE.
SE can occur in association with diabetes and urinary tract infection. It may occur in
individuals with nocturnal epilepsy. Among older adults, SE may be associated with
symptoms of congestive heart failure, OSA, depression, and dementia.
SRBD is reported in 8% to 47% of children with enuresis, compared to an overall prev-

alence of 1% to 2%. PLMS have been reported in patients with refractory SE. A large
epidemiology study of children aged 6-10 years found that a current complaint of SE
was significantly associated with increased ORs (2.7-3.4) for subjectively high arousal
threshold, night terrors, nocturia, and confusion when awakened from sleep. Other
studies have found mouth breathing, nasal congestion, snoring, and restless sleep to be
highly related to enuresis in children.
271
Parasomnias

The most important distinction is between primary and secondary SE.
Demographics
SE occurs in 15% to 20% of 5-year-olds. It is three times more common in boys than in
girls. SE is reported by 2.1% of community-dwelling older adults and is more common
among women than men.

The etiology of SE is complex. The factors that precipitate SE on a particular night
and at a particular time remain unknown. One popular model hypothesizes that SE
consists of three interrelated factors: large nocturnal urine volume production, noc-
turnal bladder overactivity, and difficulty arousing from sleep. Several studies suggest
difficulty arousing from sleep is most important in primary enuresis, whereas bladder
instability/overactivity is more important in secondary enuresis.
Children with enuresis are often described by their families as “deep sleepers” and
very difficult to arouse. A high arousal threshold has been objectively confirmed in
these children.
It has been reported that fragmentation of sleep by disorders such as sleep apnea is
highly correlated with SE. Sleep fragmenting disorders such as sleep apnea and PLMS
have been previously reported to be proximal triggers for the occurrence of disorders
of arousal—sleepwalking, confusional arousals, and night terrors. Successful treatment
of sleep apnea in these disorders has been reported to result in reduction or elimination
of disorders of arousal. Similarly, surgical treatment of sleep apneas by adenotonsillec-
tomy has been reported to cure nocturnal enuresis in 60% or more of patients, although
this is not a consistent result. Several studies have noted the presence of sleep related
breathing disorder in > 40% of enuresis patients studied. However, not all sleep studies
have noted SRBD in patients with enuresis. Those without SRBD were still found to
have high arousal threshold from sleep.
Primary SE is a disorder that occurs when an individual fails to arouse from sleep in
response to bladder sensations or fails to inhibit a bladder contraction. These are devel-
opmentally acquired skills, and, as such, there is a range in the ages of their acquisition.
A small proportion of children with primary SE lack the normal increase in vasopressin
release during sleep, leading to a high urinary volume that exceeds the bladder capac-
ity. If these children do not arouse to the sensation of a full bladder, primary SE is the
result. Secondary SE can be caused by, or be associated with, any one of the following
272
Parasomnias
identifiable problems: (1) an inability to concentrate urine due to diabetes mellitus,

diabetes insipidus, nephrogenic diabetes insipidus (idiopathic or pharmacologic [e.g.,
secondary to the use of lithium carbonate]), or sickle cell disease; (2) increased urine
production secondary to the ingestion of caffeine, diuretics, or other agents; (3) urinary
tract pathology, such as urinary tract infections, irritable bladder, malformations of
the genitourinary tract (e.g., ectopic ureter); (4) chronic constipation and encopresis;
(5) neurologic pathology, such as seizures or neurogenic bladder; or (6) psychosocial
stressors, such as parental divorce, neglect, physical or sexual abuse, and institution-
alization. The mechanisms by which secondary SE is associated with these problems
are often not understood.
Familial Patterns
Hereditary factors are suspected in children with primary enuresis. There is often a
high prevalence of enuresis among the parents, siblings, and other relatives of the
child with primary enuresis. The reported prevalence is 77% when both parents were
enuretic as children and 44% when one parent has a history of enuresis. Recent linkage
studies support the hypothesis of genetic and phenotypic heterogeneity of SE. A
putative linkage of SE to a region on chromosomes 22q, 13q, and 12q across different
families has been reported.

Voiding is a spinal reflex during wakefulness and sleep during infancy, until about 18
months of age. Between 18 months and three years of age, the child is able to delay
voiding with a full bladder, first during wakefulness and at a later age during sleep. The
primary determinant of the age at which this skill is acquired is developmental matura-
tion. Somewhat arbitrarily, primary SE is defined as a problem if it persists beyond five
years of age. The spontaneous cure rate is 15% per year. The primary complication of
SE is to the child’s self-esteem. How well the child’s family deals with the symptom is
an important determinant of whether complications develop. Secondary SE can occur
at any age. Complications of secondary SE are determined by the problem leading to
the enuresis.
The developmental pattern of enuresis is similar to NREM parasomnias, although its
first occurrence in adulthood is uncommon.

SE is a heterogeneous disorder with various underlying pathophysiological mecha-
nisms, resulting in a mismatch between nocturnal bladder capacity and the amount of
273
Parasomnias
urine produced during sleep, in association with a simultaneous failure of arousal from
sleep in response to the sensation of bladder fullness. SE can be seen in association
with sleep fragmentation disorders including SRBD, which in children is most often
secondary to adenotonsillar hypertrophy.
Objective Findings
In primary and secondary SE, enuretic episodes can occur in all sleep stages, during
nocturnal wakefulness, and in association with transient arousals. Sleep stages have
not been found to be different on nights when enuresis occurs versus nights on which it
does not occur. The results of polysomnographic studies of children with enuresis com-
pared to normal controls have been inconsistent. A computerized power analysis of
sleep data suggested an increase in delta power, whereas the majority of other studies
have reported no differences. However, a recent study found those age 6-14 years had
elevated light stage N1 sleep and reduced N3 sleep and REM sleep compared to normal
controls. The population with enuresis had a significantly elevated arousal index.
SRBD has been reported in 8% to 47% of children with SE. SE and sleep apnea are
highly correlated with an increasing prevalence of enuresis as the respiratory distur-
bance index (RDI) increases. In addition to SRBD, PLMS (range of 3.9 to 38.6 per
hour of sleep) have been reported in a group of children with treatment-resistant SE.
Recent studies have demonstrated that patients with enuresis are subjectively sleepier
than normal controls. This has been hypothesized to result from fragmented nocturnal
sleep and is consistent with a large body of sleep research in other areas.
Enuresis may be caused by a variety of medical or neurological disorders such as
diabetes mellitus, diabetes insipidus, epilepsy, sickle cell disease, bowel or bladder
dysfunction, anatomical abnormalities or infection of the urinary tract, neurological/
developmental disorders or other sleep disorders, especially OSA. Organic pathology
of the urinary tract is more prevalent in children who, in addition to sleep enuresis, also
exhibit daytime enuresis, abnormalities in the initiation of micturition, or abnormal
urinary flow.
Evaluation of sleep enuresis should include complete enuresis history, sleep history,
physical examination and laboratory studies (as indicated) to exclude these etiol-
ogies. When signs and symptoms of sleep apnea are present—mouth breathing,
snoring, adenotonsillar hypertrophy, daytime sleepiness, hyperactivity—a sleep study
should be conducted.
274
Parasomnias

Recent advances suggest that the terms primary and secondary enuresis may be overly
simplistic. Further work is necessary to understand the genetic and clinical aspects of SE.
Other sleep disorders are common in children with SE. Though it may be possible that
the apneas, hypopneas, and snoring-related arousals in children with SRBD could be
the trigger of SE, many children with SE do not have a sleep disorder. In such cases,
the underlying bladder overactivity may be the stimulus for arousal.
Studies of the relationship of sleep, sleep disorders, and sleep fragmentation to SE

performed to date have been inconsistent. This is likely due to differing definitions of
enuresis and varying research methodologies. Further sophisticated sleep laboratory
studies are necessary to elucidate the relationship. In particular, the proximal trigger
for episodes of SE has not been determined. Some studies suggest enuresis is sponta-
neous, whereas others suggest a relationship to sleep disorders that result in arousals—
similar to findings in disorders of arousal.
Bibliography
Burgio K, Locher J, Ives D, Hardin J, Newman A, Kuller L. Nocturnal enuresis in community-dwelling
older adults. J Am Geriatr Soc 1996;44:139–43.
Brooks LJ, Topol HI. Enuresis in children with sleep apnea. J Pediatr 2003;142:515–8.
Chandra M, Saharia R, Hill V, Shi QH. Prevalence of diurnal voiding symptoms and difficult arousal from
sleep in children with nocturnal enuresis. J Urol 2004;172:311–6.
Cohen-Zrubavel V, Kushnir B, Kushnir J, Sadeh A. Sleep and sleepiness in children with nocturnal
enuresis. Sleep 2011;34:191–4.
Dhondt K, Raes A, Hoebeke P, Van Laecke E, Van Herzeele C, Vande Walle J. Abnormal sleep architecture
and refractory nocturnal enuresis. J Urol 2009;182:1961–5.
Jeyakumar A, Rahman SI, Armbrecht ES, Mitchell R. The association between sleep-disordered breathing
and enuresis in children. Laryngoscope 2012 Aug;122:1873–7.
Neveus T. The role of sleep and arousal in nocturnal enuresis. Acta Paediatr 2003;92:1118–23.
Kalorin CM, Mouzakes J, Gavin JP, et al. Tonsillectomy does not improve bedwetting: results of a
prospective controlled trial. J Urol 2010;184:2527.
Neveus T, Stenberg A, Lackgren G, Tuvemo T, Hetta J. Sleep of children with enuresis: A polysomnographic
study. Pediatrics 1999;103:1193–7.
Norgaard JP, Hansen JH, Nielsen JB, Petersen BS, Knudsen N, Djurhuus JC. Simultaneous registration of
sleep-stages and bladder activity in enuresis. Urology 1985;26:316–9.
Sakellaropoulou AV, Hatzistilianou MN, Emporiadou MN, et al. Association between primary nocturnal
enuresis and habitual snoring in children with obstructive sleep apnoea-hypopnoea syndrome. Arch
Med Sci 2012;8:521–7.
Stone J, Malone PS, Atwill D, et al. Symptoms of sleep-disordered breathing in children with nocturnal
enuresis. J Pediatr Urol 2008;4:197.
275
Parasomnias
Weissbach A, Leiberman A, Tarasiuk A, Goldbart A, Tal A. Adenotonsillectomy improves enuresis in

children with obstructive sleep apnea syndrome. Int J Pediatr Otorhinolaryngol 2006;70:1351–6.
Wolfish N. Sleep arousal function in enuretic males. Scand J Urol Nephrol Suppl 1999;202:24–6.
Wolfish NM, Pivik RT, Busby KA. Elevated sleep arousal thresholds in enuretic boys: clinical implications.
Acta Paediatr 1997;86:381–4.
Yeung CK, Chiu HN, Sit FK. Sleep disturbance and bladder dysfunction in enuretic children with treatment
failure: fact or fiction? Scand J Urol Nephrol Suppl 1999;202:20–3.
Yeung CK, Diao M, Sreedhar B. Cortical arousal in children with severe enuresis. N Engl J Med
2008;359;22–4.
Parasomnia Due to a Medical Disorder

The essential feature of this diagnosis is the presence of a parasomnia that is attrib-
utable to an underlying neurological or medical condition. RBD is the parasomnia
most commonly associated with an underlying neurological condition (“symptomatic
RBD”). However, when diagnostic criteria for RBD are met, the more specific diagno-
sis of REM sleep behavior disorder should be made.
Complex nocturnal sleep related (hypnagogic and hypnopompic) visual hallucina-

tions can occur with neurological disorders such as narcolepsy, PD, DLB, visual loss
(Charles Bonnet hallucinations), and midbrain and diencephalic pathology (pedun-
cular hallucinosis). Dreaming and sleep paralysis may or may not be associated with
these hallucinations.
Parasomnia Due to a Medication or Substance

instructions)
The essential feature of this diagnosis is the close temporal relationship between expo-
sure to a drug, medication, or biological substance and the onset of the signs and symp-
toms of that disorder. A likely causal relationship can be inferred if signs and symp-
toms of the parasomnia disappear when the drug or substance is withdrawn.
The emergent parasomnia can be a de novo parasomnia, the aggravation of a

chronic intermittent parasomnia, or the reactivation of a previous parasomnia. As
discussed previously, a variety of medications and biological substances, including
276
Parasomnias
selective serotonin reuptake inhibitors, venlafaxine, tricyclic antidepressants, mono-

amine oxidase inhibitors, mirtazapine, bisoprolol, selegiline, or cholinergic treatment
for Alzheimer disease, have been reported to be associated with acute or chronic RBD.
Acute RBD can also be seen during states of withdrawal from cocaine, amphetamine,
alcohol, barbiturate, and meprobamate abuse. Caffeine and chocolate abuse have been
implicated in causing or unmasking RBD. However, when diagnostic criteria for RBD
are met, the more specific diagnosis of REM sleep behavior disorder should be made.
The use of medications such as β-adrenergic receptor-blocking agents can be associ-

ated with sleep related hallucinations. When the clinical presentation suggests a direct
relationship between a drug or substance and sleep related hallucinations, a diagnosis
of parasomnia due to a medication or substance should be employed.
Sedative-hypnotics such as zolpidem and zopiclone have been associated with apparent
NREM parasomnias including SRED and sleep driving. It has been suggested that sleep
driving is an overlap behavior in which the sedative-hypnotic increases the arousal
threshold during sleep at the beginning of the behavior, while later behavior is due to the
CNS depressing effects of the drug while awake. It has not been determined if drug-re-
lated NREM parasomnias are associated with the same genetic predisposition, priming
factors, and triggers observed in disorders of arousal. When clinical presentation sug-
gests a direct relationship between disorders of arousal and use of a drug or substance, a
diagnosis of parasomnia due to a medication or substance should be employed.
Alcohol has often appeared on lists of potential sleepwalking triggers without a basis
in reliable empirical scientific research. Recent evidence-based reviews have found
no relationship between alcohol and sleepwalking. The behavior of the alcohol-in-
toxicated individual may superficially resemble that of the sleepwalker. However, the
sleepwalker is typically severely cognitively impaired, but with only limited motor
impairment. The alcohol-intoxicated individual’s level of cognitive functioning may
be reduced, but not absent, whereas motor behavior is severely impaired.
Proponents of the theory of alcohol related sleepwalking suggest that the effects
of alcohol are similar to that of sleep deprivation—that is, alcohol increases deep
sleep. However, this claim in not substantiated by sleep laboratory-based studies
in normal controls, and no empirical sleep studies of alcohol and sleepwalking
have ever been conducted.
There is no scientific evidence that complex behaviors occurring during the sleep
period following alcohol ingestion are anything other than the nocturnal wandering of
277
Parasomnias
an alcohol-intoxicated individual. Unconsciousness, intoxication, and sleep are very

different states of consciousness. Parasomnias should be easily distinguished from
alcohol intoxication by the presence of significant alcohol ingestion prior to bedtime.
The association of therapeutic doses of sedative hypnotic drugs and apparent para-
somnias should be carefully distinguished from the expected effects of drug abuse
or misuse that result in CNS depression. Investigations of drivers who had accidents
attributed to drug-related sleep driving are reported to show that (1) blood levels of
prescribed sedative hypnotics exceeded therapeutic ranges; (2) the individuals failed
to take the medication at the correct time or remain in bed for sufficient time follow-
ing ingestion; and/or (3) the individuals combined sedative-hypnotics with other CNS
depressants and/or alcohol. Driving with a high blood level of a sedative-hypnotic
can result in significant cognitive and motor impairment. Serious accidents can result.
Sleep driving and other complex behaviors in this population are more likely to have
resulted from drug misuse and abuse rather than true parasomnias.
Parasomnia, Unspecified
This diagnosis is intended for parasomnias that cannot be classified elsewhere or for
cases in which the physician has a clinical suspicion of a parasomnia but is unable to
establish a specific diagnosis. In many cases, “parasomnia, unspecified” will be a tem-
porary diagnosis. However, in other patients, an underlying condition may not ever be
established, and in those patients, “parasomnia, unspecified” should remain an ongoing
diagnosis.
278
Parasomnias
Sleep Talking
Alternate Names
Somniloquy.
The essential feature is talking, with varying degrees of comprehensibility, during sleep.
Sleep talking may occur during REM or NREM sleep. Sleep talking can be idiopathic
or associated with parasomnias such as RBD or disorders of arousal such as confusional
arousal. Sleep talking may follow arousals from sleep or more rarely cause them. Sleep
talking is highly prevalent. A recent cross-sectional epidemiologic study found the life-
time prevalence of sleep talking to be 66% and current prevalence—in the past three
months—to be 17%. There is no apparent sex difference. Onset and course are unknown.
Complications usually arise when sleep talking is very frequent or loud or if the content
is objectionable to others. Sleep talking is usually reported by the bed partner or someone
sleeping in the same room or sleeping area as the affected individual. Sleep talking can
disrupt the sleep of a bed partner, roommate, or others in a group-sleeping situation
(such as college dormitories, military barracks, fire stations, or a tent while camping).
The content of sleep talking has not been shown to reflect actual prior waking behavior
or memories. The sleep talker is rarely aware of his or her sleep talking.
Nocturnal vocalization, including frank sleep talking, is often seen in patients with RBD
and subclinical RBD. A recent report notes that sleep talking may be a useful diagnostic
marker for differentiating DLB from Alzheimer disease and other types of dementia.
The vocalizations of RBD may be loud, emotional, profane, and associated with behav-
iors that correlate with remembered dream mentation. Nocturnal seizures may be asso-
ciated with vocalization that tends to be stereotypic. The vocalizations associated with
sleep terrors are emotionally laden and associated with behaviors of intense arousal and
agitation. In PTSD, increased vocalizations during sleep have been described.
Bibliography
Arkin AM, Toth MF, Baker J, Hastey JM. The frequency of sleep talking in the laboratory among chronic
sleep talkers and good dream recallers. J Nerv Ment Dis 1970;151:369–74.
Bjorvatn B, Grønli J, Pallesen S. Prevalence of different parasomnias in the general population. Sleep Med
2010;11:1031–4.
279
Parasomnias
Honda K, Hashimoto M, Yatabe Y, et al. The usefulness of monitoring sleep talking for the diagnosis of
Dementia with Lewy bodies. Int Psychogeriatr 2013;25:851–8.
Hublin C, Kaprio J, Partinen M, Koskenvuo M. Sleeptalking in twins: epidemiology and psychiatric
comorbidity. Behav Genet 1998;28:289–98.
Reimao RN, Lefevre AB. Prevalence of sleep-talking in childhood. Brain Dev 1980;2:353–7.
280
Sleep Related Movement
Disorders
Restless Legs Syndrome............................................................................282
Periodic Limb Movement Disorder..............................................................292
Sleep Related Leg Cramps.........................................................................299
Sleep Related Bruxism................................................................................303
Sleep Related Rhythmic Movement Disorder.............................................312
Benign Sleep Myoclonus of Infancy............................................................317
Propriospinal Myoclonus at Sleep Onset....................................................321
Sleep Related Movement Disorder Due to a Medical Disorder...................325
Sleep Related Movement Disorder Due to a Medication or Substance......326
Sleep Related Movement Disorder, Unspecified.........................................327

Excessive Fragmentary Myoclonus ............................................................328
Hypnagogic Foot Tremor and Alternating Leg Muscle Activation................330
Sleep Starts (Hypnic Jerks).........................................................................335
Sleep related movement disorders are primarily characterized by relatively simple,

usually stereotyped, movements that disturb sleep or its onset. Restless legs syndrome
(RLS) is an exception in that patients typically engage in walking or nonstereotypic
limb movement to reduce leg discomfort. However, RLS is closely associated with
periodic limb movements (PLMs), which are usually simple and stereotyped within a
series. Nocturnal sleep disturbance or complaints of daytime sleepiness or fatigue are a
prerequisite for a diagnosis of a sleep related movement disorder. For example, many
normal sleepers exhibit episodes of periodic limb movements of sleep (PLMS) but
have no complaint of a sleep disturbance, nor do they show a significant objective dis-
turbance of their sleep as a result of the movements. Such persons should not be classi-
fied as having periodic limb movement disorder (PLMD), but instead, the presence of
PLMS should simply be noted. Similar considerations relate to the distinction between
rhythmic movement disorder and the presence of rhythmic movements.
Body movements that disturb sleep also are seen in many other sleep disorder categories
(e.g., in parasomnias such as sleepwalking, sleep terrors, and rapid eye movement (REM)
sleep behavior disorder (RBD)). However, these parasomnias differ from the simple ste-
reotyped movements categorized as sleep related movement disorders in that they involve
complex behaviors during the sleep period. Parasomnia-related movements may appear
281
Sleep Related Movement Disorders
purposeful and goal directed, but are outside the conscious awareness of the individual.
Parasomnias are listed in a separate section from the sleep related movement disorders.
Although the history may be diagnostic, polysomnography is sometimes necessary to

make a firm diagnosis of sleep related movement disorders and distinguish them from
parasomnias. In these cases, it is necessary to add all-night video recording to the poly-
somnographic recording and to correlate the documented movements with the techni-
cian’s description of the patient’s behavior and level of consciousness in order to estab-
lish a diagnosis. There are some movement disorders that may occur during both sleep
and wakefulness. If the presentation during sleep is significantly different from that
during wakefulness, or if the movement is entirely confined to sleep, then the move-
ment disorder is classified here (e.g., the occurrence of bruxism exclusively in sleep).
Restless Legs Syndrome

Alternate Names
Willis-Ekbom disease.
Diagnostic Criteria
A. An urge to move the legs, usually accompanied by or thought to be
caused by uncomfortable and unpleasant sensations in the legs.1,2 These
symptoms must:
1. Begin or worsen during periods of rest or inactivity such as lying
down or sitting;
2. Be partially or totally relieved by movement, such as walking or
stretching, at least as long as the activity continues;3 and
3. Occur exclusively or predominantly in the evening or night rather
than during the day.4
B. The above features are not solely accounted for as symptoms of another
medical or a behavioral condition (e.g., leg cramps, positional discomfort,
myalgia, venous stasis, leg edema, arthritis, habitual foot tapping).
C. The symptoms of RLS cause concern, distress, sleep disturbance, or
impairment in mental, physical, social, occupational, educational,
behavioral, or other important areas of functioning.5
282
Notes
1. Sometimes the urge to move the legs is present without the
uncomfortable sensations, and sometimes the arms or other parts of the
body are involved in addition to the legs.
2. For children, the description of these symptoms should be in the child’s
own words.
3. When symptoms are very severe, relief by activity may not be
noticeable but must have been previously present.
4. As a result of severity, treatment intervention, or treatment-induced
augmentation, the worsening in the evening or night may not be
noticeable but must have been previously present.
5. For certain research applications, such as genetic or epidemiological
studies, it may be appropriate to omit criterion C. If so, this should be
clearly stated in the research report.
Essential Features
RLS is a sensorimotor disorder characterized by a complaint of a strong, nearly irresist-
ible urge to move the limbs. This urge to move is often but not always accompanied by
other uncomfortable sensations felt deep inside the limbs or by a feeling that is simply
difficult or impossible to describe. Although the legs are most prominently affected,
“restless legs” is a misnomer, in that 21% to 57% of individuals with RLS describe
some arm sensations. The most common adult RLS descriptors in English are “rest-
less,” “uncomfortable,” “twitchy,” “need to stretch,” “urge to move,” and “legs want to
move on their own.” About half express their RLS sensations as painful. “Numb” and
“cold” are very uncommon descriptors for RLS.
Criteria A1-3 specify the necessary characteristics of the RLS sensations: worse at
rest, better with movement, and predominant occurrence in the evening or night.
The separation of worsening at rest (criterion A1) from worsening in the evening/
night (criterion A3) is based on circadian rhythm studies that show an increase at
night, independent of activity level. RLS must be differentiated from other condi-
tions that can mimic RLS (criterion B). Clinically significant RLS is defined by RLS
symptoms causing substantial distress, sleep disturbance, or impairment of function
(criterion C).
Associated Features
Disturbed sleep is a common, prominent, and distressing aspect of RLS. Sleep onset
and maintenance complaints in individuals with RLS are notably higher than in con-
trols, with odds ratios (OR) between 1.7 and 3.5. In clinical populations, disturbed
283
sleep is reported in 60% to 90% of individuals with RLS, is typically the most trou-
bling symptom, and is often the primary reason for seeking medical care. The Medical
Outcomes Study Sleep Questionnaire scores for sleep quantity, sleep disturbance,
sleep adequacy, and sleep problems are significantly worse for RLS patients than con-
trols. Daytime fatigue and daytime sleepiness are also common complaints; however,
the sleepiness is not as severe as expected for the degree of sleep disruption, implying
hyperarousal in RLS. In contrast to obstructive sleep apnea, Epworth Sleepiness Scale
scores in RLS are typically in the normal range, and either no different or marginally
elevated when compared to normal controls. Clinical sleep disturbance correlates with
both severity of RLS and health impact of RLS. Some individuals with RLS may
choose to work at night, thereby shifting quiet activities and their sleep schedule away
from the circadian peak of their RLS symptoms.
PLMs, a family history of RLS, and response to dopaminergic therapy are supportive
of the diagnosis. Periodic limb movements can occur in sleep (PLMS) or wakeful-
ness (PLMW). PLMW occur during quiet rest and frequently at the transition between
waking and sleep, disrupting sleep onset or the return to sleep. PLMS are frequently
associated with arousal from sleep. RLS sensory and motor features respond initially
to treatment with dopaminergic therapy in almost all cases.
Multiple clinic-based and population-based studies have shown an increased preva-

lence of mood and anxiety disorders in individuals with RLS. Most controlled studies
using validated assessments have shown significantly increased ORs for moderately
or highly elevated depressive symptoms (OR 1.95 and 3.67), major depression (OR
2.6), major depressive disorder (OR 2.57 and 4.7), generalized anxiety disorder (OR
3.5), panic disorder (OR 4.7, 12.9, and 18.9), and posttraumatic stress disorder (OR
3.76). In addition, a positive correlation has been found between the severity of RLS
and depression/anxiety symptoms. Relevant to the RLS-depression relationship is
the emerging evidence that treatment of RLS improves depressive symptoms.
Similarly, increased rates of attention deficit hyperactivity disorder (ADHD) have

been found in RLS, both in pediatric and adult studies. Emerging data indicate that
about one fourth of individuals with RLS have ADHD symptoms, and conversely,
that 12% to 35% of those with ADHD meet criteria for RLS. Other medical condi-
tions for which there is some evidence for greater-than-chance association include
narcolepsy, migraine, chronic obstructive pulmonary disease, Parkinson disease,
multiple sclerosis, peripheral neuropathy, obstructive sleep apnea, diabetes melli-
tus, fibromyalgia, rheumatoid arthritis, nocturnal eating, obesity, thyroid disease, and
heart disease.
284

Evidence in the literature is not sufficient to support well-defined subtypes of RLS.
Early-onset RLS (prior to age 45 years) is more familial and associated with slower
progression than late-onset RLS. In addition, the classification of “secondary” RLS has
been suggested when the condition occurs in association with iron deficiency, preg-
nancy, and chronic renal failure, but this construct has been challenged based on patho-
physiological, family history, genetic, and clinical course data.
Demographics
The overall prevalence of RLS has been estimated at 5% to 10% in European and
North American population-based studies. However, in Asian countries, studies thus
far indicate a lower prevalence. Prevalence is about twice as high in women than in
men. In most studies, prevalence increases with age up to 60-70 years, except in Asian
populations where an age-related increase has not been found. Various measures of
clinical significance such as frequency (1-2 times/week), severity (moderate to severe
distress), differential diagnosis, and impact have been applied to population-based
studies. These analyses indicate the prevalence of clinically significant RLS to be 2%
to 3% in Europe and North America, but lower in Asia. Annual incidence rates have
been reported as 0.8% to 2.2%.
Pediatric prevalence rates are 2% to 4% in UK/US and Turkish studies, with moderate
to severe RLS in about 0.5% to 1%. Adolescents are more likely to have moderate to
severe RLS symptoms than younger children—one half of 12- to 17-year-olds com-
pared to one fourth of 8- to 11-year-olds with RLS. Boys are affected as often as girls,
with the sex difference not emerging until the late teens or twenties.

A positive family history of RLS, the genetic variants noted below, and female sex
confer increased risk for RLS. The best characterized precipitating factors are iron
deficiency, certain medications, pregnancy, chronic renal failure, and prolonged immo-
bility. Mild iron deficiency, characterized by serum ferritin below 50 µg/L, has been
associated with increased severity of RLS, and repletion of iron stores from below
50-75 µg/L has been found to diminish RLS symptoms. Medications that may precip-
itate or aggravate RLS and/or PLMS include sedating antihistamines, some centrally
active dopamine receptor antagonists, and most antidepressants. An exception is the
antidepressant bupropion, with its dopamine-promoting activity.
The prevalence of RLS during pregnancy is two to three times greater than in the
general population. There is a peak in the number of women affected by RLS in the
285
third trimester, with resolution of symptoms for most, but not all, by one month after
delivery. Independent predictors of RLS during pregnancy are a family history of RLS
(OR 8.43), a history of RLS in prior pregnancy (OR 53.74), a history of RLS in the
past (OR 12.91), and hemoglobin ≤11 g/dL (OR 2.05). Parity, the number of previous
pregnancies, appears to account for the 2:1 sex difference between women and men in
the general population prevalence of RLS.
In chronic renal failure patients, the prevalence of RLS is two to five times greater than
in the general population. This represents prevalence rates of 11% to 58% in US and
European chronic renal failure clinics. Compared to patients with chronic renal failure
without RLS, those with RLS have greater sleep disturbance, report poorer quality of
life, and more frequently discontinue dialysis prematurely. Typically, RLS symptoms
improve dramatically within one month after kidney transplantation but become severe
again with transplant failure.
There is limited or contradictory evidence for sleep deprivation, peripheral neuropathy,

radiculopathy, pain, caffeine, tobacco, or alcohol as exacerbating factors for RLS.
Familial Patterns
Early-onset RLS is highly familial, with 40% to 92% of cases reporting affected family
members. High concordance rates are observed in monozygotic twins. The risk of RLS
is two to six times greater for first-degree relatives of patients with RLS than for those
from the general population. Although an autosomal dominant model of RLS is sug-
gested by many family studies, recent genomewide linkage and association studies
suggest a more complex gene-environment pattern. Linkage analyses have reported
several different gene loci associated with RLS but, to date, no single causative gene.
However, genomewide association studies have identified single nucleotide poly-
morphisms in RLS, four of which have been replicated: BTBD9, MEIS1, MAP2K5/
LBXCOR, and PTPRD. Nonetheless, the relationship between familial RLS and these
findings remains to be determined.

Onset of RLS symptoms occurs at all ages, from childhood to late adult life. Mean
age of onset for familial RLS is in the third or fourth decade, with onset prior to age
21 years in about one third of cases. The clinical course of RLS differs based on age
of onset. In early-onset RLS (before age 45 years), slow progression of symptoms is
found in about two thirds of cases. Most of the remaining one third report stable symp-
toms over time, although remission has been described. In late-onset RLS, rapid pro-
gression is typical and aggravating factors are common.
286
Significant impairment of health-related quality of life (HRQoL) has been found in

moderate to severe RLS. Both physical health and mental health scores have consis-
tently been found to be lower for individuals with RLS, using standard QoL assess-
ment tools. The HRQoL impairments are strongly associated with severity of RLS and
remain after controlling for age, sex, and disease comorbidity. In addition, patients
with cancer, type 2 diabetes, or renal failure who also have RLS have been shown to
have poorer quality of life than those without RLS. Overall, RLS accounts for a major
disease burden on those who suffer from it, demonstrated to be similar to or worse
than that associated with osteoarthritis, congestive heart failure, depression, Parkinson
disease, or stroke.
Large population-based studies have found positive associations between RLS and
cardiovascular disease, including coronary heart disease and stroke. Repetitive surges
in heart rate and blood pressure associated with PLMS are a potential mediator in the
physiology of these relationships. Only limited mortality data are available, suggesting
increased risk of mortality in women and in chronic renal failure patients with RLS.
The accurate diagnosis of RLS in children and adolescents requires understanding of
developmental language and cognitive skills. Adequate verbal skills are needed for
children to communicate the sensory component of RLS and description must be in
“the child’s own words,” rather than by a parent or caretaker. For criterion A, children
rarely use or understand the word “urge.” Instead they describe that their legs “need to”
“have to” or “got to” move. Descriptors for the discomfort include: bugs, ants, weird/
funny feelings, tingle, wiggly, and shaky. Younger children often use the word “kick”
rather than “move,” e.g., “my legs want to kick.” Similar to adults, children report arm
involvement in almost half of cases. Sitting in class, lying in bed, reading a book, and
riding in a car are situations where children report onset or worsening of their symp-
toms. Relief is typically achieved by moving around, walking, rubbing, kicking, or
distraction. Perhaps as a result of prolonged periods of sitting in class, two thirds of
children and adolescents with RLS report daytime leg sensations. Because of this, for
diagnostic criterion A3 (worse in the evening/night), it is important to compare equal
duration of sitting or lying down in the day to sitting or lying down in the evening/
night. However, even with such comparisons, a significant subset of children do not
report worsening at evening/night, yet meet all other diagnostic criteria and have sup-
portive features for RLS, including a positive family history. Children who are age six
years or older and developmentally normal have been shown to report detailed, ade-
quate descriptors for RLS symptoms. For children who are too young to adequately
describe RLS sensations or are developmentally delayed, a PLMD diagnosis may be
287
the initial diagnosis, with full RLS symptomatology evident over time. Diagnosis by
observational techniques has been suggested but not yet validated.
The differential diagnosis of pediatric RLS includes positional discomfort, sore leg
muscles, joint/tendon injury, and bruises, all of which are common mimics. In child-
hood, RLS is frequently misdiagnosed as “growing pains.” Four specific domains
that are affected in pediatric RLS are sleep, daily activities, mood, and energy/vital-
ity. Difficulties with sleep onset, sleep maintenance, and sleep quality are common.
Negative influence of RLS on waking activities includes academic impact due to dis-
ruption of schoolwork, homework, and ability to concentrate. Severity assessment of
pediatric RLS has thus far been limited to simple measures of self-reported frequency
and intensity.
Because pediatric RLS is highly familial, the presence of RLS in a first-degree rela-
tive helps to increase diagnostic certainty in childhood RLS. Similarly, the presence of
PLMS or a history of PLMD is quite helpful in supporting an RLS diagnosis in chil-
dren. As in adults, approximately 70% of children with RLS demonstrate PLMS ≥ 5/
hour on a single night and nearly 90% when multiple nights are sampled. PLMS ≥ 5/
hour are uncommon in pediatric normative samples. As noted above, pediatric RLS
is comorbid with ADHD in about one fourth of cases, and, as in adults, higher rates
of anxiety and depressive symptoms are found. RLS is common in pediatric chronic
kidney disease.
Prevalence rates of RLS increase with age until late adulthood then stabilize or decrease
slightly in the elderly. However, strong associations with anxiety, mood disorders, and
decreased QoL measures remain in the elderly. Diagnostic criteria for RLS in the cog-
nitive-impaired elderly have been suggested but not validated.

Brain iron deficiency, central nervous system dopamine regulation, and genetics appear
to be primary factors in the pathophysiology of RLS. Iron is important in brain dopa-
mine production and synaptic density, as well as in myelin synthesis and energy pro-
duction. A connection between RLS and low brain iron is supported by autopsy data,
MRI, brain sonography, and cerebrospinal fluid analysis. Evidence for central nervous
system dopaminergic system involvement comes mainly from multiple randomized
clinical trials that have clearly demonstrated the effect of dopaminergic drugs for RLS
and PLMS. In addition, an altered dopaminergic profile in RLS is supported by func-
tional MRI, positron emission tomography, and autopsy data. Association of gene vari-
ants BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD with RLS has been replicated,
288
indicating a genetic substrate upon which environmental factors might act. BTBD9 is
estimated to confer a population attributable risk (PAR) of 50% for RLS. Together,
BTBD9, MEIS1, and MAP2K5/LBXCOR account for 70% of the PAR for RLS in indi-
viduals with European ancestry. Thus far, two of the variants, BTBD9 and MEIS1,
appear to influence expression of PLMS, as well as iron homeostasis. However, the full
role of RLS gene variants has not been adequately defined.
Objective Findings
Although polysomnography is not routinely indicated in the evaluation of RLS, poly-
somnographic studies demonstrate significant objective sleep abnormalities in RLS,
with increased latency to persistent sleep and higher arousal index as the most consis-
tent differences in sleep architecture. PLMS ≥5/hour occur in 70% to 80% of adults
with RLS on single-night testing but in >90% when multiple nights are sampled. In
adult RLS, PLMS are more prominent during the first half of the night and vary in
frequency from night to night. About one third of PLMS are associated with cortical
arousals, and most have associated autonomic arousals. PLMS are not influenced by
placebo effect. PLMS arousals contribute to the primary RLS morbidity of sleep dis-
turbance. Furthermore, RLS sensory symptoms impair return to sleep, and thereby
result in more prolonged awakening.
The Suggested Immobilization Test (SIT) evaluates PLMW and related sensory com-
ponents of RLS during resting wakefulness. A standard polysomnogram recording
without respiratory measures is used for one hour before the usual bedtime while the
subject sits comfortably awake and upright in bed with the legs outstretched. RLS
diagnosis is supported by a finding of more than 40 PLMW/hour.
Activity monitors with high-frequency sampling and body-position monitoring may

be attached to the ankle or foot to provide an alternate measure of PLMs. Recordings
assess the frequency and variability of PLMs from night to night, typically over three
to five nights.
The differentiation of RLS from other conditions that may have characteristics of RLS
is essential, because approximately 40% of individuals without RLS will report some
urge or need to move the legs while at rest. Fulfilling diagnostic criteria A2 (better
with movement) and A3 (worse in the evening/night) improves specificity for an RLS
diagnosis to only about 70%, based on studies that have used structured diagnostic
interviews. However, differentiating RLS from leg cramps and positional discomfort
improves specificity to 94%, emphasizing the importance of differential diagnosis. The
289
most important “mimics” of RLS are leg cramps, positional discomfort, arthralgias/
arthritis, myalgias, leg edema, peripheral neuropathy, radiculopathy, and habitual
foot tapping. Not characteristic of RLS are: “knotting” of the muscle (cramps), relief
with a single postural shift (positional discomfort), limitation to joints (arthritis), sore-
ness to palpation (myalgias), and other abnormalities on physical examination. Less
common conditions to be differentiated from RLS include neuroleptic-induced akathi-
sia, myelopathy, symptomatic venous insufficiency, peripheral artery disease, eczema,
orthopedic problems, painful legs and moving toes, and anxiety-induced restlessness.
Neuroleptic-induced akathisia differs from RLS in that akathisia is associated with the
need to move the entire body and occurs in association with use of dopamine-receptor
antagonists. Painful legs and moving toes have neither a clear circadian pattern nor the
sense of an urge to move.
Pain involving the legs occurs with numerous conditions, including arthritis, vascular
problems, sports/orthopedic injuries, and neuropathy. These pains can have a nocturnal
presentation and may be worse at rest, but improvement with movement either does
not occur or entails more exercise than simple movement of the leg. The urge to move,
if present at all, usually stems from awareness that movement produces relief rather
than the strong primary urgency of movement felt with RLS. The presence of pain,
however, does not exclude a diagnosis of RLS, because about 50% of patients with
RLS report their RLS symptoms as painful.
Although it is important that RLS symptoms not be attributable solely to another

medical or behavioral condition, it should also be appreciated that any of these mimics
can occur in an individual who also has RLS. For example, some subjects may have
both RLS and leg cramps. When the diagnosis of RLS is not certain, evaluation for the
supportive features such as the presence of PLMS or a family history of RLS may be
helpful. Diagnostic interviews that include differential diagnosis have been validated
for RLS. These demonstrate sensitivity and specificity of > 90%.

The diagnosis of RLS relies on the subjective report of sensory symptoms that lie
outside the range of common sensory experience. Many patients have difficulty
describing the sensations. Further studies of the biological bases for RLS may lead to
better classification of RLS and possibly to objective tests for diagnosis. Iron, dopa-
mine, and genetic research hold particular promise. Additional epidemiological and
genetic studies outside the US and Europe are needed to explore apparent population
differences. The diagnostic standards and severity assessment for children and cogni-
tively impaired adults require further development. Clarification of the natural course
290
and potential exacerbating factors is needed. Better understanding of RLS with comor-
bidities such as mood disorders and attention deficit hyperactivity disorder might lead
to improved outcomes in those disorders. Further evaluation of long-term complica-
tions is important, including clarification of associations with hypertension, cardiovas-
cular disease, and stroke.
Bibliography
Allen R, Picchietti D, Hening W, et al. Restless legs syndrome: diagnostic criteria, special considerations,
and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at
the National Institutes of Health. Sleep Med 2003;4:101–19.
Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary
medical care patients in western Europe: Prevalence and characteristics. Sleep Med 2010;11:31–7.
Dauvilliers Y, Winkelmann J. Restless legs syndrome: update on pathogenesis. Curr Opin Pulm med
2013;19:594-600.
Earley CJ, Silber MH. Restless legs syndrome: Understanding its consequences and the need for better
treatment. Sleep Med 2010;11:807–15.
Ekbom K. Restless legs: a clinical study. Acta Med Scand 1945;158:1–122.
Ferini-Strambi L, Walters AS, Sica D. The relationship among restless legs syndrome (Willis-Ekbom
Disease), hypertension, cardiovascular disease, and cerebrovascular disease. J Neurol 2013 Aug 21.
[Epub ahead of print]
Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ. The four diagnostic criteria for Restless Legs
Syndrome are unable to exclude confounding conditions (“mimics”). Sleep Med 2009;10:976–81.
Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: A synthesis of the literature.
Sleep Med Rev 2012;16:283–95.
Picchietti DL, Arbuckle RA, Abetz L, et al. Pediatric restless legs syndrome: analysis of symptom
descriptions and drawings. J Child Neurol 2011;26:1365–76.
Picchietti DL, Bruni O, de Weerd A, et al. Pediatric restless legs syndrome diagnostic criteria: An update
by the International Restless Legs Syndrome Study Group. Sleep Med 2013;14:1253-9.
291
Periodic Limb Movement Disorder

Alternate Names
Periodic movement disorder of sleep, sleep myoclonus syndrome, nocturnal myoclo-
nus syndrome.
Diagnostic Criteria
A. Polysomnography demonstrates PLMS, as defined in the most recent
version of the American Academy of Sleep Medicine (AASM) Manual
for the Scoring of Sleep and Associated Events.
B. The frequency is > 5/hour in children or > 15/hour in adults.1
C. The PLMS cause clinically significant sleep disturbance or impairment
in mental, physical, social, occupational, educational, behavioral, or
other important areas of functioning.2,3
D. The PLMS and the symptoms are not better explained by another
current sleep disorder, medical or neurological disorder, or mental
disorder (e.g., PLMS occurring with apneas or hypopneas should not be
scored).4,5
Notes
1. The PLMS Index must be interpreted in the context of a patient’s
sleep related complaint. In adults, normative values greater than five
per hour have been found in studies that did not exclude respiratory
event-related arousals (using sensitive respiratory monitoring) and
other causes for PLMS. Data suggest a partial overlap of PLMS
Index values between symptomatic and asymptomatic individuals,
emphasizing the importance of clinical context over an absolute cutoff
value.
2. If PLMS are present without clinical sleep disturbance or daytime
impairment, the PLMS can be noted as a polysomnographic finding, but
criteria are not met for a diagnosis of PLMD.
3. The presence of insomnia or hypersomnia with PLMS is not sufficient
to establish the diagnosis of PLMD. Studies have shown that in most
cases the cause of the accompanying insomnia or hypersomnia is
something other than the PLMS. To establish the diagnosis of PLMD,
it is essential to establish a reasonable cause-and-effect relationship
between the insomnia or hypersomnia and the PLMS. This requires
292
that other causes of insomnia such as anxiety or other causes of

hypersomnia such as obstructive sleep apnea or narcolepsy are ruled
out. PLMS are common, but PLMD is thought to be rare in adults.
4. PLMD cannot be diagnosed in the context of RLS, narcolepsy,
untreated obstructive sleep apnea, or REM sleep behavior disorder;
PLMS occur commonly in these conditions but the sleep complaint
is more readily ascribed to the accompanying disorder. The diagnosis
of RLS takes precedence over that of PLMD when potentially sleep-
disrupting PLMS occur in the context of RLS. In such cases, the
diagnosis of RLS is made and the PLMS are noted.
5. When it is reasonably certain that the PLMS have been induced by
medication, and full criteria for PLMD are met, it is preferred that the
more specific diagnosis of PLMD be used, rather than “Sleep related
movement disorder due to a medication or substance.”
Essential Features
PLMD is characterized by periodic episodes of repetitive, highly stereotyped limb
movements that occur during sleep (PLMS), in conjunction with clinical sleep dis-
turbance or fatigue that cannot be accounted for by another primary sleep disorder or
other etiology.
PLMS occur most frequently in the lower extremities. They typically involve exten-
sion of the big toe, often in combination with partial flexion of the ankle, the knee,
and sometimes, the hip. Similar movements can occur in the upper limbs. Individual
movements may be associated with an autonomic arousal, a cortical arousal, or an
awakening. Typically, the patient is unaware of the limb movements or the frequent
sleep disruption. An arousal may precede, coincide with, or follow the limb movement,
suggesting that a central generator may give rise to both the periodic movements and
the related sleep disturbance.
A clinical history of sleep onset problems, sleep maintenance problems, or unrefresh-

ing sleep attributable to the PLMS is needed for a diagnosis of PLMD. These symp-
toms have most consistently been associated with PLMS, and the presence of these
clinical symptoms differentiates PLMD from asymptomatic PLMS. Although exces-
sive daytime sleepiness has been reported with PLMD in the past, newer data do not
find significantly elevated Epworth Sleepiness Scale scores or Multiple Sleep Latency
Test (MSLT) values in subjects with PLMS. If the only complaint is sleep disruption
for the bed partner, then PLMD should not be diagnosed but the sleep disturbance of
the bed partner can be noted.
293
The PLMS index should exceed five per hour in children and 15 per hour in adult cases for
a diagnosis of PLMD. This is based on substantial normative data in children. In adults,
there is a significant increase in sleep disturbance symptoms with PLMS >15/hour.
The PLMS and the symptoms of sleep disturbance or nonrestorative sleep should not
be better explained by another etiology. Most important in the differential diagnosis are
RLS, REM sleep behavior disorder (RBD), and narcolepsy. Research studies indicate
that five or more PLMS per hour occur in 80% to 90% of patients with RLS, in about
70% with RBD, and in 45% to 65% with narcolepsy. In RBD, PLMS are often present
without arousals during nonrapid eye movement sleep (NREM) sleep but can also con-
tinue into REM sleep, which is unusual in all other settings. If significant daytime sleep-
iness and PLMS are present, a diagnosis of narcolepsy should be considered. PLMD
should not be diagnosed when criteria for one of these three disorders is met. However,
the primary disorder “with PLMS” can be specified (e.g., “RLS with PLMS”).
A sensitive technique, such as pressure transducer airflow monitoring or esophageal

manometry, should be used to monitor breathing during polysomnography to rea-
sonably exclude sleep related breathing disorders (SRBDs) as the direct cause of the
PLMS. When independent PLMS are present in patients with SRBDs, a separate diag-
nosis of PLMD may be considered if the PLMS persist despite adequate treatment of
the SRBD and otherwise unexplained sleep disturbance remains. Ideally, polysom-
nography for the diagnosis of PLMD should be performed after the biologic effect of
a medication or substance, such as an antidepressant known to induce or aggravate
PLMS, has ended.
Associated Features
Higher rates of mood disorders, anxiety, attention deficits, oppositional behaviors, and
parasomnias have been reported in some studies of patients with PLMD. In children
with PLMD, a family history of RLS is common. A sustained clinical response to dopa-
minergic therapy is supportive of the diagnosis of PLMD. Although PLMD symptoms
may be responsive to benzodiazepines, benzodiazepine responsiveness is not support-
ive of the diagnosis due to the nonspecific effect of benzodiazepines on sleep.

Demographics
Although PLMD is thought to be rare, the exact prevalence is not known. PLMD
has been reported in both children and adults. PLMS >5/hour are very uncommon in
294
children and adults younger than the age of 40 years, but then increase markedly with
advancing age, occurring in over 45% of the elderly. The population prevalence of
PLMS >15/hour has been estimated at 7.6% of 18- to 65-year-olds, with 4.5% of the
total population also reporting sleep disturbance or excessive sleepiness. However,
RLS and medication-induced PLMS were not exclusionary criteria in this popula-
tion, suggesting much lower rates for PLMD. The increase in PLMS with age may
occur as a partial expression of familial or genetic factors associated with RLS, based
on data that show very little increase in PLMS with age when individuals who have
RLS or first-degree relatives with RLS are excluded. PLMS are less common in black
adults and children than in whites. No sex difference has been described for PLMS
or PLMD.

A positive family history of RLS confers increased risk for PLMS and PLMD. The
genetic variants noted below may be a mediator of this risk. Precipitation or aggrava-
tion of PLMS has been reported with the use of several medications. Selective sero-
tonin reuptake inhibitor antidepressants, tricyclic antidepressants, lithium, and dopa-
mine receptor antagonists have most often been associated with this effect.
Low brain iron, as reflected by serum ferritin level, may worsen PLMS via the role
of iron in dopamine function. Less evidence is available for obstructive sleep apnea
(OSA), alcohol, pain, and sleep deprivation as factors that worsen PLMS.
Familial Patterns
The familial pattern of PLMD has not been studied in detail. Families with RLS have
been found to include first-degree relatives without RLS but with increased rates of
PLMS or PLMD, raising the possibility that PLMD is an attenuated manifestation or a
precursor to RLS. The gene variants BTBD9 and MEIS1, which were found in genome-
wide studies of RLS, appear to influence the expression of PLMS.

Although the typical age of onset is not known, PLMD occurs in both children and
adults, with onset as early as infancy. The natural history has not been described in
detail, but some pediatric cases of PLMD progress to RLS. Incidence and remission
rates are unknown. Impaired performance in a simulated driving task has been found
in patients with PLMD. Increased PLMS have been associated with a higher risk of
cardiovascular disease, stroke, and mortality in some studies. PLMS-related overac-
tivity of the sympathetic nervous system is postulated to be a potential mechanism
for these associations.
295
Given the low background rates of PLMS in children, PLMD has emerged as a useful
diagnostic category in pediatric sleep medicine. Pediatric PLMD has important clini-
cal and polysomnographic correlates that are comparable in severity to pediatric OSA.
However, PLMS and PLMD normative data remain sparse for children younger than
two years.
In the elderly, frequent occurrence of other conditions that can account for sleep dis-
turbance and fatigue makes application of PLMD criteria difficult, even though PLMS
are common.

Dopaminergic impairment has been implicated in the pathophysiology of PLMS and
PLMD. The study of PLMS in RLS and in children also suggests genetic diathesis
and iron status as factors. Cyclic alternating pattern, a marker of nonrestorative sleep,
is increased in individuals with PLMS and may influence the periodicity of PLMS.
Cortical arousals can precede, coincide with, or follow PLMS, indicating that PLMS
do not cause the arousals. In addition, PLMS can be dissociated from arousals pharma-
cologically, suggesting an indirect relation, possibly mediated by a central generator.
The autonomic arousals associated with PLMS are characterized by significant heart
rate and blood pressure surges, a mechanism for possible increased cardiovascular and
cerebrovascular disease risk.
Objective Findings
PLMS can appear immediately with the onset of stage N1 sleep, are frequent during
stage N2 sleep, decrease in frequency in stage N3, and are usually absent during stage R
sleep. PLMS typically occur in discrete episodes that last from a few minutes to an hour.
Both lower limbs should be monitored for the presence of limb movements. Movements
of the upper limbs may be sampled if clinically indicated. The anterior tibialis electro-
myogram (EMG) shows repetitive contractions, each lasting 0.5 to 10 seconds. The
movements may affect one or, more typically, both of the lower limbs, but not neces-
sarily in a symmetric or simultaneous pattern. Specific scoring criteria for PLMS are
described in the AASM Manual for the Scoring of Sleep and Associated Events.
Self-reports, bed partner observations, or parental reports for children have not been
found to have sufficient specificity or sensitivity to replace objective testing for PLMS.
Care must be taken to discriminate PLMS from other movements such as a simple
change in body position, stretching of a limb, or a muscle cramp. PLMS are longer in
296
duration than myoclonic jerks, which, by definition, are typically 50 to 150 millisec-
onds long. Movements associated with respiratory events, hypnagogic foot tremor, or
alternating leg muscle activation during sleep (ALMA) should not be included in the
PLMS index.
PLMS may be associated with electroencephalographic (cortical) arousals or with

awakenings. Autonomic arousals—measured by a change in heart rate, blood pressure,
or pulse transit time—have been shown to be more frequent than cortical arousals. In
some cases, periodic arousals may persist even though the PLMS have subsided. The
arousals are typically more difficult to measure than are the PLMS, and their clinical
significance is a topic of ongoing debate. As with obstructive sleep apnea, the associated
cortical arousal index has not proven more useful than the PLMS index in making clini-
cal decisions. Although a subjective report of excessive daytime sleepiness is present in
some patients with PLMD, mean sleep latency measured by MSLT has not been found
to be consistently abnormal or to correlate with the PLMS cortical arousal index.
The movements should be reported as an index of total sleep time, called the PLMS
index. The PLMS index is the number of periodic limb movements per hour of total
sleep time, as determined by polysomnography. The PLMS arousal index is the number
of PLMS associated with a cortical arousal, expressed per hour of total sleep time.
Other parameters for the description of PLMS include periodicity index, intermove-
ment interval distribution, and time of night distribution. These features have been
shown to help differentiate PLMS patterns in different conditions (e.g., a finding of the
highest periodicity indices in adult RLS and PLMD).
Leg actigraphy has been validated against PSG for the measurement of PLMS and
provides a methodology to assess PLMS in large populations, as well as night-to-night
variability.
As described in the essential features section, PLMD is a diagnosis of exclusion and it
is important to differentiate it from other conditions in which PLMS occur, particularly
RLS, RBD, narcolepsy, and SRBDs. Increased rates of PLMS have also been reported
in multiple system atrophy, dopa-responsive dystonia, sleep related eating disorder,
spinal cord injury, end-stage renal disease, congestive heart failure, Parkinson disease,
sickle cell disease, posttraumatic stress disorder, Asperger syndrome, Williams syn-
drome, and multiple sclerosis. Dopaminergic impairment and/or diminished inhibition
of the central pattern generator for PLMS have been proposed as common factors
linking various disorders and PLMS.
297
Sleep starts (hypnic jerks) need to be differentiated from PLMS. Sleep starts typically
are limited to the transition from wakefulness to sleep, are not periodic, and are briefer
(20 to 100 milliseconds) than PLMS. Normal phasic REM activity is limited to REM
sleep, typically occurs in 5- to 15-second clusters, and is usually associated with bursts
of REMs. Phasic REM EMG twitches are more variable in duration and do not have the
periodicity of PLMS. Fragmentary myoclonus is characterized by EMG activity that is
briefer (75 to 150 milliseconds), more variable in duration, less periodic than PLMS,
and has little or no associated visible movement. Also, PLMS must be differentiated
from movements associated with nocturnal epileptic seizures and myoclonic epilepsy
and from a number of forms of myoclonus seen while awake, such as in Alzheimer
disease, Creutzfeldt-Jakob disease, and other neuropathologic conditions. However, in
these disorders, the involuntary movements are prominent during the daytime, often do
not disappear with activity, are prominent in the arms and other body parts in addition
to the legs, and do not display the periodicity seen with PLMS.

There has been controversy over the clinical significance of PLMS. To date, the inter-
pretation of most studies has been confounded by multiple factors that include: impre-
cise diagnostic criteria; confusion between PLMS and PLMD; inadequate monitoring
for subtle SRBDs; a lack of consideration of medications known to induce, worsen,
or suppress PLMS; and inadequate measurement of the known night-to-night vari-
ability of PLMS. Newer respiratory monitoring techniques for polysomnography and
the use of actigraphy monitors over several nights should help address a number of
these issues. The role of associated arousals in relation to clinical symptoms is yet to
be determined, but the appreciation of autonomic arousals as well as cortical arousals
might be critical. It is possible that PLMS are a measurable marker of unstable sleep,
related to genetic diathesis and dopaminergic impairment.
Bibliography
Ferri R. The time structure of leg movement activity during sleep: The theory behind the practice. Sleep
Med 2012;13:433–41.
Gingras JL, Gaultney JF, Picchietti DL. Pediatric periodic limb movement disorder: sleep symptom and
polysomnographic correlates compared to obstructive sleep apnea. J Clin Sleep Med 2011;7:603–9.
Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb
movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006;10:169–77.
Koo BB, Blackwell T, Ancoli-Israel S, Stone KL, Stefanick ML, Redline S. Association of incident
cardiovascular disease with periodic limb movements during sleep in older men: Outcomes of Sleep
Disorders in Older Men (MrOS) Study. Circulation 2011;124:1223–31.
Pennestri MH, Whittom S, Adam B, Petit D, Carrier J, Montplaisir J. PLMS and PLMW in healthy
subjects as a function of age: prevalence and interval distribution. Sleep 2006;29:1183–7.
298
Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic
limb movement disorder: parent-child pairs. Sleep Med 2009;10:925–31.
Picchietti D. Periodic limb movements in sleep: irrelevant epiphenomenon, marker for a potential problem,
or a disorder? J Clin Sleep Med 2006;2:446–7.
Scofield H, Roth T, Drake C. Periodic limb movements during sleep: population prevalence, clinical
correlates, and racial differences. Sleep 2008;31:1221–7.
Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl
J Med 2007;357:639–47.
Walters AS, Rye DB. Review of the relationship of restless legs syndrome and periodic limb movements
in sleep to hypertension, heart disease, and stroke. Sleep 2009;32:589–97.
Sleep Related Leg Cramps

Alternate names
Leg cramps, “charley horse,” nocturnal leg cramps.
Diagnostic Criteria
A. A painful sensation in the leg or foot associated with sudden,
involuntary muscle hardness or tightness, indicating a strong muscle
contraction.
B. The painful muscle contractions occur during the time in bed, although
they may arise from either wakefulness or sleep.
C. The pain is relieved by forceful stretching of the affected muscles, thus
releasing the contraction.
Essential Features
Sleep related leg cramps are painful sensations caused by sudden and intense involun-
tary contractions of muscles or muscle groups during which there is muscle spasm and
hardness for several seconds. These painful sensations are usually in the calf or small
muscle of the foot. Occurring during the time in bed, sleep related leg cramps may
arise from either wakefulness or sleep.
Sleep related leg cramps usually start abruptly but may in some cases be preceded by
a less painful warning sensation. The muscle contractions last for a few seconds up
to several minutes and then remit spontaneously. The frequency of sleep related leg
cramps varies considerably from less than yearly to multiple episodes every night.
299
The cramps can be relieved by strongly stretching the affected muscle and sometimes
also by local massage, application of heat, or movement of the affected limb. Leg
cramps can be present primarily during the daytime.
Associated Features
The muscle cramp affects sleep. The pain from the cramp itself and from the activities
used to relieve it commonly disturb sleep onset or cause an awakening from sleep.
Often the presenting complaint is insomnia, at times severe.
Tenderness and discomfort in the muscle may persist for several hours after the cramp-
ing. Persisting discomfort after the cramping episode often delays subsequent return
to sleep.

Sleep related leg cramps are known to be either idiopathic or secondary to other
medical conditions, but there have been no indications of significant differences in the
clinical features of the disorder related to the cause.
Demographics
Sleep related leg cramps are common. It has been suggested that nearly every adult
older than 50 years has experienced sleep related leg cramps at least once. Both the
prevalence and the frequency of the events increase with age. Sleep related leg cramps
have been reported to occur at least occasionally in about 7% of children and adoles-
cents, 33% in adults older than 60 years, and 50% in adults older than 80 years, with
both older groups reporting a symptom frequency of at least once every two months.
Nightly leg cramps have been reported in 6% of adults older than 60 years. No defin-
itive sex information has been reported, though a single study reported a higher prev-
alence in women.

Predisposing factors include diabetes mellitus, amyotrophic lateral sclerosis, cramp
fasciculation syndrome, peripheral vascular disease, hypokalemia, hypocalcemia,
hypomagnesemia, and metabolic disorders. The disorder can be associated with prior
vigorous exercise, prolonged standing at work, dehydration, fluid and electrolyte distur-
bances, endocrine disorders, neuromuscular disorders, disorders of reduced mobility,
vascular disease, cirrhosis, and hemodialysis. Medications that have been associated
with sleep related leg cramps include oral contraceptives, intravenous iron sucrose,
teriparatide, raloxifene, diuretics, long-acting β-agonists, and statins. Sleep related leg
cramps occur in about 40% of pregnant women and generally resolve after delivery.
300
Familial Pattern
Not known.
Onset, Course and Complications

Sleep related leg cramps have not been reported in infancy, nor in children younger
than eight years. The peak onset is usually in adulthood, but the condition may be
seen for the first time in old age. The natural history of leg cramps is not well under-
stood. Many patients describe a waxing and waning course of many years’ duration.
Complications include muscle tenderness, insomnia, and occasional daytime fatigue
due to interrupted sleep. No marked mental or social dysfunction has been described
due to sleep related leg cramps alone.

Many sleep related leg cramps appear to be idiopathic. Although leg cramps involve
abnormal muscle tone, they are generally considered not to involve agonist-antagonist
co-contractions and, thus, are not classified as dystonias. Some nocturnal leg cramps,
particularly those in the feet, may resemble dystonias but, unlike classic dystonias,
sleep related leg and foot cramps are relieved by stretching the affected muscle or
muscles.
Electrophysiologic recordings show that the cramps typically start with spontaneous
firing of anterior horn cells followed by motor unit discharges for contractions at rates
up to 300 Hz (considerably more than with voluntary muscle contractions). The pain
may result from local metabolite accumulations or from local ischemia.
Muscle and tendon shortening due to age or lack of stretching exercise is thought to
contribute to the development of sleep related leg cramps. Exercise involving stretch-
ing the affected muscles is thought to help prevent or reduce the occurrence of sleep
related leg cramps.
Objective Findings
Polysomnographic studies of patients with chronic sleep related leg cramps reveal non-
periodic bursts of gastrocnemius EMG activity. Episodes arise from sleep without any
specific preceding physiologic changes during sleep.
Sleep related leg cramps are common in chronic myelopathy, peripheral neuropathy,
muscular pain fasciculation syndrome, and disorders of calcium metabolism. These
causes should be differentiated by clinical history and physical examination. RLS is
301
sometimes confused with sleep related leg cramps because both can present with leg
discomfort during the sleep period and RLS patients sometimes complain of a cramping
sensation. However, if patients meet the diagnostic criteria for RLS and do not describe
an actual cramp or hardening of the muscle, the diagnosis should be RLS. Because leg
cramps can mimic RLS and meet all the criteria for RLS, the description of an actual
spasm or hardening of the muscle is a critical differentiating factor. A leg cramp is also
a much briefer event than the typical symptoms of RLS, which can persist for hours.
However, RLS and leg cramps may sometimes be seen in the same individual.
Dystonia is ongoing daily spasm of muscles and is distinguished electrophysiologi-

cally from leg cramps by ongoing co-contraction of agonist and antagonist muscles.
Dystonia can be focal, as in the case of muscles of the neck (torticollis) or hand (writer’s
cramp), or generalized as in the case of torsion dystonia.

Sleep related leg cramps are common and can affect sleep. Their association with other
disorders and different medications hinder accurate epidemiological data and under-
estimate their effect on sleep and on quality of life. Instruments to quantify the sever-
ity of the disorder and its impact are needed to adequately address clinical relevance,
treatment, and the potential occupational hazards. Effective treatments for sleep related
leg cramps have yet to be developed. The prophylactic benefits of stretching exercises
remain to be adequately validated.
Bibliography
Allen RE, Kirby KA. Nocturnal leg cramps. Am Fam Physician 2012;86:350–5.
Bahk JW, Kim H, Jung-Choi K, Jung MC, Lee I. Relationship between prolonged standing and symptoms
of varicose veins and nocturnal leg cramps among women and men. Ergonomics 2012;55:133–9.
Butler J, Mulkerrin E, O’Keeffe S. Nocturnal leg cramps in older people. Postgrad Med J 2002;78:596–8.
Garrison SR, Dormuth CR, Morrow RL, Carney GA, Khan KM. Nocturnal leg cramps and prescription
use that precedes them: a sequence symmetry analysis. Arch Intern Med 2012;172:120–6.
Hawke F, Chuter V, Burns J. Factors associated with night-time calf muscle cramps; a case control study.
Muscle Nerve 2013;47:339–43.
Hawke F, Chuter V, Burns J. Impact of nocturnal calf cramping on quality of sleep and health-related
quality of life. Qual Life Res 2013;22:1281–6.
Heimisdottir F, Guddnason V, Sigurdsson G, Benediktsson R. [Foot disease in Icelandic patients with
established type 2 diabetes]. Laeknabladid 2008;94:109–14.
Hudson AJ, Brown WF, Gilbert JJ. The muscular pain-fasciculation syndrome. Neurology 1978;28:1105–9.
Jacobsen J, Rosenberg R, Huttenlocher P, Spire J. Familial nocturnal cramping. Sleep 1986;9:54–60.
Kleopa KA, Zamba-Papanicolaou E, Kyriakides T. Compressive lumbar myelopathy presenting as
segmental motor neuron disease. Muscle Nerve 2003;28:69–73.
302
Leung AK, Wong BE, Chan PY, Cho HY. Nocturnal leg cramps in children: incidence and clinical
characteristics. J Natl Med Assoc 1999;91:329–32.
Matsumoto M, Watanabe K, Tsuji T, et al. Nocturnal leg cramps: a common complaint in patients with
lumbar spinal canal stenosis. Spine (Phila Pa 1976) 2009;34:E189–94.
Norris FJ, Gasteiger E, Chatfield P. An electromyographic study of induced and spontaneous muscle
cramps. Electroencephalogr Clin Neurophysiol 1957;9:139–47.
Parisi L, Serrao M, Rossi P, et al. Afterdischarge activity in neuropathic patients with frequent muscle
cramps. Acta Neurol Scand 2000;102:359–62.
Pitkin RM. Endocrine regulation of calcium homeostasis during pregnancy. Clin Perinatol 1983;10:575–92.
Saskin P, Whelton C, Moldofsky H, Akin F. Sleep and nocturnal leg cramps. Sleep 1988;11:307–8.
Weiner I, Weiner H. Nocturnal leg muscle cramps. JAMA 1980;244:2332–3.
Sleep Related Bruxism

Alternate Names
Nocturnal bruxism, nocturnal tooth grinding, tooth clenching.
Diagnostic Criteria
A. The presence of regular or frequent tooth grinding sounds occurring
during sleep.
B. The presence of one or more of the following clinical signs:
1. Abnormal tooth wear consistent with above reports of tooth
grinding during sleep.
2. Transient morning jaw muscle pain or fatigue; and/or temporal
headache; and/or jaw locking upon awakening consistent with
above reports of tooth grinding during sleep.
Notes
1. Although polysomnography is not required for the diagnosis, sleep
bruxism, as described in the most recent version of the AASM Manual
for the Scoring of Sleep and Associated Events, is ideally recorded with
masseter muscle activity with audio-video signal to increase diagnostic
reliability.
Essential Features
Bruxism is defined as a repetitive jaw-muscle activity characterized by clenching
or grinding of the teeth and/or by bracing or thrusting of the mandible. Bruxism
303
has been divided into its two distinct circadian manifestations: sleep bruxism and
awake bruxism.
In sleep, jaw muscle contractions are frequently repeated over time and are termed
rhythmic masticatory muscle activity (RMMA). These contractions can take two forms
on electromyographic traces: a series of repetitive activity (phasic muscle contractions)
or isolated sustained jaw clenching (tonic contractions). These contractions during
sleep produce tooth-grinding sounds and are referred to as sleep related bruxism.
Sleep related bruxism can lead to abnormal tooth wear, tooth pain, jaw muscle pain,
and temporal headache. Severe sleep related bruxism may also result in sleep dis-
ruption. This may involve not only the individual affected, but also the bed partner,
because the sounds made by the friction of the teeth are usually perceived as being
unpleasant and can be quite loud and disturbing to those nearby.
The disorder is typically brought to dental or medical attention because of the tooth
damage, pain, or disturbing sounds. Less commonly, it may present as a cause of dis-
turbed sleep. Young and otherwise healthy individuals with sleep related bruxism
appear to have normal sleep structure and homeostasis. The majority of RMMA epi-
sodes during sleep occur in association with sleep arousal.
Jaw muscle pain, tenderness in the masseter and temporalis muscle regions, morning
headache, or fatigue can arise due to sleep related bruxism.
Associated Features
Additional symptoms include a variety of unpleasant muscle and tooth sensations, lim-
itation of jaw movements, orofacial pain, and temporal/tension headaches. Tooth wear,
fractured teeth, and buccal lacerations also can occur. These symptoms may be induced
by sleep related bruxism, but the connection may not be apparent to the affected indi-
vidual and diagnostic discrimination is weak.
Headaches are frequently reported by both adults and children with sleep related
bruxism. The headache usually involves the temporal regions and it has the charac-
teristics of a tension headache. It is reported either in the morning (more frequently)
or during the day (with wake bruxism). The estimated OR for headache in individuals
with sleep related bruxism is > 4 compared to controls.
There is high individual variability in the intensity and duration of sleep related
bruxism, but in the most severe cases, hundreds of events can occur during a night
304
of sleep. However, no direct relationship has been observed between the severity of
sleep related bruxism and the appearance of clinical signs and symptoms. Indeed, indi-
viduals with a mild to moderate index of sleep bruxism (2 to 4 RMMA episodes/hour
of sleep) have a higher risk of reporting painful jaw upon awakening (OR 3.9), and
masticatory muscle fatigue (OR 5.1) compared to individuals with severe sleep related
bruxism (> 4 RMMA episodes/hour of sleep).
Psychosocial components may also be linked to sleep related bruxism. The psycholog-
ical assessment of otherwise healthy adults with sleep related bruxism suggests a cor-
relation (not yet proven as a causality) between bruxism and stress/anxiety. Moreover,
both children and adults with sleep related bruxism seem to have higher scores in
stress, anxiety, and psychiatric scales compared to control individuals.

Sleep related bruxism without clear cause is termed primary or idiopathic.
Forms of sleep related bruxism associated with the use of psychoactive medications,
recreational drugs, or a variety of medical disorders (e.g., Parkinson disease, RBD,
Down syndrome) are defined as secondary sleep related bruxism. Treatment-induced
sleep related bruxism is also termed iatrogenic.
Although the primary form of sleep related bruxism is most often reported in healthy
children and adults, secondary sleep related bruxism is observed in children with cere-
bral palsy and mental retardation and in adult patients with abnormal movements such
as in oromandibular myoclonus/facio-mandibular myoclonus or with sleep related
breathing disorders. OSA and sleep related bruxism commonly co-occur.
Tooth grinding and clenching also can occur during wakefulness, as an oral parafunc-
tional activity known as awake bruxism. Awake bruxism is considered a different dis-
order, probably with different diagnostic criteria and pathophysiology; its association
with sleep bruxism is still under debate. However, the two oral activities may coexist
in the same individual.
Demographics
The prevalence of sleep related bruxism, based on reports from parents or sleep
partner, is highest in childhood (approximately 14% to 17%) and then decreases over
the life span. In teenagers to young adults, prevalence is in the 12% range. In young
to middle-aged adults, it is approximately 8% but as little as 3% in older persons. The
reported reduction in tooth grinding in the elderly probably overestimates the actual
305
reduction, because edentulism, use of dentures, and changes in sleeping behaviors (i.e.,
in isolation) may influence reporting. There is no reported sex difference for the prev-
alence of sleep related bruxism.

Predisposing factors include personality types; for example, individuals who are highly
motivated or characteristically maintain high vigilance may have an increased preva-
lence of sleep related bruxism.
Genetic predisposition is plausible but still under investigation. As described

below, there is some familial predisposition due to environmental or shared genetic
factors. Recently, a serotonin gene was described in bruxism patients but the
absence of distinction between the wake and sleep forms in this report preclude
firm conclusions.
Precipitating factors can include anxiety related to current life events, tasks requir-
ing high levels of performance, and repetitive tasks with short deadlines. The use
of cigarettes or caffeine in the hours before sleep also can contribute to the occur-
rence of sleep related bruxism (probably due to the increased arousals and sleep
instability).
The role of dental morphologic “defects” (occlusal interferences) remains controver-

sial in the etiology of sleep related bruxism. Tooth contacts do not usually set in motion
a bruxism episode; they are usually late in the series of events occurring during sleep
related bruxism/tooth grinding. Hence, the causality link between tooth contact and
sleep related bruxism is not supported by the temporal sequence.
Familial Patterns
Sleep related bruxism tends to occur in families; approximately 20% to 50% of affected
individuals have at least one direct family member with a history of tooth grinding,
and childhood sleep related bruxism appears to persist into adulthood in two thirds of
reported cases. However, no genetic variants or genetic inheritance patterns so far have
been associated with sleep related bruxism.

The onset of sleep related bruxism may occur during childhood, adolescence, or
adulthood. It is difficult to establish the time of onset with precision because it is
mainly based on the awareness of the individual or his/her family members who
report the disorder.
306
Sleep related bruxism in childhood has been reported by parents to begin as soon as
both upper and lower teeth have erupted. Secondary sleep related bruxism may occur
at any age, but is more common in younger and middle-aged adults.
Even without a tooth grinding history or complaints, RMMA may be observed in

most normal sleepers (on average, one episode per hour of sleep) across the life span.
However, in individuals with sleep related bruxism, jaw-muscle contractions are more
frequent and more intense. This may explain the secondary tooth damage and the
occurrence of pain and other symptoms.
The night-to-night variability in episodes of audible tooth grinding sounds is large

(greater than 50% coefficient of variation). In-laboratory polysomnographic record-
ings indicate that the corresponding variability in frequency of RMMA is smaller
(approximately 25%), although ambulatory recording has suggested somewhat higher
RMMA variability. First-night effect on RMMA index is minimal.
Dental damage and abnormal tooth wear are the most frequent signs of the disorder.
However, they are not a direct proof of current sleep related bruxism and many contrib-
uting factors have to be ruled out (e.g., type of diet in the occurrence of abnormal tooth
wear). Diagnostic discriminative strength of these dental findings is weak; severity of
wear cannot account for the index (i.e., frequency of RMMA). Sleep related bruxism
could lead to temporomandibular joint disorders (e.g., pain, joint sound [click], or jaw
movement limitations), although recent evidence does not support this association.
Transient morning orofacial pain, including temporal headaches, is not uncommon, as
described above. Hypertrophy of the masseter and temporalis muscles can occur, but
the diagnostic specificity of this finding for sleep related bruxism is also weak.
The natural course of this sleep disorder is usually benign. Many individuals with
sleep related bruxism remain asymptomatic for most of their lives. Others can experi-
ence associated symptoms (i.e., pain) that may interfere with their quality of life and/
or sleep and may require treatments. Further diagnostic investigations and assessment
are recommended if sleep related bruxism is associated with other more severe sleep
or medical disorders (e.g., SRBD, RBD, epilepsy).
Sleep related bruxism is frequently reported in childhood but decreases with age.
However, some individuals may experience it every night for most of their lives.
307
Conceptualizations of sleep related bruxism in children vary. Some consider this a

physiological oral parafunction while teeth are erupting or exfoliating, whereas others
view this as a sleep disorder with many associated signs and symptoms. Sleep related
bruxism, especially in children, has been associated with attention deficit hyperactivity
disorder, parasomnias, SRBD, snoring, and many psychological and medical conditions.
In the elderly, sleep related bruxism has been observed in association with movement
disorders (e.g., Parkinson disease or oral tardive dyskinesia persisting during sleep),
RBD, and dementia.

The majority of RMMA episodes during sleep (up to 80%) occur in association
with sleep arousals. Sleep related bruxism episodes typically follow a clear arousal
sequence, starting with increased sympathetic-cardiac activity and fast electroenceph-
alographic (EEG) waves in the minutes to seconds preceding the onset of an RMMA
episode. The jaw muscle contractions are then followed by, or are concomitant with,
an increase in blood pressure and ventilation. RMMA episodes sometimes conclude
with swallowing. Other causes of sleep bruxism onset are unknown, although potential
candidates include airway resistance and oropharyngeal dryness.
In the majority of individuals with sleep related bruxism, the frequency of sleep arous-
als is within the normal range. However, they may have an exaggerated responsiveness
to ongoing sleep arousals or an increased magnitude of arousal. Individuals with sleep
related bruxism show more CAP phase A3 (as described by the scoring and analysis of
cyclic alternating pattern (CAP) during sleep) than controls, an expression of increased
arousal pressure and increased sleep instability. This increased sleep instability seems
to be the “permissive window” for occurrence of RMMA during sleep.
Objective Findings
Polysomnographic (PSG) monitoring of individuals with sleep related bruxism
demonstrates increased masseter and temporalis muscle activity during sleep, along
with grinding sounds. RMMA episodes can occur during all sleep stages, but are most
common in sleep stages N1 and N2 (more than 80% of episodes), whereas fewer than
10% of RMMA episodes occur during REM sleep. However, in some individuals,
sleep related bruxism occurs predominantly in REM sleep.
As described above, the majority of sleep related bruxism episodes are temporally
associated with sleep arousal and are preceded by signs of autonomic/cardiac activa-
tion (e.g., increased heart rate and blood pressure).
308
Three subtypes of the EMG pattern of sleep related bruxism have been described:
phasic activity at 1 Hz frequency with EMG bursts lasting 0.25 to 2 seconds; sustained
tonic activity lasting longer than 2 seconds; or a mixed pattern. An episode begins after
at least a three-second interval with no muscle activity.
Polysomnography is not usually performed in otherwise healthy individuals with sleep

related bruxism in routine clinical settings. However, PSG may be indicated to demon-
strate the disorder and to rule out associated respiratory disturbances, gastroesophageal
reflux, RBD, night terrors, faciomandibular myoclonus, or epilepsy. The sensitivity of
polysomnographic study in detecting sleep related bruxism in severe cases is moderate
to high; in milder cases, however, it may be low due to the night-to-night variability in
RMMA and tooth grinding.
Ambulatory home monitoring may be used for screening, diagnosis, and treatment
outcome assessment by studying the individual in his/her usual environment, but it is
characterized by lower diagnostic specificity due to the absence of audiovisual record-
ings (i.e., 20% overestimation in RMMA frequency is expected due to poor capacity to
exclude concomitant nonspecific activities).
To record and score sleep related bruxism activity (i.e., RMMA), there must be a
minimum of one masseter muscle monitor, ideally with audiovisual recording, to
associate muscular activity with grinding sound production. Video monitoring helps
distinguish bruxism from other orofacial and masticatory movements that normally
occur during sleep (e.g., swallowing, coughing) and from specific movement disorders
(RBD, epilepsy and tooth tapping, oromandibular myoclonus).
For the best level of diagnostic specificity and sensitivity, bilateral masseter and tem-
poralis muscle EMG recordings, referenced to ear, mastoid, or zygomatic bone, are
advisable.
The disorder seldom poses diagnostic problems. Evaluation for temporomandibular
disorders and damage to dentition is indicated.
Sleep related bruxism needs to be differentiated from other faciomandibular activities

occurring during sleep, such as faciomandibular myoclonus, SRBD, RBD, abnormal
swallowing, gastro-esophageal reflux, night terrors, confusional arousals, dyskinetic
jaw movements persisting in sleep (dystonia, tremor, chorea, dyskinesia), and, rarely,
sleep related epilepsy.
309
Oromandibular or faciomandibular myoclonus has been observed in approximately

10% of individuals with severe sleep related bruxism, but it can also occur in indi-
viduals without abnormally increased RMMA events. As opposed to sleep related
bruxism, faciomandibular myoclonus consists of EMG bursts of brief duration (less
than 250 milliseconds in length) in the facial muscles; these can occur either as
isolated bursts or as a cluster of regularly or irregularly occurring brief bursts. A
high index of oromandibular myoclonus in sleep has been observed in idiopathic
RBD patients.
Rhythmic jaw movements also have been observed in association with partial complex
or generalized seizure disorders. Epilepsy needs to be considered in the differential
diagnosis, although the presentation of epilepsy as relatively isolated sleep related
bruxism is very rare.

An expert bruxism international group has proposed a diagnostic grading system
of “possible,” “probable,” and “definite” for both sleep and awake bruxism. Such a
clinical tool will help to discriminate sleep bruxism from awake bruxism, although
further validation is required for clinical and research purposes in all relevant dental
and medical domains. In summary, this group suggests that a rating of: (1) “possible”
is given if based on self-report, by means of questionnaires, and/or the anamnestic
part of a clinical examination; (2) “probable” sleep or awake bruxism is given if based
on self-report and supportive physical findings; (3) “definite” sleep bruxism if based
on self-report, physical findings, and a polysomnographic recording, preferably with
audiovisual recordings.
The clinical relevance of sleep related bruxism in cases of comorbidity with other
medical problems such as snoring, sleep related breathing disorder, RBD, attention
deficit hyperactivity disorder, headache, and orofacial pain needs to be assessed in
order to distinguish primary benign forms of sleep related bruxism from those that rep-
resent an epiphenomenon of other more severe sleep and medical disorders.
Sleep related bruxism may be concomitant to breathing disorders, including any level
of severity of OSA; further research is in progress to assess the specificity and validity
of this association.
There is currently no evidence supporting the possibility that patients with sleep related
bruxism, in its primary form, are at increased risk of neurological disorders; such a risk
factor assessment needs long- term study before any conclusion can be drawn.
310
Investigation of genetic associations to sleep related bruxism require large sample

sizes, using valid tools to assess the specificity of RMMA versus other oromandibular
activities and to discriminate gene candidates specific for bruxism from those related
to its comorbidities such as stress or other related triggers of RMMA.
Bibliography
Abe S, Yamaguchi T, Rompré PH, De Grandmont P, Chen YJ, Lavigne GJ. Tooth wear in young subjects:
a discriminator between sleep bruxers and controls? Int J Prosthodont 2009;22:342–50.
Carra MC, Macaluso GM, Rompre PH, et al. Clonidine has a paradoxical effect on cyclic arousal and
sleep bruxism during NREM sleep. Sleep 2010;33:1711–6.
Hublin C, Kaprio J, Partinen M, Koskenvuo M. Sleep bruxism based on self-report in a nationwide twin
cohort. J Sleep Res 1998;7:61–7.
Lavigne G, Guitard F, Rompre P, Montplaisir J. Variability in sleep bruxism activity over time. J Sleep
Res 2001;10:237–44.
Lavigne G, Manzini C, Huynh NT. Sleep bruxism. In: Kryger MH, Roth T, Dement WC, eds. Principles
and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders, 2011:1129–39.
Lobbezoo F, Ahlberg J, Glaros AG, et al. Bruxism defined and graded: An international consensus. J Oral
Rehab 2013;40:2–4.
Ohayon M, Li K, Guilleminault C. Risk factors for sleep bruxism in the general population. Chest
2001;119:53–61.
Rompre PH, Daigle-Landry D, Guitard F, Montplaisir JY, Lavigne GJ. Identification of a sleep bruxism
subgroup with a higher risk of pain. J Dent Res 2007;86:837–42.
Vetrugno R, Provini F, Plazzi G, et al. Familial nocturnal facio-mandibular myoclonus mimicking sleep
bruxism. Neurology 2002;58:644–7.
311
Sleep Related Rhythmic Movement Disorder

Alternate Names
Body rocking, head banging, head rolling, body rolling, jactatio capitis nocturna, jac-
tatio corporis nocturna, rhythmie du sommeil.
Diagnostic Criteria
A. The patient exhibits repetitive, stereotyped, and rhythmic motor
behaviors involving large muscle groups.
B. The movements are predominantly sleep related, occurring near nap or
bedtime, or when the individual appears drowsy or asleep.
C. The behaviors result in a significant complaint as manifest by at least
one of the following:1
1. Interference with normal sleep.
2. Significant impairment in daytime function.
3. Self-inflicted bodily injury or likelihood of injury if preventive
measures are not used.
D. The rhythmic movements are not better explained by another movement
disorder or epilepsy.
Notes
1. When there are no clinical consequences of the rhythmic movements,
the rhythmic movements are simply noted but the term rhythmic
movement disorder is not employed.
Essential Features
Sleep related rhythmic movement disorder (RMD) is characterized by repetitive, ste-
reotyped, and rhythmic motor behaviors (not tremors) that occur predominantly during
drowsiness or sleep and involve large muscle groups. The occurrence of significant
clinical consequences differentiates RMD from developmentally normal sleep related
movements.
Typically seen in infants and children, but also in adults, RMD comprises several sub-
types. Body rocking may involve the entire body, with the individual on hands and
knees, or it may be limited to the torso, with the individual sitting. Head banging often
occurs with the person prone, repeatedly lifting the head or entire upper torso, and forc-
ibly banging the head back down into the pillow or mattress. Alternately, the individual
312
may sit with the back of the head against the headboard or wall, repeatedly banging
the occiput. Combining head banging and body rocking, they may rock on hands and
knees, banging the vertex or frontal region of the head into the headboard or wall. Head
rolling consists of side-to-side head movements, usually with the child (or adult) in the
supine position. Less common rhythmic movement forms include body rolling, leg
banging, or leg rolling. Rhythmic humming or inarticulate sounds often accompany the
body, head, or limb movements and may be quite loud.
Episodes often occur near sleep onset, although they also may occur at any time during
the night and even during quiet wakeful activities, such as listening to music or trav-
eling in vehicles. The movement frequency can vary, but the rate is usually between
0.5 per second and two per second. Duration of the individual movement clusters also
varies but generally is less than 15 minutes. Cessation of movements may occur fol-
lowing environmental disturbance or being spoken to. Children who have sufficient
language development to be asked about event recall in the morning are typically
amnestic for the episodes. Rarely, adults will report a volitional component.
Sleep related rhythmic movements are common in normal infants and children. Without
evidence for significant consequences, the movements alone should not be considered
a disorder. Sleep related rhythmic movements should be considered a disorder only if
the behaviors significantly interfere with normal sleep, cause significant impairment in
daytime function, or result in self-inflicted bodily injury (or would result in injury if
preventive measures are not used).
Associated Features
The vast majority of infants and children with sleep related rhythmic movements are
otherwise developmentally and intellectually normal, as are most adolescents and adults.

Body Rocking: The whole body is rocked while on the hands and knees.
Head Banging: The head is forcibly moved, striking an object.
Head Rolling: The head is moved laterally, typically while in a supine position.
Other: Includes body rolling, leg rolling, and leg banging.
Combined: Involves two or more of the individual types.
313
Demographics
At nine months of age, 59% of all infants have been reported to exhibit one or more of
the following sleep related rhythmic movements: body rocking (43%), head banging
(22%), or head rolling (24%). At 18 months, the overall prevalence has been reported
to decline to 33%, and by five years, to only 5%. Most pediatric studies have found no
sex difference.
Over 50 cases of RMD have been reported in adolescents and adults, with a male pre-
ponderance found in adults.

The soothing effect of vestibular stimulation has been proposed as the initiating factor
in infants and toddlers. Environmental stress and lack of environmental stimulation
have also been proposed as factors. One study found higher anxiety scores in children
with body rocking than in controls. Self-stimulation has been suggested as a factor,
particularly in intellectually disabled, autistic, and emotionally disturbed children.
Rhythmic movements have been postulated to be a calming technique employed by
children to combat insomnia.
Rhythmic movements have been reported in association with RLS, OSA, narcolepsy,
RBD, and ADHD. Rhythmic movements may be used as a conscious strategy to
relieve the urge to move or the uncomfortable sensations associated with RLS. OSA-
associated RMD often improves with positive airway pressure. Individuals with narco-
lepsy may initiate rhythmic movements to terminate episodes of sleep paralysis.
In older children or adults, stereotypic movements may be associated with intellectual

disability or autism spectrum disorder. However, in most of these cases, the movements
are not predominantly sleep related, and an additional diagnosis of RMD is not indicated.
Familial Patterns
A familial pattern has been reported rarely, as has occurrence in identical twins.

The onset of sleep related rhythmic movements is typically in early childhood. Body
rocking has a mean age of onset of six months, head banging of nine months, and
head rolling of ten months. The condition may rarely present at an older age following
central nervous system trauma. Sleep related rhythmic movements commonly resolve
in the second or third year of life. Persistence at five years of age occurs in about 5%
of children. Sleep related movements rarely continue into adolescence and adulthood.
314
Worsening or spontaneous onset in adults is very rare. In some adult cases the chief
concern is disturbance of the bed partner’s sleep. Most adolescents and adults have one
form of RMD, although some have two or more.
Head banging is the most disturbing form of the problem. Typical cases in infants and
toddlers pose little risk of serious injury. Vigorous rhythmic movements can produce
loud noises when the patient hits the bed frame or when the bed bangs against the wall
or floor. The noises can be very disturbing to other family members. Parental concern
is common, and psychosocial consequences in the older individual can be distressing.
It is important to discuss appropriate safety precautions with the patient’s caretak-
ers. Under extraordinary circumstances, particularly in the developmentally disabled,
injury to soft tissues or bone has been reported.
Because age-related factors are a critical dimension for RMD, developmental issues
are discussed under Essential Features and other sections.

In infants and young children, rhythmic movements have been hypothesized to
promote motor development by stimulation of the vestibular system. More recently,
the role of inhibitory control on the central motor pattern generator has been sug-
gested as a physiologic mechanism to explain both pediatric and adult forms of sleep
related rhythmic movements.
Objective Findings
Polysomnographic scoring rules for RMD are defined in the AASM Manual for the
Scoring of Sleep and Associated Events. Video-polysomnographic studies have shown
rhythmic movements to occur most often in association with stages N1 and N2 sleep;
46% occur while falling asleep or during NREM sleep; 30% during both NREM and
REM sleep; and 24% only during REM sleep. The exclusively REM-related rhythmic
movements occur more frequently in adults. Although an epileptic etiology has been
reported in one individual, most EEG studies have shown normal activity between epi-
sodes of rhythmic behavior.
RMD must be distinguished from other repetitive movements involving restricted small
muscle groups, such as sleep related bruxism, thumb sucking, and rhythmic sucking of
a pacifier or the lips, as well as other specifically defined rhythmic movements of sleep,
such as hypnagogic foot tremor.
315
In adults, RMD can be misdiagnosed as RBD or be comorbid with RBD. Video poly-
somnography is particularly helpful in these cases. Rhythmic movements may occur as
a conscious or unconscious strategy to relieve RLS symptoms. If the rhythmic move-
ments are clearly in response to RLS sensations, then a separate diagnosis of RMD is
not needed. However, RMD may be diagnosed if RMD criteria are met and RLS does
not adequately explain the presence or extent of rhythmic movements.
Children with autism spectrum disorder often exhibit repetitive behaviors, but these
movements typically occur during wakefulness and are not predominantly sleep
related. Stereotypic movement disorder is a Diagnostic and Statistical Manual of Mental
Disorders (DSM) diagnosis that is typically seen with intellectual disability and is not
predominantly sleep related. In children with autism spectrum disorder or intellectual
disability, an additional diagnosis of RMD should be made only if the movements are
predominantly sleep related. Akathisia is seen as a complication of neuroleptic medi-
cation and is not predominantly sleep related.
Autoerotic or masturbatory behaviors may involve body rocking or other repetitive

body movements, but the primary focus is genital stimulation as is evident by direct
genital contact. Rarely, RMD needs to be differentiated from epilepsy, tic disorders, or
involuntary movements associated with other neurological conditions.

There is controversy about the classification of hypnagogic foot tremor as a separate
entity or as a subtype of sleep related rhythmic movements. Many aspects of sleep
related rhythmic movements deserve further study, including the relationship of the
typical form seen in otherwise normal infants and young children to the rhythmic
movements seen in children with intellectual disability and autism spectrum disorder.
The pathophysiology of persistent RMD is poorly understood, as is the association
with other sleep disorders in adults.
Bibliography
Dyken M, Lin-Dyken D, Yamada T. Diagnosing rhythmic movement disorder with video-polysomnography.
Pediatr Neurol 1997;16:37–41.
Kohyama J, Matsukura F, Kimura K, Tachibana N. Rhythmic movement disorder: polysomnographic
study and summary of reported cases. Brain Dev 2002;24:33–8.
Laberge L, Tremblay R, Vitaro F, Montplaisir J. Development of parasomnias from childhood to early
adolescence. Pediatrics 2000;106:67–74.
Manni R, Terzaghi M. Rhythmic movements during sleep: a physiological and pathological profile.
Neurol Sci 2005;26:s181–5.
Mayer G, Wilde-Frenz J, Kurella B. Sleep related rhythmic movement disorder revisited. J Sleep Res
2007;16:110–6.
316
Benign Sleep Myoclonus of Infancy

Alternate Names
Benign neonatal sleep myoclonus.
Diagnostic Criteria
A. Observation of repetitive myoclonic jerks that involve the limbs, trunk,
or whole body.
B. The movements occur in early infancy, typically from birth to six
months of age.
C. The movements occur only during sleep.
D. The movements stop abruptly and consistently when the infant is
aroused.
or neurological disorder, or medication use.
Essential Features
Benign sleep myoclonus of infancy (BSMI) is characterized by repetitive myoclonic
jerks that occur during sleep in neonates and infants. Although BSMI is benign and
relatively rare, it is included in the sleep related movement disorders section because it
is commonly confused with epilepsy. However, unlike the jerks of myoclonic seizures
and myoclonic encephalopathy, the jerks of BSMI occur exclusively during sleep. The
jerks are often bilateral and massive, typically involving large muscle groups. The
movements can occur in the whole body or exclusively in the limbs, the trunk, or
rarely, the face.
Associated Features

Most infants with BSMI are neurologically normal, born to mothers with no history of
illicit drug use. However, BSMI has been described in more than half of infants with
neonatal opioid withdrawal syndrome, suggesting a subtype with this specific etiology.
It must be stressed, however, that some cases of neonatal abstinence syndrome do not
follow a benign clinical course. Whether such cases should be included with those of
BSMI is an unresolved matter.
317
Demographics
The prevalence is unknown. The incidence has been estimated at 3.7 per 10,000 live
births. More than 200 cases have been described in the literature. Males are affected
more than females by a ratio of about 2:1. The typical age range is birth to six months
of age.

Predisposing factors have not been delineated. Rocking or repetitive noises may pre-
cipitate individual episodes of BSMI.
Familial Patterns
Familial occurrence has been described.

Onset is usually noted between birth and one month of age in a neurologically normal
infant. The course is self-limited and benign. The disorder may be present for only a
few days or may last for several months. Maximum expression is typically between 15
and 35 days of age. BSMI resolves by three months of age in 64% of affected infants,
by six months in 95%, and by 12 months in 97% with persistence rarely into the second
year of life or later. There are no known complications. Long-term follow-up in a
limited number of children has shown normal psychomotor development and normal
cognitive function at five to 10 years of age. There is no evidence for an increased risk
of seizures.
Because age-related factors are a critical dimension for BSMI, developmental issues
are discussed throughout this section.

The presence of a generator in the cervical spinal cord that is not adequately inhibited
due to immature myelination of descending pathways has been hypothesized.
Objective Findings
Video-polysomnographic EEG and EMG monitoring has demonstrated paroxysmal
muscle activity, without ictal or interictal EEG abnormalities. BSMI occurs predom-
inantly during quiet sleep but also may be present during active sleep. The muscle
jerks are usually seen in clusters of four or five jerks per second, each jerk lasting 40
to 300 milliseconds. BSMI clusters typically repeat in irregular series for one to 15
minutes, but, in some cases, the clusters may recur for up to 60 minutes or longer and
318
be mistaken for status epilepticus. One study showed 30% of the jerks to involve the
whole body, 20% to involve the abdominal or proximal muscles, and 50% to involve
only the arms or the legs. The arms are usually more involved than the legs. Activity is
symmetrical in over 90% of cases but can be lateralized. The myoclonus is not associ-
ated with arousals, awakenings, or sleep stage transitions.
Spontaneous or provoked awakening of the infant leads to prompt, abrupt, and consis-
tent cessation of the movements. Gentle rocking of the infant or the infant’s crib has
been shown to provoke the myoclonus. This may be a useful maneuver during EEG
monitoring when differentiation from seizures is of concern. In contrast to jitteriness
and other nonepileptic etiologies, BSMI will often increase rather than be suppressed
by gentle restraint. Neuroimaging studies are normal.
BSMI should be distinguished from myoclonic seizures; misdiagnosis may lead to
unnecessary diagnostic testing or medication use. The absence of episodes while
awake in infants with BSMI is the single most helpful clinical feature. In addition,
BSMI will stop abruptly and consistently when the infant is aroused. Neonatal sei-
zures are often seen in the context of perinatal disorders such as hypoxic-ischemic
encephalopathy, infection, or metabolic abnormalities, whereas BSMI is typically
present in neurologically normal infants. Infantile spasms (West syndrome) are most
often seen after the first month of life but sometimes occur earlier. Infantile spasms
are usually manifest by sudden head flexion with arm extension and lower extremity
flexion. They are usually associated with a hypsarrhythmic EEG pattern. Pyridoxine-
dependency seizures are responsive to treatment with vitamin B6. In cases that are dif-
ficult to differentiate, an EEG obtained during sleep will show normal patterns when
BSMI is elicited by gentle rocking. Anticonvulsant medications are ineffective and
unnecessary in BSMI.
BSMI also should be distinguished from other disorders that occur during wakeful-
ness, including myoclonic encephalopathies, hyperekplexia (startle disease), drug
withdrawal, and jitteriness. Benign myoclonus of early infancy usually occurs after
the third month of life and only occurs during wakefulness.
PLMD can occur in infants but typically has a distinctly different duration and fre-
quency. The muscle activity is of longer duration (0.5 to 10 seconds) and recurs at a
more regular and longer interval (typically 20 to 40 seconds). PLMD can be associated
with EEG arousals, whereas BSMI is not. BSMI is more often seen in the arms than the
legs, whereas PLMD predominantly occurs in the lower limbs.
319
Phasic-REM muscle activity typically involves smaller muscle groups and can be linked
to observable eye movements. Sleep starts occur at the wake-sleep transition and typ-
ically are not repetitive. Propriospinal myoclonus at sleep onset is a rare disorder that
has not been reported in children and is characterized by jerks involving the abdominal
and truncal muscles at the transition from wakefulness to sleep. Fragmentary myoclo-
nus has been described in adults and is primarily a nonspecific EMG finding with little
or no visible movement.

The prevalence, incidence, and pathophysiology of BSMI warrant further study.
Bibliography
Alfonso I, Papazian O, Aicardi J, Jeffries HE. A simple maneuver to provoke benign neonatal sleep
myoclonus. Pediatrics 1995;96:1161–3.
Di Capua M, Fusco L, Ricci S, Vigevano F. Benign neonatal sleep myoclonus: clinical features and video-
polygraphic recordings. Mov Disord 1993;8:191–4.
Held-Egli K, Rüegger C, Das-Kundu S, Schmitt B, Bucher HU. Benign neonatal sleep myoclonus in
newborn infants of opioid dependent mothers. Acta Paediatrica 2009;98:69–73.
Hrastovec A, Hostnik T, Neubauer D. Benign convulsions in newborns and infants: Occurrence, clinical
course and prognosis. Eur J Paediatr Neurol 2012;16:64–73.
Maurer VO, Rizzi M, Bianchetti MG, Ramelli GP. Benign neonatal sleep myoclonus: a review of the
literature. Pediatrics 2010;125:e919–24.
320
Propriospinal Myoclonus at Sleep Onset

Alternate Names
Spinal myoclonus, plurisegmental myoclonus, intersegmental myoclonus, axial
myoclonus.
Diagnostic Criteria
A. The patient complains of sudden jerks, mainly of the abdomen, trunk,
and neck.
B. The jerks appear during relaxed wakefulness and drowsiness, as the
patient attempts to fall asleep.
C. The jerks disappear upon mental activation and with onset of a stable
sleep stage.
D. The jerks result in difficulty initiating sleep.
or neurological disorder, mental disorder, medication use, or substance
use disorder.
Notes
1. Although there is no current definitive evidence that propriospinal
myoclonus confined to sleep onset is associated with significant
structural lesions of the spinal cord, propriospinal myoclonus that
is persistent during the day has been linked to structural spinal cord
pathology in 16% to 20% of cases.
Essential Features
Propriospinal myoclonus at sleep onset (PSM) consists of sudden myoclonic jerks
occurring in the transition from wakefulness to sleep and, rarely, during intrasleep
wakefulness and upon awakening in the morning. The jerks arise mainly in the axial
muscles and spread rostrally and caudally according to propriospinal propagation. The
jerks may be of variable intensity; they are isolated, recurring in quasi-periodic fashion
for variable durations, or may be repeated in brief clusters of a few movements, sepa-
rated by longer intervals. Jerks involve the abdominal and truncal muscles first and are
then propagated to proximal muscles of the limbs and the neck. The pattern of move-
ment is usually flexor but may be an extension of the trunk. Vocalization rarely occurs.
The jerks are most often spontaneous but, in some cases, can be evoked by external
stimulations. The jerks appear to be related to the recumbent position and a state of
321
relaxed wakefulness, particularly when the patient tries to fall asleep. Any mental acti-
vation makes the jerks disappear. The jerks eventually disappear at sleep onset and
remain absent throughout all stages of sleep, even though they sometimes reappear
during intrasleep wakefulness.
Associated Features
PSM often is associated with severe sleep-onset insomnia due to the inability of the
patient to fall asleep because of the recurrent disturbing muscular activity.

PSM may be considered a variant of the more generally described propriospinal myoc-
lonus seen during the daytime. In daytime PSM, myoclonic jerks involve the thoracoab-
dominal/paraspinal or cervical muscles and spread caudally or rostrally to the other
myotomes. The jerks are provoked or worsened by the recumbent position and cannot
be voluntarily suppressed. They are often preceded by premonitory sensations, are
stable over time, and respond unpredictably to drug treatment. The frequent presleep
worsening of daytime PSM (around 50% of the cases) suggests that patients with PSM
may have a milder or variant form of a single clinical and neurophysiologic entity.
Demographics
Epidemiologic data are lacking. PSM is probably a rare condition. A higher prevalence
in men is reported. The disorder affects adults and has not been reported in children.

Familial Patterns

PSM arises in adulthood and is usually a chronic, unremitting condition. Patients may
develop a fear of falling asleep, anxiety, and depression. Intense myoclonic jerks may
cause injury to the patient or the bed partner.

The pathophysiology of PSM is unknown. PSM is thought to originate from a focal
spinal pattern generator, set into motion by supraspinal dysfacilitatory influences
typical of the state of relaxed wakefulness and drowsiness. PSM is presumed to
propagate up and down the spinal cord via slowly conducting, long propriospinal
322
(intersegmental) pathways. A focal spinal generator thus is able to recruit muscles from
multiple segments.
Objective Findings
Polysomnography demonstrates brief myoclonic EMG bursts recurring nonperiodi-
cally with alpha activity present on the EEG and, in particular, when alpha activity
spreads from the posterior to the anterior brain regions. Epileptic EEG discharges are
not observed in PSM. Jerks disappear either with EEG desynchronization, due to mental
activation, or with appearance of sleep spindles and K-complexes. Jerks remain absent
throughout sleep but may occasionally reappear upon awakening and during intrasleep
wakefulness. Polysomnography with extended EMG recording demonstrates that the
jerks arise first in spinal innervated muscles and then propagate to more caudal and
rostral muscles according to a propriospinal pattern of propagation. Detailed analysis
of the jerks shows that the EMG activity originates in muscles innervated by thoracic
or cervical spinal segments (sternocleidomastoid, paraspinalis, rectus abdominis) and
then spreads to more rostrally and caudally innervated muscles at a slow velocity (2
to 16 milliseconds; around 5 milliseconds on average). Back-averaging of the EEG
does not show any jerk-locked cortical activity. MRI of the brain is normal. In a recent
review of PSM, only one patient with exacerbation at sleep onset had a hypersignal at
T10-T11 and a nonspecific medullary cone lesion. The remaining patients had no signs
on spinal cord MRI at sleep onset.
MRI of the spine is usually normal but demonstrates a focal lesion in around 20% of
the cases. The causal relationship of PSM with these spinal lesions is unclear, although
magnetic resonance diffusion tensor imaging with fiber tracking may demonstrate
spinal tract disorganization.
PSM shows features similar to those of the syndrome of intensified sleep starts.
However, sleep starts (hypnic jerks) usually appear during the transition between
wakefulness and sleep and during light NREM sleep, whereas PSM may sometimes
be present during relaxed wakefulness. Unlike PSM, sleep starts (hypnic jerks) some-
times affect only one or a few body segments; propriospinal propagation is not present
in neurophysiological studies of sleep starts. Phasic REM twitches, which are a normal
phenomenon during REM sleep, involve the distal muscles of the hands and face,
often without displacement of the body segment. Fragmentary myoclonus resembles
physiological hypnic myoclonus, but in an enhanced form, and persists throughout
all stages of NREM and REM sleep. Both physiological hypnic myoclonus and frag-
mentary myoclonus are EMG findings not associated with overt muscular activity and
323
do not involve muscles acting across large joints. Epileptic myoclonus is not confined
to relaxed wakefulness and may be associated with epileptic discharges on the EEG.
PLMS are longer in duration, involve mainly the lower limbs, and usually spare truncal
and abdominal muscles. PLMs may begin during presleep wakefulness but generally
occur during NREM sleep. Some patients with RLS may have prominent PLMs in
wakefulness while sitting or lying down. However, prominent leg discomfort is usually
present in these patients. Occasionally PSM may be present in RLS/PLMS patients in
wake before sleep, but the EMG morphology is different. In addition, when myoclonic
jerks involving leg muscles appear, the PSM disappears. Psychogenic myoclonus may
simulate PSM but the muscle recruitment pattern, the spread velocity, and the record-
ing of cortical premovement activity observed before voluntary movements may be
useful to differentiate the two types of jerks.

Future studies are needed to better define the distinctions between PSM and related
conditions such as sleep starts (hypnic jerks) and, in particular, the syndrome of inten-
sified sleep starts. Also, neuroimaging and possibly postmortem studies may detect the
neural structures responsible for the initiation of the myoclonic jerks.
Bibliography
Montagna P, Provini F, Plazzi G, Liguori R, Lugaresi E. Propriospinal myoclonus upon relaxation and
drowsiness: a cause of severe insomnia. Mov Disord 1997;12:66–72.
Montagna P, Provini F, Vetrugno R. Propriospinal myoclonus at sleep onset. Neurophysiologique clinique
2006;36:351–5.
Roze E, Bounolleau P, Ducreux D, et al. Propriospinal myclonusmyoclonus revisited. Clinical,
neurophysiologic, and neuroradiologic findings. Neurology 2009;72:1301–9.
Tison F, Arne P, Dousset V, Paty J, Henry P. Propriospinal myoclonus induced by relaxation and drowsiness.
Rev Neurol (Paris) 1998;154:423–5.
Vetrugno R, Provini F, Meletti S, et al. Propriospinal myoclonus at the sleep-wake transition: a new type
of parasomnia. Sleep 2001;24:835–43.
324
Sleep Related Movement Disorder Due to a Medical

Disorder
Diagnostic Criteria
A. The patient manifests sleep related movements that disturb sleep or its
onset.
B. The movement disorder occurs as a consequence of a significant
underlying medical or neurological condition.
C. The symptoms are not better explained by another sleep related
movement disorder, other untreated sleep disorder, substance use, or
mental disorder.
This diagnosis is intended for sleep related movement disorders due to an underlying
medical or neurologic condition that do not meet criteria for another specific movement
disorder. Many neurological conditions may be associated with movement abnormali-
ties that are evident in wake and sleep. In some cases, the nocturnal manifestations of
the movement abnormalities may be apparent before establishment of a firm neurolog-
ical diagnosis. Thus, in some cases, “sleep related movement disorder due to a medical
disorder” is a temporary diagnosis, given when a sleep diagnosis is required before the
underlying medical or neurological condition can be fully diagnosed. Once the pres-
ence of a medical or neurological condition is clearly established, that becomes the
sole diagnosis unless the sleep complaint is the focus of independent clinical attention.
When a movement disorder that is listed elsewhere in the sleep related movement
disorder section of the International Classification of Sleep Disorders, 3rd Edition is
caused or exacerbated by a medical or neurological condition (e.g., restless legs syn-
drome), it is preferred that the more specific diagnosis (e.g., RLS) be used rather than
“sleep related movement due to a medical disorder,” with annotation of the relation-
ship to the medical or neurological disorder.
325
Sleep Related Movement Disorder Due to a

Medication or Substance
instructions)
Diagnostic Criteria
A. The patient manifests sleep related movements that disturb sleep or its
onset.
B. The movement disorder occurs as a consequence of current medication
or substance use or withdrawal from a wake-promoting medication or
substance.
C. The symptoms are not better explained by another sleep related
movement disorder, other untreated sleep disorder, or medical,
neurological, or mental disorder.
This diagnosis is intended for sleep related movement disorders due to a medication or
substance (toxin or other bioactive substance) that do not meet criteria for another spe-
cific movement disorder. Many substances may be associated with movement abnor-
malities that are evident in wake and sleep. To the extent that the movement abnormal-
ity is an expected complication of the substance(s) involved (e.g., tardive dyskinesia
or akathisia associated with neuroleptic usage), this diagnosis is unnecessary unless
the sleep related aspects of the movement abnormality or its sequelae, are the focus of
independent clinical attention.
When a movement disorder that is listed elsewhere in the sleep related movement
disorder section of the International Classification of Sleep Disorders, 3rd Edition is
caused or exacerbated by drugs or substances (e.g., restless legs syndrome), it is pre-
ferred that the more specific diagnosis (e.g., RLS) be used rather than “Sleep related
movement disorder due to a medication or substance,” with annotation of the relation-
ship to drug or substance.
326
Sleep Related Movement Disorder, Unspecified

This diagnosis is assigned when patients have a sleep related movement disorder that
cannot be classified elsewhere or is suspected to be associated with an underlying psy-
chiatric condition. In some cases, “sleep related movement disorder, unspecified” is a
temporary diagnosis prior to establishment of an underlying psychiatric condition that
may explain the sleep related movement (e.g., movements associated with posttrau-
matic stress disorder nightmares prior to firm establishment of the psychiatric diag-
nosis). Once the psychiatric diagnosis is established, that becomes the sole diagnosis
unless the sleep complaint is the focus of independent clinical attention.
327
Excessive Fragmentary Myoclonus

Excessive fragmentary myoclonus (EFM) is a largely incidental polysomnographic
finding on EMG, characterized by small movements of the corners of the mouth,
fingers, or toes, or by no visible movement at all. The finding is associated with no
known clinical consequence. Large limb movements across large joint spaces are not
characteristic of EFM and, if present, should exclude the diagnosis of EFM. Scoring
of EFM is described in the most recent version of the AASM Manual for the Scoring
of Sleep and Associated Events. The condition is a NREM phenomenon and the move-
ments resemble the phasic twitches seen in normal REM sleep except that they are
more universally dispersed throughout a sleep epoch than phasic REM twitches, which
are generally clustered within small groups in a sleep epoch. Its importance lies in that
it is within the differential diagnosis of other sleep related movement disorders.
Patients usually are not aware of the twitch-like movements. Patients may have other
coexistent sleep disorders, but EFM does not appear to contribute to the symptoms of
these sleep disorders.
EFM, a NREM phenomenon, is less common than phasic REM twitches, which occur
in REM sleep in normal individuals without sleep complaints. Most cases have been
reported in adults. EFM is predominantly found in males. A recent study found EFM
in 100% of 62 patients with a variety of sleep disorders, bringing into question the
specificity of EFM.
Numerous causes of chronic sleep fragmentation may be associated with EFM. The
condition has been described with obstructive sleep apnea and primary central sleep
apnea, sleep related hypoxemic/hypoventilation syndromes, narcolepsy, PLMD, and
various causes of insomnia. In apneic patients, the twitching intensifies during periods
of increased hypoxemia. One report has found excessive fragmentary myoclonus to be
very common in children with Niemann-Pick disease, type C. No specific precipitating
factors have been reported. The contribution of EFM to the symptomatology of any of
these disorders is unknown.
The course is not well studied but appears to be benign and non-progressive. The dis-
order may be the sole abnormality in some cases of excessive daytime sleepiness, but
causality is questionable. No other serious consequences of the disorder have been
described when it occurs in isolation.
328
In some cases, EFM is present in normal individuals. Its relatively benign course sug-
gests that it is not associated with a neurodegenerative process. In most reported cases,
there have been associated sleep abnormalities and sleep disruption, suggesting that
EFM may be due to disruptions of normal motor-control mechanisms during sleep.
Whether there is a genetic or other basis predisposing individuals to develop the condi-
tion is unknown. In any case, it would appear to result from intensification of an other-
wise normal motor phenomenon. The predominant topographic distribution of EFM in
distal and facial muscles suggests that cortical motor centers participate in its generation.
EFM is detected as isolated, very brief (usually 75 to 150 milliseconds), asymmetrical,

asynchronous EMG potentials in various muscles of the face, trunk, arms, and legs.
The amplitude varies from approximately 50 to several hundred microvolts; the taller
amplitudes are often associated with visible movement of the fingers, toes, or corners
of the mouth, whereas the smaller ones may resemble fasciculation potentials and be
without overt movement. Large movements across large joint spaces preclude a diag-
nosis of EFM. Small twitch-like movements may be observed on video recording.
Episodes of these myoclonic potentials typically last from 10 minutes to several hours.
They often appear at sleep onset and continue through the NREM sleep stages, includ-
ing slow wave sleep. The presence of EFM in REM is difficult to determine because it
is superimposed on the normal phasic clusters of physiological phasic REM twitches.
EFM is electromyographically similar to the latter. Occasionally, the EMG activity
also persists during EEG periods of wakefulness within the sleep period or is present
in drowsiness prior to sleep onset. The EEG usually shows no changes at the time of
the movements, although high-amplitude EMG potentials may be associated with a K
complex or even with transient EEG arousal. There are no ocular or autonomic accom-
paniments. It seems possible that, depending on the digitalization rates, digital systems
may record less fragmentary myoclonus than earlier paper records. No laboratory tests
other than polysomnography (optimally with multiple EMG leads) have been reported
to be helpful in assessing EFM.
EFM generally has a maximum burst duration of only 150 milliseconds and does not
recur periodically. It can be distinguished from PLMS because PLMS are character-
ized by a longer burst duration (typically 0.5 to 10 seconds) and a long period between
bursts (5-90 seconds). EFM, which occurs in NREM, must also be differentiated from
normal physiological phasic REM twitches, which have a similar burst duration but are
limited to the REM state and tend to occur in clusters within an epoch, as opposed to
EFM in which bursts tend not to cluster within a particular epoch. Larger body move-
ments across the large joints are not a feature of excessive fragmentary myoclonus. The
presence of such movements suggests other disorders.
329
Further investigation is necessary to determine whether EFM occurs as a consequence

of sleep disruption or whether it is an independent cause of sleep disruption and daytime
symptoms in its own right. It must also be determined whether there are any physiolog-
ical differences that distinguish fragmentary myoclonus seen in many normal individu-
als from EFM. It is not known whether some additional pathophysiological element is
required to increase fragmentary myoclonus into an abnormal range. The current thresh-
old for the diagnosis of EFM should be further investigated because the scoring criteria
lack specificity. The apparent strong predominance in males also remains unexplained.
Bibliography
Broughton R. Pathological fragmentary myoclonus, intensified sleep starts and hypnagogic foot tremor:
three unusual sleep-related disorders. In: Koella WP, Schulz OF, Visser P, eds. Sleep 1986. Stuttgart:
Fischer-Verlag, 1988:240–3.
Broughton R, Tolentino MA. Fragmentary pathological myoclonus in NREM sleep. Electroencephalogr
Clin Neurophysiol 1984;57:303–9.
Broughton R, Tolentino MA, Krelina M. Excessive fragmentary myoclonus in NREM sleep: a report of
38 cases. Electroencephalogr Clin Neurophysiol 1985;61:123–33.
Frauscher B, Kunz A, Brandauer E, Ulmer H, Poewe W, Hogl B. Fragmentary myoclonus in sleep
revisited: A polysomnographic study in 62 patients. Sleep Med 2011;12:410–5.
Goyal MK, Kumar G, Sivaraman M. Sahota P. Teaching neuroimages: excessive fragmentary hypnic
myoclonus. Neurology 2011;77:e59–e60.
Lins O, Castonguay M, Dunham W, Nevsimalova S, Broughton R. Excessive fragmentary myoclonus:
time of night and sleep stage distributions. Can J Neurol Sci 1993;20:142–6.
Vankova J, Stepanova I, Jech R, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick
disease type C. Sleep 2003;26:427–30.
Vetrugno R, Plazzi G, Provini F, Liguori R, Lugaresi E, Montagna P. Excessive fragmentary hypnic
myoclonus: clinical and neurophysiological findings. Sleep Med 2002;3:73–6.
Montagna P, Liguori R et al. Physiological hypnic myoclonus Electroencephalogr Clin Neurophysiol
1988;70:172–6.
Hypnagogic Foot Tremor and Alternating Leg Muscle

Activation
Hypnagogic foot tremor (HFT) is rhythmic movement of the feet or toes that occurs
at the transition between wake and sleep or during light NREM sleep (stages N1 and
N2). Alternating leg muscle activation (ALMA) consists of brief activation of the ante-
rior tibialis in one leg in alternation with similar activation in the other leg during
sleep or arousals from sleep. HFT may be a relatively common and normal finding.
Affected individuals move the feet or the toes rhythmically for seconds to minutes
during drowsy wakefulness or lighter stages of sleep. It can be pathologically exagger-
ated in some patients. ALMA is defined by a polysomnographic pattern with unknown
330
clinical manifestations, but frequency of muscle activations, length of activations, and

occurrence primarily with arousals suggest that ALMA may be similar to HFT or rep-
resent an EMG manifestation of some episodes of HFT. The original case series that
described ALMA did not link it with movement of the lower extremity, but a subse-
quent report did. HFT and ALMA are considered together because the relationship
between them remains to be clarified, and the similarity in a number of their features
suggests they may not be fully independent entities.
Associated features of HFT and ALMA are similar. Most cases of HFT have been
reported in persons with other sleep disorders, such as RLS or SRBDs. ALMA has been
identified mainly in patients with SRBD or PLMs. Seventy-five percent of patients with
ALMA in the original series used antidepressant medication. In that study, patients
with ALMA complained of sleepiness, insomnia, or restless of the legs, but only one
reported patient had more specific complaints of sudden nocturnal muscle contractions
in his legs and a sensation that his legs were vibrating. A separately reported case of a
patient with ALMA documented absence of any SRBD, PLMs, or use of antidepressant
medication. This patient complained of frequent and easily provoked awakenings, as
well as excessive daytime sleepiness. The ALMA and symptoms responded to treat-
ment with pramipexole.
The single series in which HFT was studied found that it occurs in 7.5% of patients in
whom a polysomnogram was performed for other reasons. Affected individuals range
in age from 14 to 72 years, with a majority in the middle-age range (40 to 65 years).
Men and women are equally affected. It is possible that the frequency of these move-
ments may be increased in individuals with disorders such as RLS or SRBD, but it can
occur in individuals with otherwise normal sleep. The prevalence of the condition in
the general population and its frequency in affected individuals remains uncertain. The
initial series reporting ALMA found that it occurs in 1.1% of unselected studies from a
sleep disorder center. Patients with ALMA were mostly male (11:5) and ranged in age
from 12 to 70 years, with most aged 35 to 55 years (mean age 41 years). Therefore, the
age ranges of both conditions are similar, with both males and females affected. These
distributions may be due to the incidental discovery of both entities during routine
sleep studies for other sleep complaints.
No predisposing factors are known for HFT. The use of antidepressant medication may
increase risk for ALMA.
No longitudinal studies have been performed for either entity. In some individuals,
HFT is an occasional finding, but others appear to manifest the rhythmic movements
331
on many nights and over a span of at least months. ALMA showed some tendency
to persist between two different recordings in the originally reported series. Because
most individuals are unaware of the presence of the HFT movements, and patients with
ALMA may have no associated complaint or awareness of the phenomenon, the evo-
lution of HFT and ALMA may be difficult to follow except in the sleep laboratory or
with home monitoring. Although usually an incidental and benign finding, HFT may
cause sleep disruption and sleep-onset insomnia if sufficiently prolonged or severe.
In HFT, the patient typically reports foot movements (directly experienced or observed
by others) that occur at the transition between wake and sleep or during light sleep. On
occasion, movement has not been observed but HFT is seen as an incidental finding on
sleep study conducted for other indications. Polysomnography demonstrates a pattern
of brief, repeated activation of the anterior tibialis in one leg. The minimum frequency
is 0.3 Hz; the maximum 4.0 Hz. Multiple leg activations in a single leg occur in a train
of at least four movements. EMG recordings of the foot or leg muscles or video record-
ings of movement may show trains of recurrent 1-Hz to 2-Hz EMG potentials or move-
ments. Typical associated EMG bursts are 300 to 700 milliseconds in duration, and the
typical duration of trains is 10 to 15 seconds, although longer bursts and trains have been
reported. In morbid conditions, trains may persist much longer. Events are recorded at
the transition into sleep and during stages N1 and N2 sleep. Distribution over the night
has not been fully investigated. Persistent HFT has been found in about half of the indi-
viduals who have had multiple studies. Alternation between legs has not been described,
but its potential occurrence is suggested in two published studies of HFT.
In ALMA, polysomnography demonstrates a pattern of brief, repeated activation of

the anterior tibialis in one leg alternating with similar activation in the other leg. At a
minimum, a single leg muscle activation in one leg is followed sequentially by a similar
single activation in the other leg, reactivation in the original leg, and then reactivation
in the alternate leg, with some continued alternation beyond this minimal sequence in
most instances. The minimum frequency of alternating EMG bursts is 0.5 Hz, and the
maximum frequency is 3.0 Hz. The patient may report foot movements (directly experi-
enced or observed by others) that occur at the transition between wake and sleep or during
light sleep. As noted above, there is frequently no observation of movement reported but
alternating leg muscle activation is recorded as an incidental finding on polysomnography.
ALMA can be demonstrated by polysomnography if the surface EMG is recorded inde-

pendently from both right and left anterior tibialis muscles. A sequence of ALMA may
begin with one to several lengthy activations (one to two seconds) in one or both legs.
Some patients show unilateral activity at times. ALMA usually closely precedes or
332
follows an arousal or awakening and gradually diminishes as sleep returns. However,

ALMA can also emerge without arousals from any sleep stage. Proclivity for any spe-
cific portion of the nocturnal sleep cycle has not been identified. Leg muscle activa-
tions during REM sleep, in comparison to NREM sleep, are often briefer and some-
what less regular. Sequences of ALMA sometimes recur at intervals similar to those
of PLMs. Extensor forearm EMG study may suggest alternating muscle activity in the
upper extremities, though it is less prominent than activation in the legs. ALMA shows
some night-to-night consistency. Repeat studies are likely to show persistent ALMA.
The number of sequences recorded, on average, and the timing of ALMA with respect
to arousals tends to remain constant.
The specific polysomnographic criteria for HFT during sleep and ALMA are defined in
the most recent version of the AASM Manual for the Scoring of Sleep and Associated
Events.
Presentation of HFT or ALMA with other concurrent sleep disorders is common.
Because of the similar frequency, duration, and body part involvement of the move-
ments, HFT and ALMA may represent variants of the same disorder. Insufficient sci-
entific evidence has accumulated to make this a certainty. Thus, these entities are listed
sequentially but separately.
Of note, some have questioned whether HFT and ALMA might represent a variant of
rhythmic movement disorder in which movements are confined to the legs and an older
population is affected.
HFT and ALMA should be distinguished from other sleep-onset movements: PLMD
(especially the polyclonic form), PSM, and sleep related RMD. Movement disorders
that should be distinguished from HFT and ALMA include dyskinetic movements of
the foot, such as painful legs and moving toes; tremors or rhythmic movements of other
cause (Parkinson disease, clonus); and neuroleptic-induced akathisia. None of these
conditions involves regular alternation between sides, as seen in ALMA, or an associ-
ation with the use of antidepressant medication.
Whether HFT should be distinguished from ALMA is not known. Potential differences
based on existing reports include the presence of clear movement in HFT as opposed to
some uncertainty whether ALMA must involve movement. ALMA, in contrast to HFT,
alternates between sides, occurs in any sleep stage, can occur without arousal, and is
associated with the use of antidepressants.
333
High-frequency leg movements (HFLM) also have been described as a repetitive ante-
rior tibialis, polysomnographic activation phenomenon, possibly showing some asso-
ciation with RLS, and with potential overlap with HFT and ALMA. In contrast to
HFT, however, HFLM occur in all sleep stages, and are mostly unilateral rather than
bilateral. In contrast to ALMA, HFLM are mostly unilateral rather than alternating,
and often show sequences that last longer than those reported for ALMA. The reported
HFLM may be more common than ALMA, and the possibility exists that ALMA rep-
resents a subtype of HFLM in which leg alternation occurs.
The degree to which these movements are quasi-voluntary remains to be determined

because some are suppressible. Whether HFT and ALMA are merely alternate forms
of the same underlying motor mechanism is also unclear. As reports of these move-
ments have arisen from reviews of sleep center records, nothing is known about their
manifestation in the general population. The associations noted may be due to biased
sampling caused by a skewing of the population toward those with sleep disorders,
especially respiratory disorders. The degree to which HFT and ALMA have clinical
significance remains uncertain.
Bibliography
Berry RB. A woman with rhythmic foot movements. J Clin Sleep Med 2007;3:749–51.
Fischer-Verlag, 1988:240–3.
Chervin RD, Consens FB, Kutluay E. Alternating leg muscle activation during sleep and arousals: a new
sleep-related motor phenomenon? Mov Disord 2003;18:551–9.
Consentino FI, Iero I, Lanuzza B, Tripodi M, Ferri R. The neurophysiology of the alternating leg muscle
activation (ALMA) during sleep: Study of one patient before and after treatment with pramipexole.
Sleep Med 2006;7:63–71.
Cunningham SL, Winkelman JW, Dorsey CM, et al. An electromyographic marker for neuroleptic-induced
akathisia: preliminary measures of sensitivity and specificity. Clin Neuropharmacol 1996;19:321–32.
Wichniak A, Tracik F, Geisler P, Ebersbach G, Morrissey SP, Zulley J. Rhythmic feet movements while
falling asleep. Mov Disord 2001;16:1164–70.
Yang C, Winkelman JW, White DP. The effects of antidepressants on leg movements (abstract) Sleep
2004;27(Abst Suppl):A311–2.
Yang C, Winkelman JW. Clinical and polysomnographic characteristics of high frequency leg movements.
J Clin Sleep Med 2010;6:431–8.
334
Sleep Starts (Hypnic Jerks)

Sleep starts, also known as hypnic jerks, are sudden, brief, simultaneous contractions of
the body or one or more body segments occurring at sleep onset. Sleep starts (or hypnic
jerks) usually consist of a single contraction that often affects the body asymmetrically.
The jerks may be either spontaneous or induced by stimuli. The motor activity is often
associated with a sensory component, which may be somesthetic, often an impression
of falling or less commonly pain or tingling; auditory, such as banging, snapping or
crackling noises; or visual, including flashing lights, hypnagogic dreams, or hallucina-
tions. A sharp cry may occur. The patient may not recall a jerk that was noted by a bed
partner if the sleep start does not cause awakening. Multiple jerks occasionally occur
in succession, usually early in the sleep period. When sleep starts or hypnic jerks are
frequent, intense, or repetitive, they may lead to sleep-onset insomnia.
Purely sensory sleep starts are subjective, localized, sensory impressions that occur
at sleep onset and are not associated with motor activity. The term “Intensified sleep
starts” has been applied to both the motor and purely sensory forms when a complaint
of difficulty falling asleep as a result of the starts is present.
A prevalence of 60% to 70% has been reported, but with a highly sporadic occurrence.
Sleep starts affect all ages and both sexes.
Excessive caffeine or other stimulant intake, prior intense physical work or exercise, sleep
deprivation, and emotional stress can increase the frequency and severity of sleep starts.
Sleep starts are an essentially universal component of the sleep-onset process, although
they are often not recalled. Hypnic jerks may occur at any age, as a subjective com-
plaint; however, they are usually encountered in adulthood. The course is usually
benign. Intensified sleep starts may lead to avoidance/delay of sleep, a fear of falling
asleep and chronic anxiety. As a result, acute and chronic sleep deprivation may occur.
Sleep-onset insomnia may result either from repeated awakenings induced by the starts
or from anxiety about falling asleep. Injury, such as bruising a foot against a bedstead
or kicking a sleeping companion, may occasionally occur.
The physiological mechanisms underlying sleep starts are uncertain. No pathologic

finding has been described except for a single case of auditory sleep starts associated
with a brainstem lesion. Hypnic jerks are hypothetically caused by sudden descending
volleys originating in the brainstem reticular formation activated by the system insta-
bility at the transition between wake and sleep. However, the similarity between sleep
starts and the startle response has led some to postulate that abnormalities of sensory
335
processing are primary, with secondary motor manifestations involving the reticulo-
spinal tract. Sleep starts are a prominent symptom in hereditary hyperekplexia, some
cases of which are caused by mutations in the glycine receptor. It has also been postu-
lated that sleep starts are a response to hypnagogic imagery.
Polysomnographic monitoring shows that hypnic jerks occur during transitions from
wakefulness to sleep, mainly at the beginning of the sleep episode. Superficial EMG
recordings of the involved muscles show brief (generally 75-millisecond to 250-mil-
lisecond) high-amplitude potentials, either singly or in succession. The EEG typically
shows drowsiness or stage N1 sleep patterns, sometimes with a negative-vertex sharp
wave occurring at the time of the jerk. Autonomic activation, including tachycardia,
tachypnea or irregular breathing, and sudomotor activation may follow an intense jerk.
After the jerk, a brief arousal or a return to sustained wakefulness may occur. Physical
and neurological examinations and routine laboratory tests are otherwise normal.
Although polysomnography is not necessary for diagnosis in most individuals, it may
be indicated in occasional cases with complaints of insomnia and frequent movements.
Hypnic jerks must be differentiated from a number of physiological or pathologic

movements that occur at sleep onset or during sleep. Physiological partial hypnic
myoclonus consists of small, isolated contractions of a muscle or part thereof, occur-
ring sporadically in distal muscles and resembling fasciculation potentials. The con-
tractions are particularly evident during stage N1 and REM sleep.
Fragmentary myoclonus consists of profuse, brief, small-amplitude muscle twitches

that occur in an asynchronous, symmetrical, and bilateral manner, especially in distal
muscles. Fragmentary myoclonus occurs at sleep onset as well as within all sleep stages.
Contrary to the massive jerks of the sleep starts or hypnic jerks, the small muscle
twitches of physiological partial hypnic myoclonus and of fragmentary myoclonus
often represent only an EMG finding and are not associated with overt movements at
the joints. Normal body movements are complex, with body postural shifts usually at
the transition between one sleep stage and another. Benign sleep myoclonus of infancy
consists of myoclonic jerks at the elbow, fingers, toes, and face during sleep in infants.
PSM is characterized by jerks, usually spontaneous, but sometimes also evoked, arising
first in spinal innervated axial muscles of the trunk, neck, or abdomen and then prop-
agated at slow velocity to more rostral and caudal muscles. PSM is present during
relaxed wakefulness, characterized by diffuse EEG alpha activity, and disappears with
sleep onset or mental activation. PSM is usually a chronic condition associated with
sleep-onset insomnia.
336
Excessive startling and hypnic jerks may occur as part of the hyperekplexia syndrome,
in which generalized myoclonus is readily elicited by stimuli during either wakeful-
ness or sleep. The major form of this condition is also characterized by stiffness and
falls. Brief epileptic myoclonus can be differentiated by coexistent EEG discharge, the
presence of other features of epileptic seizures, and the occurrence of the myoclonus in
both wakefulness and during sleep rather than only at sleep onset.
The muscle contractions of PLMD are much longer in duration, involve mainly the
feet and lower legs, show periodicity, and occur within sleep. RLS consists of slower
and repetitive semivoluntary movements at sleep onset that are associated with deep,
unpleasant, and sometimes unbearable sensations, which are temporarily relieved by
getting up and exercising.
Bibliography
Fisher Verlag; 1988:240–3.
Kennard MA, Schwartzman AE, Millar TP. Sleep, consciousness, and the alpha electroencephalographic
rhythm. Arch Neurol Psychiatry 1958;79:328–35.
Montagna P, Liguori R, Zucconi M, et al. Physiological hypnic myoclonus. Electroencephalgr Clin
Neurophysiol 1988;70:172–6.
Oswald I. Sudden bodily jerks on falling asleep. Brain 1959;82:92–103.
Salih F, Klingebiel R, Zschenderlein R, et al. Acoustic sleep starts with sleep-onset insomnia related to a
brainstem lesion. Neurology 2008;70:1935–7.
Sander HW, Geisse H, Quinto C, Sachdeo R, Chokroverty S. Sensory sleep starts. J Neurol Neurosurg
Psychiatry 1998;64:690.
Vetrugno R, Montagna P. Sleep-to-wake transition movement disorders. Sleep Med 2011;12:S11–6.
337
Other Sleep Disorder
Sleep disorders that cannot be classified elsewhere in the International Classification

of Sleep Disorders, 3rd Edition are listed here. This may be due to the fact that the
sleep disorder overlaps more than one category or, more often, when insufficient data
have been collected to firmly establish another diagnosis. It is also possible that new
sleep disorders that do not fall within any of the current major categories will be dis-
covered during the lifetime of the International Classification of Sleep Disorders,
3rd Edition. When a specific diagnosis cannot yet be determined but the presenting
problem clearly falls into a specific category (e.g., a circadian rhythm sleep-wake dis-
order), the “unspecified” diagnosis within that category (e.g., circadian rhythm sleep-
wake disorder, unspecified) is preferred.
The International Classification of Sleep Disorders, 2nd Edition included a specific

diagnosis of environmental sleep disorder within this section. This diagnosis is infre-
quently employed in the clinical setting and significant controversy exists regarding
whether environmentally induced sleep disturbance represents a clinical disorder per
se. The condition is typically characterized by complaints of sleep initiation and/or
maintenance that are the direct result of an environmental factor. Associated daytime
symptoms such as sleepiness, fatigue, or cognitive or emotional disturbance may be
present. The environmental disturbance may be a physical stimulus such as noise (e.g.,
vehicular traffic, aircraft, bed partner snoring), light, temperature, movement (e.g., bed
partner movement disorder or parasomnia), an emotional stimulus such as environ-
mental danger (e.g., combat setting or disaster area), or an environmental requirement
(such as caring for an infant or elderly family member). Hospitalization is often cited
as a precipitant of environmental sleep disturbance although many additional factors
(e.g., anxiety or pain) may also contribute to sleep disturbance in this setting. If the
clinician determines that an environmental factor is the primary cause of a sleep distur-
bance, a diagnosis of Other Sleep Disorder may be employed.
It is the physical aspects of the environment, rather than their psychological meaning,
which account for the sleep complaint. Unlike insomnia disorder, the sleep disturbance
is dependent on the presence of the environmental factor. In the absence of the stimu-
lus, sleep is normal.
The prevalence of environmentally induced sleep disturbances is not known although,

as noted, the diagnosis is not commonly reported in sleep centers. Some individuals
339
Other Sleep Disorder
may be more susceptible to environmental disturbances but little is known about spe-
cific characteristics that might predispose to this condition.
Although environmental factors may play a contributing role in some cases of chronic
insomnia disorder, multiple other factors account for that condition, which is typically
evident even in the absence of the offending environmental stimulus. Distinguishing
an insomnia disorder from an environmentally induced sleep disturbance may pose a
challenge in certain clinical encounters and providers must use clinical judgment in
establishing the diagnosis.
In behavioral insomnia of childhood, the child may require certain environmental cir-
cumstances in order to sleep (e.g., a pacifier, music, lights, television, or a parent). It is
the absence of these circumstances that results in sleep initiation or maintenance prob-
lems. In such cases, a diagnosis of chronic insomnia disorder (behavioral insomnia of
childhood – sleep-onset association type) is indicated.
Bibliography
Basner M, Griefahn B, Berg MV. Aircraft noise effects on sleep: mechanisms, mitigation and research
needs. Noise Health 2010;12:95–109.
Hume KI, Brink M, Basner M. Effects of environmental noise on sleep. Noise Health. 2012;14:297–302.
Thiessen G, Lapointe A. Effect of continuous traffic noise on percentage of deep sleep, waking, and sleep
latency. J Acoust Soc Amer 1983;73:225–9.
Yilmaz M, Sayin Y, Gurler H. Sleep quality of hospitalized patients in surgical units. Nurs Forum
2012;47:183–92.
340
Appendix A:
Sleep Related Medical and
Neurological Disorders
Fatal Familial Insomnia...............................................................................342
Sleep Related Epilepsy...............................................................................345
Sleep Related Headaches...........................................................................350
Sleep Related Laryngospasm.....................................................................355
Sleep Related Gastroesophageal Reflux....................................................358
Sleep Related Myocardial Ischemia............................................................363
The disorders presented in this section may have a unique presentation during the sleep
period or may present exclusively in association with sleep. Some of these disorders
(e.g., sleep related epilepsy and sleep related headache) may be encountered during
evaluation for other sleep disorders. In addition, some of these disorders are in the dif-
ferential diagnosis of other sleep-wake disorders. Sleep related epilepsy must be con-
sidered in the differential diagnosis of certain movement disorders and parasomnias.
Sleep related headaches may be a clue to the presence of sleep apnea. Sleep related
gastroesophageal reflux may either be a precipitant of a sleep apnea episode or be trig-
gered by sleep apnea with aspiration pneumonia as its most serious consequence. Sleep
related myocardial ischemia is an important consideration because myocardial infarc-
tion has a predilection for the early morning hours during the latter phase of the sleep
period and may be precipitated by episodes of sleep apnea. It is important to be aware
of sleep related laryngospasm as a potentially life-threatening consequence of neurode-
generative diseases such as multiple system atrophy. Fatal familial insomnia, although
rare, presents with severe insomnia and has a well-understood neuropathology.
341
Appendix A: Sleep Related Medical and Neurological Disorders
Fatal Familial Insomnia

Alternate Names
Fatal progressive insomnia with dysautonomia, familial thalamic degeneration of the
anterior and dorsomedial thalamic nuclei, thalamic insomnia.
Essential Features
Fatal familial insomnia is a very rare, progressive disorder characterized by initial dif-
ficulties in falling asleep and maintaining sleep, spontaneous lapses from quiet wake-
fulness into a sleep state with enacted dreams (oneiric stupor), and loss of slow wave
sleep features. In later stages of the disease, it may not be possible to identify any dis-
tinct sleep stages.
Although loss of temporal and spatial orientation develops, cognitive function is

retained until impaired alertness makes testing impossible. The disorder progresses to
unarousable coma, and finally, death.
Associated Features
Bronchopulmonary and other infections may also be present. There is a loss of the
circadian rhythmicity of endocrine rhythms. Autonomic hyperactivity (e.g., pyrexia,
salivation, hyperhidrosis, tachycardia, tachypnea, and dyspnea) is present. The disor-
der includes somatomotor disturbances, with dysarthria, dysphagia, tremor, sponta-
neous and reflex myoclonus, dystonic posturing, ataxia, and a positive Babinski sign.
Hallucinations may be present.

None.
Demographics
Age of onset is usually in adulthood, between 36 and 62 years of age. The disorder is
rare. There are no sex differences.

Familial Patterns
Fatal familial insomnia (FFI) is transmitted according to an autosomal dominant
pattern. Patients harbor a missense GAC to AAC mutation at codon 178 of the prion
protein gene PRNP located on chromosome 20, cosegregating with the methionine
342
polymorphism at codon 129 of the same gene on the mutated allele (D178N 129M).
The clinical syndrome varies by the M129V genotype. Patients who are methionine
homozygous at the 129 codon are younger and display a shorter disease course than do
patients who are methionine-valine heterozygous at codon 129.

The disorder is always fatal, usually within eight to 72 months. The course is one of
relentless worsening of symptoms. Patients may die after a short (less than 12 months)
or long (12 to 72 months) disease course. The younger age at disease onset and, conse-
quently, a lower rate of comorbidity, may explain the generally more prolonged disease
course in FFI in comparison to other prion diseases. Complications include infections
(in particular of the lungs and bladder) that develop during the course of the disease,
especially in the late stages, and represent the usual cause of death. Other frequent com-
plications include skin ulcers when patients become bedridden and aspiration of food
due to the severe dysphagia; the latter may require nasogastric or gastrostomy feeding.

Severe bilateral loss of neurons, with reactive gliosis of the anterior and dorsomedial
thalamic nuclei and severe neuronal loss and reactive astrogliosis in the inferior olives,
are found. Spongiform changes in cortical layers in cases with a prolonged course have
been described. Deposition of proteinase K-resistant prion protein type 2 in the grey
matter but not the white matter occurs in both familial and sporadic fatal insomnia.
Both familial and sporadic fatal insomnia have been transmitted to transgenic animals
by intracerebral inoculum of brain homogenates.
Objective Findings
In early stages of FFI, periods of relaxed wakefulness alternate with episodes of elec-
troencephalographic (EEG) desynchronization, rapid eye movement (REM) bursts,
loss of antigravity muscle tone, and irregular myoclonic and tremor-like limb-muscle
activities associated with vivid dreams (oneiric stupor). Sleep spindles and features of
slow wave sleep are absent or progressively lost throughout the course of the illness. In
the final stages of the disorder, the EEG becomes unreactive and progressively flattens
until death occurs; it may display periodic spike discharges.
Positron emission tomography (PET) with (18F)-2-fluorodeoxy-d-glucose shows tha-

lamic hypometabolism. Magnetic resonance spectroscopy with multisequences can
detect prion-induced gliosis in vivo. Circadian rhythms of body temperature, systemic
blood pressure, and heart and respiratory rate and endocrine rhythms of growth hormone,
prolactin, luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic
343
hormone may be lost. Serum catecholamine and cortisol values are elevated, with low
or undetectable adrenocorticotropic hormone levels. Pathologic examination demon-
strates degeneration of the anterior and dorsomedial thalamic nuclei and atrophy of the
inferior olivary nucleus. Deposition of proteinase K-resistant prion protein type 2 is
found in the brain.
This disorder must be differentiated from REM sleep behavior disorder (RBD), which
is not associated with autonomic hyperactivity or a familial pattern. The differential
diagnosis includes dementia, familial Creutzfeldt-Jakob disease with the 178 codon
mutation in the PRNP cosegregating with the valine polymorphism at codon 129 on
the mutated allele, Morvan fibrillary chorea, delirium tremens, or even schizophrenia.
A sporadic form of fatal insomnia has also been reported.

Bibliography
Cortelli P, Perani D, Parchi P, et al. Cerebral metabolism in fatal familial insomnia: relation to duration,
neuropathology, and distribution of protease-resistant prion protein. Neurology 1997;49:126–33.
Goldfarb L, Petersen R, Tabaton M, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease:
disease phenotype determined by a DNA polymorphism. Science 1992;258:806–8.
Haik S, Galanaud D, Linguraru MG, et al. In vivo detection of thalamic gliosis. A pathoradiologic
demonstration in familial fatal insomnia. Arch Neurol 2008;65:545–9.
Krasnianski A, Bartl M, Sanchez Juan PJ, et al. Fatal familial insomnia: clinical features and early
identification. Ann Neurol 2008;63:658–61.
Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective
degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003.
Monari L, Chen S, Brown P, et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: different
prion proteins determined by a DNA polymorphism. Proc Natl Acad Sci U S A 1994;91:2839–42.
Montagna P, Cortelli P, Gambetti P, Lugaresi E. Fatal familial insomnia: sleep, neuroendocrine and
vegetative alterations. Adv Neuroimmunol 1995;5:13–21.
Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol
2003;2:167–76.
Sforza E, Montagna P, Tinuper P, et al. Sleep-wake cycle abnormalities in fatal familial insomnia.
Evidence of the role of the thalamus in sleep regulation. Electroencephalogr Clin Neurophysiol
1995;94:398–405.
Telling G, Parchi P, DeArmond S, et al. Evidence for the conformation of the pathologic isoform of the
prion protein enciphering and propagating prion diversity. Science 1996;274:2079–82.
344
Sleep Related Epilepsy

Alternate Names
Sleep epilepsy, nocturnal seizure, sleep related seizures.
Essential Features
A seizure is a paroxysmal event resulting from a sudden excessive discharge of the
neurons of the cerebral cortex, whereas epilepsy is a condition of recurrent unpro-
voked seizures. Sleep facilitates epileptic activity and seizures. The characteristics of
specific subtypes of sleep related epilepsy are discussed in the Clinical and Pathologic
Subtypes section below.
Associated Features
The different types of nocturnal frontal lobe epilepsy (NFLE) may cause severe sleep
disruption, affecting both macrostructure and microstructure of sleep, resulting in poor
sleep quality, daytime fatigue, and sleepiness in some patients. The movements also
may be so severe that injuries can occur. From one third to one half of patients with
sleep related epilepsy also have occasional attacks during the day, although these are
not necessarily of the same type as those occurring at night.
Neurocognitive impairment is typically diagnosed in almost all cases of continuous

spike waves during NREM sleep (CSWS). Motor impairment in the form of a unilat-
eral deficit is sometimes seen as an associated feature of CSWS.

Clinical and EEG criteria are used to define a variety of sleep related epilepsy subtypes.
Several types of epileptic syndromes have a marked tendency to manifest only or pre-
dominantly during sleep, or after arousal from sleep. These include NFLE, benign
epilepsy of childhood with centrotemporal spikes (BECT), benign epilepsy with occip-
ital paroxysms (BEOP), early-onset or late-onset childhood occipital epilepsy, juvenile
myoclonic epilepsy (JME), generalized tonic-clonic seizures on awakening, certain
forms of temporal lobe epilepsy, tonic seizure (as a component of Lennox-Gastaut
syndrome), Landau-Kleffner syndrome, and continuous spike waves during NREM
sleep (CSWS).
NFLE may present in three distinct ways: (1) nocturnal paroxysmal arousal, (2) noc-
turnal paroxysmal dystonia, or (3) episodic nocturnal wanderings.
345
BECT can present with focal clonic facial twitching that is often preceded by perioral
numbness. These seizures are more often seen in drowsiness and sleep than wakeful-
ness. The clinical course is often benign with disappearance of the seizures in adulthood.
BEOP is characterized by focal seizures marked by deviation of the eyes and vom-
iting. Sleep is the main precipitating factor, with most of the seizures occurring soon
after sleep onset or in the early hours of the morning. There is frequent evolution to
secondary generalized attacks. The clinical evolution of the early-onset type is benign,
whereas in the late-onset type with visual seizures, the prognosis is uncertain.
JME is characterized by massive bilaterally synchronous myoclonic jerks, which are

most frequently noted on awakening.
CSWS (formerly known as electrical status epilepticus of sleep [ESES]) is charac-

terized by continuous and diffuse slow spike-and-wave complexes persisting through
NREM sleep (at least 85% of the duration), as well as neuropsychological and motor
impairment. Despite the continuous presence of epileptic spike-wave activity on EEG
in sleep, there may be no associated visible sleep related movement. However, clinical
epileptic seizures are sometimes seen in the daytime.
Demographics
There is no significant sex predominance.
Predisposing and Participating Factors

Stress, sleep deprivation, irregularities of the sleep-wake rhythm, other sleep patholo-
gies, and the use of stimulant drugs or other drugs that modify sleep architecture may
predispose an individual to having seizures. Perinatal or prenatal problems, congenital
hemiparesis, and prior encephalopathy may be considered antecedents of the syndrome
of CSWS. OSA may exacerbate sleep related seizures and complicate their treatment.
Familial Patterns
The idiopathic generalized epilepsies form the largest category of epilepsies that appear
to be heritable but show no clear mendelian mode of transmission. Juvenile myoclonic
epilepsy and idiopathic generalized epilepsy with adolescent onset appear to be genet-
ically heterogeneous. Among the partial epilepsies, BECT shows a familial pattern. A
form of autosomal dominant NFLE with 70% to 80% penetrance has been reported in
many countries, and a genetic heterogeneity also has been reported. Genetic factors
have not been established in CSWS and seem to play a minor role. Familial anteced-
ents of epilepsy (including febrile convulsions) have been found in 15% of cases.
346

Idiopathic generalized epilepsies and partial epilepsy may start at any age. The onset
of benign epilepsies of childhood with centrotemporal or occipital spikes is between 4
and 12 years of age. The onset of NFLE is generally from age 10 to 16 years, mostly
before the age of 20 years. The average age of recognition of CSWS is between 4 and
14 years, but the appearance of the first seizure is early, typically between two months
and 12 years of age. Most patients with recurrent sleep related epilepsy continue to
have seizures restricted to sleep. In some cases, they may have seizures during both
sleep and wakefulness. For focal epilepsies (excluding BECT and the early-onset type
of BEOP), the prognosis is less favorable compared to generalized epilepsies. At least
35% of the focal seizures confined to sleep are resistant to antiepileptic drugs.
Definitive data on the natural history of NFLE are not available, although a high prev-
alence of parasomnias has been documented in NFLE patients.
CSWS resolves in many cases within three years after onset, and in almost all cases
by the mid-teen years. Despite normalization of the EEG and elimination of seizures,
neuropsychological impairment may persist. Interictal paroxysmal activity may induce
prolonged cognitive and motor impairment. Hyperkinesias, aggressiveness, and psy-
chotic states may appear. OSA may exacerbate sleep related seizures and complicate
their treatment.

In idiopathic generalized epilepsy, genetic factors are contributory. Pathogenic markers,
associated neurologic deficits, or characteristic brain imaging findings have not been
identified. However, microdysgenesis has been described in some forms of idiopathic
generalized epilepsy. EEG recordings with sphenoidal or zygomatic leads may show
epileptic activity over the mesiotemporal regions in partial complex seizures.
Video-polysomnographic (vPSG) analysis confirms that the motor pattern of NFLE

resembles that noted in orbital and mesial frontal seizures. Nocturnal frontal lobe sei-
zures involve a large neuronal network, and some of their clinical expressions are pos-
sible consequences of disinhibition of innate motor patterns produced by the central
pattern generator. Recent reports derived from stereo-EEG studies seem to show that in
some cases, the seizures (in particular nocturnal wanderings) may arise from temporal
or insular regions (rather than frontal regions) with a secondary spread to the cingulate
regions. They may sometimes mimic parasomnias.
347
Secondary bilateral synchrony is the mechanism generating CSWS. This hypothesis

is supported by EEG, intracranial recordings, EEG with coherence computer-assisted
analysis, and metabolic (positron emission tomography [PET] and single-photon emis-
sion computed tomography [SPECT]) studies. CSWS associated with Landau-Kleffner
syndrome (an acquired epileptic aphasia) is probably secondary to an alteration of
function over the temporal area.
Objective Findings
Patients with suspected sleep related epilepsy often need to be evaluated in the sleep
laboratory with video and full-head EEG monitoring in order to obtain the correct
diagnosis. The characteristic interictal epileptiform activity in idiopathic general-
ized epilepsies usually increases during NREM sleep, whereas it decreases during
REM sleep and wakefulness. Interictal epileptiform activity may be associated with
phasic arousals.
In partial epilepsies, the interictal epileptiform activity occurs in a localized distribu-

tion with an increase in spike frequency in stages N2 and N3 compared to REM sleep.
Most of the seizures are activated in stage N2 sleep. Monitoring may also detect tran-
sient autonomic alterations in cardiac rhythm, blood pressure, and respiration during
seizures. If epilepsy is suspected, a standard daytime 16-channel to 20-channel EEG
(with partial or total sleep deprivation the night before, as indicated) should be per-
formed. Ambulatory 24-hour EEG recordings may be useful to detect distribution of
interictal epileptiform activity during the sleep-wake cycle.
Nocturnal vPSG is the gold standard test for NFLE. Most of the seizures appear during
NREM sleep, with preponderance in NREM stages N1 and N2 (greater than 60%).
Rarely do they emerge from REM sleep. In some cases, particularly in paroxysmal
arousals, the motor attacks may show a periodicity (every 20 seconds to two minutes).
Due to the fact that the discharges originate deep in the frontal lobe and are not visible
using scalp EEG, the EEG during the attacks is uninformative in almost half of the
cases. In a few cases, recording using intracranial or depth electrodes confirms the
paroxysms during or preceding the motor components. The interictal sleep EEG is
generally normal, but in 30% to 40% of subjects, focal epileptic abnormalities are
seen, predominantly in the anterior regions. The video recording of the different types
of attacks in NFLE permits categorization of the seizures and characterization of the
main features.
During CSWS, diffuse spike waves at two to 2.5 Hz occur in bursts, with or without
clinical manifestations. The discharges are continuous and occupy from 85% to 100%
348
of NREM sleep stages. Abnormalities arise as soon as the patients fall asleep and dis-
appear abruptly on awakening. REM sleep is typically preserved, and the frequency
of spike-wave discharges significantly decreases but the frontal predominance of the
infrequent bursts may become more prominent. In general, EEG patterns during REM
sleep are similar to those in the awake records. The sleep structure is normal, but
the presence of almost continuous spike-wave discharges makes the recognition of
normal NREM sleep EEG elements (such as K complexes, spindles, or vertex sharp
transients) difficult.
NFLE may be mistaken for a disorder of arousal from NREM such as sleepwalking,
confusional arousal, or sleep terror. Ictal and interictal EEGs are often normal because
the focus for the epileptic discharge may be deep in the brain. Disorders of arousal
show a different pattern of episodes in that they occur out of stage N3 sleep, are not ste-
reotyped, often have a sustained autonomic component, and are frequently seen during
the first part of the night. Partial arousal disorders tend to disappear or decrease in fre-
quency after adolescence. VPSG is often useful. Sleep talking, bruxism, and rhythmic
movement disorders can be differentiated from nocturnal seizures by history and vPSG
recordings. Benign neonatal sleep myoclonus may be confused with clonic or myoc-
lonic seizures during sleep. In the elderly (older than 60 years), the main differentiation
from RBD is by vPSG recording. PLMD, sleep starts, and propriospinal myoclonus at
sleep onset do not show EEG epileptiform activity and belong in the category of move-
ment disorders during sleep. Jerks, dyskinesias, or arousal on resumption of breathing
in patients with OSA also enter into the differential diagnosis of sleep related epilepsy.
Rare cases of anoxic syncope with some clonic jerks at the end of a prolonged (longer
than two minutes) obstructive event have been described.

Bilbliography
Bazil C, Malow B, Sammaritano M. Sleep and epilepsy: the clinical spectrum. Amsterdam: Elsevier
Science; 2002.
Dinner D, Luders H. Relationship of epilepsy and sleep: an overview. In: Dinner D, Luders H, eds.
Epilepsy and sleep: physiological and clinical relationships. San Diego: Academic Press, 2001:2–18.
Malow B. Paroxysmal events in sleep. J Clin Neurophysiol 2002;19:522–34.
Nobili L, Cossu M, Mai R. Sleep-related hyperkinetic seizures of temporal lobe origin. Neurology
2004;62:482–5.
Oldani A, Zucconi M, Ferini-Strambi L, Bizzozero D, Smirne S. Autosomal dominant nocturnal frontal
lobe epilepsy: electroclinical picture. Epilepsia 1996;37:964–76.
349
Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical
and polygraphic overview of 100 consecutive cases. Brain 1999;122:1017–31.
Scheffer I, Bhatia K, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A
distinctive clinical disorder. Brain 1995;118:61–73.
Shouse M, Martins da Silva A, Sammaritano M. Circadian rhythm, sleep, and epilepsy. J Clin Neurophysiol
1996;13:32–50.
Tassinari C, Dravet C, Roger J. CSWS: Encephalography related to electrical status epilepticus during
slow sleep. Electroencephalogr Clin Neurophysiol 1977;43:529–30.
Tinuper P, Provini F, Bisulli F, et al. Movements disorders in sleep: guideline for differentiating epileptic
from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255–67.
Zucconi M. Sleep-related epilepsy. Handb Clin Neurol 2011;99:1109–37.
Sleep Related Headaches

Alternate Names
Various (see Clinical and Pathologic Subtypes).
Essential Features
Sleep related headaches are a group of unilateral or bilateral cephalalgias of varying
severity and duration that occur during sleep or upon awakening from sleep. It is a
heterogenous group of different headache entities with the common feature of occur-
rence during sleep or upon awakening. The characteristics of specific subtypes of sleep
related headache are discussed in the Clinical and Pathologic Subtypes section below.
Associated Features
Individual features associated with specific sleep related headache types are discussed
in the following section.

Most sleep related headaches are daytime headache conditions that also may occur
during sleep. These include the primary headaches such as migraine, cluster head-
ache, and chronic paroxysmal hemicrania. There are other primary headaches that
occur solely with sleep; for example, hypnic headaches. In addition, secondary head-
aches related to medical, neurological, psychiatric, and sleep disorders can cause sleep
related headaches.
Migraines are common recurrent headaches of moderate to severe intensity that

last between four and 72 hours. Pain is typically unilateral and pulsating, aggra-
vated by routine physical activity and associated with nausea, and/or photophobia
350
or phonophobia. They occur during the day or during sleep; approximately 50% of
migraine attacks occur between 4:00 a.m. and 9:00 a.m. Migraine headaches do not
have a fixed association with a particular sleep stage. The patient may awaken with a
migraine out of REM sleep, or the headaches may occur in relationship to stage N3
sleep. A “classic migraine” headache is preceded by an aura (if the patient is awake),
which usually lasts four to 60 minutes and typically consists of homonymous visual
field defects and scintillating scotomas. In some patients, the aura may continue or even
begin during the headache phase. In contrast, “common migraine” does not start with
an aura. Other signs of neurological dysfunction may include unilateral paresthesias,
weakness, and aphasia. Features of brainstem involvement may include vertigo, tinni-
tus, dysarthria, decreased hearing, diplopia, ataxia, bilateral paresthesias, and impaired
level of consciousness. A familial syndrome with hemiplegia is well described. The
hemiplegia is ipsilateral or contralateral to the side of the headache.
Cluster headaches are severe, unilateral, periorbital or temporal headaches that start
quickly and peak within 10 to 15 minutes. They have a relatively shorter duration,
usually lasting 15 minutes to three hours (mean, 60 minutes). The headaches occur
daily during cluster periods—usually one to three attacks per day over a period of one
to two months. Most patients have one cluster period per year, though this can vary
from patient to patient. The headaches tend to occur at the same hour each day, with
75% of cluster episodes reported to occur between 9:00 p.m. and 10:00 a.m. One or
more cranial autonomic features (e.g., ipsilateral conjunctival injection, lacrimation,
nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis, or eyelid
edema) invariably accompany attacks of cluster headaches. A strong predilection for
attacks to occur during sleep is well recognized, and these attacks are strongly related
to REM sleep.
Chronic paroxysmal hemicrania closely resembles cluster headaches and consists of

severe unilateral orbital, supraorbital, or temporal pain associated with one or more
cranial autonomic features. However, the attacks are usually of shorter duration (lasting
two to 30 minutes) and occur more frequently, most often at a frequency of more than
five per day. In contrast to cluster headaches, chronic paroxysmal hemicrania is exqui-
sitely sensitive to indomethacin. Attacks are also strongly associated with REM sleep.
Hypnic headaches are an uncommon type of headache that awakens the patient from
sleep with a generalized or lateralized headache that lasts at least 15 minutes (range,
one to 180 minutes) with a frequency of at least 15 times per month. Onset is typically
after the age of 50, although similar headaches are described rarely in younger indi-
viduals, including children. In comparison to cluster headaches, hypnic headaches are
351
less severe, often bilateral and not associated with cranial autonomic features. Isolated
nausea, photophobia, or phonophobia may be present. They may occur one to three
times during the night, with many patients reporting that the headaches occur at the
same time of the night. The headaches tend to occur during REM sleep. However, they
also have been reported to occur during stage N3 sleep. A positive therapeutic response
to lithium, indomethacin, and caffeine has been reported in many patients.
Other medical (e.g., hypertension), neurologic (e.g., brain tumors, arteriovenous mal-
formations, cerebral venous thrombosis and trauma), psychiatric (e.g., depression),
and sleep disorders (e.g., snoring and OSA) also can give rise to headaches that may
occur during sleep or upon awakening from sleep. Patients with increased intracranial
pressure (due, for example, to brain tumor, hematoma, arteriovenous malformations,
or cerebral venous thrombosis) may complain of headache in the morning or head-
ache that starts after recumbence and improves after the patient is up for 30 to 60
minutes. Nausea, vomiting, signs of focal neurological deficits, and papilledema may
be present. The headache may worsen with bending down or sneezing or with other
activities that may cause further increase in intracranial pressure.
Sleep related headaches can disrupt nocturnal sleep, although the exact prevalence of
this complication is unknown.
Demographics
The exact prevalence of sleep related headaches is not known. One study from a head-
ache clinic suggested that 17% of all headache patients complain of nocturnal or early
morning headaches, and roughly half of these were related to an identifiable sleep
disorder. However, many primary headache disorders can occur during sleep as well.
Sleep related migraines have been reported to increase in frequency with age.

Migraine headaches have several predisposing factors that vary from patient to patient.
However, stress, relaxation, changes in weather and barometric pressure, changes in
sleep pattern, hypoglycemia, and specific foods (e.g., chocolate, Chinese food, alcohol)
have been known to trigger migraine headaches. Alcohol can also predispose an indi-
vidual to having cluster headache and chronic paroxysmal hemicrania. OSA and atten-
dant hypoxia have been reported to be a trigger for cluster headache. However, sleep
apnea may also predispose a person to having other types of headache and may inde-
pendently lead to morning headaches. Change of sleep pattern and insomnia can pre-
dispose the patient to developing headaches.
352
Familial Patterns
There is a positive family history for migraine in up to 80% of patients with this disor-
der. Familial hemiplegic migraine is inherited in an autosomal dominant pattern with
a variety of genetic mutations identified on chromosomes 1 and 19. Cluster headache
does not have as strong of a familial disposition as migraine headache, but first-degree
relatives of probands with cluster headache are seven times more likely to develop
cluster headaches, and the concordance rates in monozygotic twins is 100%. The
inheritance patterns of hypnic headache are not known.

Migraine headache usually starts in the second or third decade of life, with a slightly
earlier onset in men than in women. The mean age of onset of cluster headache is 28
years. Chronic paroxysmal hemicrania has a wide range of onset, from childhood to
old age. Most patients with hypnic headache are elderly, with the age of onset from 40
to 82 years. Brain tumors are more prevalent in the elderly, most occurring from the
fifth decade to late life.
Most sleep related headaches are benign and tend to decrease in frequency with age.
There may be spontaneous remissions that last from months to years. Pregnancy has a
variable effect on these headaches. Migraines tend to decrease with age and, in women,
may stop after menopause. Cluster headaches, as the name suggests, occur in clusters
and are accompanied by pain-free intervals lasting months to a couple of years. They
also tend to decrease with age. Hypnic headache occurs infrequently. Headaches in
patients with brain tumors are related to an increase in intracranial pressure and tend
to improve with treatment of the primary lesion and a decrease in intracranial pres-
sure. Some patients with OSA report improvement of the headache after treatment
of the apnea.
The sleep related headaches can cause sleep disruption and insomnia with decreased
sleep efficiency. Cluster headaches occurring regularly in sleep can also lead to tran-
sient situational insomnia that may resolve after the remission or the treatment of the
cluster headache. Depending on the etiology of the sleep related headache (e.g., brain
tumor), other complications may occur.
353

Several anatomic areas are common to the physiology of both sleep and headaches;
these include the brainstem and diencephalon, specifically the ventrolateral periaque-
ductal gray and the posterior hypothalamus. From a neurochemical perspective, ade-
nosine, melatonin, and orexin also are involved in both the regulation of sleep and
the evolution of headaches. Dysfunction of REM sleep and arousal mechanisms are
common to many headache disorders. Data from transgenic models indicate that dis-
ruption of sleep occurs in two forms of familial migraine. However, current mechanis-
tic explanations of the relationship between sleep and headache are speculative.
Objective Findings
Polysomnographic aspects of sleep related headaches need to be better defined.
Migraine headache is reported to occur in association with REM sleep or stage N3
sleep. An excess of stage N3 sleep also has been reported in patients with migraine.
However, large controlled studies are not available. Fifty percent of cluster headaches
and a majority of chronic paroxysmal hemicrania are associated with REM sleep. OSA
and hypoxia during sleep may aggravate other sleep related headaches or may be an
independent cause of headache. Hypnic headache occurs during sleep, with recent
reports of headache during REM sleep and uncommonly during stage N3 sleep. Thus,
the majority of sleep related headaches seem to have some relationship with REM
sleep, but there are no defining or pathognomonic polysomnographic aspects of indi-
vidual headache syndromes.
Neuroimaging studies (computed tomography or magnetic resonance imaging head

scans or angiography) may be performed to rule out structural, vascular, or infectious
disease processes that may cause headaches.
Sleep related headaches are a heterogeneous group of different headache entities with
a common expression of occurrence during sleep. They need to be differentiated from
other headache conditions that are not sleep related. These include tension-type head-
aches and headaches associated with paranasal sinus inflammation, tooth infection,
ear infection, febrile illness, benign intracranial hypertension, intracranial hypoten-
sion, vasculitis, head trauma, alcohol intoxication, or bruxism. Although the initial
presentation may be one of headache, detailed history and examination will identify
one of these contributing conditions.
Tension-type headaches are bilateral headaches with a feeling of a band-like tighten-

ing sensation around the head. In patients older than 50 years, giant cell arteritis may
354
present with lateralized or bilateral headache with tenderness over the temporal area,
accompanied by polymyalgia rheumatica and visual problems, including loss of vision.
Exploding head syndrome is in the differential diagnosis of headache because it may

occur in association with the sleep period. Patients report hearing an explosion in the
head which is unaccompanied by pain.

Bibliography
Brennan KC, Charles A. Sleep and headache. Semin Neurol 2009;29:406–17.
Sleep Related Laryngospasm

Alternate Names
Stridor, laryngeal dysfunction.
Essential Features
Sleep related laryngospasm is a disorder in which tracheal muscle dysfunction or para-
tracheal soft-tissue swelling causes stridor or interruption of airflow, with associated
awakening from sleep. Patients may have total or near-total cessation of airflow while
asleep, and suddenly arouse. This brief respiratory blockage (lasting an estimated five
to 45 seconds) is often followed by a period of stridor that lasts several minutes and
gradually evolves to normal breathing. Episodes are associated with panic and fear of
suffocation; cyanosis may be observed. In some cases of laryngospasm during sleep,
patients may have frequent laryngeal stridor (which may be difficult for families to dif-
ferentiate from snoring), associated tachypnea, and intermittent upper airway blockage.
Associated Features
Fear and panic upon awakening often accompany events and may, at times, lead
to insomnia. In some cases of sleep related laryngospasm, gastroesophageal reflux
has been identified. Less commonly, sleep related laryngospasm has been related to
underlying OSA.

Sleep related laryngospasm may be associated with multisystem atrophy, a neurode-
generative disorder.
355
Demographics
Prevalence data do not exist. Typical age of onset is unknown, although when the con-
dition is due to multisystem atrophy, affected individuals are typically older.

Sleep related laryngospasm may be associated with gastroesophageal reflux. Laryngeal
dysfunction seen in other disorders, including laryngeal tumors and multisystem
atrophy, may cause sleep related stridor and intermittent laryngospasm. Precipitating
factors include use of hypnotic or other central nervous system depressant medications.
Tonic-clonic seizures may be a rare cause of sleep related laryngospasm in children.
Familial Patterns

Laryngospasm is a common cause of death in multiple system atrophy.
Not known.

When not associated with neurodegenerative disorders of known pathology (e.g., mul-
tisystem atrophy), the pathology and pathophysiology is uncertain. Sleep related laryn-
gospasm can be related to tracheal muscle dysfunction, postnasal drip, or reflux of gas-
troesophageal contents causing irritation of soft tissue in the upper airway. Laryngeal
tumors and multisystem atrophy can cause laryngeal dysfunction, resulting in sleep
related laryngospasm.
Objective Findings
Sleep related laryngospasm may be observed on PSG with accompanying audio record-
ing. It is seen in all stages of sleep but is most severe in REM sleep. Laryngospasm
can appear to be similar to snoring on the polysomnographic snoring channel, but
the audio recording will confirm the high-pitched inspiratory sound as laryngospasm.
OSA has also been detected in some cases. Patients or family members may mistake
laryngospasm for snoring or sleep apnea. PSG evaluation may be necessary to distin-
guish these disorders. In children, PSG or sleep-deprived EEG may demonstrate sei-
zures that manifest solely as nocturnal laryngospasm. Endoscopy of the upper airway
is necessary to examine vocal cord function and to exclude upper airway pathology.
Gastroesophageal studies may reveal evidence of reflux.
356
OSA may cause awakenings, with choking or gasping for air, excessive daytime som-
nolence, restlessness, or insomnia. If OSA is a diagnostic consideration, sleep study
is warranted. Sleep related gastroesophageal reflux may result in coughing or choking
episodes during the night without true laryngospasm. However, these episodes usually
are described in the setting of chest pain or “heartburn.” One possible cause of sleep
related laryngospasm may be occult acid reflux into the upper airway, causing irritation
or swelling. Sleep terrors may be associated with sensations of impaired breathing or
choking, rapid heartbeat, and agitation. However, sleep terrors are most common in
children, and most patients do not focus on upper airway choking. Panic disorder can
involve abrupt awakening with respiratory distress, signs of sympathetic activity, and
fear of dying. However, most patients also have daytime episodes of panic. Nocturnal
asthma can result in sleep related coughing, wheezing, or shortness of breath. REM
sleep behavior disorder (RBD) may be in the differential diagnosis of laryngospasm,
but is generally recognizable by polysomnographic features of RBD and a history of
dream enactment.

Published reports generally have been limited to case series. Clarification of the rela-
tionship between laryngospasm, sleep related breathing disorders, and gastroesopha-
geal reflux is needed.
Bibliography
Aloe F, Thorpy M. Sleep-related laryngospasm. Arq Neuropsiquiatr 1995;53:46–52.
Campbell A, Pierce R. Brief upper airway dysfunction. Respir Med 1994;88:125–9.
Guilleminault C, Eldridge F, Phillips J, Dement W. Two occult causes of insomnia and their therapeutic
problems. Arch Gen Psychiatry 1976;33:1241–5.
Iriarte J, Urrestarazu E, Alegre M, Goni C, Viteri C, Artieda J. Sleep-related laryngospasm: A video
polysomnographic recording. Epileptic Disord 2006;8:70–2.
Kavey N, Whyte J, Blitzer A, Gidro-Frank S. Sleep-related laryngeal obstruction presenting as snoring or
sleep apnea. Laryngoscope 1989;99:851–4.
Roland MM, Baran AS, Richert AC. Sleep related laryngospasm caused by gastroesophageal reflux. Sleep
Med 2008;9:451–3.
Thorpy M, Aloe F. Choking during sleep. Sleep Res 1989;18:314.
Thorpy M, Aloe F. Sleep related laryngospasm. Sleep Res 1989;18:313.
Thurnheer R, Henz S, Knoblauch A. Sleep-related laryngospasm. Eur Respir J 1997;10:2084–6.
357
Sleep Related Gastroesophageal Reflux

Alternative Names
Gastroesophageal reflux, nocturnal gastroesophageal reflux, supine gastroesophageal
reflux, nocturnal heartburn, reflux esophagitis, esophagitis, heartburn.
Essential Features
Sleep related gastroesophageal reflux (GER) occurs when gastric contents cross the
lower esophageal sphincter (LES) into the esophagus and, potentially, into more prox-
imal sites during sleep time. Symptoms are usually noticed during arousals or awak-
enings. Symptoms may include heartburn, substernal burning, chest discomfort, a sour
or bitter taste in the mouth, regurgitation, water brash, coughing, choking, or unex-
plained excessive daytime sleepiness, even in the absence of typical reflux symptoms.
Sleep related GER is associated with sleep onset and sleep maintenance insomnia,
early morning awakenings, sleep disturbances, arousals, unrefreshing sleep, daytime
functioning difficulties, and excessive daytime sleepiness. GER is a potential asthma
trigger, predisposes to aspiration, and is a cause of cough. GER commonly coexists in
patients with chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmo-
nary fibrosis, and bronchiolitis obliterans syndrome in lung transplant recipients. Sleep
related GER is associated with sleep related laryngospasm and is prevalent in patients
with OSA.
Associated Features
Associated features of this disorder include dysphagia, odynophagia, laryngopharyn-
gitis, laryngospasm, epigastric burning, chronic cough, wheezing, or chest pain that
may mimic angina. Other associated features of sleep related GER include sleep onset
and sleep maintenance insomnia, excessive daytime sleepiness, daytime fatigue, poor
daytime functioning, and reduced work productivity. Patients with sleep related GER
also have a decrease in health-related quality of life and more health care visits.

Demographics
GER symptoms affect up to 44% of adults in the United States monthly, and 20%
weekly. Among patients with weekly heartburn, 79% report GER symptoms during
sleep time, 57% report waking up during sleep, and 40% report that GER during sleep
time affected their ability to work the next day. Among the 15,315 subjects of the
Sleep Heart Health Study, 25% reported heartburn during sleep. In a review of 5 large
358
population studies, the mean prevalence of heartburn during sleep time was 54% ±
22% (standard deviation). In patients with OSA, sleep related reflux symptoms are
present in up to 62%. Furthermore, in a trial examining consecutive asthmatics, 50%
had awakenings from sleep because of heartburn. Thus, GER symptoms during sleep
time are common. There is no known predilection for men or women. However, men
are more likely than women to develop Barrett esophagus.

Predisposing factors for sleep related GER include eating within two hours of bedtime,
an elevated body mass index, erosive esophagitis, and hiatal hernia. Predictors of heart-
burn during sleep include consumption of alcohol or carbonated beverages, or the use of
benzodiazepines before sleep time. Other predictors of heartburn during sleep include
the presence of insomnia, hypertension, asthma, snoring, or daytime sleepiness. The
relationship between GER and sleep disturbance is bidirectional. Sleep related GER
is associated with short sleep duration, difficulty falling asleep, arousals, poor sleep
quality, and early morning awakenings. Conversely, sleep deprivation induces a state
of esophageal hyperalgesia to acid, thus worsening heartburn symptoms.
Familial Patterns

GER occurs in all age groups, including infants and children. Sleep disruption occurs
more frequently in infants and children with GER, compared to infants and children
without GER. The incidence of GER increases with age. GER may be more severe and
is associated with more complications in older adults.
GER is a chronic disease which is rarely cured, but it may be controlled with lifestyle,
and medical and/or surgical therapies. In patients with sleep related GER, medical
GER therapy improved sleep disturbances and daytime functioning in placebo-con-
trolled trials. Long-term outcome data are currently lacking. If GER is left untreated,
the disease generally progresses and can be associated with many complications.
Esophageal complications include esophagitis, esophageal erosions, esophageal stric-
ture, ulcerations with stricture, and Barrett esophagus, which is thought to be a precur-
sor to esophageal adenocarcinoma. Reflux can also result in dysphagia, weight loss,
and upper gastrointestinal bleeding. Sleep related GER is more commonly associated
with erosive esophagitis, stricture, Barrett esophagitis, and esophageal adenocarci-
noma, compared to diurnal reflux. Extraesophageal complications include pulmonary
complications previously discussed in the Essential Features section.
359

Two major pathophysiologic mechanisms cause individual reflux episodes. Transient
LES relaxations (LES relaxations occurring without esophageal contractions) account
for 53% to 74% of GER episodes. Transient LES relaxations decrease the LES pres-
sure to the gastric pressure gradient, facilitating the retrograde flow of gastric contents.
An LES pressure of 10 mm Hg or less is the second mechanism by which intra-abdom-
inal pressure overcomes the LES pressure, resulting in the retrograde flow of gastric
contents into the esophagus.
Pathophysiology of sleep related GER is similar to diurnal GER (i.e., transient LES
relaxations and a low LES pressure). However, sleep impacts esophageal physiology
through the impairment of esophageal acid clearance mechanisms when GER events
occur. With sleep onset, the upper esophageal sphincter (UES) pressure decreases and
is lowest during N3 sleep, thus predisposing to aspiration. The UES contractile reflex
remains intact during sleep, including REM sleep. Lower esophageal sphincter (LES)
pressure remains unchanged during sleep. Sleep increases the vagal threshold for trig-
gering transient LES relaxations, so they usually do not occur during stable sleep and
are usually confined to arousals. When GER events occur during sleep, esophageal
refluxate clearance is prolonged and an arousal is required. Sleep facilitates proxi-
mal refluxate migration toward the UES. Saliva secretion, with its acid-neutralizing
bicarbonate, ceases during sleep. Swallowing, required for esophageal peristalsis and
refluxate clearance, does not occur during sleep and is dependent on an arousal. Sleep
also delays gastric emptying by disrupting gastromyoelectric function. Events causing
arousals, including periodic limb movements and apneas, could trigger transient LES
relaxations and thus GER events. Because refluxate clearance requires an arousal,
medications decreasing the arousal response (including benzodiazepines and zolp-
idem) may prolong refluxate clearance and increase the risk of aspiration during sleep.
The pathology of GER includes abnormal esophageal manometry, endoscopy, and

esophageal biopsy findings. Esophageal manometry findings include an increased
frequency of transient LES relaxations, altered or decreased esophageal peristaltic
contraction amplitude, and a decrease in LES pressure. Endoscopic findings include
changes ranging from mild erythema, erosions, and ulcerations to severe erosions with
stricture. Barrett esophagus is identified when columnar tissue replaces the normal
squamous epithelium of the distal esophagus.
Objective Findings
Diagnostic testing is not required for sleep related GER. The diagnosis can be made
if typical symptoms of heartburn and/or regurgitation are present during sleep time.
360
PSG is not indicated. Esophageal pH monitoring, which may be combined with

esophageal impedance, objectively measures individual GER events. Esophageal
monitoring is recommended in difficult, refractory cases, or when symptoms
continue despite therapy.
Sleep related GER is more likely to occur during the first two hours of sleep time.
Furthermore, in studies using combined esophageal pH monitoring with actigraphy,
acid reflux events occurred primarily during the recumbent-awake period, versus the
recumbent-asleep period. Reflux events are more likely to occur in the right side down
and supine positions than in the left side down position.
PSG without esophageal pH or impedance monitoring reveals arousals that are often
associated with swallows and a notable increase in chin EMG tone. Esophageal pH
monitoring detects acid reflux events and can be integrated with PSG. Esophageal pH
monitoring should be performed over a 24-hour period to improve the test’s sensitiv-
ity and specificity, which approximate 90%. The distal pH probe is placed 5 cm above
the LES. A proximal pH probe is often placed near the UES. An acid reflux event
is defined when the pH drops to less than 4.0, and this variable is reported as time
(%) where pH is less than 4.0. The percent time where pH is less than 4 is reported
over the total recording time, upright time and supine time. Note that supine (in this
testing) is defined as the period of time that the patient is in bed. Symptom correlation
is also helpful using the event marker on the device or diaries. Normal esophageal
pH times during the “supine” or sleep period are: 1) distal pH < 4 - less than 3.5%
of the time; and 2) proximal pH < 4 - less than 0.6% of the time. If esophageal pH
monitoring is integrated with polysomnography, esophageal acid events can be cor-
related with sleep events, including arousals, apneas, laryngospasm, and increased
chin EMG tone. Esophageal pH monitoring also can be performed simultaneously
with actigraphy to correlate acid reflux events with sleep and wake periods. Catheter-
free wireless pH systems are also available and are deployed into the esophagus,
usually by endoscopy.
Esophageal impedance monitoring can be combined with pH probes detecting liquid,

gas, or liquid gas in the esophagus, and can assess both acid and nonacid reflux events.
Use of esophageal impedance monitoring is often performed in esophageal centers,
and this technique would be difficult to integrate with polysomnography.
Other objective measures include esophageal endoscopy with or without biopsy in

order to evaluate for esophagitis and other esophageal complications. A histologic
evaluation is required to establish a diagnosis of Barrett esophagus.
361
The differential diagnosis is primarily with peptic ulcer disease and angina. The
chest pain associated with GER is sometimes indistinguishable from that of angina.
Duodenal ulcer disease is commonly associated with a burning epigastric pain, and
this can sometimes be similar to the pain experienced by patients with GER. Other
conditions that may be associated with GER include OSA, sleep related abnormal
swallowing, and sleep related laryngospasm. PSG evaluation with respiratory and pH
monitoring can differentiate these disorders.

Bibliography
Allen L, Poh CH, Gasiorowska A, et al. Increased oesophageal acid exposure at the beginning of
the recumbent period is primarily a recumbent-awake phenomenon. Aliment Pharmacol Ther
2010;32:787–94.
Bajaj JS, Bajaj S, Dua KS, et al. Influence of sleep stages on esophago-upper esophageal sphincter
contractile reflex and secondary esophageal peristalsis. Gastroenterology 2006;130:17–25.
Fass R, Johnson DA, Orr WC, et al. The effect of dexlansoprazole MR on nocturnal heartburn and GERD-
related sleep disturbances in patients with symptomatic GERD. Am J Gastroenterol 2011;106:421–31.
Fass R, Quan SF, O’Connor GT, et al. Predictors of heartburn during sleep in a large prospective cohort
study. Chest 2005;127:1654–66.
Fujiwara Y, Arakawa T, Fass R. Gastroesophageal reflux disease and sleep disturbances. J Gastroenterol
2012;47:760–9.
Gagliardi GS, Shah AP, Goldstein M, et al. Effect of zolpidem on the sleep arousal response to nocturnal
esophageal acid exposure. Clin Gastroenterol Hepatol 2009;7:948–52.
Gerson LB, Fass R. A systematic review of definitions, prevalence, and response to treatment of nocturnal
gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2009;7:372–8.
Ghaem M, Armstrong KL, Trocki O, et al. The sleep patterns of infants and young children with gastro-
oesophageal reflux. J Paediatr Child Health 1998;34:160–3.
Green BT, Broughton WA, O’Connor JB. Marked improvement in nocturnal gastroesophageal reflux in a
large cohort of patients with obstructive sleep apnea treated with continuous positive airway pressure.
Arch Intern Med 2003;163:41–5.
Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive therapy
improves asthma outcome. Am J Med 1996;100:395–405.
Harding SM. Gastroesophageal reflux during sleep. Sleep Med Clin 2007;2:41–50.
Locke GR 3rd, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a
population-based study in Olmstead County, Minnesota. Gastroenterology 1997;112:1448–56.
Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite
acid suppressive therapy: a multicentre study using combined ambulatory impedance pH monitoring.
Gut 2006;55:1398–402.
362
Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with

gastroesophageal reflux disease. Gastroenterology 2007;133:1787–95.
Shaheen NJ, Weinberg DS, Denberg TD, et al. Upper endoscopy for gastroesophageal reflux disease: Best
Practice Advice from the Clinical Guidelines Committee of the American College of Physicians. Ann
Intern Med 2012;157:808–16.
Shaker R. Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem
that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the
American Gastroenterological Association. Am J Gastroenterol 2003;98:1487–93.
Sontag SJ, O’Connell S, Miller TQ, et al. Asthmatics have more nocturnal gasping and reflux symptoms
than nonasthmatics, and they are related to bedtime eating. Am J Gastroenterol 2004;99:789–96.
Sleep Related Myocardial Ischemia

Alternate Names
Unstable angina, coronary insufficiency-acute, nocturnal angina, angina decubitus,
variant angina, Prinzmetal angina, vasospastic angina, angina pectoris, atherosclerotic
heart disease, asymptomatic cardiac ischemia, silent ischemia.
Essential Features
Sleep related myocardial ischemia is characterized by nocturnal reduction of blood
flow to the myocardium, typically during sleep. The symptoms of sleep related myo-
cardial ischemia are very similar to those that characterize episodes of cardiac isch-
emia during the daytime. Classically, there is a feeling of chest pressure or pain that
awakens the patient from sleep and may be described as a “viselike” discomfort. The
discomfort may radiate to the chin and jaw and to the arm, especially the left arm.
Associated Features
Acute episodes of sleep related myocardial ischemia sometimes elicit atrial or ventric-
ular arrhythmias. Other associated presentations include acute onset of shortness of
breath that wakes the patient from sleep and that may be secondary to left ventricular
diastolic dysfunction or ischemic mitral regurgitation. Other related features depend
on the trigger for the cardiac ischemia. Ischemic events related to OSA may present
during those times of sleep when nocturnal desaturation is most severe. Cardiac isch-
emia related to hemodynamic changes or vasospasm occurring during REM sleep may
present in the early hours of the morning, around the time of waking, when REM sleep
is most likely to occur. Ischemia associated with nocturnal hypotension is most likely
to occur during slow wave (N3) sleep, when blood pressure is lowest.

None known.
363
Demographics
The specifics of prevalence, sex ratios, and age ranges have not been comprehensively
evaluated. Some insights into demographics can be extrapolated, depending on the
cause of nocturnal angina. For sleep related myocardial ischemia triggered by OSA,
the preponderance of OSA in men suggests that middle-aged men with severe OSA
are more likely to experience nocturnal angina, particularly if they have more severe
coronary artery disease. Variant angina (also referred to as vasospastic or Prinzmetal
angina) more commonly affects younger populations, particularly women and those
of Asian descent. Cardiac ischemia secondary to nocturnal hypotension is more com-
monly manifested in older individuals, particularly those with severe vasculopathy
who are taking multiple antihypertensive medications, and especially those in whom
autonomic dysfunction (related to either age or diabetes) may impair blood pressure
homeostatic mechanisms.

Predisposing factors include established coronary artery disease or valvular disease
such as aortic stenosis. Because coronary filling occurs during diastole, conditions
associated with reduced diastolic blood pressure, such as severe aortic regurgita-
tion, may elicit nocturnal angina, particularly in the presence of preexisting coro-
nary artery disease. Similarly, any predisposition to hypotension, which is most
likely to occur during slow wave (N3) sleep, may heighten risk. Usual risk factors
for coronary artery disease that predispose an individual to the development of
sleep related myocardial ischemia include hypertension, diabetes mellitus, cigarette
smoking, and hyperlipidemia.
Retrospective and prospective studies suggest that OSA may be a trigger for myo-
cardial infarction and sudden death that occurs at night. Deeper oxyhemoglobin
desaturations, which may be encountered in REM, particularly with coexisting
pulmonary disease or truncal-abdominal obesity, are more likely to trigger cardiac
ischemia. In patients with vasospastic angina, use of nonselective β-adrenergic
receptor-blocking agents may theoretically increase the likelihood of vasospasm.
In patients with nocturnal angina secondary to hypotension, an excess of antihy-
pertensive medications, as well as long-acting nitroglycerin administered prior to
sleep, may contribute. Finally, in the proper clinical context, abuse of drugs such as
amphetamine, cocaine, and other stimulants, needs to be considered in the evaluation
of myocardial ischemia.
Familial Patterns
Familial patterns reflect those of the underlying disease process.
364

For angina related to OSA, the first presentation of nocturnal angina may occur only
when the severity of both the sleep apnea and the coronary artery disease are suffi-
cient to elicit sleep related myocardial ischemia. This is likely to be most common in
middle-aged to older men, particularly those who are overweight, although several
studies have documented life-threatening OSA related cardiac ischemia in women. It
is notable that several studies have reported cardiac ischemia in patients with OSA
even in the absence of severe coronary artery stenosis. ST segment changes occur-
ring as a result of OSA would be expected to resolve with treatment of the OSA.
Regardless of the underlying etiology, potential complications of sleep related myo-
cardial ischemia include acute left ventricular dysfunction, ischemic mitral regur-
gitation and pulmonary edema, arrhythmias, and even progression to myocardial
infarction and death.

For sleep related myocardial ischemia related to OSA, the apnea-related hypoxemia
and surges in blood pressure and heart rate at termination of apnea may all result in rel-
ative myocardial oxygen deficiency. A substrate of preexisting severe coronary artery
disease is expected to exacerbate this problem. Variant angina may be more likely to
occur during sleep because of the significant and abrupt fluctuations in cardiovascular
neural control during REM sleep. For nocturnal angina related to hypotension, perfu-
sion of the coronary arteries during diastole makes maintenance of diastolic pressures
during sleep important for adequate myocardial perfusion. Autonomic insufficiency
due to old age, diabetes, and medication effects blunts the ability of the cardiovascular
system to maintain adequate blood pressure.
Objective Findings
Electrocardiographic monitoring during sleep reveals horizontal or downsloping ST
segment depression of greater than or equal to 1 mm, or ST segment elevation of 1 mm
or more. The electrocardiographic evidence of sleep related coronary artery ischemia
is sometimes unaccompanied by chest discomfort or other symptoms (silent ischemia)
and may be incidentally noted on either Holter monitoring or telemetry.
In general, ST segment abnormalities indicative of myocardial ischemia are 1 mm or

more horizontal or down-sloping depression or ST segment elevation, which may be
detected on the single lead electrocardiogram (ECG) employed in most sleep labo-
ratories. However, because the sensitivity of single-lead ECG in detecting ischemic
changes is poor, the patient with symptoms compatible with angina with a normal-ap-
pearing single ECG channel should be further evaluated with multichannel ECG.
365
Sleep related myocardial ischemia in patients without sleep related breathing disor-
ders may be associated with REM sleep. Slow wave sleep with a fall in blood pressure
and heart rate can be associated with ischemia. Sleep related breathing disorders, par-
ticularly OSA, may elicit oxygen desaturation and consequent sleep related myocar-
dial ischemia. The presence of cardiac arrhythmias should prompt an evaluation for
nocturnal ischemia.
Sleep related myocardial ischemia must be differentiated from gastroesophageal
reflux, which may also be associated with chest discomfort. The nature of the pain,
associated symptoms and prior history are helpful in making a distinction, although
12-lead ECG may be necessary in some cases. Nocturnal panic attacks may be asso-
ciated with chest wall pain and respiratory distress. Although the majority of patients
with nocturnal panic will have a history of daytime panic attacks, a small percentage
have only nocturnal events. Nocturnal panic attacks typically occur during transition
from N2 to N3 sleep.
Other causes of nocturnal respiratory distress, including heart failure and pulmonary
disease, may be confused with myocardial ischemic episodes, although typical anginal
chest pain is not evident in these cases.
Chest pain due to thoracic mass, pleuritic pain, aortic aneurysm, or other thoracic
disease should be considered in the differential diagnosis. Chest wall pain may be sec-
ondary to a variety of causes such as trauma, muscle spasm, or immobility.

More comprehensive data are needed to identify the prevalence and demographics of
the various causes of sleep related myocardial ischemia. Further information is also
needed to explore the relationship between sleep related myocardial ischemia and the
circadian variation in myocardial infarction and sudden death, particularly the role of
treatment on outcomes.
Bibliography
Caples S, Rosen C, Shen W, et al. The scoring of cardiac events during sleep. J Clin Sleep Med
2007;15:147–54.
Franklin K, Nilsson J, Sahlin C, Naslund U. Sleep apnoea and nocturnal angina. Lancet 1995;345:1085–7.
Gami A, Howard D, Olson E, Somers V. Day-night pattern of sudden death in obstructive sleep apnea.
New Engl J Med 2005;352:1206–14.
366
Muller J, Ludmer P, Willich S, et al. Circadian variation and the frequency of sudden cardiac death.
Circulation 1987;75:131–8.
Nowlin J, Troyer WJ, Collins W, et al. The association of nocturnal angina pectoris with dreaming. Ann
Intern Med 1965;63:1040–6.
Schroeder J, Motta J, Guilleminault C. Hemodynamic studies in sleep apnea. In: Guilleminault C, Dement
W, eds. Sleep Apnea Syndromes. New York: Alan R. Liss, 1978:177–96.
Sert Kuniyoshi F, Garcia-Touchard A, Gami A, et al. Day-night variation of acute myocardial infarction in
obstructive sleep apnea. J Amer Coll Cardiol 2008;52:343–6.
Verrier R, Muller J, Hobson J. Sleep, dreams, and sudden death: the case for sleep as an autonomic stress
test for the heart. Cardiovasc Res 1996;31:181-211.
367
Appendix B:
ICD-10-CM Coding for Substance-
Induced Sleep Disorders
ICD-10-CM coding for substance-induced disorders is more complex than ICD-9-CM
coding. The series F10.xxx-F19.xxx (which is the general section for substance-in-
duced mental and behavioral disorders in ICD-10-CM) contains the pertinent codes for
substance-induced sleep disorders. There are specific codes for sleep disorders induced
by alcohol, opioids, sedatives, cocaine, other stimulants and other psychoactive sub-
stances. However, in the case of cannabis, hallucinogens, nicotine and inhalants, there
are no sleep-specific codes. In these instances, the coder must use an “unspecified” or
“other” code. A detailed list of the appropriate codes for substance-induced sleep dis-
orders is included in the table below.
Substance Relevant ICD-10-CM Codes
Alcohol F10.182 Alcohol abuse with alcohol-induced sleep disorder

F10.282 Alcohol dependence with alcohol-induced sleep disorder
F10.982 Alcohol use, unspecified with alcohol-induced sleep disorder
Opioid F11.182 Opioid abuse with opioid-induced sleep disorder

F11.282 Opioid dependence with opioid-induced sleep disorder
F11.982 Opioid use, unspecified with opioid-induced sleep disorder
Cannabis F12.188 Cannabis abuse with other cannabis-induced disorder

F12.288 Cannabis dependence with other cannabis-induced disorder
F12.988 Cannabis use, unspecified with other cannabis-induced
disorder
Sedative, F13.182 Sedative, hypnotic or anxiolytic abuse with sedative,

Hypnotic or hypnotic or anxiolytic-induced sleep disorder
Anxiolytic F13.282 Sedative, hypnotic or anxiolytic dependence with sedative,
hypnotic or anxiolytic-induced sleep disorder
F13.982 Sedative, hypnotic or anxiolytic use, unspecified with
sedative, hypnotic or anxiolytic-induced sleep disorder
369
Appendix B: ICD-10-CM Coding for Substance-Induced Sleep Disorders
Substance Relevant ICD-10-CM Codes
Cocaine F14.182 Cocaine abuse with cocaine-induced sleep disorder

F14.282 Cocaine dependence with cocaine-induced sleep disorder
F14.982 Cocaine use, unspecified with cocaine-induced sleep
disorder
Other F15.182 Other stimulant abuse with stimulant-induced sleep disorder

Stimulant F15.282 Other stimulant dependence with stimulant-induced sleep
(includes disorder
amphetamine
F15.982 Other stimulant use, unspecified with stimulant-induced
and caffeine)
sleep disorder
Hallucinogen F16.188 Hallucinogen abuse with other hallucinogen-induced

(includes disorder
ecstasy, PCP, F16.288 Hallucinogen dependence with other hallucinogen-induced
phencyclidine) disorder
F16.988 Hallucinogen use, unspecified with other hallucinogen-
induced disorder
Nicotine F17.208 Nicotine dependence, unspecified, with other nicotine-

induced disorders
F17.218 Nicotine dependence, cigarettes, with other nicotine-induced
disorders
F17.228 Nicotine dependence, chewing tobacco, with other nicotine-
induced disorders
F17.298 Nicotine dependence, other tobacco product, with other
nicotine-induced disorders
Inhalant F18.188 Inhalant abuse with other inhalant-induced disorder

(includes F18.288 Inhalant dependence with other inhalant-induced disorder
volatile
F18.988 Inhalant use, unspecified with other inhalant-induced
solvents)
disorder
Other F19.182 Other psychoactive substance abuse with psychoactive

Psychoactive substance-induced sleep disorder
Substance F19.282 Other psychoactive substance dependence with psychoactive
(includes substance-induced sleep disorder
polysubstance
F19.982 Other psychoactive substance use, unspecified with
drug use)
psychoactive substance-induced sleep disorder
370
Glossary
Actigraphy: A measurement of physical activity, typically via a wrist-worn movement
sensor, employed to estimate sleep and wakefulness based on relative levels of physical
inactivity and activity.
Alveolar Hypoventilation: A condition in which ventilation of the lung gas exchanging units
is decreased relative to the carbon dioxide production (excretion) such that the arterial
partial pressure of carbon dioxide is increased. Alveolar ventilation is equal to the minute
ventilation (tidal volume × respiratory rate) minus the dead space ventilation.
Apneic Threshold: The value of PaCO2 below which central apnea occurs during NREM
sleep.
Ataxic Breathing: A breathing pattern consisting of irregular variation in tidal volume and
respiratory rate, characteristic of the effects of opioids on breathing.
Autonomic Arousal: An abrupt shift in autonomic nervous system activity during sleep
characterized by an increase in sympathetic activity, including heart rate and blood
pressure.
Biological Day/Night: In humans, biological day refers to the internal circadian time when
wakefulness and associated functions are promoted (e.g., when endogenous melatonin
levels are low). Biological night refers to the internal circadian time when sleep and
associated functions are promoted (e.g., when endogenous melatonin levels are high).
Cataplexy: More than one episode of generally brief (< 2 minutes), usually bilaterally
symmetrical sudden loss of muscle tone with retained consciousness. The episodes are
precipitated by strong emotions, usually positive, with almost all patients reporting some
episodes precipitated by emotions associated with laughter.
Chemosensitivity: The sensitivity of the chemoreceptors to increases in PCO2 or decreases in

PO2. In humans this is measured by increases in ventilation associated with these stimuli.
Chronotype: Individual timing preference for various physical and mental activities, and
sleep and wakefulness, over the course of a day. “Morningness” refers to preference for
earlier timing of activities and sleep initiation; “eveningness” refers to preference for later
timing of activities and sleep initiation.
371
Glossary
Circadian Misalignment: Incorrect or inappropriate timing of sleep and wakefulness with

respect to internal circadian timing (e.g., the wake episode occurring entirely or partially
during the biological night and/or the major sleep episode occurring entirely or partially
during the biological day).
Circadian Period (tau): The time it takes to complete one circadian cycle (e.g., time from
one circadian phase on day 1 to the same circadian phase on day 2).
Circadian Phase: The time at which a particular event occurs within the circadian cycle (e.g.,
onset, offset, trough, peak).
Circadian Rhythm: Biological oscillation, with a periodicity near 24 hours, which is clock-
driven (i.e., not caused by external or non-circadian clock factors).
Comorbid Insomnia: An insomnia syndrome thought to have partial or total independence

from a co-occurring sleep disorder or sleep-disruptive medical, psychiatric, substance
dependence/abuse disorder.
Conditioned Arousal: An arousal response developed by the repeated association of a

specific setting such as the bedroom with unsuccessful sleep attempts.
Cortical Arousal: An abrupt shift of EEG frequency to a faster frequency lasting at least 3
seconds, indicating cortical activation.
Cyclic Alternating Pattern (CAP): The occurrence in NREM sleep of transient EEG events
(phase A, subtypes A1, A2 and A3) interrupting the background activity (phase B).
CAP is a sensitive marker of sleep instability, usually increased in sleep disorders that
adversely affect sleep continuity.
Dim Light Melatonin Onset (DLMO): A marker of internal circadian phase designated by
the rise in melatonin above low daytime levels, typically assessed via blood or salivary
melatonin levels. Melatonin levels are reduced by exposure to light and thus need to be
assessed in dim light to be accurate.
Dopaminergic: Related to the neurotransmitter dopamine.
Dystonia: Involuntary muscle contractions that result in slow repetitive movements or

abnormal postures.
372
Glossary
Early Morning Awakening: The termination of sleep at least 30 minutes before the desired
rising time with a concomitant reduced total sleep time compared to the usual premorbid
sleep pattern.
Electromyogram (EMG): Physiological recording of muscle activity, based on electrical

activity that accompanies muscle contraction. For sleep monitoring purposes, EMG is
typically recorded from skin surface rather than intramuscular electrodes.
Entrained/Entrainment: The successful end result (entrained) or process of (entrainment)

synchronization of an internal circadian clock to the environment (e.g., light dark cycle),
producing a stable phase relationship between the circadian clock and environmental
time.
Fatigue: A lack of energy, accompanied by a desire to reduce or limit activity levels. This
symptom should be differentiated from reports of subjective sleepiness as well as from
unintended sleep episodes.
Homeostasis: The tendency of a living organism to maintain internal equilibrium by adjusting

and regulating its physiological processes.
Hypercapnia: Elevation of the arterial partial pressure of carbon dioxide (PaCO2) to a level >
45 mm Hg during wakefulness.
Hypersomnolence: Excessive sleepiness during the normal wake period.
Hypersomnia: A disorder characterized by excessive sleepiness (e.g. idiopathic

hypersomnia).
Hypnagogic Hallucinations: Vivid dreamlike experiences occurring at the transition from

wake to sleep.
Hypnopompic Hallucinations: Vivid dreamlike experiences occurring at the transition from

sleep to wake.
Myalgia: Muscle pain.
Nonrestorative Sleep: Sleep that is perceived to be poor in quality and unrefreshing,

resulting in a sense of feeling unrested upon awakening.
373
Glossary
Odds Ratio: A statistical term that provides a measure of the strength of relationship between
two variables; the odds of an event occurring in one group compared to the odds of it
occurring in another group.
Oneirism: Acting-out of dreams, usually from REM sleep.
Out of Center Sleep Testing: A sleep study performed outside of the sleep center, usually at
a patient’s home and with limited (typically respiratory related) channels (parameters)
recorded.
Parasomnia Pseudo-Suicide: A death, erroneously attributed by authorities to suicide, which

results from complex parasomnia, usually from NREM sleep.
Parkinson Disease: A neurodegenerative movement disorder which may result in

bradykinesia, rigidity, tremor, and/or postural instability, and eventually cognitive
decline.
Phase Advance/Delay: A shift in the timing of the internal circadian clock in which circadian
phase is moved earlier (advance, such as required for eastward jet travel or to assume
an earlier sleep schedule) or later (delay, such as required for westward jet travel or to
assume a later sleep schedule).
Phase Response Curve: Graphic representation that describes the circadian phase shifting
response to a time cue (e.g., light) as a function of the internal circadian time at which the
cue is presented.
Phase Tolerance: The ability to be awake or asleep at an inappropriate internal circadian

time.
Physiological Hyperarousal: A state of chronic physiologic arousal as reflected by measures

such as increased mean latency on MSLT, increased metabolic rate and glucose metabolism
in the CNS (PET scan), decreased heart rate variability and increased heart rate.
PHOX2B: A paired-like homobox gene, mutation of which is the defining abnormality of

Congenital Central Hypoventilation Syndrome.
Prevalence: The proportion of the population affected by a disease or condition at a given

time; prevalence indicates how widespread a disease or condition is, thereby serving as a
measure of its burden on society.
374
Glossary
REM Sleep without Atonia, REM-without Atonia: The intermittent or continuous loss of
the normal muscle atonia of REM sleep.
Reverse First Night Effect: A propensity to sleep better than usual on the first night in the
sleep laboratory.
Sleep Attacks: Inappropriate falling asleep with few or no prodromal symptoms of

sleepiness.
Sleep Diary (sleep log): An instrument used by individuals to keep records of their nightly
sleep duration and quality over a period of days to weeks.
Sleep Drunkenness (prolonged sleep inertia): Prolonged difficulty waking up after a

night’s sleep or a nap with repeated returns to sleep, irritability, automatic behavior and
confusion.
Sleep Homeostasis: A process which describes the propensity for sleep driven by duration of
prior time awake and sleep history.
Sleep Hygiene: A set of rules/instructions about lifestyle (caffeine intake, alcohol and tobacco
use, diet, etc.) and environmental factors (light, noise, temperature) that affect overall
sleep duration and quality.
Sleep Onset REM Period (SOREMP): REM sleep occurring within 15 minutes of sleep
onset on a multiple sleep latency test or overnight polysomnogram.
Sleep Related Abnormal Sexual Behaviors: Any of a spectrum of sexualized behaviors

which arise from sleep, typically NREM sleep.
Sleep Related Violence: Violent behavior which is associated with a NREM parasomnia
when the affected individual is accidentally provoked by another person in close
proximity – usually a family member.
Suggested Immobilization Test: A procedure for evaluation of periodic leg movements

and related sensory components of RLS during resting wakefulness. A standard
polysomnogram recording without respiratory measures is used for one hour while the
subject sits quietly awake and upright in bed with the legs outstretched.
375
Index
A Attention deficit hyperactivity disorder 66,
Actigraphy 35, 144, 152, 159, 161–163, 192, 193, 195, 271, 284, 288, 291, 308,
165, 182, 185, 187, 189, 191, 196, 199, 310, 314
204, 207, 209, 213, 215, 218, 223, 224, Augmentation 59, 283
297, 298, 361 Autism (see also pervasive developmental
Adenotonsillar hypertrophy 65, 66, 139, disorder) 119, 195, 200, 206, 211, 251,
274 314, 316
Advanced sleep-wake phase disorder
198–203 B
Agrypnia excitata 248 Barrett esophagus 359–361
Akathisia 290, 316, 326, 333 Behavioral insomnia of childhood (see also
Alcohol 27, 31, 43, 54, 57, 110, 122, 125, limit-setting sleep disorder and sleep-
130, 139, 167, 168, 175, 176, 192, 194, onset association disorder) 21, 27, 29,
200, 212, 217, 219, 220, 221, 234, 237, 340
238, 241, 242, 247, 268, 276–278, 286, Benign epilepsy of childhood with
295, 326, 352, 354, 359, 369 centrotemporal spikes (BECT)
Alpha-1 antitrypsin 129, 130, 136 345–347
Alternating leg muscle activation 330–334 Benign epilepsy with occipital paroxysms
Alzheimer disease 204, 205, 224, 277, 279, (BEOP) 345–347
298 Benign sleep myoclonus of infancy
Amyotrophic lateral sclerosis 300 317–320
Angina 61, 358, 362–366 Biot breathing 87
Antidepressant 148, 153, 176, 249, 250, Blindness 202, 209–213
253, 259, 277, 285, 294, 295, 331, 333 Body rocking 312–314, 316
Anxiety disorder 26, 28, 31, 38, 148, 192, Breathing disorders (see sleep related
234, 257, 269, 284 breathing disorders)
Anxiolytic 110, 122, 130, 255, 369 Bruxism (see sleep related bruxism)
Apneic threshold 72, 73, 82, 91, 92
Apparent life-threatening event (ALTE) 94, C
96, 97, 114, 117 Cataplexy 141, 145–162, 171, 242, 250,
Arrhythmia 58, 65, 101, 110, 122, 126, 256
130, 136, 363, 365, 366 Catathrenia 141
Asperger syndrome 206, 297 Central disorders of hypersomnolence
Asthma 61, 357–359 143–188
Ataxic breathing 74, 76, 85, 87, 88, 105, Central sleep apnea due to a medical
121, 125, 127, 128 disorder without Cheyne-Stokes
Atrial fibrillation 53, 55, 58, 69, 71, 139 breathing 75–79
377
Index
Central sleep apnea due to a medication or Complex sleep apnea (see also treatment-
substance 85–89 emergent central sleep apnea) 102
Central sleep apnea syndromes 69–107 Conditioned arousal 20, 23, 26, 28
Central sleep apnea with Cheyne-Stokes Confusional arousal 228–239
breathing 69–75 Congenital central alveolar hypoventilation
Cerebrovascular accident (see also stroke) syndrome 113–117
77, 78, 93 Congestive heart failure 50, 53, 55, 58, 61,
Charley horse 299 69, 71, 72, 93, 271, 287, 297
Chemoresponsiveness 80, 81, 91, 92, 121, Continuous spike and wave in sleep (CSWS)
123, 129 345, 346, 347, 348
Chemosensitivity 111, 123, 126, 130, 131, Coronary artery disease (see also angina)
136 53, 55, 58, 61, 139, 364, 365
Chiari malformation 76–78, 93, 116 Cor pulmonale 55, 66, 77, 91, 109, 110,
Children’s Chronotype Questionnaire 196 114, 115, 117, 119, 122, 125, 129, 135
Choking (see also sleep related Cyclic alternating pattern 296, 308
laryngospasm) 53, 54, 96, 357, 358 Cystic fibrosis 129, 130, 136, 358
Chronic bronchitis 129
Chronic fatigue syndrome 39, 154, 160, D
165, 181, 206 Delayed sleep-wake phase disorder
Chronic insomnia disorder 21–41 191–198
Chronic obstructive pulmonary disease (see Dementia with Lewy bodies 249, 250
also lower airway) 55, 56, 129, 131, Diabetes 53, 55, 58, 62, 118, 119, 187, 241,
136, 138, 284, 358 271, 273, 274, 284, 287, 300, 364, 365
Chronic pain 22, 31, 86, 87 Diagnostic and statistical manual 26, 28,
Chronic renal failure 285, 286, 287 192, 261, 316
Chronotype 184, 189–193, 195–197, 199, Dim-light melatonin onset 196, 199, 209
202, 219 Disorders of arousal (from NREM sleep)
Circadian period 195, 197, 201, 209, 212, 228–239
213, 222 Dopamine 172, 176, 259, 284, 285, 288,
Circadian phase 191–196, 199, 200 290, 294–298
Circadian rhythm sleep-wake disorders Down syndrome 57, 65, 305
189–224 Dystonia 297, 301, 302, 309, 345
Circadian sleep-wake disorder not otherwise
specified 224 E
Cluster headache 266, 350–354 Early morning awakening 24, 33, 37, 45,
Comorbid insomnia 21 195, 202, 221, 358, 359
Complex nocturnal visual hallucinations Electromyogram (EMG) 60, 226, 237, 247,
267–269 251, 296, 298, 301, 309, 310, 318, 320,
323, 324, 328, 329, 331–333, 336, 361
378
Index
Emphysema (see also chronic obstructive Human leukocyte antigen 149, 150, 152,
pulmonary disease) 129, 130, 136 153, 157–160, 164, 168, 169, 194
Entrainment 189, 197, 206, 210–213 Huntington disease 205, 224
Environmental sleep disorder 339 Hypernychthemeral 209
Epilepsy (see also sleep related epilepsy and Hypersomnia associated with psychiatric
seizure) 68, 236, 237, 252, 271, 274, disorders 179–182
298, 307, 309, 310, 312, 316, 317, 341, Hypersomnia due to a medical disorder
345–349 171–175
Epworth Sleepiness Scale 55, 86, 144, 163, Hypersomnia due to a medication or
173, 181, 196, 284, 293 substance 175–178
Esophageal manometry 60, 294, 360 Hypertension 32, 53, 55, 56, 58, 60, 61, 66,
Esophageal pH 361 77, 91, 110, 112, 116, 120, 122–126,
Excessive fragmentary myoclonus 328–330 128–132, 134–137, 139, 140, 291, 352,
Excessive time in bed 47 354, 359, 364
Exploding head syndrome 264–266 Hyperthyroidism 234
Hypnagogic foot tremor 330–334
F Hypnagogic hallucination 148, 150, 151,
Fatal familial insomnia 342–344 156, 158, 163, 171, 183, 261, 267–269,
Ferritin 285, 295 276
Fibromyalgia 39, 284 Hypnic headache 266, 350, 351, 353, 354
Free-running (see non-24-hour sleep-wake Hypnic jerks (see also sleep starts) 335–337
rhythm disorder) Hypnopompic hallucination 148, 252, 267,
268, 276
G Hypnotic 22, 33, 110, 122, 130, 176, 178,
Gastroesophageal reflux (see also sleep 192, 194, 212, 234, 242, 243, 247, 277,
related gastroesophageal reflux) 22, 23, 278, 356, 369
31, 33, 38, 55, 61, 99, 101, 117, 309, Hypocretin 145, 146, 149–156, 158–160,
341, 355–358, 362, 363, 366 164, 169, 172, 250
Hypothyroidism 57, 112, 118, 123, 127, 173
H Hypoventilation (see sleep related
Hcrt 149, 156–160, 171 hypoventilation disorders)
Headaches (see sleep related headaches)
Head banging 312–315 I
Head trauma 149, 156, 157, 168, 170, 172, Idiopathic central alveolar hypoventilation
354 121–124
High-altitude periodic breathing 79–84 Idiopathic hypersomnia 161–166
hPer2 (clock gene) 201 Idiopathic insomnia 20, 27
hPer3 (clock gene) 193, 194 Inadequate sleep hygiene 20, 27, 197
Insomnia 19–48
379
Index
Insomnia due to (a) medical condition 28 Menstrual-related Kleine-Levin syndrome

Insomnia due to (another) mental disorder 167
28 Methadone (see also opioid) 86, 87, 105,
Insomnia due to drug or substance 28 126
Insomnia with objectively short sleep Migraine 170, 234, 265, 266, 269, 284,
duration 29 350–354
Insufficient sleep syndrome 182–186 Mood disorder (see also major depression)
Iron deficiency 285, 288 28, 53, 168, 179, 192, 193, 212, 244,
Irregular sleep-wake rhythm disorder 260, 268, 288, 291, 294
204–208 Morningness-eveningness questionnaire
189, 190, 196
J Movement disorders (see sleep related
Jet lag disorder 220–224 movement disorders)
Juvenile myoclonic epilepsy (JME) 345, Multiple sclerosis 34, 156, 170, 247, 248,
346 251, 284, 297
Multiple sleep latency test 35, 55, 61, 144,
K 146, 151–165, 169, 171–174, 177, 179,
Kleine-Levin syndrome 166–170 181, 185, 188, 218, 266, 293, 297
Multisystem atrophy 355, 356
L Munich Chronotype Questionnaire 190, 196
Laryngospasm (see sleep related Muscular dystrophy 67, 117
laryngospasm) Myocardial ischemia (see sleep related
Late-onset central hypoventilation with myocardial ischemia)
hypothalamic dysfunction 118–120 Myotonic dystrophy 57, 156, 172, 175
Leg cramps (see sleep related leg cramps)
Limit-setting sleep disorder 21 N
Long sleeper 187–188 Narcolepsy type 1 146–155
Lower airway (lung disease) (see also Narcolepsy type 2 155–161
chronic obstructive pulmonary disease, Negative expectations 23, 219, 223
emphysema and chronic bronchitis) 52, Neuromuscular (disease/disorder) 52, 64,
129, 135 65, 66, 67, 93, 112, 121, 123, 126–131,
134–137, 153, 300
M Night eating syndrome 244, 245
Major depression (see also mood disorder) Nightmare disorder 257–263
180, 193, 284 Nocturnal frontal lobe epilepsy (NFLE)
Melatonin (see also dim-light melatonin 252, 345–349
onset) 173, 176, 189, 191, 195, 196, Nocturnal paroxysmal hemicrania 266
200, 201, 206, 207, 209, 213, 218, 354 Non-24-hour sleep-wake rhythm disorder
Menopause 57, 353 209–214
380
Index
Nonrestorative sleep 23, 33, 39, 43, 53, 69, Periodic limb movements of sleep 148,
75, 79, 85, 89, 241, 294, 296 271, 272, 274, 281, 284, 285, 287–290,
292–298, 324, 329
O Periodic limb movements of wake 284, 289
Obesity 51, 53, 55, 57, 58, 61, 65, 66, 68, Pervasive developmental disorder (see also
108–111, 116, 118–121, 123, 124, 126, autism) 206
128, 139, 148, 151, 173, 241, 244, 284, Phase response curve 193, 201
364 PHOX2B 113, 114, 116, 118–120, 123
Obesity hypoventilation syndrome 108–113 Physiological hyperarousal 33, 35
Obstructive sleep apnea, adult 53–62 Posttraumatic stress disorder 249, 252, 258,
Obstructive sleep apnea disorders 53–68 259, 260, 262, 279, 284, 297, 327
Obstructive sleep apnea, pediatric 63–68 Prader-Willi syndrome 120, 156, 172
Oneirism 248 Pramipexole 176, 331
Opioid (see also methadone) 51, 69, 74, Pregnancy 139, 140, 285, 286, 353
85–88, 93, 103, 126, 176, 317, 369 Prematurity 91, 98–101
Opioid withdrawal 88, 317 Primary central sleep apnea 89–94
Other insomnia disorder 46 Primary central sleep apnea of infancy
Other parasomnias 264–278 94–98
Other sleep disorder 339–340 Primary central sleep apnea of prematurity
Out-of-center sleep testing (OCST) 50, 53, 98–102
54, 60, 61, 134, 137, 139 Primary insomnia 20, 21, 26, 28, 29
Prion protein 342–344
P Propriospinal myoclonus at sleep onset
Paradoxical insomnia 20, 27, 35 321–324
Parasomnia due to a medical disorder 276 Psychophysiological insomnia 20, 26
Parasomnia due to a medication or substance Pulmonary hypertension 55, 56, 66, 77, 91,
276–278 110, 112, 113, 116, 120, 122–124, 126,
Parasomnia overlap disorder 237, 248, 249, 128, 130–132, 134, 136, 137
252
Parasomnias 225–280 R
Parasomnia, unspecified 278 Recurrent hypersomnia 145, 166
Parenchymal (lung disease) 52, 93, 109, Recurrent isolated sleep paralysis 254–256
112, 121, 123, 124, 127–131, 134–137 REM-related parasomnias 246–263
Parkinson disease 156, 172, 205, 224, 227, REM sleep behavior disorder 246–253
249, 250, 284, 287, 297, 305, 308, 333 REM sleep without atonia 151, 152, 159,
Performance anxiety 26 246, 247, 251, 252
Periodic breathing 50, 74, 78–83, 87, 92, Renal failure 70–74, 285–287
93, 95, 98, 101 Residual hypersomnia 173
Periodic limb movement disorder 292–299
381
Index
Respiratory depressant 51, 85, 121, Sleep related bruxism 303–311

125–127 Sleep related eating disorder 240–245
Respiratory effort related arousal (RERA) Sleep related epilepsy 345–350
53, 54, 56, 60, 61, 65, 102, 139, 164 Sleep related gastroesophageal reflux
Restless legs syndrome 282–291 358–363
Reverse first-night effect 34 Sleep related hallucinations 267–270
Rhythmic masticatory muscle activity 304, Sleep related headaches 350–355
305, 307–311 Sleep related hypoventilation disorders
108–133
S Sleep related hypoventilation due to a
Secondary insomnia 20, 21, 28, 29 medical disorder 128–133
Sedating medication 54, 57, 165, 176, 177 Sleep related hypoventilation due to a
Sedative 86, 125, 175–178, 192, 194, 200, medication or substance 124–128
212, 234, 242, 247, 277, 278, 369 Sleep related hypoxemia 134–138
Seizures (see also epilepsy) 55, 66, 68, Sleep related injury 227, 241, 247, 250
97, 101, 115, 153, 170, 176, 252, 256, Sleep related laryngospasm 355–357
260, 261, 266, 269, 273, 279, 298, 310, Sleep related leg cramps 299–303
317–319, 337, 345–349, 356 Sleep related medical and neurological
Sexsomnia 232, 242, 248 disorders 341–367
Shift work disorder 215–219 Sleep related movement disorder due to a
Short sleeper 47–48 medical disorder 325
Short-term insomnia disorder 41–45 Sleep related movement disorder due to a
Sleep attack 143, 147 medication or substance 326
Sleep drunkenness 154, 160, 162, 163 Sleep related movement disorders 281–337
Sleep enuresis 270–276 Sleep related movement disorder,
Sleep inertia 162, 192, 197, 226, 236 unspecified 327
Sleep log 144, 152, 159, 162, 182, 187, 189, Sleep related myocardial ischemia 363–367
191, 196, 199, 204, 207, 209, 213, 215, Sleep related rhythmic movement disorder
218, 224 312–316
Sleep-onset association disorder 21 Sleep starts (see also hypnic jerks) 335–337
Sleep onset REM period 144, 146, 152, Sleep talking 279–280
154–162, 164, 165, 169, 171, 174, 177, Sleep terrors 228–239
185, 247, 269 Sleepwalking 228–239
Sleep paralysis 148, 150, 151, 153, 156, Smith-Magenis syndrome 173, 200, 206
158, 163, 171, 183, 254–256, 261, 266, Snoring 139–140
267, 269, 276, 314 Status cataplecticus 148
Sleep related abnormal sexual behaviors Status dissociatus 248, 252
232
Sleep related breathing disorders 49–141
382
Index
Stroke (see also cerebrovascular accident)

34, 50, 53, 55, 58, 61, 70–74, 76, 140,
172, 173, 234, 249, 264, 287, 291, 295
Sudden infant death syndrome (SIDS) 94,
97, 98
Suggested immobilization test 289
Synucleinopathies (see also Parkinson
disease and multisystem atrophy) 227,
250
T
Treatment-emergent central sleep apnea
102–107
V
Ventilatory drive 50, 59, 66, 72, 74, 87, 90,
92, 122, 124, 125
Violence (in sleep) 232, 249
W
Willis-Ekbom disease 282
383

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Copies of the manual are available from the American Academy of

All rights reserved. Unless authorized in writing by the AASM, no portion

Correspondence regarding copyright permissions should be directed to the

American Academy of Sleep Medicine. International classification of sleep

International classification of sleep disorders, 3rd ed. American Academy of

1. Sleep Disorders – Classification. 2. Sleep Disorders – Diagnosis

ISBN: 0991543416 (print)

ISBN: 0991543408 (online)

Sleep Related Breathing Disorders...........................................................49

ISOLATED SYMPTOMS AND NORMAL VARIANTS

Central Disorders of Hypersomnolence..................................................143

Circadian Rhythm Sleep-Wake Disorders...............................................189

Sleep Enuresis...................................................................................................... 270

Sleep Related Movement Disorders........................................................281

Other Sleep Disorder................................................................................339

Michael Sateia, MD, Editor

ICSD Revision Workgroups

Jack Edinger, PhD, Chair Michael Silber, MB, ChB, Chair

Phyllis Zee, MD, PhD, Chair Arthur Walters, MD, Chair

Richard Berry, MD, Chair Members of the Movement

Michel Cramer Bornemann, MD, Chair

International Society Reviewers Reviewers

Ideally, classification systems are based largely on pathophysiology. However, such an

Although classification systems are, by their nature, intended to define disorders in

within the International Classification of Sleep Disorders include a criterion, or cri-

Alternate Names Pathology and Pathophysiology

Relationship to Other Classification Systems

With the publication of International Classification of Sleep Disorders, 2nd Edition, a

Isolated Symptoms and Normal Variants

Chronic Insomnia Disorder

complaints. Moreover, the degree of sleep disturbance required to connote clinical

In children, the sleep disturbance may be accompanied by daytime behavioral prob-

Clinical and Pathophysiological Subtypes

Psychophysiological insomnia is characterized primarily by heightened arousal and

Idiopathic insomnia is characterized by a longstanding complaint of sleep difficulties

Inadequate sleep hygiene is presumed to result from or be sustained by daily living

Behavioral insomnia of childhood is presumed to result from improper sleep train-

characterized by features of sleep-onset association difficulties and bedtime resistance

Insomnia due to (another) mental disorder is thought to be caused by or secondary

Insomnia due to (a) medical condition is thought to be caused by or secondary to

Insomnia due to drug or substance is thought to be caused by or secondary to use of

and secondary subtypes mentioned are considered. There is substantial symptom

International Classification of Sleep Disorders, 2nd Edition additionally delineates

In addition to these various subtypes, a distinctive subtype of insomnia with objectively

insomnia is currently limited, it is premature to delineate a separate insomnia category

Insomnia associated with requirements of parental/caregiver presence at bedtime

Predisposing and Precipitating Factors

Onset, Course, and Complications

Pathology and Pathophysiology

heightened activity of the sympathetic nervous system and hypothalamic-pitu-

Unresolved Issues and Further Directions

Short-Term Insomnia Disorder

C. The reported sleep/wake complaints cannot be explained purely by

Clinical and Pathophysiological Subtypes

Predisposing and Precipitating Factors

symptoms and disorders also may predispose an individual to develop a short-

An acute, identifiable event or stressor usually precipitates this form of insomnia.

Onset, Course, and Complications